Rapid deterioration of renal insufficiency after magnetic resonance imaging with gadolinium-based contrast agent.

Gadolinium (Gd)-based contrast media were introduced as alternatives to iodinated media for magnetic resonance imaging (MRI). Although originally thought to be non-nephrotoxic, Gd-based contrast media have recently been reported to be associated with acute kidney injury. The underlying mechanism of Gd-induced renal injury is not completely understood. We report an 80-year-old patient with buccal mucosa cancer for whom MRI with Gd-based contrast agent was conducted 3 times within 3 weeks. The patient developed rapid deterioration of preexisting renal insufficiency, and developed uremic symptoms and pulmonary edema. The patient was hemodialyzed 3 times. This resulted in improvement of renal function and clinical symptoms. This case emphasizes the potential nephrotoxicity of Gd-based contrast media and suggests that renal insufficiency, diabetes mellitus, old age and high dose of Gd-based contrast medium are risk factors for acute kidney injury.

A cellular mechanism for the bidirectional pain-modulating actions of orphanin FQ/nociceptin.

Orphanin FQ/nociceptin (OFQ/N) and its receptor share substantial structural features and cellular actions with classic opioid peptides and receptors, but have distinct pharmacological profiles and behavioral effects. Currently there is an active debate about whether OFQ/N produces hyperalgesia or analgesia. Using a well-defined brainstem pain-modulating circuit, we show that OFQ/N can cause either an apparent hyperalgesia by antagonizing mu opioid-induced analgesia or a net analgesic effect by reducing the hyperalgesia during opioid abstinence. It presumably produces these two opposite actions by inhibiting two distinct groups of neurons whose activation mediates the two effects of opioid administration. OFQ/N antagonism of the hyperalgesia may have significance for the treatment of opioid withdrawal and sensitized pain.

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

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

Glycochenodeoxycholic acid inhibits calcium phosphate precipitation in vitro by preventing the transformation of amorphous calcium phosphate to calcium hydroxyapatite.

Calcium hydroxyapatite can be a significant component of black pigment gallstones. Diverse molecules that bind calcium phosphate inhibit hydroxyapatite precipitation. Because glycine-conjugated bile acids, but not their taurine counterparts, bind calcium phosphate, we studied whether glycochenodeoxycholic acid inhibits calcium hydroxyapatite formation. Glycochenodeoxycholic acid (2 mM) totally inhibited transformation of amorphous calcium phosphate microprecipitates to macroscopic crystalline calcium hydroxyapatite. This inhibition was not mediated by decreased Ca2+ activity. Taurocholic acid (2-12 mM) did not affect hydroxyapatite formation, but antagonized glycochenodeoxycholic acid. Both amorphous and crystalline precipitates contained a surface fraction relatively rich in phosphate. The surface phosphate content was diminish by increasing glycochenodeoxycholic acid concentrations, and this relationship was interpreted as competition between bile acid and HPO4(-4) for binding sites on the calcium phosphate surface. A phosphate-rich crystal surface was associated with rapid transition from amorphous to crystalline states. These results indicate that glycochenodeoxycholic acid prevents transformation of amorphous calcium phosphate to crystalline hydroxyapatite by competitively inhibiting the accumulation of phosphate on the crystal embryo surface.

Bi-directional changes in affective state elicited by manipulation of medullary pain-modulatory circuitry.

