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In Clostridium perfringens , a 5-membered thiolactone peptide acts as an autoinducing peptide (AIPCp) to activate the VirSR two-component signal transduction system, which in turn controls the expression of genes encoding multiple toxins, including α, θ, and κ. To develop anti-pathogenic agents against virulent C. perfringens , quorum-quenching peptides were rationally designed based on the structure-activity relationship (SAR) data on AIPCp. Alanine scanning study of AIPCp suggested that Trp3 and Phe4 are involved in receptor binding and activation, respectively. On the basis of the SAR, we designed two quorum-quenching peptides with different modes of action: Z-AIPCp-L2A/T5A (partial agonist) and Z-AIPCp-F4A/T5S (partial antagonist). Both peptides significantly attenuated transcription of θ toxin gene ( pfoA ) in a virulent strain of C. perfringens with IC50 = 0.32 and 0.72 μM, respectively.

Cyclic peptides are commonly used as quorum-sensing autoinducers in Gram-positive Firmicutes bacteria. Well-studied examples of such molecules are thiolactone and lactone, used to regulate the expression of a series of virulence genes in the agr system of Staphylococcus aureus and the fsr system of Enterococcus faecalis, respectively. Three cyclodepsipeptides WS9326A, WS9326B and cochinmicin II/III were identified as a result of screening actinomycetes culture extracts for activity against the agr/fsr system. These molecules are already known as receptor antagonists, the first two for tachykinin and the last one for endothelin. WS9326A also inhibited the transcription of pfoA regulated by the VirSR two-component system in Clostridium perfringens. Receptor-binding assays using a fluorescence-labeled autoinducer (FITC-GBAP) showed that WS9326A and WS9326B act as receptor antagonists in this system. In addition, an ex vivo assay showed that WS9326B substantially attenuated the toxicity of S. aureus for human corneal epithelial cells. These results suggest that these three natural cyclodepsipeptides have therapeutic potential for targeting the cyclic peptide-mediated quorum sensing of Gram-positive pathogens.

Background and Purpose— The role of high-sensitivity C-reactive protein (hsCRP) in the development of stroke is not clearly understood. We investigated the relationship between serum hsCRP levels and stroke occurrence in a general Japanese population. Methods— We followed 2692 subjects ≥40 years of age for 12 years. The relative risks and 95% CIs for ischemic and hemorrhagic stroke occurrence were calculated according to the hsCRP quintiles. Results— During the follow-up, 129 first-ever ischemic and 59 hemorrhagic strokes occurred. In men, the age-adjusted incidence of ischemic stroke significantly increased with elevated serum hsCRP levels; the difference between the first and fifth quintiles was statistically significant (1.4 versus 6.6 per 1000 person-years; P =0.02). This association remained significant even after adjustment for other confounding factors, such as age, systolic blood pressure, ECG abnormalities, diabetes, body mass index, total cholesterol, high-density lipoprotein cholesterol, smoking habits, alcohol intake, and regular exercise (adjusted relative risks, 3.11; 95% CI, 1.04 to 9.32; P =0.04). However, such associations were not observed for ischemic stroke in women or in hemorrhagic stroke in either sex. Among male subjects who were both in the fifth hsCRP level and had hypertension, diabetes, obesity, hypercholesterolemia, or a smoking habit, the risk of ischemic stroke was extremely increased, even after adjustment for other risk factors. Conclusions— Our findings suggest that elevated serum hsCRP levels are an independent risk factor for future ischemic stroke in Japanese men and that the coexistence of a high hsCRP level with another risk factor extremely increases the risk of ischemic stroke.

