Dominant contribution of atmospheric nonlinearities to ENSO asymmetry and extreme El Niño events.

Extreme El Niño events have outsized impacts and strongly contribute to the El Niño Southern Oscillation (ENSO) warm/cold phase asymmetries. There is currently no consensus on the respective importance of oceanic and atmospheric nonlinearities for those asymmetries. Here, we use atmospheric and oceanic general circulation models that reproduce ENSO asymmetries well to quantify the atmospheric nonlinearities contribution. The linear and nonlinear components of the wind stress response to Sea Surface Temperature (SST) anomalies are isolated using ensemble atmospheric experiments, and used to force oceanic experiments. The wind stress-SST nonlinearity is dominated by the deep atmospheric convective response to SST. This wind-stress nonlinearity contributes to ~ 40% of the peak amplitude of extreme El Niño events and ~ 55% of the prolonged eastern Pacific warming they generate until the following summer. This large contribution arises because nonlinearities consistently drive equatorial westerly anomalies, while the larger linear component is made less efficient by easterly anomalies in the western Pacific during fall and winter. Overall, wind-stress nonlinearities fully account for the eastern Pacific positive ENSO skewness. Our findings underscore the pivotal role of atmospheric nonlinearities in shaping extreme El Niño events and, more generally, ENSO asymmetry.

Small size of metastatic lymph nodes with extracapsular spread greatly impacts treatment outcomes in oral squamous cell carcinoma patients.

Extracapsular spread (ECS) of metastatic lymph nodes from oral carcinoma is the most significant prognostic predictor of a poor treatment outcome. However, only a few reports on prognostic factors in ECS-positive cases have been investigated. To address this problem, a detailed examination of ECS pathology was conducted to determine the prognostic factors of oral squamous cell carcinoma (OSCC) with ECS of metastatic lymph nodes. This study involved 63 OSCC patients with at least one pathologically metastatic node with ECS. Among the 229 metastatic lymph nodes, 149 exhibited ECS. Univariate analysis revealed that a poor outcome and recurrence were significantly associated with the number of ECS-positive nodes, density of ECS, and the minor axis of the smallest ECS-positive node. However, multivariate analysis identified only small size of ECS-positive nodes as a significant and independent factor predicting recurrence and a poor outcome. Thus, small size of ECS-positive nodes is the most important prognostic indicator for OSCC with ECS in metastatic lymph nodes. The classification of ECS status using the minor axis of ECS-positive nodes may be useful for further prediction of a poorer prognosis in OSCC cases. Standardization of ECS diagnosis and multicenter prospective studies will be required to confirm and refine these findings.

Inhibition of neutrophil elastase-induced goblet cell metaplasia by tiotropium in mice.

Airway occlusion by mucus in chronic obstructive disease (COPD) is associated with a poor prognosis. We hypothesised that tiotropium has the ability to inhibit neutrophil elastase (NE)-induced goblet cell metaplasia in mice and mucin production in vitro. On days 1, 4, and 7, tiotropium or vehicle was administered to C57BL/6 mice by inhalation and they were allowed to intranasally aspirate human NE. Bronchoalveolar lavage fluid (BALF) and lung sections were analysed on days 8, 11 and 14. The effect of late administration of tiotropium on the goblet cell metaplasia by NE aspiration was also assessed. NE-induced MUC5AC production by NCI-H292 cells was measured with ELISA. Repeated NE aspiration induced marked goblet cell metaplasia. The grading of goblet cell metaplasia, neutrophil count and eosinophil count in BALF, keratinocyte-derived chemokine level and leukotriene B(4) level in BALF, and M(3) receptor expression by immunohistochemistry, were lower in the tiotropium group than in the vehicle group. Late administration of tiotropium inhibited the established goblet cell metaplasia. Tiotropium inhibited NE-induced MUC5AC production. Tiotropium inhibited NE-induced goblet cell metaplasia and mucin production, probably mediated by suppression of inflammation and a direct action on epithelial cells. This result suggests that tiotropium may be useful for the treatment of mucus overproduction in COPD.

