Combination therapy of cyclosporine with steroid inhibits γ-interferon and interleukin-1 gene expression at the level of mRNA synthesisin vivo

The present study examined the effect of cyclosporine (CsA) administered with steroidin vivo on the capacity of peripheral blood mononuclear cells (PBMC) from kidney transplant recipients to generate cytokines and their gene expression at the level of messenger RNA (mRNA). PBMC from CsA-prednisolone (Pred)-treated recipients displayed 66.9% inhibition (54.3±12.4 IU/ml;N=42;P<0.01) of -interferon (-IFN) production compared with normal individuals (134.6±18.6 IU/ml;N=23). Azathioprine (Az)-Pred-treated recipients displayed significantly less inhibition of -IFN generation (96.0±16.1 IU/ml;N=22;P<0.05) than CsA-treated patients. Macrophages (m) from CsA-Pred-treated recipients displayed 60.0% inhibition (5.1±0.7 U/ml;N=20;P<0.01) of interleukin-1 (IL-1) production compared with normal individuals (13.0±2.9 U/ml;N=21). These results were confirmed by the experiments using cDNA probe for -IFN or IL-1 (, ). High levels of -IFN mRNA in phytohemagglutinin (PHA)-stimulated PBMC or IL-1() mRNA in lipopolysaccharide (LPS)-stimulated m were present in normal individuals but not in CsA-treated recipients as judged by hybridization to a cloned human -IFN or IL-1() cDNA probe. These studies demonstrated that combination therapy of CsA with steroid inhibits both -IFN and IL-1 gene expression at the level of mRNA at physiological concentrations.     

Tissue penetration and clinical experiences of aztreonam in obstetrics and gynecology

Tissue penetration and clinical efficacy were studied on aztreonam (SQ 26,776, AZT) in obstetrics and gynecology with the following results. Number of cases was too small to sufficiently review the penetration into each uterine tissue, the ovary and the tube after the intravenous injection of AZT 1 g. Overall clinical effect for all the 6 cases reviewed was more than "good". Also, neither side effect nor abnormal laboratory findings were reported. From the above results, AZT was considered to be a highly useful antibiotic in obstetrics and gynecology.     

Results of definitive radiotherapy with concurrent chemotherapy for maxillary sinus carcinomas with neck lymph node metastasis

The purpose of this study was to describe the results of definitive radiotherapy (RT) with concurrent chemotherapy for maxillary sinus carcinomas (MSCs) with neck lymph node metastasis to clarify its limitation. Local control (LC), progression-free survival (PFS) and overall survival (OS) rates were calculated using the Kaplan–Meier method and were compared between subgroups using the log rank test. Toxicity was classified using common terminology criteria of adverse events version 5.0. Eighteen patients with inoperable MSC with neck lymph node metastasis including 12 men and 6 women with a median age of 67 years were analyzed. The histologic diagnoses were as follows: 16 patients had squamous cell carcinomas and 2 had other histology. Four patients had stage T3 MSC, 6 had T4a and 8 had T4b. Among 18 patients, 7 received concurrent systemic chemotherapy and 11 received selective arterial chemo-infusion. The median follow-up period was 17 months. The 2-year LC, PFS and OS rates for the entire cohort were 34, 31 and 46%, respectively. No significant differences were observed for LC, PFS and OS rates between systemic chemotherapy and selective arterial chemo-infusion cohorts. Grade 3 or higher acute toxicity, including both non-hematological and hematological, was observed in nine patients (50%), while no grade 3 or higher late toxicity was observed. In conclusion, we described the results of definitive RT for MSCs with neck lymph node metastasis. Local recurrence of primary tumor was a frequent pattern of failure and it should be addressed in future study.     

Infiltration and tissue concentration of intravesically instilled (2"R)-4'-O-tetrahydropyranyladriamycin or adriamycin in rat bladder tumor induced by BBN

Rats with bladder tumor induced by BBN were treated by intravesical instillation of 0.8 mg of (2"R)-4'-O-tetrahydropyranyladriamycin (THP) (9 rats) or adriamycin (ADM) (8 rats) dissolved in 0.2 ml of distilled water. Thirty minutes later, the bladder was removed surgically. Rats without the tumor received the same treatment of THP (8 rats) or ADM (9 rats). THP and ADM infiltrations to the normal bladder tissue and the tumor were estimated by the use of the photonic microscope system, since both drugs were known to emit characteristic fluorescence. It was found that infiltration of THP to the tumor tissue was more prominent in amounts and deeper than that of ADM, while smaller amounts of THP infiltrated into the normal mucosa compared to ADM. The fact might explain the clinical finding that THP instilled intravesically in half a concentration of ADM showed the same effect on the tumor as ADM. Subsequently, tissue concentrations of THP and ADM were estimated by high performance liquid chromatography. Either THP or ADM was instilled intravesically for 30 minutes to 6 rats with bladder tumor. Similarly, either THP or ADM was instilled in 5 rats without the tumors. Contrary to the result of the photonic microscope system, the tissue concentration of THP was not different from that of ADM not only in the tumor tissues but also in the normal bladder ones. Furthermore, the tissue concentration of both drugs in the normal bladder was higher than that in the bladder tumor.(ABSTRACT TRUNCATED AT 250 WORDS)     