To examine secular trends in the incidence and mortality of gastric cancer in a Japanese community, Hisayama, we established three study-cohorts of Hisayama residents aged >40 years in 1961 (1637 subjects), 1974 (2054), and 1988 (2602). Each cohort was followed up for ten years. The age-standardized mortality from gastric cancer significantly decreased from 2.4 per 1000 person-years in the first cohort to 0.8 in the third cohort for men, and from 1.0 to 0.2, respectively, for women (p < 0.01 for trend in both sexes). The five-year survival rate after gastric cancer significantly improved from the first (32.6%) to the third cohort (73.0%, p < 0.01) for men and from 43.2% to 72.3% (p < 0.05), respectively, for women. The age-standardized incidence of cancer in men was not different among the cohorts (4.3 per 1000 person-years in the first, 5.0 in the second, and 4.9 in the third cohort), while it decreased significantly in women (2.0, 1.8, and 1.2, respectively, p < 0.01 for trend). In conclusion, our findings suggest that in a Japanese population, the mortality from gastric cancer declined during the past 40 years, due mainly to the improvement of survival in both sexes and a decrease in the incidence for women.

症例: 66歳, 男性. 平成5年12月より糖尿病性腎症による慢性腎不全のため維持透析を受けていた. 平成14年3月21日, 夕食後約1時間より左臍周囲痛が出現し, 徐々に増悪したため, 翌22日に当院へ緊急入院となった. 以後, 同様の腹痛にて計5回の入退院を繰り返した. 血液データ上炎症反応を認めず, 腹部CTにて上腸間膜動脈 (SMA) および下腸間膜動脈 (IMA) の壁に石灰化がみられた. 血管造影では腹腔動脈 (CA) およびSMAの描出は良好なるも, IMA領域では, 本幹の狭窄像とその末梢動脈に内腔狭窄と考えられる造影不良領域を認めた. いずれの領域にも血栓形成はみられなかった. また, 胃カメラ, 注腸および大腸鏡では, 異常を認めなかった. 以上の臨床経過と検査所見より食事により誘発された腹部アンギーナと診断した. しかし, 血管造影で, IMA本幹の狭窄に加え, さらにその末梢動脈におけるびまん性の内腔狭窄が強く疑われたことから外科的治療の適応はないと判断された. 退院後は, 関連透析施設にてドライウェイトを甘めにするなどの管理にとどまっている. 主な3本の腹部臓器動脈である, 腹腔動脈, 上・下腸間膜動脈の間には豊富な側副血行路が発達しているため, 腹部アンギーナの出現に関する過去の報告例では, これら3本の主幹動脈のうち2本以上が関与する例が大多数を占めている. 本例は, IMA領域のみの慢性虚血が原因と考えられたまれな1例であった.

Background and Purpose— The slowdown of a steeply declining trend in cardiovascular mortality has been reported in Japan, but precise reasons for this trend are uncertain. Methods— We established 3 study cohorts of Hisayama residents aged ≥40 years without a history of stroke or myocardial infarction in 1961 (1618 subjects, first cohort), 1974 (2038 subjects, second cohort), and 1988 (2637 subjects, third cohort). We followed up with each cohort for 12 years, comparing the incidence, mortality, and survival rate of cardiovascular disease. Results— The age-adjusted incidence of cerebral infarction significantly declined by 37% for men and by 32% for women from the first to the second cohort. It continued to decline by 29% for men, but the decline decelerated for women in the third cohort. The incidence of cerebral hemorrhage steeply declined by 61% from the first to the second cohort in men only, while it was sustained for both sexes in the third cohort. Stroke mortality continuously declined as a result of these incidence changes and significant improvement of survival. In contrast, the incidence and mortality rate of coronary heart disease were unchanged except for the increasing incidence in the elderly. The prevalence of severe hypertension and current smoking significantly decreased, while that of glucose intolerance, hypercholesterolemia, and obesity greatly increased among the cohorts. Conclusions— Our data suggest that the decline in stroke incidence is slowing down and that the incidence of coronary heart disease has been increasing in the elderly in recent years. Insufficient control of hypertension and the increase in metabolic disorders may contribute to these trends.

