Role of interferon-gamma in the development of murine bronchus-associated lymphoid tissues induced by silica in vivo

Several compounds have been shown to cause acute toxicity to cadmium (Cd). The mechanism of tolerance to Cd toxicity induced by glucocorticoids or by inflammation involves induction of metallothionein (MT) synthesis via glucocorticoid response elements or by inflammatory cytokines. We have demonstrated previously that the synthetic glucocorticoid dexamethasone suppresses inflammation-mediated induction of hepatic MT synthesis. Here we investigated the effect of glucocorticoid on tolerance to Cd induced by inflammation in mice. The LD50 of Cd for mice with induced inflammation by injection with turpentine oil (Tur-mice) was higher than the LD50 in control mice. Pretreatment of Tur-mice with dexamethasone to the Tur-mice (Dex+Tur-mice) resulted in a decrease in LD50 after Cd treatment. A significant increase in plasma alanine aminotransferase and aspartate aminotransferase levels in the Dex+Tur-mice was observed at lower doses of Cd than in the Tur-mice and at higher doses of Cd than in control mice. Dexamethasone did not suppress tolerance to cadmium toxicity in the testes of the Tur-mice. Pretreatment of Tur-mice with dexamethasone resulted in suppression of both plasma interleukin (IL)-6 elevation and in suppression of hepatic MT levels when induced by inflammation but not when induced by Cd. These data suggest that suppression of tolerance to Cd toxicity induced by glucocorticoid may involve hepatic MT synthesis mediated by inflammatory cytokines, such as IL-6. We suggest that the inflammatory response can modulate Cd toxicity by induction of MT by inflammatory cytokines.     

Vacuolar H(+)-ATPase: functional mechanisms and potential as a target for cancer chemotherapy

Tumor cells in vivo often exist in a hypoxic microenvironment with a lower extracellular pH than that surrounding normal cells. Ability to upregulate proton extrusion may be important for tumor cell survival. Such microenvironmental factors may be involved in the development of resistant subpopulations of tumor cells. In solid tumors, both intracellular and extracellular pH differ between drug-sensitive and -resistant cells, and pH appears critical to the therapeutic effectiveness of anticancer agents. Four major types of pH regulators have been identified in tumor cells: the sodium-proton antiporter, the bicarbonate transporter, the proton-lactate symporter and proton pumps. Understanding mechanisms regulating tumor acidity opens up novel opportunities for cancer chemotherapy. In this minireview, we describe the structure and function of certain proton pumps overexpressed in many tumors--vacuolar H(+)-ATPases--and consider their potential as targets for cancer chemotherapy.     

Bupivacaine attenuates contractility by decreasing sensitivity of myofilaments to Ca2+ in rat ventricular muscle

BACKGROUND: Bupivacaine exhibits a cardiodepressant effect, the molecular mechanism(s) of which have yet to be fully understood. Bupivacaine may directly act on contractile proteins and thereby decrease myofibrillar Ca2+ sensitivity. METHODS: Rat ventricular muscle was used. First, the effect of bupivacaine was examined on tetanic contractions in isolated intact myocytes. Next, Triton X-100-treated ventricular trabeculae were used to investigate the effect of bupivacaine on the pCa (= -log [Ca2+ ])-tension relation as well as on maximal Ca2+ -activated tension. Furthermore, to test whether bupivacaine inhibits the pathway downstream from Ca2+ binding to troponin C, tension was elicited in the skinned preparations by lowering the Mg-adenosine triphosphate (MgATP) concentration in the absence of Ca2+. The effect of bupivacaine on the pMgATP (= -log [MgATP])-tension relation was examined. RESULTS: In myocytes, 3 microm bupivacaine significantly (P < 0.01) increased intracellular Ca2+ concentration required for 5% cell shortening from the resting cell length. In skinned preparations, bupivacaine shifted the pCa-tension relation to the lower pCa side; the midpoint of the pCa curve (pCa50) was significantly (P < 0.05) changed by 10 and 100 microm bupivacaine. A highly correlated linear relation (R = 0.81; P< 0.0005) was present between pCa50 and maximal Ca2+ -activated tension. Bupivacaine (10 and 100 microm) significantly (P < 0.05) shifted the midpoint of the pMgATP-tension relation to the higher pMgATP side. CONCLUSIONS: Bupivacaine decreases myofibrillar Ca2+ sensitivity in ventricular muscle, and this is coupled with the compound's inhibitory effect on the pathway beyond Ca2+ binding to troponin C, possibly on the actomyosin interaction. The current results may partly explain the overall cardiodepressant effect of bupivacaine in vivo.     

A case of recurrent advanced gastric cancer suggesting the efficacy of TS-1 and CDDP combination chemotherapy

The patient, a 53-year-old male, underwent radical surgery for advanced gastric cancer (stage IV). On the second day after surgery, adjuvant chemotherapy consisting of 250 mg/day 5-FU (i.v.) for 14 days, followed by 450 mg/day of UFT-E for about 12 months, was initiated. About 21 months after surgery (7 months after cessation of medication), the CA19-9 level had risen (136 U/ml). After 26 months, the patient experienced a backache and his CEA and CA19-9 levels had risen 11.7 ng/ml and 869 U/ml, respectively. The results from an imaging examination were suggestive of multiple bone metastases and para-aortic lymphatic metastasis. Chemotherapy was resumed with only TS-1 (100 mg/day). Because the tumor markers (TM) continued to rise, he was hospitalized and the medication was combined with daily administration of 10 mg of CDDP (TS-1 + CDDP protocol). When the total dose of CDDP reached 160 mg, there was a dramatic drop in the TM (surrogate marker) level. The patient was discharged and medication of TS-1 and 10 mg/day of CDDP twice a week was continued on an outpatient basis. Five months after the initial administration of FP, the CEA and CA19-9 returned to normal levels (4.3 ng/ml and 33 U/ml, respectively). Metastases to the para-aortic lymph nodes had disappeared and the sites of bone metastases were reduced in size. The patient was able to resume his full social activities. Since that time, a second-line therapy has been added. Currently (about two years after the recurrence), he is still undergoing therapy with TS-1 + CDDP.     

