Indications for partial parotidectomy using retrograde dissection of the marginal mandibular branch of the facial nerve for benign tumours of the parotid gland.

The aims of this study were to evaluate the efficacy of partial parotidectomy using retrograde dissection of the marginal mandibular branch of the facial nerve for benign tumours of the parotid gland and to establish the indications for its use. We examined 106 consecutive patients with previously untreated benign tumours in the lower portion of the parotid gland who were treated by parotidectomy. The first group (anterograde group, n=52) consisted of those who had standard anterograde parotidectomy. The remaining patients, who underwent retrograde parotidectomy, were further divided into two groups: those in whom the upper edge of the tumour was located below the mastoid tip (below mastoid group, n=46) or those in whom it was above the mastoid tip (above mastoid group, n=8). The operating time was significantly shorter in the below mastoid group (141.2, 127.5, and 98.1minutes, respectively) as was intraoperative blood loss (41.1, 53.0, and 24.4ml, respectively), compared with the other two groups. There was a higher incidence of facial nerve dysfunction in the above mastoid group postoperatively (4/8) than in the other two groups. The results suggested that the presence of a tumour of any size located below the mastoid tip is a good indication for parotidectomy using retrograde dissection of the marginal mandibular branch of the facial nerve.

Assessment of the AAV-mediated expression of channelrhodopsin-2 and halorhodopsin in brainstem neurons mediating auditory signaling.

The physiology and circuitry associated with dorsal cochlear nucleus neurons (DCN) have been well described. The ability to remotely manipulate neuronal activity in these neurons would represent a step forward in the ability to understand the specific function of DCN neurons in hearing. Although, optogenetics has been used to study the function of pathways in other systems for several years, in the auditory system only neurons in the auditory cortex have been studied using this technique. Adeno-associated viral vectors with either channelrhodopsin-2 fused with GFP (ChR2-GFP) or halorhodopsin fused with mCherry (HaloR-mCherry), capable of expressing light sensitive cation channels or chloride pumps, respectively, were delivered into the dorsal cochlear nucleus (DCN). One to 18 months later, expression of ChR2 and HaloR was observed throughout the DCN. Rhodopsin distribution within the DCN was determined to be within several cell types identified based on morphology and location within the DCN. Expression of ChR2-GFP and HaloR-mCherry was found at both the injection site as well as in regions receiving projections from the site. Wavelength appropriate optical stimulation in vivo resulted in neuronal activity that was significantly increased over pre-stimulation levels with no return to baseline levels during the time of the light exposure. We also examined the effects of optically driven neuronal activity on subsequent tone driven responses in the DCN. In the DCN 75% of the 16 electrode sites showed decreased neuronal activity in response to a tone immediately following light stimulation while six percent were decreased following tone stimulation and 19% of the electrode sites showed no change. This is in contrast to tone driven neuronal activity prior to the light exposure in which the majority of electrode sites showed increased neuronal activity. Our results indicate that expression and activation of rhodopsin within neurons involved in auditory processing does not appear to have deleterious effects on hearing even 18 months following expression. In addition, virally targeted rhodopsins may be useful as tract tracers to delineate as well as modulate the activity of pathways and specific neurons. In the future rhodopsins can be targeted to specific subpopulations of auditory neurons. Ultimately, photostimulation may provide a physiologically relevant method for modulating the function of auditory neurons and affecting hearing outcomes. This article is part of a Special Issue entitled Optogenetics (7th BRES).

Evaluation of postoperative function in patients undergoing reconstruction following resection of superior and lateral oropharyngeal cancer: long-term outcomes of reconstruction with the Gehanno method.

Resection of the superior or lateral wall of the cancer-affected oropharynx can often lead to disturbed nasal breathing, dysphagia, and dysarthria. The authors used the Gehanno method to reconstruct these surgical defects and achieved favourable functional recovery soon after surgery. The present study was undertaken to analyze the long-term outcome and usefulness of this method. Reconstruction was carried out using the Gehanno method in 36 patients during the 10-year period between 1997 and 2007. Both short-term and long-term evaluations of the postoperative function were performed in 12 of the 36 cases. The postoperative function was favourably maintained in all 12 cases, but gradual deterioration was noted in some cases in which the forearm flap had been used for reconstruction. Conventionally, the forearm flap is considered suitable for the reconstruction of complex structures such as the oropharynx because of its excellent flexibility. The results suggest that if the forearm flap is used for reconstruction using the Gehanno method, the surrounding tissue is likely to undergo change over time. The rectus abdominis myocutaneous flap should be considered as the first-choice flap for reconstruction using the Gehanno method.

Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders.

BACKGROUND: Mikulicz's disease (MD) has been considered as one manifestation of Sjögren's syndrome (SS). Recently, it has also been considered as an IgG(4)-related disorder. OBJECTIVE: To determine the differences between IgG(4)-related disorders including MD and SS. METHODS: A study was undertaken to investigate patients with MD and IgG(4)-related disorders registered in Japan and to set up provisional criteria for the new clinical entity IgG(4)-positive multiorgan lymphoproliferative syndrome (IgG(4)+MOLPS). The preliminary diagnostic criteria include raised serum levels of IgG(4) (>135 mg/dl) and infiltration of IgG(4)(+) plasma cells in the tissue (IgG(4)+/IgG+ plasma cells >50%) with fibrosis or sclerosis. The clinical features, laboratory data and pathologies of 64 patients with IgG(4)+MOLPS and 31 patients with typical SS were compared. RESULTS: The incidence of xerostomia, xerophthalmia and arthralgia, rheumatoid factor and antinuclear, antiSS-A/Ro and antiSS-B/La antibodies was significantly lower in patients with IgG(4)+MOLPS than in those with typical SS. Allergic rhinitis and autoimmune pancreatitis were significantly more frequent and total IgG, IgG(2), IgG(4) and IgE levels were significantly increased in IgG(4)+MOLPS. Histological specimens from patients with IgG(4)+MOLPS revealed marked IgG(4)+ plasma cell infiltration. Many patients with IgG(4)+MOLPS had lymphocytic follicle formation, but lymphoepithelial lesions were rare. Few IgG(4)+ cells were seen in the tissue of patients with typical SS. Thirty-eight patients with IgG(4)+MOLPS treated with glucocorticoids showed marked clinical improvement. CONCLUSION: Despite similarities in the involved organs, there are considerable clinical and pathological differences between IgG(4)+MOLPS and SS. Based on the clinical features and good response to glucocorticoids, we propose a new clinical entity: IgG(4)+MOLPS.

Identification of candidate genes involved in the radiosensitivity of esophageal cancer cells by microarray analysis.

Radiotherapy plays a key role in the control of tumor growth in esophageal cancer patients. To identify the patients who will benefit most from radiation therapy, it is important to know the genes that are involved in the radiosensitivity of esophageal cancer cells. Hence, we examined the global gene expression in radiosensitive and radioresistant esophageal squamous cell carcinoma cell lines. Radiosensitivities of 13 esophageal cancer cell lines were measured. RNA was extracted from each esophageal cancer cell line and a normal esophageal epithelial cell line, and the global gene expression profiles were analyzed using a 34 594-spot oligonucleotide microarray. In the clonogenic assay, one cell line (TE-11) was identified to be highly sensitive to radiation, while the other cell lines were found to be relatively radioresistant. We identified 71 candidate genes that were differentially expressed in TE-11 by microarray analysis. The up-regulated genes included CABPR, FABP5, DSC2, GPX2, NME, CBR3, DOCK8, and ABCC5, while the down-regulated genes included RPA1, LDOC1, NDN, and SKP1A. Our investigation provided comprehensive information on genes related to radiosensitivity of esophageal cancer cells; this information can serve as a basis for further functional studies.

Gene expression profiling of the response of esophageal carcinoma cells to cisplatin.

Cisplatin is the most common chemotherapeutic agent used in esophageal cancer. However, sensitivity to cisplatin varies greatly between patients. It is important to identify the gene(s) that are related to the sensitivity to cisplatin in esophageal cancer patients. The IC50 for cisplatin was measured for 15 esophageal cancer cell lines (TE1-5, TE8-15, KYSE140, and KYSE150). RNA was extracted from each of these cell lines and a normal esophageal epithelial cell line, namely, Het1A, and gene expression profiles were analyzed using an oligonucleotide microarray consisting of 34 594 genes. TE4 was highly resistant and TE12, 14, and 15 were sensitive to cisplatin. Thirty-seven genes were differentially expressed in the cisplatin-resistant esophageal cancer cell line. Our investigation provides a list of candidate genes that may be associated with resistance to cisplatin in esophageal cancer cells, which may serve as a basis for additional functional studies.

