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Most patients diagnosed with secondary hemochromatosis have had repeated blood transfusions. Cardiac failure accounts for approximately one-third of the deaths associated with hemochromatosis. Liver dysfunction or hormonal disorders such as diabetes generally precede cardiac failure. A 23-year-old woman with hemochromatosis had, despite significant left ventricular dysfunction, liver function within the normal range on biochemical evaluation. She was treated for congestive heart failure and given desferoxamine intravenously. She did not have primary hemochromatosis, and had not received multiple blood transfusions or iron supplement. As a child the patient had been diagnosed with congenital non-spherocytic hemolytic anemia not requiring transfusion; thus, this is a unique case of secondary hemochromatosis.

Hepatocyte growth factor (HGF) is a multifunctional protein that exerts trophic effects on neural cells. HGF is expressed in normal brains and increased after brain injury. Recent studies suggest that neurons and astrocytes are the main producers of HGF in the brain. Here we report that microglia also produce HGF both in vitro and in vivo. Treatment of cultured microglia with prostaglandin E(2) (PGE(2)), one of the major inflammatory mediators in the brain, induced significant production of HGF, and this induction was suppressed by pretreatment with the adenylate cyclase inhibitor SQ22536, suggesting that the induction of HGF by PGE(2) in microglia proceeds via a cAMP-mediated pathway. We further investigated whether microglia also produce HGF in vivo under the pathological condition of cerebral ischemia. We found that HGF expression was increased after permanent occlusion of the middle cerebral artery (MCA), and double immunohistochemical staining revealed that the most of HGF-positive cells were microglia. PGE(2) level was increased 8 hr after start of MCA occlusion, and this enhancement is in parallel with the increase in HGF expression, suggesting that PGE(2) not only may induce HGF production in microglia in vitro but may also be an inducer in vivo., (Copyright 2000 Wiley-Liss, Inc.)

Virtual endoscopy (VE) is a recently developed technique to provide a realistic surface rendering of various organs, which can be applied to the use of three-dimensional (3D) studies of several lesions. However, its advantages in otological disease have not been well investigated. In this study, we evaluated the application of VE in patients with ossicular chain anomalies. Virtual middle ear endoscopy was a time-saving method, however, we needed the appropriate technical procedures of algorithm and reconstruction spacing to generate accurate 3D images of ossicles. We obtained virtual surgical views of middle ear structures and related anomalies, and confirmed by intraoperative findings that these images were mostly compatible with the actual lesions of ossicles. VE allowed an identification of the anatomy of the ossicles and adjacent structures simultaneously. The elements of the stapedial crura were clearly visualized with VE images in 93.3% of normal ears. Pathological ossicular chain findings such as malleus or incus fixation, dislocation and disruption, except footplate fixation were investigated successfully. One possible procedure, using alterable CT value in the obtained VE images on the monitor, is proposed for further detection of fine lesions of the ossicles. These observations suggest that virtual middle ear simulations accurately represent major intraoperative findings. This technique may have an important role in preoperative planning, surgical training, and/or postoperative evaluation in otology., (Copyright 2000 S. Karger AG, Basel)

Alloiococcus otitidis is detected in middle ear effusion of otitis media with effusion (OME). Only a limited number of studies are available concerning the immunological profile of A. otitidis. We have studied the ability of A. otitidis and three other representative pathogens of otitis media to stimulate the production of interleukin-12 (IL-12) from a monocytic cell line THP-1. Viable A. otitidis induced the production of IL-12 in THP-1 cells but IL-12 production was reduced if glutaraldehyde-fixed bacteria were used as stimulants. When viable bacteria were physically separated from THP-1 cells during the stimulation period, remarkable reductions of IL-12 secretion were shown after challenge with gram-positive bacteria A. otitidis and S. pneumoniae. When stimulated with soluble extracts of A. otitidis, THP-1 secreted IL-12 in a dose-dependent manner. The subfraction with a molecular mass over 100 kDa showed a strong ability to induce IL-12 production. Our results show that A. otitidis has immunostimulatory capacity with regard to IL-12 production. We also show that soluble antigen(s) of A. otitidis can modulate the immune response in OME.

Antigen-induced changes of cell adhesion molecules and their relationships to infiltrating cells were investigated immunohistochemically in nasal mucosa of perennial allergic rhinitis patients. An increased expression of E-selectin and VCAM-1 was noted on the vascular endothelium of the nasal mucosa 15-25 h after the topical antigen challenge. Although there was no increased expression of ICAM-1, we noted a positive correlation between the expression of E-selectin and ICAM-1. The expression of E-selectin and VCAM-1 as well as ICAM-1 was revealed to be correlated with the number of EG2-positive cells and CD4-positive cells, but not with elastase-positive cells. These findings suggest that all these adhesion molecules play a role in the topical influxes of eosinophils and CD4-positive cells in allergic nasal mucosa.

Otitis media with effusion (OME) is characterized by persistent effusion in the middle ear cavity and by chronic inflammation in the middle ear mucosa. Alloiococcus otitidis, a gram-positive aerobic bacterium, has been isolated in middle ear effusion, and by means of sensitive polymerase chain reaction detection assays it has been detected in as many as 20% of middle ear aspirates of patients with OME. Because A otitidis may freely interact with leukocytes in the middle ear effusion, it may potentially modulate the inflammatory reaction in OME. To study the nature of these interactions, we applied an in vitro assay in which killed A otitidis bacteria were incubated with peripheral blood and adenoidal mononuclear cells. The expression of the proliferation-associated surface marker CD69 was then measured in B lymphocytes and in CD4+ helper and CD8+ cytotoxic-suppressor T lymphocytes by means of multicolor flow cytometry. Alloiococcus otitidis induced the expression of CD69 in both peripheral blood and adenoidal T and B cells. Among the T cells, the cytotoxic-suppressor T lymphocytes were preferentially activated. It was also tested whether A otitidis would have an effect in another cytotoxic and immunoregulatory system, namely, the induction of natural killer cell activity in peripheral blood mononuclear cells. However, the effect was minimal compared with that of Salmonella minnesota or Staphylococcus aureus. The results show that A otitidis has a unique immunostimulatory capacity in vitro that is mainly confined to CD8+ T lymphocytes.

