Cerivastatin inhibits fetal calf serunvinduced DNA synthesis in cultured rat mesangial cells

SUMMARY: Inhibition of mevalonate synthesis by several statins has been shown to suppress DNA synthesis in glomerular mesangial cells. In the present study, we investigated the effect of a new statin, cerivastatin, on fetal calf serum (FCS)-induced DNA synthesis of cultured rat mesangial cells. Cultured rat mesangial cells were stimulated by 10% FCS in the presence or absence of cerivastatin and mevalonate. 5-bromo-2-deoxyuridine (BrdU) incorporation was used to assess DNA synthesis. the present study showed that 10% FCS caused marked stimulation of DNA synthesis in the mesangial cells. Cerivastatin inhibited FCS-stimulated BrdU incorporation in a dose-dependent manner. IC₅₀ was approximately 1 umol/L. Exogenous mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate significantly prevented the inhibitory effect of cerivastatin on DNA replication. It appears that cerivastatin, by inhibiting the synthesis of mevalonate, may suppress DNA synthesis in the mesangial cells.     

Successful treatment for squamous cell carcinoma of the female urethra with combined radio- and chemotherapy

We report on two cases of women with locally advanced squamous cell carcinoma of the urethra. Patient 1 also displayed regional lymph node metastasis. Treatment comprised combined radiotherapy to 60 Gy and chemotherapy with 5-fluorouracil and cisplatin. Complete response was obtained in both patients, including the inguinal lymph nodes of Patient 1. Patient 1 experienced recurrent inguinal lymph node metastasis on the contralateral side at 42 months after initial treatment, and the same treatment was performed followed by surgical excision. Both patients remain alive with no evidence of disease, at 12 months after recurrence in Patient 1, and at 27 months after treatment in Patient 2.     

Inhibition of Lipid Peroxidation by Sesquiterpenoid in Heterotheca inuloides

A sesquiterpenoid, 7-hydroxy-3,4-dihydrocadalin, isolated from a Mexican medicinal plant Heterotheca inuloides was evaluated as an antioxidant. This sesquiterpenoid inhibited mitochondrial and microsomal lipid peroxidation induced by Fe(III)-ADP/NADH or Fe(III)-ADP/NADPH. Furthermore, 7-hydroxy-3,4-dihydrocadalin protected red cells against oxidative haemolysis. This sesquiterpene was thus shown to be effective in protecting biological systems against oxidative stresses.     

Cyclosporine therapy affects aminotransferase activity but not hepatitis C virus RNA levels in chronic hepatitis C

Interferon (IFN) therapy is of proven efficacy in chronic hepatitis C, but it is not universally effective and is often limited by side effects. Cyclosporine A (CsA) is a potent immunosuppressant widely used in organ transplantation. We conducted a pilot study to determine whether CsA therapy could affect aminotransferase activity and hepatitis C virus RNA levels in patients with chronic hepatitis C. Cyclosporine A was administered to 10 patients (mean age of 59 years; male: female = 9:1) who did not respond to IFN therapy previously and who had elevated serum alanine aminotransferase (ALT) values for at least 6 months. All patients were positive for HCV-RNA by RT-PCR with genotype 1b. Their mean duration of hepatitis was 15 years. Oral CsA was given for 3 months in a dose that was increased at 1 month intervals from 1.5–2.0 to 2.0–3.0 and 3.0–4.0 mg/kg per day. All patients completed the treatment schedule, although two patients developed mild non-symptomatic hypertension. Serum ALT levels gradually decreased in all but one patient. The mean percentage decrease was 59.5% at the end of therapy (from 153 ± 82 to 62 ± 48 IU/L; P < 0.02). The ALT levels fell to the normal range in five patients, although once therapy was discontinued the enzyme levels tended to return to pretreatment levels. Serum aspartate aminotransferase and g-glutamyl transpeptidase levels similarly decreased. The serum HCV-RNA titre, determined by competitive RT-PCR, did not change in any patient throughout the study period. There were no appreciable alterations in other laboratory tests, such as serum creatinine levels and lymphocyte subsets, except for an increase in serum alkaline phosphatase levels. These findings suggest that CsA, even in a relatively low dose, reduces serum aminotransferase levels without serious side effects in patients with chronic-hepatitis C, although an antiviral effect was not noted.     