Effects of a leukotriene B4 receptor antagonist on bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with poor prognosis. Leukotrienes play an important role in IPF, and leukotriene (LT)B(4) is one of the key eicosanoids in IPF. In this study, we investigated whether ONO-4057, a LTB(4) receptor (BLTR) antagonist is capable of preventing bleomycin-induced pulmonary fibrosis. On day 1, C57BL/6 male mice were given a single intratracheal injection of bleomycin (2.5 mg x kg(-1)), and ONO-4057 (1.0 mg x kg(-1)) or vehicle alone, administered by intraperitoneal injection on days 1-5 each week for 3 weeks after the bleomycin injection. ONO-4057 reduced the total cell count in bronchoalveolar lavage fluid (BALF) on days 7, 14 and 21 and the Ashcroft score and the lung hydroxyproline content on days 14 and 21. The LTB(4), interleukin (IL)-6, IL-13, transforming growth factor (TGF)-beta levels in BALF and the TGF-beta expression in lung tissue, assessed by immunohistochemistry were decreased on day 7, whereas interferon (IFN)-gamma level in BALF was increased on day 14. The results of this study indicated that the BLTR antagonist inhibited the development of bleomycin-induced pulmonary fibrosis in mice by decreasing inflammation and altering TGF-beta, IL-6, IL-13 and IFN-gamma.

Outcome of patients with non-Hodgkin's lymphoma of the stomach after gastrectomy: clinicopathologic study and reclassification according to the revised European-American lymphoma classification.

BACKGROUND: The best treatment for patients with non-Hodgkin's lymphoma (NHL) of the stomach is still uncertain. The revised European-American lymphoma (REAL) classification has helped to define new, potentially more appropriate classification schemes for gastric lymphomas. METHODS: Fifty-one resected gastric lymphomas were reclassified according to the REAL classification, and the efficacy of multimodal treatment was examined retrospectively. The principal treatment plan consisted of: (1) surgical resection of the stomach with lymph node dissection, followed by (2) systemic chemotherapy, mainly using the cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) regimen. RESULTS: According to the Ann Arbor classification, 27 patients had stage IE, 19 had stage IIE, and 5 had stage IV NHL. Using the REAL classification, we diagnosed diffuse large B-cell lymphoma (DLBL) in 23 patients, marginal zone B-cell (low-grade mucosa-associated lymphoid tissue [MALT]-type) lymphoma in 22, follicle center lymphoma in 4, mantle cell lymphoma in 1, and peripheral T-cell lymphoma in 1 patient. Nine of the 51 patients relapsed, and 8 patients with DLBL died of cancer. Survival rates at 5 years after surgery were 96.0% for stage IE, 83.3% for stage IIE, and 87.0% for all patients. Univariate analysis indicated that the tumor histology (according to the REAL classification), depth of invasion, degree of nodal involvement, Ann Arbor staging, and chemotherapy had an impact on patient outcome (P = 0.0018; P = 0.0002; P = 0.0308; P = 0.0016, and P = 0.0118, respectively). CONCLUSIONS: These data reveal that gastric NHL, especially of the low-grade MALT-type, often remains localized and has a good prognosis after surgery. The REAL classification was useful for classifying new categories of NHL, including the MALT-type, in the clinical setting, and for determining the optimal treatment modality for gastric NHL.

Effects of stereotactic radiosurgery on metastatic brain tumors of various histopathologies.

Although reports have been published describing clinical results in a large series of patients with metastatic brain tumors treated by stereotactic radiosurgery (SRS), clinical neuropathological correlation has rarely been available. The present paper describes three autopsy cases and one surgical case treated with linear accelerator based radiosurgery. The cases comprised a lung cancer, a rectal cancer, an osteosarcoma, and a malignant melanoma. Histological sections of each tumor were analyzed by light microscopy based on the Ohosi and Shimosato's histopathological classification of the effects of radiation therapy. In three cases (pulmonary squamous cell carcinoma, rectal adenocarcinoma and osteosarcoma), a large area of the tumors consisted of coagulation necrosis and non-viable tumor cells, while coagulation necrosis and non-viable tumor cells comprised a very small part of the malignant melanoma. Histopathological type of the metastatic brain tumor may be one of the factors influencing outcome after SRS.

Genetically high susceptibility to oral squamous cell carcinoma in terms of combined genotyping of CYP1A1 and GSTM1 genes.

An association of oral squamous cell carcinoma (SCC) susceptibility with an MspI restriction site polymorphism of the CYP1A1 gene and GSTM1 polymorphism were reported in our previous study (Sato M, Sato T, Izumo T, Amagasa T. Genetic polymorphism of drug-metabolizing enzymes and susceptiblility to oral cancer. Carcinogenesis 1999;20:1927-31). We report here that genetic risk for oral SCC was associated with another isoleucine-valine (Ile-Val) polymorphism, which resulted in an Ile-Val amino acid replacement in the heme-binding region of CYP1A1, and combined genotyping of CYP1A1 and GSTM1 genes in relation to the cumulative cigarette-smoking dose. The genetic polymorphisms of CYP1A1 and GSTM1 genes in oral cancer susceptibility were assessed by examining polymorphic prevalences in 142 oral SCC patients and 142 healthy controls who were individually matched to the patients with respect to sex and age (+/-1 year). Individuals with a combined genotype of Val/Val and GSTM1(-) were at an increased risk for oral SCC compared with other combined genotypes, in particular, at a low dose level of cigarette smoking.