In order to study the role of VLA-4 in allergic rhinitis, the effects of anti-mouse VLA-4 monoclonal antibody (mAb) were evaluated in a murine model. BALB/c mice were sensitized first by i.p. injections (general sensitization) and then by daily nasal dripping of antigen (local sensitization) before performing a nasal antigen challenge. The mAb was applied either before the antigen challenge (BC group), before the local sensitization (BL group) or before the general sensitization (BS group). The effects were evaluated in terms of antigen-induced early-phase nasal symptoms (sneezing), late-phase nasal eosinophilia and the serum level of antigen-specific IgE. Antigen-induced nasal eosinophilia was significantly (p = 0.009) reduced in the BL group but not in the BC group (number of eosinophils = 114 +/- 15.1, 244 +/- 52.8 and 347 +/- 50.5 in the BL, BC and control groups, respectively). The serum level of the specific IgE was also significantly (p = 0.038) reduced in the BL group but not in the BC group (optical density = 1.18 +/- 0.07, 1.28 +/- 0.13 and 1.58 +/- 0.14 in the BL, BC and control groups, respectively). The suppressive effect on sneezing was not significant in either the BL or BC groups. In the BS group, suppressive effects on antigen-induced nasal responses and the specific IgE level were not statistically significant. These findings suggest that VLA-4 plays an important role in the topical booster or priming effects during repeated nasal antigen exposures in pre-sensitized animals.

During development, control of proliferation of neuronal precursor cells plays a crucial role in determining the number of neurons. Proliferation is driven by mitogens, but how it is terminated remains a mystery. In this study, we examined the role of cyclin-dependent kinase inhibitors in the control of proliferation of cerebellar granule cell precursors (GCPs). Among the inhibitors we examined, only p27/Kip1 (p27) was expressed at significant levels in cells of the granule cell lineage in the developing and adult cerebellum. In developing cerebella, p27 was expressed in the external germinal layer (the deeper regions), the molecular layer, and the granule layer. In adult cerebella, p27 was expressed in the cells of the granule layer. We isolated and purified GCPs from cerebella of developing mice and examined their bromodeoxyuridine (BrdU) uptake and p27 expression at various times. We found that there was an inverse correlation between BrdU uptake and p27 expression. Even in the presence of saturating amounts of Sonic hedgehog, a potent mitogen, the cells eventually stopped dividing and differentiated, expressing p27 strongly. We also examined mice in which one or both copies of the p27 gene have been inactivated by targeted gene disruption and found that their cerebella were larger than those of wild-type mice. In cell cultures, GCPs prepared from p27-deficient mice showed enhanced proliferation compared with GCPs from wild-type mice. Taken together, these results suggest that there is an intracellular mechanism that stops GCP division and causes GCPs to differentiate and that p27 is part of this mechanism.

Osteosarcomatosis (also known as multifocal osteosarcoma or multiple sclerotic osteosarcoma) is a rare condition, characterized by multiple skeletal lesions at initial presentation. We describe a case of osteosarcomatosis involving craniofacial bones presenting with cranial nerve palsies. In addition, a brief review of the literature is given, with a discussion of this highly aggressive form of osteosarcoma.

Recent studies suggest that hepatocyte growth factor (HGF) functions as a neurotrophic factor in the central nervous system. In this study, we investigated the neuroprotective effect of HGF and its mechanism of action. We used cultured cerebellar granule neurons that underwent apoptosis when the culture medium was changed from that containing serum with 25 mM K(+) to serum-free medium containing 5 mM K(+), and HGF prevented apoptotic cell death. HGF stimulated both mitogen-activated protein (MAP) kinase and phosphatidylinositol-3 (PI3)-kinase activity in cerebellar granule neurons. Two specific inhibitors of PI3-kinase, wortmannin and LY294002, efficiently blocked this neuroprotective effect of HGF. In contrast, PD98059, a selective inhibitor of MAP kinase kinase (MEK), did not affect the anti-apoptotic effect of HGF. The downstream signal of PI3-kinase in this protection was further investigated. HGF-induced phosphorylation of Akt and pretreatment of the cells with wortmannin completely impaired Akt activation. These results suggest that HGF prevents apoptosis in cerebellar granule neurons via the PI3-kinase/Akt pathway., (Copyright 2000 Wiley-Liss, Inc.)

Otitis media with effusion (OME) is one of the most common diseases in children. Alloiococcus otitidis, a new gram-positive bacterial species, was isolated from the middle ear fluid of children with OME; however, the pathogenic role of this bacteria is yet unknown. In this study, the ability of cultured epithelial cell lines (Hep-2 and Hela) and monocytic cell lines (THP-1 and U 937) to secrete chemokine interleukin-8 (IL-8) in response to the A. otitidis organism and three bacterial organisms mainly detected from middle ear fluid in OME, and bacterial cell components was investigated. When stimulated with four viable bacterial cells, epithelial cells and monocytes secreted IL-8 in a time-dependent manner. The monocytes produced significantly higher levels of IL-8 than the epithelial cells. Compared with that by viable bacterial cells, IL-8 secretion by stimulated epithelial cells and monocytes was reduced when the bacteria were heated and treated with glutaraldehyde. With bacterial stimulations, cell treatment of interferon-gamma caused monocytes to increase the induction of IL-8 production, however, the induction of monocyte differentiation caused monocytes to reduce the induction of IL-8 production. Furthermore, epithelial cells and monocytes stimulated by four viable bacterial organisms physically separated from cultured cells reduced the induction of IL-8 compared with directly stimulated cells, and monocytes stimulated with soluble extracts prepared from A. otitidis organisms produced IL-8 in a dose-dependent manner. These results suggest that part of the IL-8 stimulation of the A. otitidis organism may exist in a diffusable factor released by the bacteria or soluble components of the bacteria itself.