We examined the role of Rho/Rho-kinase in renal afferent and efferent arteriolar tone induced by angiotensin (Ang) II, KCl and elevated renal arterial pressure (from 80 to 180 mm Hg), using isolated perfused rat hydronephrotic kidney. In the condition with no vasoconstrictor stimuli, Y-27632, a Rho-kinase inhibitor, dilated only afferent (from 11.6 ± 0.4 to 14.1 ± 0.5 µm) but not efferent arterioles (from 11.6 ± 0.2 to 12.6 ± 0.7 µm) at 10–5 mol/l. During renal vasoconstriction by Ang II, Y-27632 restored the afferent arteriolar constriction (141 ± 10% reversal at 10–5 mol/l), whereas the ability of Y-27632 to inhibit the Ang II-induced efferent arteriolar constriction was diminished (73 ± 7% reversal). A similar action was observed with fasudil, another Rho-kinase inhibitor. Furthermore, Y-27632 impaired myogenic afferent arteriolar constriction, with 117 ± 17% inhibition at 10–5 mol/l. The inhibition by Y-27632 of the myogenic vasoconstriction was almost the same as that of the Ang II-induced tone of this vessel type. However, Y-27632 had a modest effect on KCl-induced vasoconstriction of afferent arterioles. In conclusion, the present study demonstrates a predominant role of Rho/Rho-kinase in mediating the basal and Ang II-induced tone of afferent, but not efferent, arterioles. Furthermore, the role of Rho/Rho-kinase in afferent arteriolar constriction differs, with a substantial contribution to Ang II-induced and myogenic constriction but a minimal role in depolarization-induced constriction. Since Ang II-induced, KCl-induced and myogenic constriction of afferent arterioles require calcium entry through voltage-dependent calcium channels, the interaction between Rho/Rho-kinase and the calcium entry pathway may determine the afferent arteriolar tone induced by these stimuli.

Aims: The role of cyclooxygenase (COX)-1/2-induced prostaglandins (PG) in unilateral chronic renal ischemia of anesthetized dogs was examined. Methods: Ischemic kidneys were established by reducing renal blood flow of left renal artery to 10% of baseline with an adjustable clip. After 4 weeks, changes in intrarenal contents of PGE2/PGI2 and angiotensin (Ang) II were evaluated with renal microdialysis and biopsy. Furthermore, the effect of a non-specific COX inhibitor (sulpyrine), a COX-2-specific inhibitor (NS398), and an Ang receptor antagonist (CS866) on renal function and renal PG contents were evaluated. Results: Unilateral renal artery clipping reduced renal plasma flow (RPF) in clipped (from 59 ± 2 to 17 ± 1 ml/min, n = 18) and nonclipped kidneys (from 59 ± 2 to 44 ± 2 ml/min) and natriuresis. Intrarenal PGE2 increased only in clipped kidneys (from 114 ± 7 to 375 ± 25 pg/ml), whereas 6-keto-PGF1α increased in both kidneys. Sulpyrine reduced intrarenal PG contents, and decreased RPF, GFR, and urinary sodium excretion (UNaV), whereas NS398 reduced UNaV in clipped (from 4.0 ± 0.9 to 1.7 ± 0.2 µEq/min) and nonclipped kidneys (from 5.4 ± 0.5 to 2.9 ± 0.3 µEq/min), without affecting renal hemodynamics. Intrarenal Ang II contents increased in clipped (from 0.70 ± 0.06 to 2.32 ± 0.33 pg/mg, n = 18) and nonclipped kidneys (from 0.65 ± 0.06 to 2.45 ± 0.33 pg/mg, n = 18), and CS866 improved renal hemodynamics and natriuresis. The elevated intrarenal Ang II content was suppressed by NS398 only in clipped kidneys. Conclusion: Unilateral renal ischemia elevates intrarenal PGE2 contents in clipped kidneys, which serves to countervail the aggravation of renal function. Furthermore, intrarenal COX isoforms may play differential roles, with COX-1 participating in modulation of renal hemodynamics, and COX-2 contributing to sodium excretion and Ang II formation.