Efficacy of etanercept in patients with AA amyloidosis secondary to rheumatoid arthritis.

OBJECTIVE: The efficacy of biological therapies in rheumatoid arthritis (RA) is well known, but their hypothetical benefit in amyloid A (AA) amyloidosis secondary to RA still remains to be considered. We evaluated the efficacy and safety of etanercept in serum amyloid A (SAA) 1.3 allele Japanese patients with AA amyloidosis secondary to RA. METHODS: Seven RA patients with histologically confirmed AA amyloidosis and renal involvement who were treated with etanercept were enrolled. They all had the SAA1.3 allele, which has been shown to be a risk factor not only for the association of AA amyloidosis but also for a poor prognosis in Japanese RA patients. Efficacy was assessed as a sustained decrease in RA inflammation and an amelioration of renal function. RESULTS: RA inflammation and AA amyloidosis were improved and stabilized after 43.4 +/- 16.5 weeks. At week 20 the number of tender (p = 0.017) and swollen (p = 0.017) joints, and levels of serum C-reactive protein (p = 0.018) and albumin (p = 0.045) had improved. The values for SAA, serum creatinine, calculated creatinine clearance, and proteinuria also ameliorated. No severe adverse events were observed. One patient eventually had to go on hemodialysis but her tolerance of etanercept remained stable. CONCLUSION: Etanercept can be used safely and effectively in AA amyloidosis secondary to RA with renal involvement, and is of clinical benefit in the short-term, even in patients on hemodialysis. It appears that SAA1.3 allele may be used as a clinical parameter for the introduction of etanercept in Japanese RA with AA amyloidosis.

Decreased expression of NDRG1 is correlated with tumor progression and poor prognosis in patients with esophageal squamous cell carcinoma.

NDRG1 (N-myc downstream regulated gene-1) was reported to be necessary for p53-mediated apoptosis and to be regulated by PTEN (phosphatase and tensin homolog). In several cancers, it was suggested to be a tumor suppressor gene. Its significance in esophageal squamous cell carcinoma (ESCC) has not been studied. The objective of this study was to clarify the relation between clinicopathological and biologic factors in esophageal carcinoma and to determine the prognostic significance of the expression of NDRG1. Expression of NDRG1 mRNA was quantified by real-time reverse transcription polymerase chain reaction using a Lightcycler in 47 esophageal ESCC specimens. The data were analyzed with reference to clinicopathological factors. Among the esophageal cancer tissues, NDRG1 mRNA expression was significantly lower in tumors of more advanced pathological stage (0-I vs. II-IV; P = 0.0027) and local tumor invasion (T1-2 vs. T3-4; P = 0.0136). Patients who had low NDRG1 mRNA expression had a significantly shorter survival after surgery compared with patients who had high NDRG1 mRNA expression (log-rank test, P = 0.0478). Impaired NDRG1 expression may lead to more aggressive invasion of ESCC.

Significance of SAA1.3 allele genotype in Japanese patients with amyloidosis secondary to rheumatoid arthritis.