The rostral ventromedial medulla contains three physiologically defined classes of pain-modulating neuron that project to the spinal and trigeminal dorsal horns. OFF cells contribute to anti-nociceptive processes, ON cells contribute to pro-nociceptive processes (i.e. hyperalgesia) and neutral cells tonically modulate spinal nociceptive responsiveness. In the setting of noxious peripheral input, the different cell classes in this region permit bi-directional modulation of pain perception (analgesia vs hyperalgesia). It is unclear, however, whether changes in the activity of these neurons are relevant to the behaving animal in the absence of a painful stimulus. Here, we pharmacologically manipulated neurons in the rostral ventromedial medulla and used the place-conditioning paradigm to assess changes in the affective state of the animal. Local microinjection of the alpha(1)-adrenoceptor agonist methoxamine (50.0 microg in 0.5 microl; to activate ON cells, primarily), combined with local microinjection of the kappa-opioid receptor agonist U69,593 (0.178 microg in 0.5 microl; to inhibit OFF cells), produced an increase in spinal nociceptive reactivity (i.e. hyperalgesia on the tail flick assay) and a negative affective state (as inferred from the production of conditioned place avoidance) in the conscious, freely moving rat. Additional microinjection experiments using various concentrations of methoxamine alone or U69, 593 alone revealed that the rostral ventromedial medulla is capable of eliciting a range of affective changes resulting in conditioned place avoidance, no place-conditioning effect or conditioned place preference (reflecting production of a positive affective state). Overall, however, there was no consistent relationship between place-conditioning effects and changes in spinal nociceptive reactivity. This is the first report of bi-directional changes in affective state (i.e. reward or aversion production) associated with pharmacological manipulation of a brain region traditionally associated with bi-directional pain modulation. We conclude that, in addition to its well-described pain-modulating effects, the rostral ventromedial medulla is capable of modifying animal behavior in the absence of a painful stimulus by bi-directionally influencing the animal's affective state.

SCCA1 expression in T-lymphocytes peripheral to cancer cells is associated with the elevation of serum SCC antigen in squamous cell carcinoma of the tongue.

Squamous cell carcinoma (SCC) antigen has been used for the management of SCC arising in various cites including head and neck region. However, the true mechanism of the elevation of this protein in the serum of patients with SCC is still unknown. SCC antigen belongs to the superfamily of serine protease inhibitors. Recently, molecular studies show that serum SCC antigen is transcribed by two nearly identical genes (SCCA1 and SCCA2), and is mainly produced by SCCA1. The objective of this study is to clarify the mechanism of the elevation of SCC antigen in oral tongue SCC patients and to identify cells histologically, which are responsible for serum SCC antigen production. In this study, we examined SCCA1 expression in a series of four head and neck SCC (HNSCC) cell lines, and found that all expressed equal to low SCCA1 protein as compared with the normal human oral keratinocyte. Using the double immunohistochemical technique to examine the expression pattern of SCCA1 in 86 cases of oral tongue squamous cell carcinoma, SCCA1 immunostaining was observed in the cytoplasm of cancer cells and T-lymphocytes peripheral to cancer cells. We also compared the clinicopathological features including serum SCC antigen level of the oral tongue SCC cases with the immunohistochemical SCCA1 expression pattern, and found that elevated serum SCC antigen level was significantly correlated with SCCA1 expression not in cancer cells, but in T-lymphocytes peripheral to cancer cells. These results suggest that T-lymphocytes peripheral to cancer cells may be responsible for serum SCC antigen production in HNSCC patients.

Overexpression of bcl-2 protein in synovial sarcoma: a comparative study of other soft tissue spindle cell sarcomas and an additional analysis by fluorescence in situ hybridization.

The expression of bcl-2 protein was analyzed in 19 synovial sarcomas and 29 additional soft tissue spindle cell sarcomas as controls by the immunohistologic staining of paraffin-embedded specimens; 15 of 19 (79%) synovial sarcoma cases were positive, but all other spindle cell sarcomas were negative including 20 leiomyosarcomas, 4 malignant peripheral nerve sheath tumors, and 4 fibrosarcomas. In 4 cases of bcl-2-positive synovial sarcoma (3 biphasic and 1 focally glandular type), bcl-2 protein staining was much stronger in the spindle cells than in the epithelial cells. A fluorescence in situ hybridization (FISH) analysis with centromeric and whole chromosome painting probes for chromosome 18 and X was performed on 7 synovial sarcomas. The six cases of bcl-2-positive synovial sarcoma consisted of five cases with the t(X; 18) and one case with tetrasomy of chromosome 18 and X. It has been speculated that bcl-2 protein expression is caused by the 14; 18 translocation and other abnormalities of chromosome 18. This study thus showed the feasibility of such a correlation between bcl-2 protein expression and the characteristic cytogenetic abnormality in the synovial sarcoma-X; 18 translocation. In addition, bcl-2 protein also appears to be a characteristic marker of synovial sarcoma and is thus considered to be potentially useful in distinguishing synovial sarcoma from other spindle cell sarcomas.

