Effects of systemic hypoxia on pH outside rod photoreceptors in the cat retina.

We studied the effect of systemic hypoxia on intraretinal pH in the intact cat eye using double-barreled H(+)-sensitive microelectrodes. Hypoxia in the dark further acidified the extracellular space surrounding rods in the distal retina and this effect was maximal in the outer nuclear layer (ONL). An acidification occurred in response to essentially any decrease in PaO2 below the normoxic level. Light-evoked alkalinizations in the ONL were larger in amplitude during hypoxia than in normoxia and this difference increased with the severity of hypoxia. Background illumination suppressed the hypoxic acidification of the ONL, completely inhibiting it at rod saturating intensities, at levels of hypoxia down to PaO2s of 40 mmHg. Systemic hyperoxia produced a small alkalinization in the ONL, and a reduction in the amplitude of the light-evoked alkalinizations. This suggests that systemic hyperoxia can partially suppress the ongoing glycolysis of dark-adapted rods. Changes in blood flow during hypoxia also altered intraretinal pH. Hypoxia led to an alkalinization in the choroid in both dark and light adaptation that spread into the distal retina. This alkalinization is most likely caused by the increase in CO2 removal that occurs as systemic blood pressure, and as a consequence, choriocapillaris blood flow increase during hypoxia. The alkalinization attenuated the acidification that was observed outside rods during hypoxia. There was also an alkalinization of the proximal portion of the retina, which spread into the vitreous. This alkalinization was attributed to the autoregulatory increase in blood flow that occurs in the retinal vessels during hypoxia. These findings provide further evidence for the hypothesis that the energy metabolism of dark-adapted rods is exquisitely sensitive to systemic hypoxia so that any small decrease in PaO2 increases rod glycolysis. Rod-saturating illumination can completely suppress this increase in glycolysis for all but severe hypoxia. An increase in blood flow in the choriocapillaris during hypoxia appears to mitigate the effects of hypoxia on the distal retina.     

A case-control study of breast cancer among Japanese women: with special reference to family history and reproductive and dietary factors

Summary To study the effects of family history and reproductive, anthropometric, and dietary factors on the risk of breast cancer among low risk populations, we conducted a hospital-based case-control study involving 908 patients with breast cancer and their matched controls, in Japan. A positive family history of breast cancer significantly increased the risk of breast cancer (odds ratio = 1.52, 95% confidence interval: 1.14–2.03). The risk further increased with increasing number of family members affected. Obesity, single marital status, fewer births, a late childbirth, and less consumption of green-yellow vegetables and dairy products were also associated with an increased risk of breast cancer. These associations were independent in multivariate analyses. There was no increase in risk associated with consumption of high fat foods. When analyzed by menopausal status, the association with family history of breast cancer, especially in the first degree of relatives, was more evident for premenopausal breast cancer. The associations with obesity and lower consumption of dairy products were more pronounced for postmenopausal breast cancer, while those with lower parity and single marital status were stronger for premenopausal breast cancer.     

Cutaneous thermal-cooling and -warming detection thresholds in distal extremities of normal subjects]

The cutaneous thermal-cooling and -warming detection thresholds were evaluated on the dorsal side of the right distal forearm and on the dorsum of the right foot in 134 normal subjects (66 men and 68 women) without sensory symptoms and signs, aged from 11 to 87 years by using a Thermal Threshold Tester (Vickers Medical International, England). The normative data for the clinical evaluation of the severity and the pathologic process of the sensory disturbance of the patients were obtained. The data obtained included 1) the mean of each threshold and 2) its upper limit value of 95% confidence interval for each decade. The mean of each threshold was significantly increased with aging (P less than 0.0001). Therefore, the cutaneous thermal-cooling and -warming detection thresholds of the patients with sensory disturbances should be compared with the normative data adjusted for the age of each subject obtained in this study. Based on the evaluation, repeated six times for three weeks, of each threshold of six volunteers (ages from 21 to 66), high reliability of each threshold (intraclass correlation coefficient from 0.78 to 0.96) was observed.     

A one-year series of pediatric ED water-related injuries: the Hawaii EMS-C project.

During a 12-month period ending on November 30, 1988, data on 133 pediatric patients visiting a pediatric emergency department with water-related injuries were collected. Of these patients, 70% were male. There were 13 submersions, seven cases of head trauma, three cases of neck trauma, 88 cases of external injury, and 34 other injuries. Incidents took place at beaches (75%) in public pools (12%), in friends' pools (4%), and in home pools (4%). Eighty-six percent of the cohort knew how to swim. Swimming, playing, and surfing activity accounted for most of the injuries. Measures for prevention are described.     

Comparison of ascorbic acid and ascorbic acid 2-O-alpha-glucoside on the cytotoxicity and bioavailability to low density cultures of fibroblasts.