Background: The etiology of otitis media with effusion (OME) is unclear. Although the majority of effusions show inflammation, culture methods yield positive results for bacteria in only 20 to 30% of cases., Methods: The polymerase chain reaction was used for detection of three upper respiratory tract pathogens, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae, and a fairly recently described bacterium, Alloiococcus otitis (A. otitidis), that is solely found in OME. The study included 67 middle ear effusions that were collected from 48 pediatric OME patients during ventilation tube placement., Results: PCR tested positive for 57 (85.1%) of the middle ear effusions. Thirty-one (46.3%) A. otitis-, 12 (17.9%) H. influenzae-, 25 (37.3%) M. catarrhalis- and 14 (20.9%) S. pneumoniae-positive effusions were obtained. All four study organisms showed similar distribution in effusions of various duration (P = 0.72) and in different effusion types (P = 0.59). Only the proportion of M. catarrhalis-positive effusions was lowered by recent antimicrobial therapy (P < 0.05). Although the study organisms had equal distributions among singly and multiply positive specimens (P = 0.90), A. otitis was detected significantly more often with one of the three other species (15 of 19, 78.9%) than the other species with each other (4 of 19, 21.1%, P < 0.001)., Conclusions: The findings suggest a bacterial etiology for OME. Association of A. otitis with the three other species implies that this organism might have the capability of augmenting bacterial colonization in the middle ear.

Objective: High-resolution magnetic resonance imaging (MRI) provided clear images of three-dimensional (3D) reconstruction of the inner ear in candidates for cochlear implantation. In this study. semiquantitative analysis of the 3D MRI findings was performed to investigate topographic lesions of the inner ear caused by tympanogenic and meningogenic labyrinthitis., Study Design: This was an observational study., Setting: The study was performed in an academic, comprehensive, multispecialty group practice., Patients: Postlingual deafened patients with cochlear implantation. The cause of deafness was tympanogenic or meningogenic labyrinthitis., Intervention: High-resolution 3D MRI and postoperative speech recognition tests were used., Results: Abnormal findings in the inner ear detected with MRI were found before surgery in 58.3% of the patients with meningogenic labyrinthitis, although the incidence was lower in patients with tympanogenic labyrinthitis. Abnormal MRI findings were frequently observed in the cochlear basal turn and semicircular canals more than in the middle and apical turn in cases with meningogenic etiology. Patients with tympanogenic labyrinthitis suffered less with a vestibular apparatus than did those patients with meningogenic labyrinthitis. Regarding the analysis of the inner ear lesions at the implanted side, the postoperative speech recognition ability did not correlate to the extent of abnormal MRI findings of the implanted ear., Conclusion: Improvement in 3D MRI technology provided an accurate preoperative picture of the inner ear apparatus. In cochlear implant patients with infectious labyrinthitis, the extent of the inner ear lesion detected with 3D MRI was different among etiologies of deafness.

Previous studies in patients with idiopathic dilated cardiomyopathy (IDC) have suggested that myocardial perfusion is impaired and spatially heterogeneous in such cases. Our objective was to identify any association between an abnormality in myocardial perfusion and the prognosis of patients with IDC. We collected data on N-13 ammonia positron emission tomography (PET) studies performed in 26 patients with IDC (9 nonsurvivors, 17 survivors) and in 8 normal control subjects. Regional myocardial blood flow (rMBF) was quantified using N-13 ammonia positron emission tomography and the Simple flow model. The spatial heterogeneity of myocardial perfusion was assessed by calculating the coefficient of variance of rMBF. Mean rMBF of the survivors was significantly lower (0.54 +/- 0.13 ml/min/g) than that of control subjects (0.66 +/- 0.06 ml/min/g) (p = 0.03 vs control), but did not differ significantly between nonsurvivors (0.58 +/- 0.15 ml/min/g) and control subjects. The coefficient of variance of rMBF was significantly higher in nonsurvivors than in either survivors or control subjects (0.24 +/- 0.08 vs 0.15 +/- 0.08, p = 0.007, and 0.16 +/- 0.05, p = 0.03, respectively). The probability of 3-year survival (Kaplan-Meier method) was 33.0% in subjects whose coefficient of variance of rMBF was above the median compared with 90.0% in subjects whose coefficient of variance of rMBF was below the median (p = 0.01). The probability of 3-year survival did not differ among subjects whose mean rMBF was above versus below the median (61.5% vs 62.9%, respectively). The results suggest that the prognosis of patients with IDC is associated with the spatial heterogeneity of myocardial perfusion, not with initial absolute rMBF.

A case with unilateral hypoplasia of the internal carotid artery was reported. The rerouting of anomalous vessels in the middle ear, visualized by otoscopy, was demonstrated with CT and MRI. Associations with internal carotid hypoplasia, the intercarotid collaterals, both anomalous middle ear arteries and the enlarged internal maxillary artery were confirmed with MRI. MR images were helpful to diagnose not only the anomalous vessels but also the multiple anastomoses.

The surgical anatomy of the facial nerve (FN), chorda tympani nerve (CT) and round window (RW) in 26 Japanese temporal bone specimens was analyzed. The relationships were classified according to the relative position of these structures and the posterior wall of the external auditory canal (EAC). Most frequently, the widest approach route through the facial recess did not point directly at the RW, but rather at the basal turn. Moreover, the approach route crossed the FN-RW line in a posterior to anterior direction (76.9%) and the CT-RW line frequently crossed the posterior wall of the EAC (92.3%). The latter seemed to provide a critical landmark for avoiding damage to the CT during cochlear implant surgery. Therefore, we recommend inserting the electrode into the basal turn at the promontory. Several other anatomical indices were measured and we extracted the index which was related to the maximum approach amplitude and direction. Preoperative diagnosis may be possible using these indices.