This study examined the effects of different types of calcium channel antagonists on renal haemodynamics and natriuresis. The intravenous infusion of nifedipine (L-type blocker), efonidipine (L/T-type blocker) or mibefradil (predominant T-type blocker) into anaesthetized dogs elicited similar, albeit modest, reductions in blood pressure. Nifedipine (1 microgram.min(-1).kg(-1)) increased renal plasma flow (RPF) (23+/-6%; P

Background. Although glucocorticoids elicit systemic hypertension, they are also demonstrated to cause marked increases in renal blood flow. The mechanism of this alteration, however, remains undetermined. Methods. Dogs were treated with dexamethasone (DEX) for 7 days, and renal, as well as systemic hemodynamic, responses to DEX were assessed. In addition, the role of intrarenal angiotensin (ANG) II in mediating the glucocorticoid-induced renal vasodilation was examined in conscious unrestrained dogs. Results. Seven-day treatment with DEX caused prominent increases in mean arterial pressure (MAP; from 80 ± 2 to 98 ± 5 mmHg) and in renal plasma flow (RPF; from 142 ± 4 to 191 ± 7 ml/min), with decreases in renal vascular resistance [RVR; from 0.26 ± 0.01 to 0.22 ± 0.01 mmHg/(ml/min)] and in the filtration fraction (FF; from 0.24 ± 0.01 to 0.20 ± 0.01). DEX treatment did not alter plasma ANG II levels, but enhanced candesartan-induced reduction in MAP. In contrast, the candesartan-induced increase in RPF (19 ± 2% increase) was completely abolished by DEX. DEX treatment markedly reduced renal tissue ANG II content (from 1.09 ± 0.07 to 0.71 ± 0.04 pg/mg tissue), which paralleled the response of renal tissue angiotensin-converting enzyme (ACE) activity (−20 ± 4%). Finally, intravenous ANG II administration caused a greater reduction in RPF during the DEX treatment period (−17 ± 2% vs −11 ± 1% in the control period). Conclusions. Glucocorticoids cause hypertension, but they also cause a paradoxical decrease in RVR and increase in RPF. The renal responses to candesartan and exogenous ANG II during DEX treatment suggest that the attenuation of intrarenal ANG-mediated vascular tone plays an important role in the altered renal hemodynamics. The decreased ANG tone is likely caused by reduced ANG II formation, resulting in part from suppressed ACE activity, but not from decreased sensitivity to ANG II.

C-reactive protein (CRP), a marker of systemic inflammation, is emerging as an independent risk factor for cardiovascular disease (1,2). It has also been reported that serum CRP levels are elevated in patients with impaired glucose tolerance (IGT) (3) or diabetes (4). A few prospective studies have shown that increased CRP levels are an independent risk factor for future diabetes (5,6). Although these findings indicate that CRP levels in peripheral blood are closely associated with glucose levels, it remains unclear whether a relationship exists between CRP levels and plasma glucose levels in the pre-diabetic range. The purpose of the present study was to investigate the relationship between CRP concentrations and pre-diabetic plasma glucose levels in a general Japanese population. A population-based prospective study of cardiovascular disease has been underway since 1961 in the town of Hisayama, Kyushu Island, Japan. In 1988, as a part of the study, a cross-sectional diabetes survey of Hisayama residents was conducted (7). Of all 3,227 residents aged 40–79 years in the town registry, 2,587 (80.2%) consented to take part in a comprehensive assessment, including a fasting 75-g oral glucose tolerance test. After excluding 82 nonfasting participants, 15 of whom failed to complete the oral glucose tolerance test, 302 with diabetes based on the American Diabetes Association …

Anorectal amelanotic malignant melanoma is an extremely rare. There have been only 17 cases in the Japanese literature so far. We report a case of anorectal amelanatic malignant melanoma. A 58-year-old woman was seen at the hospital because of anal bleeding and anal pain. An elastic soft and elevated mass was palpated in the anal canal. The patient was diagnosed as the desease by histolagical examination of biopsy specimen which was stained by hematoxylin and eosin. Abdominoperitoneal resection was performed. The resected specimen showed a light grey tumor resembling Borrmann I type, sized 6.5×3.5×2.2cm just above the dentate line. The tumor stained positive for S-100 protein and HMB-45 monoclonal antibody. Adjuvant chemotherapy with dacarbazine, cisplatine, tamoxifen was done, but the patient died of cachexia seven months after the operation. To imorove the prognosis of the desease, we would emphasize the importance of preoperative diagnosis, especially our surgion's careful attitude to suspect the disease based on macroscopic findings.

