Carcinogenic potential of tobacco tar-resistant Staphylococcus aureus in buccal cavity.

PURPOSE: The effects of cigarette smoking on the association between inflammation and cancer were studied, since some bacteria induce the production of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine and endogenous tumor promoter, in cells. METHODS: Bacteria from a gargled solution from the buccal cavity of 20 individuals were cultured in the presence of 4 mg/ml cigarette-smoke condensates. Although cigarette-smoke condensates inhibited growth of Staphylococcus aureus strongly and that of Staphylococcus warneri weakly, tobacco tar-resistant S. aureus and S. warneri were obtained. RESULTS: One tobacco tar-resistant S. aureus strain (Sa-TA10) induced expression of the TNF-alpha gene in both Bhas 42 cells (v-Ha-ras transfected BALB/3T3 cells) and human lung cancer cell line H226B, while one tobacco tar-resistant S. warneri (Sw-TA75) did not induce it significantly. Moreover, Sa-TA10 induced formation of transformed foci and soft-agar colony in Bhas 42 cells in cooperation with the v-Ha-ras gene. The results suggested that Sa-TA10 has carcinogenic potential, whereas Sw-TA75 does not. CONCLUSION: These data suggest that tobacco tar-resistant S. aureus, with carcinogenic potential, is present in the buccal cavity of some individuals, and that cigarette smoking simultaneously inhibits growth of most of the bacteria and selects carcinogenic bacteria.

Discrete roles of cytokines, TNF-alpha, IL-1, IL-6 in tumor promotion and cell transformation.

Based on our previous results, which pointed to tumor necrosis factor-alpha (TNF-alpha) as the essential cytokine in tumor promotion in mouse skin, we present here three principal findings related to the specific roles of TNF-alpha, interleukin-1 (IL-1) and IL-6 in tumor promotion (using TNF-alpha- and IL-6-deficient mice) and in BALB/3T3 cell transformation: i) The previously reported residual tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) in TNF-/- mice was confirmed by experiments with TNF+/+ and TNF-/- 129/Svj mice of the same strain, using two-stage carcinogenesis experiments. TPA produced tumors in 100% of TNF+/+ and 78% of TNF-/- mice at 20 weeks, and the average number of tumors per mouse was 11.1 in the former group and 2.1 in the latter. Judging from the expression of various inflammatory cytokine genes in TNF+/+ and TNF-/- mice, the residual tumor promoting activity of TPA in TNF-/- mice may be dependent on expression of IL-1alpha and IL-1beta genes. ii) Tumor promotion by TPA and okadaic acid in IL-6+/+ and IL-6-/- C57/BL6 mice was studied, with TPA producing tumors in 57.1% of IL-6+/+ and 40.0% of IL-6-/- mice at 20 weeks, and okadaic acid in 40.0% of IL-6+/+ and 53.3% of IL-6-/- mice. Thus, there was no significant difference between TPA or okadaic acid tumor promotion in either group. In addition, expression of IL-6 gene in skin of both types of mice suggested that IL-6 is not the essential cytokine in tumor promotion, since it can be replaced by other cytokines. iii) In transformed clones of BALB/3T3 cells induced by TNF-alpha alone, IL-1alpha gene expression was induced after transformation by TNF-alpha had occurred, which did not occur in parental cells. Expression patterns of TNF-alpha, IL-1beta, IL-6 and IL-10, along with TGF-beta, were similar in both parental and transformed cells. Considering all these results, we conclude that various cytokines have discrete roles in tumor promotion and cell transformation.

Helicobacter pylori membrane protein 1: a new carcinogenic factor of Helicobacter pylori.