Unlabelled: To validate functional analysis of gated SPECT in detecting myocardial viability, seventeen patients (male 15, female 2, mean age 58) with angiographically proven chronic ischemic heart disease (RCA 6, LAD 10, LCX 1) and eight normal volunteers (all male) were studied. All patients underwent 18F FDG PET and 99mTc tetrofosmin (TF) gated SPECT within a week. After being displayed in a polar map, myocardial perfusion was regionally determined by the mean count in 9 segments at end diastole (ED) and end systole (ES) in gated SPECT. Systolic function was determined by the count increase ratio from ED to ES (WTI: ES - ED/ED). Glucose metabolism was assessed by 18F FDG PET in the segments correspondent to those defined for SPECT. TF %uptake of < 60% was defined as hypoperfusion, and FDG %uptake of < 50% was defined as reduced glucose metabolism., Results: The myocardial segments were classified into 3 categories: "normal" perfusion (n = 85), "mismatch" (reduced perfusion with reserved FDG uptake, n = 25) and "matched" reduced perfusion and metabolic reduction (n = 26). Mean WTI in "mismatch" segment was 0.38 +/- 0.21, and was significantly greater than that in "matched reduced" segments, 0.15 +/- 0.20 (p < 0.001). It was also greater than that in "normal" segments, 0.27 +/- 0.16. Regression analysis showed that association between WTI and FDG %uptake was significant (r = 0.57, p < 0.0005) for the ischemic segments ("mismatch" + "matched", n = 51), but the association was weak for the entire segments although it was statistically significant (r = 0.26, p = 0.02, n = 136)., Conclusion: For the segments determined as infarct by perfusion image, systolic functional analysis by gated SPECT is helpful in differentiation of a viable myocardial region or artifact from a scar. Nevertheless, further clinical and technical assessment is required for ECG gating to eliminate overestimation of viability and to warrant clinical use.

A case of a 64-year-old male with low-grade chondrosarcoma of the left posterolateral lamina of the cricoid cartilage is reported, in which a total cricoidectomy and partial resection of the left thyroid cartilage were performed. The rest of the thyroid cartilage and the arytenoid mucosa were approximated with sutures to the first tracheal ring, and a silastic T-tube was placed through the tracheostoma as a stent. The postoperative course has been successful except for the existence of a tracheal stoma and slight hoarseness. There has been no evidence of laryngeal stenosis nor recurrence at about 9 years postoperatively.

A free radical, nitric oxide (NO), besides being a messenger molecule in the brain, becomes a neurotoxin if overproduced. We recently reported that methylmercury (MeHg) induces neuronal NO synthase (nNOS) in Purkinje cells. In the present study, we examined the distribution and the mechanism of nNOS induction by MeHg. Subcutaneous administration of MeHg chloride to mice, 10 mg/kg/day for 9 days, increased calcium-dependent NOS activity to 60% more than the controls only in the cerebellum but not in other brain regions. The Western blots showed a comparable increase in nNOS protein in the cerebellum. A N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, did not block, but rather enhanced, the increase in the nNOS activity. Another NMDA antagonist, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), did not affect the nNOS activity. The Western blots of protein kinase C (PKC), which is an important cofactor regulating nNOS, did not change after the administration of MeHg. These results show that MeHg induces biologically active nNOS selectively in the cerebellum. The induction is independent of PKC and is not reduced by the blockade of the NMDA receptor.

Purpose: To examine the usefulness of MR imaging for predicting local control of nasopharyngeal carcinoma (NPC) and the value of MR imaging in the newly published fifth edition of the TNM classification., Methods and Materials: We studied 29 patients with NPC with MR imaging and CT before and after treatment. Staging was done according to the fourth and newly published fifth editions of the International Union Against Cancer (UICC) staging system. The radiotherapy protocol was designed to deliver 66 to 68 Gy to the primary tumor and clinically involved nodes., Results: MR proved better than CT at identifying obliteration of the pharyngobasilar fascia, invasion of the sinus of Morgagni, through which the cartilaginous portion of the eustachian tube and the levator veli palatini muscle pass, invasion of the skull base, and metastases to lymph nodes in the carotid and retropharyngeal spaces. All seven patients without invasion of the pharyngobasilar fascia had local control. The local control rates of patients with invasion of the skull base were not good (60 to 73%). There was no apparent relationship between tumor volume determined by T1-weighted MR images and local control when the tumor volume was more than 20 cc. The newly published N staging system appears to successfully identify the high-risk group for distant metastasis as N3. In our series, four of five patients with N3 disease developed distant metastases., Conclusion: Deep infiltration of the tumor is a more important prognostic factor in NPC than tumor volume. Since the newly published T staging system requires a search for tumor invasion into soft tissue such as parapharyngeal space and bony structures, MR imaging may be indispensable for the newly published NPC staging system.

Lipoteichoic acid (LTA) is one of the components present within the cell wall layer of most gram-positive bacteria. It plays an important role in the initiation and progression of bacterial infection. In this study, we performed a rat middle ear and nasal perfusion with LTA purified from two different gram-positive bacterial species. Using ELISA and RT-PCR, the production and mRNA expression of rat chemokine, GRO/CINC-1, proinflammatory cytokine, TNF-alpha, in rat middle ear lavage and mucosa were investigated. GRO/CINC-1 in middle ear lavage was produced by stimulation of LTA in a time-dependent fashion; however, TNF-alpha production into the lavage was not detectable using ELISA assay. The mRNA expressions of GRO/CINC-1 and TNF-alpha in the middle ear mucosa were both induced after LTA and exotoxin exposures. The expression of IL-10 mRNA was also induced after 6 h of LTA and exotoxin exposures. The profile of the production of GRO/CINC-1 and TNF-alpha in rat nasal lavage was similar to that in the middle ear; however, the mRNA expressions of GRO/CINC-1, TNF-alpha and IL-10 in the nasal mucosa were different from those in the middle ear mucosa. These results suggest that the cell wall component and exotoxin of gram-positive bacteria can induce several cytokines in vivo and play an important role in the initiation of the inflammatory cascade in the middle ear.