The present study examined the role of L-/T-type Ca channels and the interaction between these channels and protein kinase C (PKC) in hypertension. The isolated perfused hydronephrotic rat kidney model was used to visualize directly the renal microvascular effects of L-/T-type Ca channel blockers (nifedipine and mibefradil, respectively). Nifedipine reversed the angiotensin II-induced constriction of afferent, but not efferent, arterioles in kidneys from Wistar-Kyoto rats (WKY), and similar magnitude in dilation was observed in spontaneously hypertensive rats (SHR). Although mibefradil elicited dilation of both arterioles, the afferent arteriolar dilation was less in SHR than in WKY (57+/-5% vs. 80+/-4% reversal at 1 micrommol/L). The pretreatment with staurosporine did not alter the angiotensin II-induced afferent arteriolar constriction in WKY, but attenuated this response in SHR. Furthermore, staurosporine enhanced the nifedipine-induced afferent arteriolar dilation (62+/-3% vs. 50+/-3% reversal at 10 nmol/L), and restored the attenuated afferent arteriolar response to mibefradil in SHR. The pretreatment with thapsigargin (a blocker of IP3-mediated intracellular calcium release) prevented the angiotensin II-induced afferent arteriolar constriction in WKY, but caused a significant constriction of afferent arterioles in SHR and efferent arterioles in WKY and SHR; in this setting, mibefradil did not alter efferent arteriolar tone. In conclusion, although both L-type (nifedipine) and T-type Ca channel blockers (mibefradil) exerted potent vasodilation of rat renal microvessels, these actions were modified by PKC, which determined the afferent arteriolar sensitivity to these blockers in SHR. Furthermore, the enhancement in nifedipine-induced afferent arteriolar dilation by staurosporine in SHR suggests that L-type Ca channel activity is augmented in hypertensive animals.

We examined whether endothelial function of the renal microcirculation was impaired in a model of chronic renal failure (CRF), and further assessed the role of asymmetrical dimethylarginine (ADMA) and its degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH), in mediating the deranged nitric oxide (NO) synthesis in CRF. CRF was established in male mongrel dogs by subtotal nephrectomy, and the animals were used in experiments after a period of 4 weeks. The endothelial function of the renal afferent and efferent arterioles was evaluated according to the response to acetylcholine, using an intravital needle-lens charge-coupled device camera. Intrarenal arterial infusion of acetylcholine (0.01 microg/kg/min) elicited 22+/-2% and 20+/-2% dilation of the afferent and efferent arterioles in normal dogs. In dogs with CRF, this vasodilation was attenuated (afferent, 12+/-2%; efferent, 11+/-1%), and the attenuation paralleled the diminished increments in urinary nitrite+nitrate excretion. In the animals with CRF, plasma concentrations of homocysteine (12.2+/-0.7 vs. 6.8+/-0.4 micromol/l) and ADMA were elevated (2.60+/-0.13 vs. 1.50+/-0.08 micromol/l). The inhibition of S-adenosylmethionine-dependent protein arginine N-methyltransferase by adenosine dialdehyde decreased plasma ADMA levels, and improved the acetylcholine-induced changes in urinary nitrite+nitrate excretion and arteriolar vasodilation. Acute methionine loading impaired the acetylcholine-induced renal arteriolar vasodilation in CRF, but not normal dogs, and the impairment in CRF dogs coincided with the changes in plasma ADMA levels. Real-time polymerase chain reaction revealed downregulation of the mRNA expression of DDAH-II in the dogs with CRF. Collectively, these results provide direct in vivo evidence of endothelial dysfunction in canine CRF kidneys. The endothelial dysfunction was attributed to the inhibition of the NO production by elevated ADMA, which involved the downregulation of DDAH-II. The deranged NO metabolic pathway including ADMA and DDAH is a novel mechanism for the aggravation of renal function.