Comparison of the severity of atopic dermatitis lesions and the density ofStaphylococcus aureus on the lesions after antistaphylococcal treatment

We examined the relationship between atopic dermatitis (AD) andStaphylococcus aureus by comparing changes in AD lesions and the bacterial density on the lesions after antimicrobial treatment with cefdinir. We found that there was a greater density ofS. aureus on red erythemas and exudative lesions than in light/dark red erythemas and non-exudative lesions of AD. Forty-one of 59 cases (69%) showed a decrease in colony count following antimicrobial treatment. In 28 of 39 cases (72%) there was a decrease of erythema, and in 18 of 22 cases (82%) there was a decrease in the amount of exudate both associated with a decrease in colony density following antimicrobial treatment. Because acute phases of atopic dermatitis, such as red erythemas and exudative lesions, were closely related to the colonization ofS. aureus, dense colonization withS. aureus may be an important factor in the exacerbation of AD. We believe that staphylococcal products such as α-toxin, various enzymes, coagulase, and superantigenic exotoxins affect some aspect of the inflammatory process, resulting in exacerbation of AD.     

Plaunotol prevents the progression of acute gastric mucosal lesions induced by compound 48/80, a mast cell degranulator, in rats

We examined the preventive effect of plaunotol, an antiulcer drug, on acute gastric mucosal lesion progression in rats treated once with compound 48/80 (C48/80). Rats treated with C48/80 (0.75 mg/kg BW, i.p.) received plaunotol (10, 25 or 50 mg/kg BW, p.o.) 0.5 h after the treatment at which time gastric mucosal lesions appeared. The gastric mucosa of C48/80-treated rats showed progressed lesions and had increased myeloperoxidase (an index of neutrophil infiltration) activity and thiobarbituric acid reactive substances (an index of lipid peroxidation) content and decreased ascorbic acid and adherent mucus contents and Se-glutathione peroxidase activity at 3 h after C48/80 treatment. Postadministered plaunotol attenuated all these changes dose-dependently. These attenuating effects of plaunotol were not counteracted by pretreatment with indomethacin (5 mg/kg BW, i.p.), a prostaglandin synthesis inhibitor. These results indicate that plaunotol prevents the progression of C48/80-induced acute gastric mucosal lesions in rats possibly by its anti-inflammatory and antioxidant actions, but not by affecting gastric mucosal prostaglandin levels.     

Radiation-induced apoptosis is independent of caspase-8 but dependent on cytochrome c and the caspase-9 cascade in human leukemia HL60 cells

We investigated the role of the caspase activation cascade in apoptosis induced by ionizing radiation or hydrogen peroxide (H(2)O(2)) in human leukemia HL60 cells. Electron paramagnetic resonance (EPR) spectra revealed that hydroxyl and hydrogen radicals were generated in the culture medium after exposure to radiation or H(2)O(2). Initial accumulation of DNA fragments at 2 h after exposure was delayed in irradiated cells compared with H(2)O(2)-treated cells, although formation of abasic sites immediately after exposure was significantly higher in irradiated cells and similar quantities of hydroxyl radicals were produced under both conditions. Activity assay of caspases revealed that caspase-3, -8 and -9 were activated 2 h after exposure to H(2)O(2), whereas in irradiated cells caspase-3 and -9 activation occurred 4 h after exposure but increased caspase-8 activation was not observed. Release of cytochrome c into cytosol was seen at 2 h after radiation and H(2)O(2) treatment. Radiation did not affect proapoptotic proteins (Bax and Bid), whereas H (2)O(2) increased accumulation of Bax in the mitochondrial membrane 2 h to 6 h after treatment, independently of the truncation of Bid by activated caspase-8. Moreover, treatment with the caspase-8 inhibitor Z-IETD-FMK increased cell survival and prevented accumulation of DNA fragments in H(2)O(2)-treated cells, but not in irradiated cells. These results suggest that, unlike the caspase cascade of H(2)O(2)-induced apoptosis, cytochrome c and caspase-9 are important for the intrinsic pathway of radiation-induced apoptosis, independent of caspase-8.     

Performance of the fontan procedure using extra-cardiac direct anastomosis on patients treated for penicillin-resistant <Emphasis Type="Italic">Streptococcus pneumoniae</Emphasis> endocarditis

Streptococcus pneumoniae is now a rare cause of endocarditis in humans. We report a patient with a double outlet right ventricle and mitral atresia, who underwent the Fontan procedure without prosthetic materials after treatment for penicillin-resistant Streptococcus pneumoniae endocarditis. Postoperative infectious endocarditis was not found. In patients with a history of infectious endocarditis, direct anastomosis of the main pulmonary artery and inferior vena cava would reduce the risk of recurrent infectious endocarditis.     

Infective endocarditis developing as uremia

A 49-year-old man presented with fever and uremic symptoms such as general malaise, leg edema and decreased urine output. He was diagnosed as having infective endocarditis (IE) accompanied by renal failure. Although he had been receiving hemodialysis for a long time, renal function dramatically improved after heart valve replacement. This case suggests that uremia can develop as an initial manifestation of IE and removal of an infected heart valve can improve renal function despite persistent renal failure. From the perspective of recovery of renal function, early surgery should be considered in patients with renal failure following IE.