To test for a possible role of nitric oxide (NO) in the neurotoxicity of ethanol, we studied the effects of ethanol on the neuronal NO synthase (nNOS) both in vitro and in vivo. Ethanol, up to 200 mM, did not change the NOS activity in the cerebellar homogenate or the production of NO by the cultured cerebellar granule cells. The number of NADPH diaphorase-positive cells in the culture did not change after the exposure to 200 mM ethanol in vitro. The NOS activity in the various brain regions of mice remained similar to the controls after the acute (3 g/kg) and the chronic (33 g/kg/day, 3.5 days) administration of ethanol. N(omega)-nitro-L-arginine, a NOS inhibitor, did not affect the ethanol-withdrawal behavior. These results indicate that nNOS is resistant to ethanol at clinically relevant concentrations and that ethanol affects the NO-operated system in the brain through a pathway other than that of nNOS.

Objective: Recent studies have shown that bacterial DNA is present in a significant percentage of middle ear effusions, suggesting that persistent bacterial infection may be more important in pathogenesis and recurrence of otitis media with effusion (OME) than previously considered. Although Moraxella (M.) catarrhalis is one of the most common pathogens of otitis media, relatively little is known about immune response to the organism. The objective of the present study is to investigate how systemic and local immune activities against M. catarrhalis may be associated with severity of OME., Methods: The antibody levels specific to outer membrane antigens of M. catarrhalis in sera and middle ear effusions (MEEs) from 59 children with OME were measured by enzyme-linked immunosorbent assay. Their ages ranged from 1 to 12 years with a median 5.0 years. The children were followed 1 year prospectively and classified into two groups with or without recurrent/persistent OME according to severity of OME during the follow-up 1 year., Results: Serum IgG, IgM, and IgA antibodies specific to outer membrane antigens of M. catarrhalis were detected in all samples and the median levels were 35, 0.93, and 1.2 microg/ml respectively. The MEE IgG, IgM, IgA, and secretory IgA antibodies were detected in over 95% samples tested and the median levels were 371, 158, 20, and 50 ng/mg total protein respectively. A comparison between acute and subacute/chronic phases revealed that the median levels of MEE IgG and IgM antibodies were higher at the acute phase (692 vs. 340, P = 0.06; 35 vs. 10, P = 0.02, respectively); while the MEE secretory IgA antibody level was increased at the subacute/chronic phase (74 vs. 35, P = 0.02). Either serum or MEE IgG antibody level was significantly lower in recurrent/persistent OME group than that in nonrecurrent/non-persistent OME group (13 vs. 43 ,microg/ml, P = 0.009; 238 vs. 577 ng/mg protein, P = 0.006, respectively)., Conclusions: These data provide additional information on the immunologic aspects of children with OME. Decreased serum and MEE IgG antibody levels specific to outer membrane antigens of M. catarrhalis may lead to failure to eliminate this organism, resulting in persistent and/or recurrent appearance of MEE.

A clinical study was performed of 83 patients with hypopharyngeal cancer treated in the Sapporo Medical University Hospital from 1982 to 1995. Five-year cumulative survival rate was 34.9% in the whole group and 37.2% in the radical surgical and/or radiation treatment group. In the radiation treatment group, the patients with T1, T2, N0 or N1 stage disease, especially those whose original disease responded almost completely to 40Gy irradiation, showed high tumor control rates following full-dose irradiation with or without radical neck dissection. In the radical surgery group, the patients with T4 or N2 stage disease showed better prognosis than those in the radiation group. However, among the patients with N3 lymph node metastases, there were no long-term survivors in either the radiation or the surgery groups.

Unlabelled: The Simple and Patlak models for estimating myocardial blood flow with 13N-ammonia have become attractive for clinical applications with PET because of their simplicity and ease of implementation. However, these models are sensitive to factors such as the data acquisition times and data integration times, which can cause errors in the estimation of myocardial blood flow, as demonstrated in this study. Limiting the application of these models to specific conditions can minimize the errors., Methods: Dynamic PET images of the uptake of 13N-ammonia in the heart were obtained in seven humans under rest and dipyridamole stress. Myocardial blood flow was estimated using the Simple and Patlak models for different data acquisition times and data integration times. Blood flow values were compared to flow values computed with the two-compartment model as a reference., Results: Blood flow values calculated with the Simple and Patlak models during the first 2 min of data acquisition were closely correlated to the two-compartment model values. Longer acquisition times resulted in significant underestimation of blood flow for the Simple model. Long integration times of greater than 60 sec also resulted in significant underestimation of blood flow for both models., Conclusion: The Simple and Patlak models produce estimates of myocardial blood flow that are well correlated with the two-compartment model estimated blood flows for the integration time of 60 sec from 60 to 120 sec postinjection. Because of the errors associated with longer data acquisition times and longer integration times, use of these models should be limited to a well-documented data acquisition paradigm.

Background: Three cases with intracranial facial neurinoma underwent tumor removal and facial nerve reconstruction with or without tympanoplasty. Surgical strategy for each case was tailored to: (1) the site of main tumor mass, (2) its extension along the facial nerve, and (3) involvement of the auditory organs., Methods: Surgeries adopted in the three cases were: transpetrosal approach with intracranial-intratemporal facial nerve anastomosis, middle fossa and transmastoid approach with intratemporal facial nerve anstomosis and tympanoplasty, and middle fossa and transmastoid approach with intracranial-intratemporal facial nerve anastomosis and tympanoplasty. The greater auricular nerve was used as the nerve graft for all three cases., Results: In the follow-up period of 8-13 months there was no tumor recurrence; facial function was scored 20/90 in modified May's scoring system in each case, but two are still in the process of functional recovery. One of the two cases who underwent tympanoplasty showed complete recovery of hearing within 1 month, and the other showed worsened hearing, which was not serviceable at 3 months postoperatively., Conclusion: Systematic surgical approach for tumor removal, facial nerve reconstruction, and auditory reconstruction should be considered in cases with intracranial facial neurinoma due to its varied clinical features.