OBJECTIVE: To clarify the clinical significance of the SAA1.3 allele in the development and outcome of AA amyloidosis in Japanese patients with rheumatoid arthritis (RA). METHODS: One hundred and twenty RA patients (60 alive and 60 dead) fulfilling the 1987 ACR criteria and 62 RA patients with biopsy-confirmed amyloid A (AA) amyloidosis (36 alive and 26 dead) were enrolled. The SAA1 genotypes were determined by PCR-based restriction fragment length polymorphism. To predict the clinical outcome of AA amyloidosis, we investigated characteristics and survival, focusing on the SAA1.3 allele retrospectively. RESULTS: The SAA1.3 allele genotype was not only a risk factor for the association of AA amyloidosis but also a poor prognostic factor for the development of AA amyloidosis (P=0.015). Both the association of AA amyloidosis arising early in the RA disease course and symptomatic variety and severity were found in amyloidotic patients with the SAA1.3 allele. The presenting factors adversely influenced were age (P=0.001), lowered serum albumin (P=0.001) and creatinine concentration (P=2.14 x 10(-5)). Renal involvement was associated with poor survival in patients with AA amyloidosis (P=0.011) and the presence of cardiac involvement was likely to be a risk factor for survival (P=0.062). The rate of the causes of death in respect to the category of infection, gastrointestinal diseases, and renal failure was higher in patients with AA amyloidosis than in those without amyloidosis, gastrointestinal diseases and renal failure. Cyclophosphamide was found to be superior to methotrexate in the management of RA patients with AA amyloidosis. CONCLUSION: Our data support the fact that homozygosity for the SAA1.3 allele is a univariate predictor of survival in addition to a risk factor for the association of AA amyloidosis adversely influencing the outcome in Japanese RA patients. Renal involvement is a pivotal clinical manifestation in the development of AA amyloidosis, as is likely to be cardiac involvement in AA amyloidosis secondary to RA.

[Clinical study on mortality of rheumatoid arthritis compared with malignant rheumatoid arthritis].

OBJECTIVE: To determine how the mortality of patients with rheumatoid arthritis (RA) behave in comparison with that of patients with malignant rheumatoid arthritis (MRA). METHODS: The mortality of RA patients selected at randam identified in 1991-2000 (n = 104) was compared with that of 18 MRA patients. Hazard ratios of death were calculated with a multivariate survival analysis. A clinical study of patients with both RA and MRA was performed in mortality. RESULTS: Excess mortality was seen in MRA patients in Kaplan-Meier survival curves (p = 0.02 by log-rank test). MRA patients were treated more often with cytostatic and immunosuppressive drugs. Infection was the main cause of death in both RA and MRA patients. Vasculitis was not reported as the cause of death in MRA patients. Secondary amyloidosis played an important role in RA death rather than MRA. CONCLUSION: There remained an excess mortality in MRA patients compared with RA, and infection was attributable to the key cause of death in both RA and MRA suggesting therapeutic side effects.

Prevention of accelerated presbycusis by bone marrow transplantation in senescence-accelerated mice.

A substrain of the senescence-accelerated mouse (SAM), the SAMP1 mouse, is an animal model for accelerated senescence including the age-related acceleration of both immunological dysfunction and hearing loss caused by the impairment of spiral ganglion cells. In the present study, we examine whether the accelerated presbycusis can be prevented by allogeneic BMT. Young SAMP1 (H-2(k)) mice were irradiated with 9 Gy and then reconstituted with bone marrow cells from normal BALB/c (H-2(d)) mice. Allogeneic BMT was found to prevent the development of immunological dysfunction, hearing loss, and apoptosis of spinal ganglion cells in SAMP1 mice. These findings indicate that some types of accelerated presbycusis do not result from defects in the cochlea, but do from defects in the hematopoietic stem cells (HSC) and immunocompetent cells derived from the HSC. If this is the case, either allogeneic BMT, which replaces abnormal HSC with normal HSC and reconstructs a normal immune system in the recipients, or autologous BMT using genetically modified bone marrow cells, could become a new strategy for the treatment of presbycusis.

Direct binding of the signal-transducing adaptor Grb2 facilitates down-regulation of the cyclin-dependent kinase inhibitor p27Kip1.

Ectopic expression of Jab1/CSN5 induces specific down-regulation of the cyclin-dependent kinase (Cdk) inhibitor p27 (p27(Kip1)) in a manner dependent upon transportation from the nucleus to the cytoplasm. Here we show that Grb2 and Grb3-3, the molecules functioning as an adaptor in the signal transduction pathway, specifically and directly bind to p27 in the cytoplasm and participate in the regulation of p27. The interaction requires the C-terminal SH3-domain of Grb2/3-3 and the proline-rich sequence contained in p27 immediately downstream of the Cdk binding domain. In living cells, enforcement of the cytoplasmic localization of p27, either by artificial manipulation of the nuclear/cytoplasmic transport signal sequence or by coexpression of ectopic Jab1/CSN5, markedly enhances the stable interaction between p27 and Grb2. Overexpression of Grb2 accelerates Jab1/CSN5-mediated degradation of p27, while Grb3-3 expression suppresses it. A p27 mutant unable to bind to Grb2 is transported into the cytoplasm in cells ectopically expressing Jab1/CSN5 but is refractory to the subsequent degradation. These findings indicate that Grb2 participates in a negative regulation of p27 and may directly link the signal transduction pathway with the cell cycle regulatory machinery.