Practical utility of the revised European-American classification of lymphoid neoplasms for Japanese non-Hodgkin's lymphomas.

A clinicopathological study of 515 non-Hodgkin's lymphoma (NHL) cases was performed using the revised European-American classification of lymphoid neoplasms (REAL classification) in an HTLV1-nonendemic area of Japan. The following characteristics were revealed: 1) frequency of extranodal lymphomas was high (59%) with 79% B-cell lymphomas in this series, while the overall ratio of B:T/NK lineage was 3.7:1; 2) the most common type was the diffuse large B-cell lymphoma (46%), follicle center lymphomas occurred at an incidence lower (15%) than that in European and American populations, and marginal zone B-cell lymphomas accounted for as much as 12%; 3) peripheral T-cell lymphomas were common (19%), with the unspecified type predominant (11%), while adult T-cell lymphomas were present at a level equivalent to that among European and American patients (1%). Clear segregation of survival curves was rated according to cell lineage and B-cell lymphomas had a better prognosis than T / NK-cell lymphomas. Furthermore, new subtypes in the REAL classification, such as marginal zone B-cell and mantle cell lymphomas, exhibited distinct curves. Taken altogether, the REAL classification demonstrated advantages for assessment of Japanese NHL cases.

Genetic polymorphism of drug-metabolizing enzymes and susceptibility to oral cancer.

An individual difference in the susceptibility to chemical carcinogens is one of the most important factors in the estimate of risk of human cancer. Recently, it has been reported that genetic risk for tobacco-related cancers is associated with polymorphisms of the CYP1A1 and GSTM1 genes in terms of genotype frequencies and cigarette smoking dose. In this study, we investigated the inter-individual difference in genetically determined susceptibility to oral squamous cell carcinoma (SCC) in relation to cigarette smoking dose in a Japanese population. DNA samples were obtained from both patients and controls. We identified individuals at high risk genetically for oral SCC in terms of polymorphisms of the CYP1A1 and GSTM1 genes. This study then compared the estimated total number of cigarettes smoked by patients with those smoked by controls. In this case-control study, we estimated the odds ratios of susceptible to non-susceptible individuals. CYP1A1 genotype C and GSTM1 deficiency were frequently found among oral SCC patients. Patients with genotype C and GSTM1 deficiency contracted carcinoma after fewer cigarettes than those with other genotypes. Individuals with these two genotypes were at remarkably high risk at a low dose level of cigarette smoking. Individual differences in polymorphisms of the CYP1A1 and GSTM1 genes is one important factor in the estimate of risk of oral SCC at a low dose level of cigarette smoking.

Effects of certain cerebral circulation activating drugs on regional cerebral blood flow in rats.

The effects of certain cerebral circulation activating drugs on regional cerebral blood flow (rCBF) in the frontal cortex (FCOR), hippocampus (HPC) and nucleus caudatus (CAD) were investigated using the hydrogen clearance method in rats. All the drugs used in the present study, i.e., ozagrel, ifenprodil, pentoxifylline, cinnarizine and dilazep, caused an increase in rCBF in the FCOR, HPC and CAD. Ozagrel was the most potent in increasing rCBF at the FCOR. Ozagrel, ifenprodil, cinnarizine and dilazep were more effective than pentoxifylline in increasing rCBF at the HPC. On the other hand, all the drugs showed almost the same potency in increasing rCBF at the CAD. These results suggested that measurement of rCBF is useful for estimating the efficacy of cerebral circulation activating drugs.

Amplification of the TCL1 flanking region at 14q32.1 with no TCL1 gene transcription in a patient with peripheral T cell lymphoma.

Cytogenetic and molecular-genetic characteristics in peripheral T cell lymphoma (PTL) have not been well defined, except for those in adult T cell leukemia/lymphoma (ATL/L). Translocations and inversions involving a chromosome band 14q32 were extremely common abnormalities reported in PTL and ATL/L. We studied the involvement of TCL1, a recently isolated gene located in 14q32.1, in tumor tissues from 20 patients with PTL including three with 14q32 translocations by two color fluorescent in situ hybridization (FISH) using two cosmid probes flanking the TCL1 gene. The two cosmid signals were separated in none of them, but much increased in number in one tumor without 14q32 translocation, indicating that the TCL1 genomic region was amplified in this tumor. Reverse transcription-polymerase chain reaction (RT-PCR), however, failed to detect the TCL1 transcript in the tumor. These findings suggest that an oncogene other than TCL1 may be located in 14q32.1, and its amplification may be involved in the neoplastic process of PTL.