Evaluation of Epstein-Barr virus infection in sinonasal small round cell tumors.

Sinonasal undifferentiated carcinoma, olfactory neuroblastoma and malignant melanoma of the sinonasal regions are included within the category of small round cell tumors of the sinonasal region. It is difficult to diagnose these tumors on the basis of light-microscopic features alone, but, in some instances, immunohistochemical staining evaluating cytokeratin and S-100 protein, for example, is of value. On the other hand, the sinonasal region is a significant site for Epstein-Barr-virus (EBV)-related tumors, including sinonasal undifferentiated carcinoma or malignant lymphoma. Twenty-three sinonasal small round cell tumors (SSRCT) comprising 5 sinonasal undifferentiated carcinomas, 9 olfactory neuroblastomas and 9 malignant melanomas were evaluated for the presence of EBV infection by in situ hybridization for EBV-encoded RNA, combined with immunostaining for EBV-related proteins (LMP-1 and EBNA2). Furthermore, 55 SSRCT comprising 37 sinonasal undifferentiated carcinomas, 9 olfactory neuroblastomas, and 9 malignant melanomas were examined for the presence of cytokeratins (AE1/ AE3 and CAM5.2), S-100 protein and p53 protein using immunohistochemical staining. According to in situ hybridization for detecting EBV-encoded RNA 1 (EBER1), all of the sinonasal undifferentiated carcinomas showed clear, intense hybridization signals localized over the nuclei of the tumor cells and, in 3 out of 9 (33.3%) malignant melanomas, hybridization signals were also recognized. However, none of the olfactory neuroblastomas revealed hybridization signals. Immunohistochemically, 4 out of 5 (80%) sinonasal undifferentiated carcinomas were positive for LMP-1, whereas only 2 out 9 (22.2%) malignant melanomas and no olfactory neuroblastomas were positive. With regard to EBNA2, sinonasal undifferentiated carcinomas, malignant melanomas and olfactory neuroblastomas were all negative. Out of 37 sinonasal undifferentiated carcinomas 35 (94.6%) showed a diffuse positive immunoreaction for AE1/AE3, whereas neither olfactory neuroblastoma nor malignant melanoma revealed a positive reaction. All 9 malignant melanomas and 6 out of 9 olfactory neuroblastomas (75%) were positive for S-100 protein, whereas only 6 cases of sinonasal undifferentiated carcinomas (19.4%) were positive. As for p53 protein, 16 of 37 sinonasal undifferentiated carcinomas (43.2%) were positive, whereas neither olfactory neuroblastoma nor malignant melanoma revealed any positive reaction. The above results suggest that EBV infection is closely associated with sinonasal undifferentiated carcinomas, and that some malignant melanomas may also have a relationship with its infection. For the differential diagnosis of SSRCT, it is important to evaluate EBV infection along with immunohistochemical staining for cytokeratins and S-100 protein. The overexpression of p53 protein was found to be related to the oncogenesis of sinonasal undifferentiated carcinoma; however, there was no association between its overexpression and malignant melanoma or olfactory neuroblastoma.

Highly delta selective antagonists in the RVM attenuate the antinociceptive effect of PAG DAMGO.