A Subset of Patients With Recurrent Spontaneous Abortion Is Deficient in Transforming Growth Factor β-2-Producing “Suppressor Cells” in Uterine Tissue Near the Placental Attachment Site

PROBLEM : To determine if patients with unexplained recurrent miscarriage have a deficiency of decidual immunosuppressor cells that produce transforming growth factor β type 2, as has been found in mice with abortion due to rejection and/or trophoblast failure. METHODS : Decidual biopsy specimens were taken as near to the placental attachment site as possible under ultrasound guidance from first trimester legal termination (control) patients with recurrent miscarriage and non-viable pregnancy, and from patients with sporadic missed abortion. The tissue was tested for TGFβ-2⁺ suppressor cells by in situ hybridization, immunohistochemistry, and analysis of supernatants. RESULTS : TGFβ-2-related suppressor molecules similar but not identical to those identified in pregnant mice were released by decidual lymphoid cells. Fifty percent of 14 recurrent miscarriage patients showed a lack of suppressor cells and 59% were subnormal in comparison to 20 controls and 5 sporadic miscarriage patients, where 80–85% of the patients had detectable suppressor cells. CONCLUSIONS : Suppressor cell deficiency is compatible with a role for rejection and/or trophoblast failure in some patients with recurrent miscarriage. Presence of suppressor cells in most patients with missed abortion (4/5) is compatible with an alternative cause of fetal death, similar to findings reported in genetic fetal death mice.     

A protease inhibitor attenuates gastric erosions and microcirculatory disturbance in the early period after thermal injury in rats

The effects of camostat mesilate, a synthetic serine protease inhibitor on gastric microcirculation and active oxygen species generated by leucocytes from the gastric and jugular veins in the early period after thermal injury were assessed. Male Wistar rats were anaesthetized and a 30% full skin-thickness dorsal burn was inflicted. Camostat mesilate (100 mg/kg) was dissolved in distilled water and administered orally to rats 40 min before thermal injury (the camostat group). The control animals (the vehicle group) were administered distilled water orally. Rolling leucocytes as well as Monastral blue B deposits in venules were observed using in vivo microscopy. Active oxygen species were measured by chemiluminescence. Camostat mesilate decreased the total length of gastric erosion, venular deposits of Monastral blue B, and rolling of leucocytes in venules, and relatively increased luminol-dependent chemiluminescence activity generated by zymosan-stimulated leucocytes 15 min after thermal injury. These results suggest that serine proteases are involved in the formation of gastric erosions and gastric microcirculatory disturbance in the early period after thermal injury.     

Bacterial invasion into the colonic mucosa in ulcerative colitis

Abstract This study investigated interactions between mucosal lesions and bacterial invasion in ulcerative colitis using the acridine-orange staining method. In all 16 cases of ulcerative colitis, the mucosa was found to be invaded by small rods and cocci. In five of 10 controls, bacteria were seen only adhering to the mucosa and no bacteria were detected in the five remaining cases. It is suggested that the presence of bacteria in the colonic mucosa may be a factor responsible for the persistence or aggravation of ulcerative colitis.     

Modulation of Fas-mediated apoptosis of human thyroid epithelial cells by IgG from patients with Graves' disease (GD) and idiopathic myxoedema