Extracellular adenosine 5'-ATP-induced calcium signaling in isolated vestibular ganglion cells of the guinea pig.

Extracellular adenosine 5'-triphosphate (ATP)-induced intracellular calcium concentration ([Ca2+]i) changes in acutely isolated vestibular ganglion cells (VGCs) of the guinea pig were investigated using the Ca2+ -sensitive dye Fura-2. Extracellular ATP induced an increase in [Ca2+]i in VGCs in a dose-dependent manner. ATP induced an increase in [Ca2+]i even in the absence of extracellular Ca2+ (1 mM Ethylene Glycol-bis (beta-aminoethyl Ether) N,N,N',N'-Tetraacetic Acid (EGTA)), thus suggesting that ATP induces Ca2+ release from the intracellular stores. The P2-receptor antagonists suramin and reactive blue 2 inhibited the ATP-induced [Ca2+]i increase in a dose-dependent manner. The P1-receptor agonist adenosine did not induce any changes in [Ca2+]i. These results suggest that VGCs may possess a P2-purinergic receptor but not a P1-purinergic receptor. La3+, a receptor-mediated calcium channel blocker, inhibited the ATP-induced [Ca2+]i increase but, in contrast, nifedipine, a L-type calcium channel blocker, did not. These results suggest that ATP induces both a Ca2+ -release from the intracellular stores and a Ca2+ influx from the extracellular space through La3+ -sensitive and nifedipine-insensitive Ca2+ channels in VGCs. Our results also suggest that extracellular ATP may act as a neurotransmitter or neuromodulator of the vestibular peripheral system in the guinea pig.

Prevention of autoimmune hearing loss in MRL/lpr mice by bone marrow transplantation.

We examined the effects of bone marrow transplantation (BMT) on immune-mediated inner ear diseases in MRL/Mp-lpr/lpr (MRL/lpr) mice, which manifest not only lupus nephritis but also sensorineural hearing loss (SNHL) at the age of 20 weeks. These mice were treated with cyclophosphamide (CY) and irradiation (5 Gy x 2), followed by the transplantation of bones plus bone marrow cells from allogeneic normal C57BL/6 mice at the age of 12 weeks. Hematolymphoid cells were reconstituted with donor-derived cells 3 months after BMT. Thus-treated MRL/lpr mice showed neither lupus nephritis nor SNHL even 24 weeks after BMT. No pathological findings were observed in either glomeruli or cochleae. These findings suggest that BMT can be used to prevent the development of autoimmune SNHL in MRL/lpr mice.

Helical CT imaging of gastric cancer: normal wall appearance and the potential for staging.

PURPOSE: To evaluate the CT appearance of the normal gastric wall and the effectiveness of contrast enhanced helical CT for T-staging of gastric cancer. METHODS: For the basic experiment, two resected stomachs with gastric cancer were filled with water and examined by helical CT imaging. For the clinical study, 59 consecutive patients with gastric cancer who had received preoperative helical CT examination and had also been operated on were entered in this study. Helical CT images were evaluated independently by three radiologists without knowledge of histological staging results. RESULTS: The basic examination of a histopathological correlation with CT images revealed that the inner layer with high attenuation corresponded to the mucosa and the muscular layer of the mucosa, the middle layer with low attenuation to the submucosal layer consisting of coarse tissues and containing fatty tissues, and the outer layer with slightly high attenuation to the proper muscle with serosa. The clinical study revealed that the rate of correct diagnosis through consensus reading was 66.1%. CONCLUSION: The entire stomach with a well-stained mucosa can be visualized by contrast enhanced helical CT. However, T-staging of gastric cancer by helical CT did not appear to improve the accuracy of staging.