Caspases play a critical role in the cell death machinery in various cell types. Here we investigated the involvement of caspases in the delayed neuronal death after transient global forebrain ischaemia in the gerbil. Intrahippocampal injection of benzyloxycarbonyl-Asp-CH2-dichlorobenzene (zD), an irreversible inhibitor of caspases, saved hippocampal CA1 neurones from chromatin condensation and DNA fragmentation at post-ischaemia day 4, and these neurones maintained normal morphology at day 8 post-insult. Intrahippocampal injection of interleukin-1beta (IL-1beta) after ischaemic insults did not influence the neuroprotective effect of zD, suggesting that the neuroprotective effect does not depend on the inhibition of mature IL-1beta production. Animals that received zD-injection showed significant improvement in step-through and step-down passive avoidance learning at post-ischaemia days 4 and 5, suggesting that neural functions were preserved in these animals. At post-ischaemia day 4, the cleavage of poly(ADP-ribose)polymerase was observed, and this cleavage was almost completely suppressed in zD-injected hippocampus, suggesting involvement of caspase-3 and caspase-3-like caspase in the delayed neuronal death. Our findings indicate that caspases play important roles in the delayed neuronal death after transient global forebrain ischaemia in the gerbil, and suggest that ischaemia-induced brain damage can be blocked by caspase inhibitors.

Adhesive interactions between leukocytes and endothelium are required for subsequent leukocyte extravasation toward inflammatory sites. Understanding the possible kinetic expression of vascular cell adhesion molecule-1 (VCAM-1) in the middle ear cavity during an inflammatory cascade in vivo may be important for clarifying local immunological responses in otitis media. Two inflammatory models were produced in the rat and involved acute middle ear mucosal and cutaneous inflammation induced after inoculation or intradermal injection of lipopolysaccharide (LPS). After intravenous injection of both 125I-labeled anti-VCAM-1 and 131I-labeled control monoclonal antibody (mAb), the kinetic expression of VCAM-1 in the middle ear and skin was assessed by local radionuclide uptake. The biodistribution of an 125I-labeled anti-VCAM-1 mAb as a potential detector of focal inflammation was examined in normal rats. Both inflammatory lesions were characterized by early and sustained (up to 24 h) expression of VCAM-1, with maximal expression at 4 h after LPS stimulation. The kinetics of VCAM-1 expression was similar among the middle ear mucosa or skin specimens studied and different stimulation methods. A similar biodistribution and clearance of radioactivity between 125I-labeled anti-VCAM-1 mAb and 131I- or 99mTc-labeled control mAb were observed. The present result suggest that functional VCAM-1 induced by LPS is expressed in both middle ear tissue and skin lesions and may play a role in the initial stage of inflammatory response produced. Although VCAM-1 upregulation is a very early event in the inflammatory cascade, 125I-labeled anti-VCAM-1 mAb may be useful for the early detection of focal inflammation in the middle ear.

It is well known that the frequency of upper respiratory infection is clinically increased after radiotherapy of the head and neck region. This study found higher antibacterial secretory immunoglobulin A (S-IgA) activity against three indigenous streptococci (Streptococcus mitis, S. salivarius, and S. sanguis I) and S. pneumoniae in patients who had undergone radiation therapy of the head and neck region than in control subjects. This showed no relation to the extent of the radiation field. Compared with before radiotherapy, the S-IgA titer against S. pneumoniae and its ratio to the activities against the indigenous streptococci were significantly higher in patients with fully irradiated major salivary glands. These results indicated that the radiotherapy promoted the antigen-specific S-IgA production of virulent streptococci in most patients with head and neck cancer, even more than 6 months after radiotherapy. The resulting altered balance in the S-IgA system of normal indigenous streptococci may also impair the ability to maintain the stable bacterial interference between normal indigenous and virulent streptococci in the oropharyngeal cavity.

We report 10 postlingually deafened adults in whom the electrophysical criteria for cochlear implant were fulfilled, except that they showed the following unfavorable middle ear lesions: otitis media with effusion, chronic perforative otitis media, cholesteatoma and previous radical ear operation. Staged operations for cochlear implant were performed in 8 cases, and 2 patients who had undergone radical ear operation had a single-stage operation. As a first step, one of the following was performed in each patient as surgically indicated: myringoplasty with or without mastoidectomy, mastoidectomy with reconstruction of the posterior wall of the external canal, mastoidectomy with the insertion of a ventilation tube, radical mastoidectomy or surgical cleansing of the radical cavity. From 6 months to 2.5 years after the first operation, the actual cochlear implant was performed in the second or third stage. There was no major complication as a result of electrode insertion into the cochlea and the results of speech perception in these cases were not different from those in patients with normal middle ears. In our experience, it was considered that the staged operations would enable successful cochlear implants in selected patients with pathological middle ear lesions even if they had previously been diagnosed as contraindicated for this procedure. In a case with radical ear cavity a single-stage operation could be performed when there was no cavity problem.

Objective: This study aimed to evaluate the diagnostic value of radioimmunoimaging by radionuclide-labeled monoclonal antibody F023C5 (MAb), raised originally against carcinoembryonic antigen (CEA), in patients with glomus tympanicum tumors., Study Design: Prospective., Setting: Preoperative imaging versus radioactivity of removed tumor., Patients: Two patients with paraganglioma (glomus tympanicum)., Intervention: Diagnostic., Main Outcome Measure: Radiolabeled MAb accumulates in paraganglioma tissue. Single photon emission computed tomography (SPECT) provides improved detection of lesions., Results: SPECT using F023C5 MAb detected the abnormal accumulation of radioactivity in the middle ear region. This method detected paraganglioma less than 1 cm in diameter., Conclusions: Successful detection of glomus tympanicum in two patients using In-111-labeled F023C5 MAb is reported. The result suggests the radioimmunoimaging using this antibody is useful for the detection of not only primary glomus tumors, but also of local recurrence and unsuspected lesion in patients with paragangliomas.