No population-based cohort studies have been undertaken to evaluate the incidence and prognosis of gastric cancer. The purpose of this investigation was to clarify the incidence and fatal prognosis of gastric cancer and to determine the factors that contribute to the prognosis in a general Japanese population in Hisayama using a prospective study design.From 1988 to 1998 a total of 2605 subjects aged 40 years or older with no history of gastrectomy or gastric cancer were followed-up prospectively after a health examination. The diagnosis of gastric cancer was based on clinical records or autopsy findings.During the follow-up period, 76 subjects developed gastric cancer. The age-adjusted incidence of gastric cancer for men (4.9 per 1000 person-years) was 4-fold higher than that for women (1.2, P0.05). In men, the incidence of gastric cancer increased with advancing age, but this trend was not observed in women. The age- and sex-adjusted 5-year survival rate was significantly higher in cancers of the middle third of the stomach than in those of the upper third of the stomach. The survival rate was higher in cancers of well-differentiated adenocarcinoma than in those of the other histological types. There were no cases of cancer-related death among the early gastric cancers during the follow-up period.Our data suggest that men are at higher risk of gastric cancer than women in the general Japanese population. Clinical stage, histological type, and site of cancer in the stomach contribute to a fatal prognosis.

Although acute renal ischaemia alters the production of various paracrines, there has been little investigation examining the role of intrarenal vasoactive substances. In the present study, we investigated the role of intrarenal nitric oxide and prostaglandins in modulating the acute renal hypoperfusion-induced alterations in renal function. After a 90% clipping of the left renal artery for 60 min, the clip was released, and the renal haemodynamics and sodium excretion were evaluated in both clipped and non-clipped kidneys of anaesthetized dogs. Furthermore, the changes in renal contents of nitrate/nitrite (NOx) and prostaglandin E2 (PGE2) were assessed by using the renal microdialysis technique. The release of the clipping elicited a gradual recovery of renal plasma flow and glomerular filtration rate, and a sustained increase in fractional sodium excretion (FENa) in the clipped kidney. Renal interstitial NOx was reduced in both the cortex (from 8.2 +/- 1.1 to 2.5 +/- 0.3 micromol/L, P < 0.01) and medulla (from 10.1 +/- 0.9 to 3.1 +/- 0.2 micromol/L, P < 0.01), but the levels gradually elevated after declamping. The treatment with nitro-l-arginine methylester only modestly impaired the recovery of renal plasma flow (RPF; at hour 4) and glomerular filtration rate (GFR; at hours 3 and 4 after declamping), without affecting FENa. Conversely, the renal PGE2 levels increased prominently upon the onset of ischaemia (medulla, from 149 +/- 19 to 378 +/- 39 pg/mL, P < 0.01; cortex, from 107 +/- 13 to 302 +/- 34 pg/mL, P < 0.01). Furthermore, the pretreatment with a non-specific cyclo-oxygenase (COX) inhibitor, sulpyrine, and a COX-2-specific inhibitor, NS398, prominently inhibited the increases in FENa induced by the acute renal arterial clipping in a similar manner. In conclusion, in acute renal hypoperfusion, nitric oxide (NO) plays a permissive role in the recovery of the renal haemodynamics. In contrast, sustained increases in renal PGE2 in both clipped and non-clipped kidneys indicate that the COX-2-mediated PGE2 contributes importantly to the failure of the sodium reabsorption in response to acute renal hypoperfusion.