Ascorbic acid 2-O-alpha-glucoside (AA-2G) is a stable ascorbate derivative which has vitamin C activity in vivo and in vitro. We studied whether AA-2G exerts a prooxidant action in cultured fibroblasts from chick embryo and human skin, as does ascorbic acid. At concentrations of 0.1-1.0 mM, ascorbic acid markedly reduced the viable cell number of low density cultures within 24 hr, whereas AA-2G had no such effect. The ascorbate cytotoxicity was dependent on the cell density at the time of its addition and it was characteristic of low density cultures. This cytotoxicity was completely prevented by catalase and partially by an Fe3+ ion chelator, desferrioxamine. In the early culture stage at which a morphological change in the fibroblasts began to occur, intracellular ascorbate concentrations in low density cultures after addition of ascorbic acid were much higher than in high density cultures. However, at the same concentrations, AA-2G did not cause an elevation even in low density cultures and it was also effective on collagen synthesis at high and medium densities. These results suggest that the abnormally accumulated ascorbic acid in the cells cultured at low density possibly amplifies the generation of oxygen radicals through the reduction of Fe3+ ions and subsequent oxidative reactions, leading to cell death. Therefore, it is concluded that AA-2G which supplies an adequate amount of ascorbic acid during culture period is a bioavailable ascorbate source without cytotoxicity.     

Inhibition of inward rectifier K+ currents by angiotensin II in rat atrial myocytes: lack of effects in cells from spontaneously hypertensive rats.

We examined the effects of angiotensin II (Ang II) on inward rectifier K+ currents (IK1) in rat atrial myocytes. [125I]Ang II-binding assays revealed the presence of both Ang II type 1 (AT1) and type 2 (AT2) receptors in atrial membrane preparations. Ang II inhibited IK1 in isolated atrial myocytes with an IC50 of 46 nmol/l. This inhibition was abolished by the AT, antagonist RNH6270 but not at all by the AT2 antagonist PD123319. Treatment of cells with pertussis toxin or a synthetic decapeptide corresponding to the carboxyl-terminus of Gialpha-3 abolished the inhibition by Ang II, indicating the role of a Gi-dependent signaling pathway. Accordingly, Ang II failed to inhibit IK1 in the presence of forskolin, dibutyryl-cAMP or protein kinase A catalytic subunits. In spite of the increased binding capacities for [125I]Ang II, Ang II failed to affect IKI in cells from spontaneously hypertensive rats (SHR). AT, immunoprecipitation from atrial extracts revealed decreased amounts of Gialpha-2 and Gialpha-3 proteins associated with this receptor in SHR as compared with controls. The reduced coupling of AT, with Gialpha. proteins may underlie the unresponsiveness of atrial IK1 to Ang II in SHR cells.     

A double-blind dose-ranging study of risedronate in Japanese patients with osteoporosis (a study by the Risedronate Late Phase II Research Group)

To determine the clinical recommended dosage regimen of risedronate for the treatment of involutional osteoporosis in Japanese patients, dose-response relationships for the efficacy and safety of this drug were investigated using a multi-center, randomized, double-blind, parallel group comparative design with four dose levels of risedronate (placebo, 1 mg, 2.5 mg and 5 mg per day). A total of 211 patients diagnosed with involutional osteoporosis according to the criteria proposed by the Japanese Society for Bone and Mineral Research were randomized and received one of the four doses once daily for 36 weeks. All patients were supplemented with 200 mg of calcium daily in the form of calcium lactate. The primary efficacy endpoint was the percent change in bone mineral density of the lumbar spine (L2-L4 BMD) determined by dual-energy X-ray absorptiometry (DXA) from baseline to the time of final evaluation. Changes in biochemical markers of bone turnover and safety profile were also compared. Percent changes in L2-L4 BMD at final evaluation in the placebo, and 1-, 2.5-, and 5-mg risedronate groups were 0.79+/-5.30, 2.71+/-4.93, 5.29+/-3.96, and 5.15+/-4.25% (mean+/-SD), respectively. A linear dose-response relationship was obtained up to a dose of 2.5 mg, whereas no further increase in BMD was observed at 5 mg. The decrease in bone turnover markers, including N-terminal osteocalcin, phosphorus, and urinary deoxypyridinoline, also showed a linear dose-response relationship up to a dose of 2.5 mg. Alkaline phosphatase level decreased linearly up to a dose of 5 mg. Risedronate was well tolerated in this 36-week study with 1- to 5-mg doses. Neither the overall incidence of adverse events nor the percentage of patients without problem in overall safety assessment differed significantly among the dose groups including the placebo group. Based on these results, a once-daily dose of 2.5 mg of risedronate, which is half that used in Caucasians, is recommended for the treatment of involutional osteoporosis in Japanese patients.