Interleukin-8 possesses chemotactic-activating properties toward neutrophils, and may contribute to the pathogenesis of middle ear inflammation. GRO/CINC-1 is a rat chemokine with structural and functional homology to human interleukin-8, the induction and regulation of which in the middle ear cavity in vivo remains to be established. The production of GRO/CINC-1 in middle ear lavage and gene expression in the middle mucosa was investigated using topical inoculation with lipopolysaccharide (LPS) in the rat in vivo model. GRO/CINC-1 in middle ear lavage showed time- and dose-dependent production under LPS stimulation. The peak of the GRO/CINC-1 production was reached by 4 h after LPS 1 h exposure, whereas the level of production subsequently returned to the level without LPS stimulation at 8 h after LPS stimulation. The topical corticosteroid perfusion in the middle ear after LPS stimulation significantly reduced the production of GRO/CINC-1 in the middle ear cavity compared with that without corticosteroid. At the time of peak production, the expression of GRO/CINC-1 mRNA, evaluated using the polymerase chain reaction, was considerable in the middle ear mucosa. This investigation of the characteristics of interleukin-8-like cytokine in the middle ear cavity using a rat in vivo model has extended the functional concept of chemokines at the initial stage in otitis media.

Thirty-one postlingually deafened adults with 22-channel cochlear implants were evaluated preoperatively using vestibular function tests, the caloric test and stabilometry. The results of caloric response were classified into two diagnostic groups: normo- or hyporeflexia and areflexia. Stabilometric recordings were made using a computerized static posturographic platform. Between the two categories of caloric response, there was a significant difference in consonant recognition, but the recognition of vowels showed no significant difference. The results of the distance of body sway in stabilometry, but not of the area, correlated to the results of consonant recognition in speech perception tests. The degree of residual vestibular function seems to be one of the indicators influencing postoperative speech recognition by cochlear implant patients.

Prognostic factors and treatment outcome of 71 patients with non-Hodgkin's lymphoma of Waldeyer's ring were analyzed retrospectively. In univariate analyses, unfavorable prognosis was associated with primary disease in the base of the tongue, stage III-IV diseases, B-symptoms, high-grade histology, T-cell phenotype, elevated serum LDH levels, decreased peripheral blood lymphocyte counts, and negative response on delayed type hypersensitivity skin reactions. Multivariate analysis showed that stage III-IV and T-cell phenotype were significant independent risk factors for death. In stage I-II lymphomas, patients with unilateral large or bilateral cervical lymph node involvement had a poorer prognosis. In stage I-II lymphomas with intermediate or high-grade histology, patients who had received radiotherapy with MTCOP-P chemotherapy (pirarubicin, cyclophosphamide, vincristine, methotrexate with leucovorin rescue, peplomycin, and predonisolone) showed significantly better 5-year disease-free survival rate compared with patients treated with radiotherapy alone.

Growth-regulated gene product/cytokine-induced neutrophil chemoattractant (GRO/CINC)-1 is a rat chemokine with structural and functional homology to human IL-8. Chemokines are a family of cytokines whose participation in nasal inflammation in vivo remains to be established. Using ELISA and RT-PCR, we investigated the production and gene expression of GRO/CINC-1 in rat nasal lavage and mucosa in vivo. GRO/CINC-1 in nasal lavage was produced by stimulation of LPS, ConA and IL1-beta. GRO/CINC-1 showed time- and dose-dependent production under all stimulants, but was more slowly induced by IL-1 beta. The steady-peak of the GRO/CINC-1 production remained at 3 h with LPS or ConA exposure, whereas it lasted 4 h or more after IL-1 beta exposure. At the time of peak production of GRO/CINC-1, we found that mRNA for the GRO/CINC-1 was induced in the nasal mucosa. The mRNA of the related inflammatory cytokines TNF-alpha and IFN-gamma were also expressed in nasal mucosa with stimulation of these reagents. Thus, this study revealed that exposure to bacterial endotoxin, mitogenic reagent and also IL-1 beta induced the production and gene expression of the neutrophil chemoattractant GRO/CINC-1 in rat nasal mucosa in vivo. This investigation of the characteristics of IL-8 family in nasal mucosa using rat models has extended the functional concept of cytokines in the inflammatory condition of nasal cavity in humans.

The ability of the nasal mucosa to produce various cytokines has been shown to correlate closely with the capacity to regulate an inflammatory condition in the nasal cavity. Immune senescence is characterized by a dysregulation of the immune system. This change is reflected by the altered production of cytokines during aging. We measured the in vivo production and gene expression of IL-8-like cytokines (GRO/CINC-1) in nasal lavages and mucosa from young (2- to 4-week-old and 11- to 15-week-old) and older (81-to 98-week-old) rats by using enzyme-linked immunosorbent assays and reverse transcription-polymerase chain reactions. Significant increases of GRO/CINC-1 levels were found in unstimulated nasal lavages of the older rats compared to that of the 2- to 4-week-old animals. GRO/CINC-1 showed time-dependent production with lipopolysaccharide (LPS) stimulation in nasal lavages. The GRO/CINC-1 production reached a plateau by 4 h with LPS in any group. However, the manner of the initial time course showed no significant differences among these three groups. At the time of peak production of GRO/CINC-1, messenger RNA for the GRO/CINC-1 was found to be induced in the nasal mucosa. These findings may be important for understanding the mechanisms of the altered immune response and inflammation in the nasal cavity associated with aging.

Beta 2 integrins are located on the surface of neutrophils and have important roles in cell migration to an inflammatory site. We investigated the inhibitory effect of antibodies to the beta 2 integrin family for neutrophil migration into middle ear effusion (MEE) during acute otitis media in children and chronic otitis media with effusion in both children and adults. Neutrophil migration to MEE samples was assessed in vitro in a 48-well Boyden chamber. The migration index value and the activity of chemoattractants in MEE was found to be proportional to the number of infiltrated cells. Migration of activated neutrophils into MEE was significantly inhibited by blocking surface-expressed cell adhesion molecules (CAM) with anti-CD11b (Mac-1 alpha) and anti-CD18 (common beta 2 subunit) antibodies (P < 0.001) but not with anti-CD11a (LFA-1 alpha) antibody. These inhibitory effects of anti-CAM antibodies were found in all types of MEE in all age groups studied. A new therapeutic approach to inflammation has been considered recently that utilizes inhibition of neutrophil migration with a blocking antibody to CAM. Our in vitro data support a possible therapeutic effect of anti-CAM antibody, indicating that administration of anti-CD11b and CD18 antibodies may be useful for treating human otitis media.

