Increased expression of gp91phox homologues of NAD(P)H oxidase in the aortic media during chronic hypertension: involvement of the renin-angiotensin system.

Although vascular cells express multiple members of the Nox family of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, including gp91phox, Nox1, and Nox4, the reasons for the different expressions and specific roles of these members in vascular injury in chronic hypertension have remained unclear. Thus, we quantified the mRNA expressions of these NAD(P)H oxidase components by real-time polymerase chain reaction and evaluated superoxide production and morphological changes in the aortas of 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar Kyoto rats (WKY). The aortic media of SHRSP had an approximately 2.5-fold greater level of Nox4 mRNA and an approximately 10-fold greater level of Nox1 mRNA than WKY. The mRNA expressions of gp91phox and p22phox in SHRSP and WKY were comparable. SHRSP were treated from 24 weeks of age for 8 weeks with either high or low doses of candesartan (4 mg/kg/day or 0.2 mg/kg/day), or a combination of hydralazine (30 mg/kg/day) and hydrochlorothiazide (4.5 mg/kg/day). The high-dose candesartan or the hydralazine plus hydrochlorothiazide decreased the blood pressure of SHRSP to that of WKY, whereas the low-dose candesartan exerted no significant antihypertensive action. Media thickening and fibrosis, as well as the increased production of superoxide in SHRSP, were nearly normalized with high-dose candesartan and partially corrected with low-dose candesartan or hydralazine plus hydrochlorothiazide. These changes by antihypertensive treatment paralleled the decrease in mRNA expression of Nox4 and Nox1. These results suggest that blood pressure and angiotensin II type 1 receptor activation are involved in the up-regulation of Nox1 and Nox4 expression, which could contribute to vascular injury during chronic hypertension.     

Effect of cystathionine beta-synthase variant 844ins68bp and methylenetetrahydrofolate reductase A1298C polymorphisms in xenografts on 5-FU efficacy and doubling time

The association of MTHFR and CBS variants with the doubling time and responsiveness to several chemodrugs was analyzed in 26 human cancer xenografts. The tumors homozygous for the absence of insertion (NN) for the CBS 844ins68bp were more chemosensitive than those with insertion (NI) to TS-1 (P=0.0048), suggesting a potential effect of this variant on fluoropyrimidine efficacy. Furthermore, the doubling time of tumors with a variant C allele (AC or CC) in MTHFR-A1298C was significantly longer than that of tumors with a normal allele (AA) (P=0.0008). Twenty-nine cellular proliferation-related genes were associated with MTHFR-A1298C genotyping and with the doubling time.     

PEUTZ‐JEGHERS SYNDROME ASSOCIATED WITH RENAL AND GASTRIC CANCER THAT DEMONSTRATED AN STK11 MISSENSE MUTATION

A 75‐year‐old male was admitted to the gastroenterology unit of Nagoya City University Hospital due to epigastralgia after surgical treatment for right renal cancer. Endoscopy revealed advanced type 1 gastric cancer in the corpus of the stomach and multiple polypoid lesions in the stomach and duodenum. X‐ray examination of the small intestine using barium showed multiple polyps in the upper jejunum. Faint pigmentation on the palm was also detected. Peutz‐Jeghers syndrome (PJS) was diagnosed, despite a lack of family history. Total gastrectomy, resection of part of the upper jejunum and intraoperative endoscopic polypectomy of duodenal polyps was performed. This is the second reported case of PJS associated with renal cancer. We also detected a missense mutation in the tumor suppressor gene STK11 that, when mutated, is causative for PJS.     

Extremely Well Differentiated Papillary Adenocarcinoma of the Lung with Prominent Cilia Formation

We describe a 54-year-old woman with primary pulmonary adenocarcinoma showing a characteristic papillary architecture and prominent cilia formation. Immunohistochemically, the tumor cells were positive for carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA) and Leu Ml, and negative for lactoferrin and surfactant apoprotein. An ultrastructural study also indicated differentiation toward bronchial surface epithelial cells. To our knowledge, this type of neoplasm has not been reported as peripheral-type adenocarcinoma of the lung. Acta Pathol Jpn 42: 745–750, 1992.     

Extended total arch replacement for type B aortic dissection with ascending aneurysm following healed aortic dissection

We describe a case of type B aortic dissection with large ascending aortic aneurysm occurring 12.8 years after aortic root replacement (Cabrol procedure) in a non-Marfan patient with cystic medial necrosis of the aorta. We have successfully performed an extended total aortic arch replacement using a four-branched graft through the “L-indsion” approach (a combination of a left anterior thoracotomy and upper half median sternotomy). Of note, a histological specimen from the aneurysmal ascending aortic wall revealed “healed aortic dissection” with fibrous tissue replacing the media and intima in addition to multiple foci of cystic medial necrosis.     

