Augmentation of intrarenal angiotensin II levels in uninephrectomized aldosterone/salt-treated hypertensive rats; renoprotective effects of an ultrahigh dose of olmesartan.

Recent studies have suggested that aldosterone plays a role in the pathogenesis of renal injury. In this study, we investigated whether local angiotensin II (Ang II) activity contributes to the progression of renal injury in aldosterone/salt-induced hypertensive rats. Uninephrectomized rats were treated with 1% NaCl in a drinking solution and one of the following combinations for 6 weeks: vehicle (2% ethanol, s.c.; n=9), aldosterone (0.75 mug/h, s.c.; n=8), aldosterone+Ang II type 1 receptor blocker olmesartan (10 mg/kg/day, p.o.; n=8), or aldosterone+olmesartan (100 mg/kg/day, p.o.; n=9). Aldosterone/salt-treated hypertensive rats exhibited severe proteinuria and renal injury characterized by glomerular sclerosis and tubulointerstitial fibrosis. Aldosterone/salt-induced renal injury was associated with augmented expression of angiotensin converting enzyme and Ang II levels in the renal cortex and medullary tissues. Renal cortical and medullary mRNA expression of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) as well as the collagen contents were increased in aldosterone/salt-treated hypertensive rats. Treatment with olmesartan (10 or 100 mg/kg/day) had no effect on blood pressure but attenuated proteinuria in a dose-dependent manner. Olmesartan at 10 mg/kg/day tended to decrease renal cortical and medullary Ang II levels, TGF-beta and CTGF expression, and collagen contents; however, these changes were not significant. On the other hand, an ultrahigh dose of olmesartan (100 mg/kg/day) significantly decreased these values and ameliorated renal injury. These data suggest that augmented local Ang II activity contributes, at least partially, to the progression of aldosterone/salt-dependent renal injury.     

Chemically induced forestomach papillomas in transgenic mice carry mutant human c-Ha-ras transgenes.

Forestomach papillomas and skin papillomas were induced very efficiently by a single dose administration of the chemical carcinogen methylnitrosourea (MNU) in transgenic mice (rasH2 line) carrying human hybrid c-Ha-ras genes, which encode the prototype p21 gene product. The incidence of forestomach papillomas was dose dependent; when 50 mg/kg of MNU were administered i.p., all of the transgenic mice (56 of 56) developed forestomach papillomas within 12 weeks after administration, whereas 5 and 0.5 mg/kg of MNU induced papillomas in 2 of 19 and 1 of 19 mice, respectively. Nine of 56 transgenic mice (16%) also developed skin papillomas at sites wounded by bites or scratches. Only 1 of 77 nontransgenic littermates developed forestomach papillomas after administration of 50 mg/kg of MNU, and no skin papillomas appeared within 12 weeks after MNU administration. The transgenes (integrated copy number, 5-6) in the tumors developed in 55 of 56 affected transgenic mice (98%) contained at least 1 copy of the transgene that was activated by somatic point mutation at the 12th codon, from GGC (Gly) to GAC (Asp). Because somatic point mutations at the 12th or 61st codon of transgenes have never been detected in normal tissues of transgenic mice thus far examined, these mutational activations of transgenes are tumor-specific events. RNA expression of these activated transgenes was also detected. From these results, it is suggested that somatic mutational activation of the human c-Ha-ras transgene plays a causative role in the occurrence of forestomach and skin papillomas induced by MNU administration in these transgenic mice. This transgenic mouse provides a unique screening system for chemicals that induce or suppress papillomagenesis.     

Investigation of etiologies for acute renal failure due to rhabdomyolysis in 5 patients

We experienced 5 cases of acute renal failure due to rhabdomyolysis during the last two years and investigated those etiologies. Diagnosis of rhabdomyolysis was established by the detection of elevated serum creatine phosphokinase, myoglobin, aldolase, myoglobinuria as well as by the clinical course. The respective underlying illness of the 5 cases were grand mal seizures, infection (high fever), heat stroke, diabetes mellitus with hyperosmolar nonketotic coma and cerebral infarction treated by barbiturate. In this investigation, however, any single cause was not enough as the etiologies of rhabdomyolysis. There were multiple factors responsible to rhabdomyolysis in each case, such as hypokalemia, hypophosphatemia, shock, arteriosclerosis, etc. Some cases could not be classified as traumatic or non-traumatic rhabdomyolysis. Thus, in one case, acute renal failure due to rhabdomyolysis induced by the combination of grand mal seizures and serum potassium/phosphate depletion. 2 cases recovered without hemodialysis. 3 cases died in multiple organ failure, included a case treated by hemodialysis. We conclude that acute renal failure due to rhabdomyolysis induced easily by numerous diseases and early diagnosis is recommended.     

Pemphigoid Nodularis: A Case with 230 kDa Hemidesmosomes Antigen Associated with Bullous Pemphigoid Antigen

We report a 73-year-old woman with typical clinical, histological and immunofluorescence features of pemphigoid nodularis. Direct immunofluorescence studies of prurigo nodularis-like lesions and peribullous skin showed the linear deposition of IgG and C3 at the basement membrane zone. Circulating IgG against the basement membrane was also detected by indirect immunofluorescence. The serum from the patient was shown to contain the autoantibody against 230 kDa hemidesmosomal antigen associated with bullous pemphigoid antigen.     