Recent advanced techniques for the reconstruction of three-dimensional (3D) images allow further visual recognition of the fine structures of the temporal bone. We demonstrate the advantages of reconstruction 3D imaging in helical CT scans of the normal temporal bone and in patients who have received cochlear implants. After the temporal bone was scanned in the axial plane in the helical scan mode, the data were transferred to a workstation and 3D reconstruction was performed. The normal temporal bone structures were well recognized on these 3D images. The spatial relationship between the lymphatic space of the inner ear and the electrode array is visible. This method provides a detailed anatomy of the insertion of the electrodes into the cochlea and provides precise images of electrode routes by means of varying the angles of view on the computer display. Individual electrodes could not be distinguished. The information from 3D images may be useful not only for pre-but also postoperative investigations in cochlear implantation.

We examined the expression of cell adhesion molecules (CAM) in immune-mediated otitis media using keyhole limpet haemocyanin (KLH) in the rat, as well as the regulation of these CAM in peripheral blood polymorphonuclear leucocytes (PMN) and lymphocytes upon exposure to middle ear effusion (MEE). After general immunization, a topical antigen was introduced into the middle ear cavity. One day after exposure, CD18+ cells, primarily PMN, had maximally invaded the middle ear mucosa and mucosal epithelium. Mucosal epithelium strongly expressed intercellular adhesion molecule-1 (ICAM-1), only on the first day. The total number of cells in MEE reached a peak on day 3. On day 3, ICAM-1+ cells had reached a peak of 24.5% of the total cells. On day 2. CD18+ cells had reached a peak at 75.3% of the total cells. We examined the regulation of CAM in peripheral blood upon exposure to MEE. The percentage of fluorescent CD18+ PMN increased with MEE compared to those incubated in its absence, but those of L-selectin-positive PMN significantly decreased CAM on the surface lymphocytes did not change when incubated with MEE. The expression of CAM (CD18, ICAM-1) appears important for the initiation of otitis media. Moreover, it was thought that the interaction between the infiltrated PMN and MEE may modify the expression of CAM during the inflammatory process in the middle ear cavity.

To evaluate the effect of the duration of fasting on myocardial fluorine-18-fluorodeoxyglucose (FDG) uptake and distribution, 16 FDG-positron emission tomography (PET) studies were performed in 7 normal volunteers under three different conditions: glucose loading, 6 h fasting and overnight fasting. In the glucose-loaded condition, all subjects had good image quality, and myocardial metabolic rates of glucose (MRGlc) were significantly higher than those in the other two conditions. In the 6 h and overnight fasting conditions, image qualities varied according to MRGlc. Although there were visually distinct regional differences with MRGlc ranging from 0.05 to 0.15 mumol/min per g, these differences were not impressive by a quantitative analysis. The ranges of MRGlc in these two fasted conditions overlapped each other. There was a significant negative linear correlation between MRGlc and serum free fatty acid levels. Thus, MRGlc and image quality in fasted normal subjects varied with the extent of the fed-to-starved transition under clinical fasting conditions (6 h to overnight), and this transition does not depend solely on the duration of fasting. These findings may explain the heterogeneity in FDG studies under fasting conditions.

To study the effects of chemical injury on the cerebellar nitric oxide synthase (NOS), we administered methylmercury chloride subcutaneously to mice, 10 mg/kg/day for 9 days. In the methylmercury-treated cerebellum. Purkinje cells were positive both for NADPH-diaphorase and for neuronal NOS. Calcium-dependent NOS activity was increased to 160% of the controls. The present study suggests the ability of Purkinje cells to produce NO through the expression of neuronal NOS.

We examined the inducible form of nitric oxide synthase (iNOS) activity in cerebellar primary cultures enriched with granule neurons. Treatment with lipopolysaccharide (LPS) for 24 h was performed in two different cultures in which the survival of neurons was controlled by the levels of extracellular K+. Treatment of the granule neurons with the contaminating non-neuronal cells (< 5%) in a high K+ (25 mM) -containing culture medium with LPS induced four-fold NOS activity compared to that of the control, and the induced NOS activity was calcium-independent. LPS did not induce the NOS activity at all in the contaminating non-neuronal cells alone which were obtained by eliminating all the granule neurons from the culture by lowering the K+ concentration (5 mM). We conclude that the LPS-activated granule neurons can express iNOS activity and that this induction is not attributable to the contaminating nonneuronal cells.

Observed myocardial activities in static image of 13N ammonia positron emission tomography (PET) contains factors about not only myocardial blood flow but also wall motion, wall thickness and glutamine synthetase activity. Those factors may help to delineate myocardial viability in 13N ammonia static image. To assess the role of 13N ammonia static image in prediction of reversibility of regional wall motion abnormalities after revascularization, we studied 20 patients with coronary artery disease. Of these patients, 15 patients underwent successful coronary revascularization (8 PTCA, 7 CABG). Regional 13N concentration before revascularization was expressed as a percent of maximal myocardial concentration and compared with regional wall motion. Wall motion was assessed by visual analysis using left ventriculography. Regional myocardial 13N concentration in normal, hypokinetic, akinetic and dyskinetic segments was 85 +/- 9.3%, 75 +/- 11%*, 71 +/- 17%* and 58 +/- 7.7%*#+, respectively (*p < 0.05 vs. normal, #p < 0.05 vs. hypokinesis, +p < 0.05 vs. akinesis). The segments with functional improvement showed significantly higher concentration of 13N than those without functional recovery (80 +/- 9.7% vs. 67 +/- 8.3%, p < 0.05). By using an optimized threshold value for normalized 13N activities, the sensitivity and specificity reached to 67% and 100%, respectively, to predict functional recovery. Our data suggested that myocardial 13N concentration in static PET image is closely related to the left ventricular wall motion in the patients with coronary artery disease and that it has a possible value of prediction of myocardial viability.