Considering a suspected link between Helicobacter pylori infection and human stomach cancer, a new H. pylori gene for membrane protein 1 (HP-MP1) was recently cloned. Because HP-MP1 induces release of inflammatory cytokines and tumor necrosis factor-alpha acts as both initiator and tumor promoter, we studied the possible involvement of HP-MP1 in carcinogenesis of H. pylori. Two cell lines, BALB/3T3 cells as control and v-Ha-ras-transfected BALB/3T3 cells (Bhas 42 cells) as putative initiated cells, were each transfected with HP-MP1, urease B genes, or vector alone. All of the Bhas/mpl clones showed strong expression of tumor necrosis factor-alpha gene and produced tumors in 100% of nude mice. Two Bhas/ure clones showed weak tumorigenicity; the other Bhas and BALB clones showed none. Results indicate strong carcinogenic activity of HP-MP1 in cooperation with viral Ras protein and weak activity of urease B.

Translational repression determines a neuronal potential in Drosophila asymmetric cell division.

Asymmetric cell division is a fundamental strategy for generating cellular diversity during animal development. Daughter cells manifest asymmetry in their differential gene expression. Transcriptional regulation of this process has been the focus of many studies, whereas cell-type-specific 'translational' regulation has been considered to have a more minor role. During sensory organ development in Drosophila, Notch signalling directs the asymmetry between neuronal and non-neuronal lineages, and a zinc-finger transcriptional repressor Tramtrack69 (TTK69) acts downstream of Notch as a determinant of non-neuronal identity. Here we show that repression of TTK69 protein expression in the neuronal lineage occurs translationally rather than transcriptionally. This translational repression is achieved by a direct interaction between cis-acting sequences in the 3' untranslated region of ttk69 messenger RNA and its trans-acting repressor, the RNA-binding protein Musashi (MSI). Although msi can act downstream of Notch, Notch signalling does not affect MSI expression. Thus, Notch signalling is likely to regulate MSI activity rather than its expression. Our results define cell-type-specific translational control of ttk69 by MSI as a downstream event of Notch signalling in asymmetric cell division.

Genetic control of development of the mushroom bodies, the associative learning centers in the Drosophila brain, by the eyeless, twin of eyeless, and Dachshund genes.

Mushroom bodies (MBs) are the centers for olfactory associative learning and elementary cognitive functions in the Drosophila brain. By high-resolution neuroanatomy, we show that eyeless (ey), twin of eyeless, and dachshund (dac), which are implicated in eye development, also are expressed in the developing MBs. Mutations of ey completely disrupted the MB neuropils, and a null mutation of dac resulted in marked disruption and aberrant axonal projections. Genetic analyses demonstrated that, whereas ey and dac synergistically control the structural development of the MBs, the two genes are regulated independently in the course of MB development. These data argue for a distinct combinatorial code of regulatory genes for MBs as compared with eye development and suggest conserved roles of Pax6 homologs in the genetic programs of the olfactory learning centers of complex brains.

Musashi and seven in absentia downregulate Tramtrack through distinct mechanisms in Drosophila eye development.

We have examined the roles played by the Drosophila neural RNA-binding protein Musashi (MSI) in eye development. MSI expression was observed in the nuclei of all photoreceptor cells (R1-R8). Although a msi loss-of-function mutation resulted in only weak abnormalities in photoreceptor differentiation, we found that the msi eye phenotype was significantly enhanced in a seven in absentia (sina) background. sina is known to be involved in the degradation of the Tramtrack (TTK) protein, leading to the specification of the R7 fate. We demonstrated that MSI also functions to regulate TTK expression. The sina msi mutants showed significantly high ectopic expression of TTK69 and failure in the determination of the R1, R6, and R7 fates. Other photoreceptor cells also failed to differentiate with abnormalities occurring late in the differentiation process. These results suggest that MSI and SINA function redundantly to downregulate TTK in developing photoreceptor cells.

Ventilatory responses and subjective sensations during arm exercise and hypercapnia in patients with lower-cervical and upper-thoracic spinal cord injuries.

We measured the ventilatory responses and subjective sensations during arm exercise in patients with lower cervical and upper thoracic spinal cord injuries in order to evaluate the effects of chest wall deafferentation on these responses. Visual analog scales with verbal descriptors were used to quantify respiratory sensations of different affectional qualities. Patients as well as normal subjects reported stronger respiratory sensations upon CO2 rebreathing as compared to during arm exercise with an equivalent minute ventilation (p<0.05). There were no qualitative nor quantitative differences in the respiratory sensations during CO2 rebreathing between the patients and normal subjects. However, patients with spinal cord injuries showed a higher minute ventilation and a lower end-tidal PCO2 during incremental arm exercises (p<0.01), and thus tended to hyperventilate. We conclude that chest wall afferent denervation does not contribute significantly to the perception of breathlessness in patients with spinal cord injuries.