Surgical treatment of syphilitic ascending aortic aneurysm: a case report

A 67-year-old man with positive serum reaction for syphilis had been followed by cardiologist for his moderate-sized saccular ascending aortic aneurysm and small-sized abdominal aortic aneurysm. Because of his transient ischemic attack probably secondary to the thrombo-embolism of the aneurysm and rapid growing of its size, surgical treatment was recommended. Resection of the saccular aneurysm with patch plasty of the ascending aorta was performed under the cardiopulmonary bypass associated with right side cerebral perfusion. At the time of operation, the mildly dilated ascending aorta and arch with multiple intimal ulceration were noted. Although his postoperative hemodynamic condition was stable, he suffered from multiple cerebral infarction, probably due to embolism migrated from the fragile aortic intima. His neurological condition was improved promptly, trivial hemi-paralysis was remained. The specimen of resected aneurysmal wall revealed syphilitic changes microscopically. We concluded that the extent of the aortic replacement with prosthetic graft should be deceived not only with its external appearance, but also with the changes of its inside.     

Association of BRCA2 polymorphism at codon 784 (Met/Val) with breast cancer risk and prognosis.

PURPOSE: The association of BRCA2 polymorphisms at codon 372 [Asn (N)/His (H)]and codon 784 [Met (M)/Val (V)] with breast cancer risk was evaluated in Japanese women. In addition, the prognostic significance of these polymorphisms was studied in breast cancer patients. EXPERIMENTAL DESIGN: A case-control study was conducted to examine the association of the BRCA2 N/H372 polymorphism and M/V 784 polymorphism with breast cancer risk (cases = 149, controls = 154). The prognostic significance of these polymorphisms was evaluated in 139 patients with primary breast cancer. RESULTS: No significant association was observed between the N/H372 polymorphism and breast cancer risk. In contrast, a significant increase in breast cancer risk (odds ratio, 2.03; 95% confidence interval, 1.07-3.87) was observed in carriers of the variant allele (V784) of the M/V784 polymorphism as compared with noncarriers after adjustment for the classical risk factors, age, family history, parity, body mass index, and so forth. Among breast cancer patients, various clinicopathological parameters including menopausal status, tumor size, lymph node status, histological grade, and estrogen-receptor status were not significantly different between the carriers and noncarriers of the variant allele with regard to both N/H372 and M/V784 polymorphisms. The N/H 372 polymorphism was not significantly associated with patient prognosis. On the other hand, breast cancer patients carrying the variant allele of M/V784 polymorphism showed a significantly (P = 0.014) lower 3-year disease-free survival rate (63%) than noncarriers (92%). Multivariate analysis has revealed that the M/V784 polymorphism is a significant prognostic factor, being independent of the other conventional prognostic factors such as lymph node status and estrogen receptor status. CONCLUSION: These results suggest that the M/V784 polymorphism, but not the N/H372 polymorphism, would be useful in the selection of women at high risk for developing breast cancer and would also serve as a clinically useful prognostic factor in breast cancer patients.     

Synthesis and antitumor activity of tropolone derivatives. 7. Bistropolones containing connecting methylene chains.

Bistropolone derivatives (4-12) containing differing lengths of linkage between the two tropolone rings were prepared and examined for their antitumor activity in in vitro (KB cell) and in vivo (leukemia P388 in mice) systems. Parent compound 3, related compounds previously prepared, and the new compounds 4-12 were evaluated for inhibitory activity against ribonucleotide reductase by indirect means to measure their effects on the dNTP pool imbalance. Present structure-activity relationship results would suggest that potently active bistropolones in vivo inhibit intracellular ribonucleotide reductase through chelating with the two irons at the two active sites of the enzyme.     

Cervical lung hernia in a case of severe chronic asthma and bronchitis

A case of a bilateral pulmonary hernia of the lungs into the supraclavicular fossae is described. A man, aged 79, with severe chronic asthma and chronic bronchitis due to air pollution, complained of a cervical mass off and on for several years. The herniation was greater on the right side. It could be identified on physical examination by the presence of a soft painless supraclavicular bulge which was exaggerated by strain or cough. Radiologically this herniation could best be identified on lateral cervical roentgenogram. It is said that cervical lung hernia is a rare condition, but in our experience supraclavicular herniation of the lung is not unusual in cases of severe chronic obstructive lung disease.     

Rapid detection of mecA gene by nested PCR for diagnosis of methicillin resistance in Staphylococcus aureus]

In recent years, the most common causative organism of hospital infections has been methicillin resistant Staphylococcus aureus (MRSA). The major mechanism of beta-lactam resistance in MRSA is attributed to the production of a specific penicillin binding protein (PBP2'), which is a product of mecA gene, with extremely low binding affinities to beta-lactams. In the present study, we have established a rapid identification method of MRSA by sensitive detection of mecA gene using nested PCR. Nested PCR method amplifying the target DNA in two steps enhanced the efficiency of the second round amplification. By means of this method, mecA gene was successfully detected in clinical samples, such as blood, pus, sputum and feces within 3-4 hrs. Rapid diagnosis of MRSA-bacteremia is particularly important for prevention of sever systemic infection. There are some strains of S. aureus which possess mecA gene in spite of low minimal inhibitory concentration of DMPPC. In these strains expression of mecA gene is induced by contact of beta-lactams and they obtain methicillin resistance. Using nested PCR method, these latent MRSA are rapidly and certainly detectable. This method should be useful for early and effective detection of MRSA hospital infections.