The Protective Role of Glutathione, Cysteine and Vitamin C against Oxidative DNA Damage Induced in Rat Kidney by Potassium Bromate

The roles of glutathione (GSH), cysteine, vitamin C., liposome-encapsulated superoxide dismutase (L-SOD) and vitamin E in preventing oxidative DNA damage and cytotoxicity in the rat kidney after administration of potassium bromate (KBrO₃) to male F344 rats were investigated by measuring 8-hydroxydeoxyguanosine (8-OH-dG), an oxidative DNA product, lipid peroxidation (LPO) levels and relative kidney weight (RKW). Combined pre- and posttreatment of animals with 2 × 800 mg/kg GSH i.p. inhibited the increase of 8-OH-dG, LPO levels and RKW caused by 80 mg/kg KBrO₃ i.p. administration. In contrast, pretreatment with 0.3 ml/kg diethylmaleate (DEM) i.p., a depletor of tissue GSH, was associated with elevation of 8-OH-dG, LPO levels and RKW after a 20 mg/kg KBrO₃ i.p. treatment, which itself caused no change. Administration of KBrO₃ itself reduced renal non-protein thiol levels, but this was inhibited by the two doses of exogenous GSH. Combined treatment with DEM and KBrO₃ lowered the non-protein thiol level in the kidney more than did DEM treatment alone. Protective effects against the oxidative damage caused by KBrO₃ were also observed for pre- and posttreatment with 400 mg/kg cysteine i.p., another sulfhydryl compound, and daily i.g. application of 200 mg/kg vitamin C for 5 days. However, no influence was evident after pre- and posttreatment with 18,000 U/kg L-SOD i.p. or daily i.g. 100 mg/kg of vitamin E for 5 days. The results suggest that intracellular GSH plays an essential protective role against renal oxidative DNA damage and nephrotoxicity caused by KBrO₃.     

Reversible low-molecular-weight proteinuria in patients with distal renal tubular acidosis

Four patients with untreated renal tubular acidosis had a urinary excretion of low-molecular-weight (LMW) proteins which was restored to normal by alkali therapy. Hypokalaemic proximal tubular damage in untreated patients with distal renal tubular acidosis is believed to be the cause of LMW proteinuria. An examination of urinary excretion of LMW proteins is useful for determining hypokalaemic proximal tubular dysfunction, as well as the efficiency of alkali therapy.     

Expression of Lewis Y (Ley) Antigen in Human Anagen Hair Follicles

Lewis Y (Le^y) antigen, a difucosylated tetrasaccharide found on type 2 blood group oligosaccharides of glycolipids and glycoproteins, is thought to be a phenotypic marker predictive of cell differentiation. The distribution of this antigen in human anagen hair follicles was examined by immunohistochemical staining using a monoclonal antibody (AH-6) to Le^y. In the bulbar and suprabulbar portion of anagen hair follicles, Le^y antigen was detected in the three layers of the inner root sheath. Subsequently, the positive staining became translocated to the innermost layer of the outer root sheath in the middle part of the hair follicles. In the upper portion of the hair follicles, Le^y antigen was found in the outer cells of the outer root sheath. These findings suggested that the expression of Le^y antigen in the anagen hair follicles was correlated with the processes of keratinization or terminal differentiation.     

Surgical results of performing R4 gastrectomy for gastric cancer located in the upper third of the stomach

Because gastric cancers located in the upper third of the stomach are difficult to detect at an early stage, the surgical results remain poor. We performed R4 gastrectomy as a radical procedure for 25 patients, involving complete resection of the latero-aortic and interaorticovenous lymph modes above and below the left renal vein, in combination with the ordinary R2 or R3 gastrectomy (the R4 group). These patients were compared with 156 others who underwent R2 gastrectomy alone (the R2 group). There were no significant differences in operation time, blood loss, or the incidence of complications between the two groups; however, when the survival rates of the patients with tumors invading beyond the subserosa were compared, the 5-year survival rate was found to be significantly higher in the R4 group than in the R2 group. Furthermore, in patients with para-aortic nodal involvement, a significant survival advantage was observed in the R4 group, as compared with the R2 group. These results suggest that the R4 gastrectomy is a rational approach for patients with advanced gastric cancer located in the upper third of the stomach.