Cardiorespiratory function as assessed by exercise testing in patients with non-insulin-dependent diabetes mellitus.

Exercise testing was used to examine 19 cardiorespiratory diabetes mellitus patients, aged 32-68 years (body mass index, 27.8 +/- 4.8 kg/m2), and 16 healthy volunteers, aged 23-57 years (body mass index, 22.7 +/- kg/m2). A graded cycling exercise test was done, monitoring gas exchange, ventilation and heart rate. Values were significantly higher in the non-insulin-dependent diabetes mellitus (NIDDM) patients than in the controls for fasting blood glucose (P < 0.01), glycosylated haemoglobin (P < 0.01), body weight (P < 0.05) and body mass index (P < 0.05). The exercise testing produced values that were significantly lower in the patients with NIDDM than in the controls for percentage oxygen uptake (P < 0.05), maximum load (P < 0.05), maximum metabolic equivalent (P < 0.01) and maximum oxygen uptake per unit body weight (P < 0.01). Ventilatory capacity and forced expiratory volume at 1 sec did not differ significantly in the two groups. These results suggest that general fitness is diminished due to reduced cardiorespiratory function in patients with NIDDM.

[A case of alveolar hydatid disease of the lung in the Kansai district of Japan].

A 78-year-old man was admitted to hospital because of episodes of high grade fever and multiple nodular shadows on chest roentgenogram. He had a past history of percutaneous drainage and partial resection of the left lobe of the liver for liver abscess of unknown origin in 1987. The high grade fever was secondary to sepsis due to Citrobacter freundii. The sepsis improved with antibiotic therapy, but the abnormal shadows on chest roentgenogram did not improved. Immunoserological tests indicated a probable diagnosis of alveolar hydatid disease of the lung, which is very rare in the Kansai district of Japan. Open lung biopsy was performed and the diagnosis of alveolar hydatid disease of the lung was confirmed.

[A case of sustained-release theophylline (Theodur)-induced asthma].

Theophylline is used as a prophylactic agent for controlling bronchospasm in patients with asthma. Sustained-release theophylline (Theodur) is widely used for this purpose. In this report, we describe a patient who developed asthma due to administration of Theodur. A 38-year-old man was referred to our hospital for assessment of the relationship between his respiratory symptoms and theophylline. He had been admitted to the hospital several times for dyspneic attacks. Theophylline ethylenediamine (Aminophylline) and hydrocortisone sodium succinate had been administered intravenously for the acute phase, followed by Theodur orally. Following administration of Theodur, he had developed dyspnea, chest tightness and dizziness. An inhalation challenge test with sulpyline showed a negative reaction. Although an oral challenge test with theophylline also showed a negative reaction, that with Theodur evoked an asthmatic response. We were unable to determined any possible cause or the mechanism for this reaction. We concluded that the vehicle or preservative (i.e., inactive ingredients) contained in Theodur were likely to be related to his asthmatic response.

[A case of aortitis syndrome preceded by pulmonary artery involvement].

A 31-year-old woman was hospitalized with bloody sputum and chest pain in August 1985. The first angiographic examination demonstrated obstructions in the right upper and middle pulmonary arteries without any changes in the thoracic aorta or its branches. The case was, therefore, diagnosed as pulmonary embolism, and treated with some anti-coagulants. In June 1987, she was readmitted since systolic bruit became audible in her right supraclavicular areas. The second angiographic examination revealed narrowings of both the carotid and right vertebral arteries and extension of lesions in pulmonary artery. The diagnosis of aortitis syndrome was made. This case may be the first one in Japan in which a pulmonary lesion was verified by angiogram before remarkable involvement in the aorta or its branches.