The expression of two autoimmune thyroid diseases, GD and idiopathic myxoedema, is associated with antibodies to the thyroid-stimulating hormone (TSH) receptor. Thyroid stimulating antibodies (TSAb) in GD are TSH agonists and cause hyperthyroidism as well as goitre, whereas thyroid stimulation blocking antibodies (TSBAb) in idiopathic myxoedema are TSH antagonists and cause hypothyroidism and thyroid atrophy. We investigated the effect of antibodies to TSH receptor on Fas-mediated apoptosis of thyroid epithelial cells (thyrocytes). Human IgG was isolated from healthy donors, patients with GD and idiopathic myxoedema. Human thyrocytes were obtained from surgical specimens. Thyrocytes were cultured in the presence or absence of human IgG with or without interferon-gamma (IFN-γ) or IL-1β for a specified time. After incubation, we examined the level of cAMP in cultured supernatants and both Fas and Bcl-2 expression on thyrocytes. In addition, we examined anti-Fas-mediated apoptosis of thyrocytes. Fas expression on thyrocytes was significantly down-regulated by Graves' IgG and TSH, although idiopathic myxoedema IgG did not affect Fas expression on thyrocytes. Idiopathic myxoedema IgG abrogated the effect of TSH on both cAMP production and inhibition of Fas expression on thyrocytes. Treatment of thyrocytes with IL-1β or IFN-γ caused a marked augmentation of Fas expression on thyrocytes. The increase of Fas expression of thyrocytes induced by IL-1β or IFN-γ was significantly suppressed in the presence of TSH or Graves' IgG. Anti-Fas-induced apoptosis of thyrocytes was observed in thyrocytes treated with IL-1β or IFN-γ, but was markedly inhibited in the presence of TSH or Graves' IgG. Furthermore, idiopathic myxoedema IgG abrogated most of the inhibitory effect of TSH on Fas-mediated apoptosis of thyrocytes treated with IL-1β or IFN-γ. Bcl-2 expression of thyrocytes did not change after stimulation with TSH, Graves' IgG, idiopathic myxoedema IgG, IL-1β or IFN-γ. These results suggest that TSAb found in Graves' patients may be potentially involved in the development of goitre by inhibition of Fas-mediated apoptosis of thyrocytes. In addition, TSBAb inhibit the action of TSH and increase the sensitivity toward Fas-mediated apoptosis of thyrocytes, inducing thyroid atrophy seen in patients with idiopathic myxoedema.     

Atypical polypoid adenomyomas of the uterus

We performed a clinicopathological immunohistochemical, ultrastructural, and flow cytometric study on six cases of atypical polypoid adenomyoma of the uterus including one with an adenocarcinoma within it. The tumours occurred in nulliparous women aged 22–48 years (average, 33.0 years); three arose in the uterine corpus, and three in the endocervix. Histologically, they were composed of endometrial glands admixed with a stromal component of interlacing bundles of smooth muscle cells. The glands exhibited varying degrees of architectural and cytological atypia. Most of the stromal cells showed strong staining for HHF35, alpha-smooth muscle actin, and vimentin, and some cells contained desmin. Electronmicroscopy, in one case, confirmed the presence of a well-differentiated smooth muscle component. The stromal component may arise as a result of extensive metaplasia of endometrial stromal cells. Uninvolved endometrium showed ciliated cell metaplasia in three patients, and atypical complex hyperplasia in two. One patient had a well-differentiated adenocarcinoma of endometrioid type arising in an endocervical atypical polypoid adenomyoma. All tumours had a diploid DNA content and relatively small S phase fraction (average, 6.23%). The follow-up periods ranged from 4 to 42 months (average, 13.5 months), and all patients were alive and well. Although the histogenesis of atypical polypoid adenomyoma of the uterus remains uncertain, it is suggested that it may arise because of oestrogen-related factors.     

The Effect of Cimetidine on Natural Killer Activity of Peripheral Blood Lymphocytes of Patients with Ovarian Carcinoma

The effect of cimetidine on the natural killer (NK) activityof peripheral blood lymphocytes (PBL) of 32 patients with ovariancarcinoma was studied before and after surgery or chemotherapy.There was no significant difference in the NK activity betweennormal healthy women and patients who had been disease-freefor more than a year after initial surgery, while those in patientswith a large residual tumor after surgery were profoundly suppressed.Cimetidine stimulated the NK activity in the disease-free patientsin vivo or in Vitro. In addition, cimetidine augmented the responseto phytohemagglutinin of PBL from the disease-free patients.The NK activity of PBL of patients with a large residual tumorunder chemotherapy consisting of cisplatinum, adriamycin andcyclophosphamide, "CAP," was about half of that before initiationof chemotherapy. The inhibition of the NK activity by chemotherapywas abrogated by in vitro exposure of the PBL to cimetidine.