Effects of ethanol, acetoin and 2,3-butanediol on EEG power spectra in conscious rats.

Effects of ethanol, acetoin and 2,3-butanediol on the central nervous system (CNS) were investigated by using the analysis of EEG (electroencephalogram) spectral powers recorded at the frontal cortex in rats. High doses of ethanol were required for exhibiting an increase of EEG spectral powers in the delta (0-4 Hz) and theta (4-8 Hz) waves when it was given either orally or intravenously. On the other hand, when ethanol was injected intracerebroventricularly, the drug caused a potent increasing effect of EEG spectral powers. Both acetoin and 2,3-butanediol were found to increase in EEG spectral powers by oral and intravenous administrations at relatively low doses. In addition, acetoin and 2,3-butanediol were more effective than ethanol in increasing EEG spectral powers in the delta and theta bands after intracerebroventricular administration. From these findings it can be concluded that both acetoin and 2,3-butanediol have a potent CNS depressant effect.

Primary non-Hodgkin's lymphoma of the larynx.

Three cases of primary non-Hodgkin's lymphoma of the larynx are described. Histologically, two tumours belonged to the category of low grade B-cell lymphomas of the small cell type (extranodal marginal zone B-cell lymphoma and lymphoplasmacytoid lymphoma), and the third was classified as a peripheral T-cell lymphoma of unspecified type. The clinical stage was IE in two cases, and IV in another case. In two cases, complete remission was obtained with radical radiotherapy. But in the other case, which was histologically lymphoplasmacytoid lymphoma, the response to radiotherapy was poor, and surgery was required. There was no relapse subsequent to treatment. Primary non-Hodgkin's lymphoma of the larynx is rare. Several reported cases have clinical features similar to those of MALT-type lymphomas arising in other extranodal sites. Although most of the reported cases have been cured with radiotherapy, in some cases dissemination to other extranodal sites may occur. Therefore careful periodic evaluation is imperative.

Effect of the new antiallergic agent olopatadine on EEG spectral powers in conscious rats.

The central effect of olopatadine (((Z)-11-[3-dimethylamino)propylidene)-6, 11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride, CAS 140462-76-6, KW-4679) was studied in comparison with those of ketotifen and doxepin using spontaneous EEG and EEG spectral powers in conscious rats. Both ketotifen (20 mg/kg p.o.) and doxepin (20 mg/kg p.o.) caused drowsy patterns in spontaneous EEG characterized by slow waves of high amplitude at the frontal cortex, occipital cortex and amygdala, and by disappearance of the regularity in theta waves recorded from the hippocampus. In EEG spectral powers, both drugs caused a significant increase in the power densities of the delta band recorded from the frontal cortex, occipital cortex and amygdala. On the contrary, no visible changes were elicited by the treatment with olopatadine (20 mg/kg p.o.) in both spontaneous EEG and EEG spectral powers recorded from the frontal cortex, occipital cortex, hippocampus and amygdala. These results indicate that olopatadine provides no remarkable effect on the central nervous system.

Cytoplasm rescues an arrhythmic mutant on the circadian rhythm of mating reactivity in Paramecium bursaria.

Cells of an unusual Paramecium bursaria stock (Sj2) expressed rhythmic mating reactivity in a light/dark cycle (LD) and under continuous illumination (LL). When placed in continuous darkness (DD), did not show rhythmicity but rather demonstrated a continuous high mating reactivity. However, mating reactivity was reduced following exposure to a 6-h light pulse interrupting the DD, and then recovered to its former condition. Genetic analysis showed the arrhythmicity in DD to be a dominant character inherited in a Mendelian ratio. On the other hand, a clone (MC1w) that did not show the rhythmicity in either DD or LL was isolated from the parent stock Sj2w following a 5-h treatment with 2 micrograms/ml nitrosoguanidine (MNNG). The MC1w cells expressed weak rhythmicity in LD, but were insensitive to a 6-h light pulse in DD. The arrhythmicity in LL was inherited cytoplasmically. In addition to this, rhythmicity in LL could be recovered by injection of cytoplasm from the wild-type cell when the recipient cell was homozygous for the wild-type nuclear gene (+/+). The cytoplasmic components or factors are assumed to control the functional circadian system and genetically determine the rhythmicity of mating reactivity.

Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK: a distinct clinicopathologic entity.

Anaplastic large cell lymphoma (ALCL) is a subtype of non-Hodgkin's lymphoma characterized by the CD30+ large neoplastic cells and sometimes carries a t(2;5)(p23;q35). Recently, we found a novel hyperphosphorylated 80-kD protein tyrosine kinase, p80, in ALCLs with t(2;5). Subsequent cDNA cloning showed p80 to be a fusion protein of two genes, the novel tyrosine kinase gene and the nucleophosmin gene, in accordance with the sequence of the NPM/ALK gene (Morris et al, Science 263:1281, 1994). Meanwhile, the clinicopathologic features of p80-carrying ALCLs have remained unclear. Paraffin sections of 105 cases of ALCL were immunostained using anti-p80 antibody, and 30 of them were shown to express p80. Clinicopathologic comparison between p80-positive and -negative ALCLs showed that p80-positive cases occurred in a far younger patient age group (16.2 +/- 12.9 years; p80-negative cases, 51.0 +/- 22.3 years; P < .0001) and the patients showed a far better 5-year survival rate (79.8%; p80-negative group, 32.9%; P < .01). These data showed that p80-positive ALCL is a distinct entity both clinically and pathogenetically and should be differentiated from p80-negative ALCL.

Expression of the proto-oncogene bcl-2 in uterine cervical squamous cell carcinoma: its relationship to clinical outcome.

We studied bcl-2 expression in patients with uterine cervical squamous cell carcinoma and correlated this phenomenon with survival. Immunohistochemical analysis with a monoclonal antibody specific for bcl-2 was used to detect the protein in tumor samples from 259 patients undergoing surgery for squamous cell carcinoma of the uterine cervix. Of the total, 67% (174) of the tumors were bcl-2 negative, and 33% (85) were positive. No significant difference in survival at five years was noted between patients with negative (78%) and positive (82%) tumors. However, when bcl-2 positive tumors were divided into partially stained (62 of 85, 73%), and diffusely stained (23 of 85, 27%) groups, the patients with partial staining had a better prognosis than those with diffused or negative (p < 0.01), staining (p < 0.05) (5 year survivals, respectively; 92%, 61%, and 78%). Though detection of bcl-2 positivity may itself not have clinical value for uterine cervical squamous cell carcinoma, the staining characters may add to predicting prognosis.

Risk factors for the postoperative local recurrence of tongue carcinoma.

Clinical and histologic studies on the risk factors for the postoperative local recurrence of tongue carcinoma were analyzed in 51 patients. Postoperative local recurrence occurred in 12 (23.5%), with almost all developing within the first 12 months after surgery. A comparison of patients with and without recurrence indicated that the risk factors for recurrence were 1) endophytic tumor growth, 2) grade 4 pattern of histologic invasion, and 3) tumor within 5 mm of the surgical margin (especially the deep margin). All T1 tumors were less than 5 mm deep, indicating that it is reasonable for partial glossectomy to be performed in patients with T1 carcinoma. However, for T2 through T4 carcinoma it seems that more extensive surgery should be performed because of the variability in depth of tumor invasion. The 5-year survival rate of the patients with recurrence was 45% and that of patients without recurrence was 73.7% (P < .01). The overall prognosis of tongue carcinoma should improve when surgeons take a more prudent attitude to the treatment of patients with these risk factors.

Expression of cytochrome b558 on B cell- and CD 30 positive-lymphomas.

Expression of cytochrome b558, an essential constituent of the superoxide generating system in phagocytes, was demonstrated in B-lymphocytes. To determine its expression in malignant lymphoma (ML), 103 non-Hodgkin's MLs and 18 Hodgkin's (HD) MLs, together with non-tumorous lymphoid tissues were immunohistochemically analyzed, using two antibodies specific for the cytochrome. In non-tumorous tonsils and lymph nodes, B-lymphocytes, especially in the mantle zones, and histiocytes stained heavily, while T-lymphocytes failed to stain. Among the 55 B-MLs, all follicular lymphomas (9/9) and 18/46 of the diffuse lymphomas were found to express cytochrome b558. Among 48 T-MLs, 46 were unstained by antibodies against the cytochrome. The two cytochrome b558-positive cases were CD 30-positive anaplastic large cell lymphomas. Sixteen of 18 HD patients had CD 30-positive Reed-Sternberg cells which also stained with antibody alpha LC (an anticytochrome b558 antibody). Thus, cytochrome b558, represents a new lymphocyte differentiation antigen.