The present study tested the hypothesis that endogenous opioid peptides acting at the delta-opioid receptor (DOR) in the rostral ventromedial medulla (RVM) contribute to the antinociception elicited by the mu-opioid receptor (MOR) agonist DAMGO in the midbrain periaqueductal gray (PAG). Following microinjection of DAMGO into the PAG, either the highly selective DOR antagonist TIPP[psi] or the DOR2 antagonist naltriben (NTB) was microinjected into the RVM. Both TIPP[psi] (1.0 microg) and NTB (5.0 ng) significantly attenuated the analgesic effect of PAG DAMGO but had no effect when given before PAG saline. These results confirm and extend previous studies suggesting that PAG mu-opioids activate a descending system with a DOR mediated endogenous opioid link in the RVM.

Sympathetic innervation of the young canine heart using antero- and retrograde axonal tracer methods.

The present study was performed to determine the origin of cardiac sympathetic postganglionic fibers and to demonstrate their distribution in the heart. Young dogs were used in this study. Wheat germ agglutinin-horseradish peroxidase (WGA-HRP) was injected into various regions of the heart, and cholera toxin B subunit (CTB) and WGA-HRP were injected into the middle cervical ganglion or the stellate ganglion. In our retrograde axonal transport study, a large number of WGA-HRP-labeled cells were observed in the middle cervical and stellate ganglia bilaterally. Only a small number of the labeled cells were observed in the superior cervical ganglia bilaterally. In the anterograde axonal transport study, CTB and WGA-HRP labels showed terminal-like structures in the intrinsic ganglia located in the sinoatrial node, left atrium, and the origin of the ascending aorta. The labeled fibers were also observed around the coronary arteries.

A progression to dermatofibrosarcoma protuberans with a fibrosarcomatous component: a special reference to the chromosomal aberrations.

Dermatofibrosarcoma protuberans (DFSP) with fibrosarcomatous areas (DFSP-FS) is differentiated from ordinary DFSP by its unfavourable prognosis. We carried out sequential analysis of numerical chromosomal abnormalities in two cases of DFSP during their progression to metastatic disease with FS areas (DFSP-M-FS). They were compared with nine cases of ordinary DFSP and three cases of DFSP-FS, but without metastases. Numerical chromosomal changes were examined by fluorescence in situ hybridization (FISH) using alpha-satellite centromeric probes for chromosomes 1, 8, 11 and 17. Numerical imbalances of chromosome 1 were not clarified. A gain of chromosome 8 was demonstrated in the two cases of DFSP-M-FS. A gain of chromosome 11 was observed in one of the two cases of DFSP-M-FS and in one case of DFSP-FS. A gain of chromosome 17 was demonstrated in both metastatic tumours and in recurrent tumours in two cases of DFSP-M-FS, in addition to two cases of DFSP-FS and four cases of ordinary DFSP with recurrent tumours or large tumours. This study raised the hypothesis that a gain of chromosome 17 developed in recurrent or large-sized DFSP, which occurs in high-risk groups with the possibility of a progression to FS.

A study of the role of sex hormones in rat ovarian cancer.

The effects of estrogen, progesterone, and testosterone on the growth of 7,12 dimethylbenz(a)anthracene (DMBA) induced adenocarcinomas in rats (Wistar strain) were evaluated. Estrogen resulted in the highest acceleration of tumor volume. The histologic features were a solid structure associated with a significant proliferation of connective tissues and with many signet ring cells with intracytoplasmic canaliculi. Progesterone changed the histologic features to a more immature adenocarcinoma associated with a notable solid area with many mitotic figures, although the growth rate of the tumor was the same as the controls. On the contrary, testosterone induced the slowest tumor growth and a histologically scirrhus pattern. The results of this preliminary observation indicate a possible role for sex steroids in the ovarian tumorigenic process.

An experimental model for advanced ovarian cancer.