Probability of hepatocellular carcinoma of small hepatocellular nodules undetectable by computed tomography during arterial portography.

Recent advances in imaging modalities enable the identification of small hepatocellular nodules. Among the imaging techniques currently used for detecting hepatocellular carcinomas (HCC), computed tomography (CT) during arterial portography (CTAP) is one of the most sensitive techniques available for detecting hemodynamic change. Even so, well-differentiated HCCs that display only limited hemodynamic change, a feature shared with nonmalignant hepatocellular nodules, are not always detectable by CTAP. To improve our ability to distinguish well-differentiated HCCs from nonmalignant hepatocellular nodules, we have attempted to clarify how the characteristics of the nodules are shown by each imaging technique. We studied the imaging and pathological characteristics of 31 nodules (in 22 patients) detected by ultrasonography (US), but not by CTAP. Histological diagnoses were as follows: HCC, 17 of 31 nodules (55%); high-grade dysplastic nodules, 1 of 31 (3%); and nonmalignant nodules, 13 of 31 (42%). Neither digital substraction angiography (DSA) nor CT arteriography (CTA) were able to detect any of the nodules. Detection rates for plain CT were: 5 of 17 (29%) HCC, 1 of 1 (100%) high-grade dysplastic nodules, and 1 of 13 (8%) nonmalignant nodules. Detection rates for T1/T2-weighted magnetic resonance imaging (MRI) were: 4 of 17 (24%) HCC, 1 of 1 (100%) high-grade dysplastic nodules, and 3 of 13 (23%) nonmalignant nodules. Dynamic CT and dynamic MRI provided no additional information. In conclusion, there is some probability that hepatocellular nodules detected by US, but not by CTAP, are HCC. Presently, it is difficult to distinguish between benign nodules and malignant ones with these imaging techniques, and our findings indicate that biopsy may be advisable for nodules detected under these conditions.

Combined treatment with cyclophosphamide and prednisolone is effective for secondary amyloidosis with SAA1γ/γ genotype in a patient with rheumatoid arthritis.

Abstract A 41-year-old woman, who had been diagnosed with rheumatoid arthritis (RA), was admitted because of proteinuria, and rheumatoid and gastrointestinal symptoms just 1 year after onset. Renal biopsy revealed marked amyloid deposits of AA (amyloid A)-type. Genotyping of serum amyloid A (SAA) showed that she was homozygous for SAA1γ. Combined treatment with cyclophosphamide and prednisolone led to remission of both RA disease activity and proteinuria. Since the renal dysfunction arose from amyloidosis, arrested renal deterioration and a remission of proteinuria would result from a reduction of amyloid deposits. Therefore, early usage of immunosuppresive therapy such as a combined treatment with these two medicines would be useful against systemic amyloidosis secondary to RA, even if the patient has the risky SAA1γ/γ genotype.

Optimal phases of dynamic CT for detecting hepatocellular carcinoma: evaluation of unenhanced and triple-phase images.

BACKGROUND: To determine the optimal phases of dynamic computed tomography (CT) for detecting hepatocellular carcinoma (HCC). METHODS: Fifty-two patients with 85 HCC nodules were examined by means of unenhanced and triple-phase CT images of the whole liver. The time for obtaining the arterial-phase images was 25-55 s after intravenous bolus injection of contrast material, the time for obtaining the portal venous-phase images was 65-100 s, and the time for obtaining late-phase images was 145 s to 4 min. Detectability of the HCC nodules for all phases was statistically compared. RESULTS: The detection rates for the arterial- and late-phase images were significantly higher than for the unenhanced and portal venous-phase images (p < 0.01). The combination of arterial- and late-phase images showed the same number of HCC nodules in the same number of patients as did the combination of unenhanced and triple-phase images. CONCLUSION: The combination of the arterial- and late-phase imagings was best for detecting HCC nodules.

MR imaging of non-squamous vaginal tumors.

We reviewed the MR images and pathologic findings of five cases of primary vaginal neoplasms of non-squamous origin. Histologic types consisted one case each of adenocarcinoma, adenosarcoma, melanoma, lymphoma, and neurilemoma. Magnetic resonance imaging was found useful for evaluating the type and the extension of vaginal tumors.