A clinicopathologic evaluation of "depth" in cases of endometrial adenocarcinoma

A total of 573 cases of endometrial adenocarcinomas, composed of patients that had been hysterectomized from 1949 to 1985 at the Cancer Institute Hospital in Tokyo, have been clinicopathologically investigated to evaluate the degree of the myometrial invasion, meaning the "Depth" as a postoperative prognostic factor of this type of cancer. These patients were classified into groups, depending on the depth of the invasion. The Depth d group, showing a myometrial invasional depth of over two-thirds of the uterine wall, revealed a rate of 61.3% of the lymph node metastasis positive cases, and accounted for 50.0% of the postoperative survivals. These values were statistically worse, when compared to those of the Depth a to c groups, which showed less invasional depth. Thus it was concluded that "Depth" is an important prognostic factor in cases of an endometrial adenocarcinoma.     

Negative chronotropic actions of endothelin-1 on rabbit sinoatrial node pacemaker cells

1. The effects of endothelin-1 (ET-1) on sinoatrial (SA) node preparations of the rabbit heart were studied by means of whole-cell clamp techniques.
2. ET-1 at 1 nM slowed the spontaneous beating activity and rendered half of the cells quiescent. At a higher concentration of 10 nM, the slowing and cessation of spontaneous activity were accompanied by hyperpolarization.
3. In voltage-clamp experiments, ET-1 decreased the basal L-type Ca²⁺ current (I_Ca(L)) dose-dependently with a half-maximal inhibitory concentration (EC₅₀) of 0.42 nM and maximal inhibitory response (E_max) of 49.5%. The delayed rectifying K⁺ current (I_K) was also reduced by 33.2±11.1% at 1 nM. In addition, an inwardly rectifying K⁺ current was activated by ET-1 at higher concentrations (EC₅₀=4.8 nM). These ET-1-induced changes in membrane currents were abolished by BQ485 (0.3 μM), a highly selective ET_A receptor antagonist.
4. When I_Ca(L) was inhibited by ET-1 (1 nM), subsequent application of 10 μM ACh showed no additional decrease in I_Ca(L), suggesting the involvement of cyclic AMP in the effects of ET-1 on I_Ca(L). In contrast, 1 nM ET-1 further decreased I_Ca(L) in the presence of 10 μM ACh, suggesting that ET-1 activates some additional mechanism(s) which inhibit I_Ca(L). The ET-1-induced I_Ca(L) inhibition was abolished by protein kinase A inhibitory peptide (PKI, 20 μM) or H-89 (5 μM). However, the I_Ca(L) inhibition was not affected by methylene blue (10 μM), suggesting a minor role for cyclic GMP in the effect of ET-1 under basal conditions.
5. ET-1 failed to inhibit I_Ca(L) when the pipette contained GDPβS (200 μM). However, incubation of the cells with pertussis toxin (PTX, 5 μg ml⁻¹, >6 h) only reduced the ET-1-induced inhibition to 21.5±9.5%, whereas it abolished the inhibitory effect of ACh on I_Ca(L).
6. Intracellular perfusion of 8-bromo cyclicAMP (8-Br cyclicAMP, 500 μM) attenuated, but did not abolish the inhibitory effect of ET-1 on I_Ca(L). This 8-Br cyclicAMP-resistant component (17.5±14.4%, n=20) was not affected by combined application of 8-Br cyclicAMP with 8-bromo cyclicGMP (500 μM), ryanodine (1 μM) or phorbol-12-myristate-13-acetate (TPA; 50 nM).
7. In summary, ET-1 exerts negative chronotropic effects on the SA node via ET_A-receptors. ET-1 inhibits both I_Ca(L) and I_K, and increases background K⁺ current. The inhibition of I_Ca(L) by ET-1 is mainly due to reduction of the cyclicAMP levels via PTX-sensitive G protein, but some other mechanism(s) also seems to be operative.