Intraperitoneally transplanted tumors implanted and began developing with ascites in about 62% of the female rats within 4 to 6 weeks after transplantation. The tumor used in this study was an adenocarcinoma and which originated from a primary ovarian cancer in rats of the same strain (Wistar). The morphology and biological behavior of the tumor were very similar to the tumor in humans. Moreover, the preliminary results with cisplatin therapy indicate that intraperitoneal cancer corresponding to stage III or IV in the FIGO classification is a promising model for experimental therapeutic studies of common epithelial carcinoma at an advanced stage.

[Circadian rhythm of parasympathetic nervous function in asthmatic children].

We examined the circadian rhythm of parasympathetic nervous function in asthmatic children. The subjects were 80 patients with asthma (mild 54 patients, moderate 15 patients and severe 11 patients) and 90 individuals in healthy children. All the patients underwent 24-electrocardiography in normal condition. We measured the %RR50 for hour and analyzed the rhythm using the single cosine fitting method, comparing the values of the Amplitude, the MESOR and the Acrophase in terms of the therapy and also the severity of asthma. Circadian rhythm disappeared in 9 of the 80 asthmatic children and was observed in all the individuals in the healthy children. The value of MESOR was lower in the asthmatic children than in the healthy children. There was no significant difference between the different severity or therapies in each group. In some asthmatic children, the circadian rhythm of parasympathetic nervous function disappeared, the parasympathetic nervous function was low in remission. It is suggested that the disorder of biologic rhythm is related to the pathogenesis of asthma.

Diffusion of alcohol upon application of neuroadenolysis of the pituitary gland (NALP). An experimental study using HRP and WGA-HRP in the cat.

Diffusion of alcohol in neuroadenolysis of pituitary gland (NALP) was observed by injection of horseradish peroxidase (HRP) or wheat germ agglutinin-HRP conjugates (WGA-HRP) into the pituitary of the cat. After small-amount injection of WGA-HRP into the pituitary, WGA-HRP labeling was observed markedly around the third ventricle and the ventral part of the hypothalamus. While, in large-amount injection of WGA-HRP, it extended to all of the ventricular systems and dipped into the substances of the brain and spinal cord through the ependyma. These results suggest that the main site of action for alcohol injected into the pituitary is probably the hypothalamus.

Three-dimensional analysis of the intrinsic cardiac ganglia in a young dog.

The intrinsic ganglia of the heart of a young dog were studied by computer graphic reconstruction to determine the accurate location. The heart was embedded in celloidin, and transverse sections were cut. Using every third 60 microns section, a series of 49 sections was mapped. Three-dimensional (3D) images were constructed by a personal computer. Numerous intrinsic ganglia, most of which were located in the epicardiun, were observed. The intrinsic ganglia were found in the base of the aorta and pulmonary vessels and from the base of the superior vena cava to the right atrium, i.e., the sinoatrial nodal region. Using the 3D reconstruction technique, the locations of the intrinsic ganglia could be accurately identified. Furthermore, it was demonstrated that these ganglia formed several groups which formed a continuity. This study suggested that it was necessary to consider the existence of the numerous intrinsic ganglia, when we studied the cardiac innervation.

[Clinical analysis of parotid cancer].

A clinical study was performed on 42 patients with parotid cancers initially treated in our hospital from 1972 to 1997. The five-year cumulative survival rate was 69% in the whole group and 72% in the radical surgical treatment group (n = 40). The five-year survival rates according to stage were as follows: stage I, 95% (21); stage II, 75% (4); stage III, 0% (1); and stage IV, 37% (16). The factors influencing prognosis were cases of T3 and T4 (p < 0.05), stage III and IV (p < 0.01), and cervical lymph node metastasis (p < 0.01). Regarding treatment modalities, a partial parotidectomy appeared to be a curable surgical procedure for T1 cases. However, a lobectomy is recommended for T2 cases. Furthermore our study proposed that prophylactic supraomohyoid neck dissection should be necessary for mucoepidermoid carcinoma (high-grade malignancy) and undifferentiated carcinoma of T4N0 cases.