The aims of this study were to compare the ability of tests measuring fasting plasma glucose, 2-h plasma glucose and HbA1c levels in predicting specific diabetic retinopathy, and to determine the cut-off level of each measurement for diagnosing diabetes in a Japanese population.In a total of 1637 subjects, fasting plasma glucose, 2-h plasma glucose and HbA1c levels were measured in a 75-g oral glucose tolerance test, and diabetic retinopathy was assessed by ophthalmic examination. We calculated receiver operating characteristic (ROC) curves as well as the prevalence of diabetic retinopathy by deciles of the distribution of these glycaemic measurements.Of the subjects, 37 (2.3%) had diabetic retinopathy. The prevalence of retinopathy dramatically increased in the tenth decile of each variable. Analysis with ROC curves showed that the optimal cut-off levels for diagnosis of diabetes were 6.4 mmol/l for fasting plasma glucose, 11.1 mmol/l for 2-h plasma glucose, and 5.7% for HbA1c. The sensitivities for the cut-off point of the three measurements were identical (86.5%), and the specificities were similar (fasting plasma glucose 87.3%; 2-h plasma glucose 89.6%; HbA1c 90.1%). The area under the ROC curve for 2-h plasma glucose (96.1%) was slightly but not significantly larger than that for fasting plasma glucose (90.0%) and that for HbA1c (94.5%).. Our findings suggest that measuring fasting plasma glucose or HbA1c is just as useful as measuring 2-h plasma glucose for the diagnosis of diabetes, and that the cut-off point for diagnostic fasting plasma glucose level is lower than that of the current diagnostic criteria.

Background and Purpose— There have been very few population-based cohort studies of long-term prognosis and risk factors for death after stroke. We examined the 10-year prognosis, causes, and risk factors of death after stroke in a Japanese cohort. Methods— During a 26-year follow-up of a cohort of 1621 subjects ≥40 years of age, 333 subjects developed first-ever stroke and were prospectively followed up for 10 years after onset. During these 10-year follow-up periods, 268 of the 333 stroke patients died. Of those, 239 (89.2%) underwent autopsy. Results— The risk of death was greatest in the first year after first-stroke onset in both sexes (men, 40.3%; women, 43.7%). Thereafter, the survival curves decreased gradually, and risk of death reached 80.7% for men and 80.2% for women by the end of the 10-year follow-up. The 30-day case fatality rate was substantially greater in patients with cerebral hemorrhage (63.3%) or subarachnoid hemorrhage (58.6%) than in patients with cerebral infarction (9.0%). The risk of dying after the first stroke was twice the risk for stroke-free subjects. The most common cause of death was the index stroke in the first year. Thereafter, the impact of the first stroke gradually decreased, while that of recurrent stroke increased. Multivariate analysis revealed that age, lower body mass index, and hemorrhagic stroke were significant risk factors for death after stroke. Conclusions— Our findings suggest that the risk of death after first-ever stroke is high, in part because of the larger proportion of hemorrhagic stroke in Japanese relative to stroke victims in Western countries.

OBJECTIVE—To report the age- and sex-specific prevalence of diabetes and impaired glucose regulation (IGR) according to revised World Health Organization criteria for diabetes in Asian populations. RESEARCH DESIGN AND METHODS—We performed 11 studies of 4 countries, comprising 24,335 subjects (10,851 men and 13,484 women) aged 30–89 years who attended the 2-h oral glucose tolerance test and met the inclusion criteria for data analysis. RESULTS—The prevalence of diabetes increased with age and reached the peak at 70–89 years of age in Chinese and Japanese subjects but peaked at 60–69 years of age followed by a decline at the 70 years of age in Indian subjects. At 30–79 years of age, the 10-year age-specific prevalence of diabetes was higher in Indian than in Chinese and Japanese subjects. Indian subjects also had a higher prevalence of IGR in the younger age-groups (30–49 years) compared with that for Chinese and Japanese subjects. Impaired glucose tolerance was more prevalent than impaired fasting glycemia in all Asian populations studied for all age-groups. CONCLUSIONS—Indians had the highest prevalence of diabetes among Asian countries. The age at which the peak prevalence of diabetes was reached was ∼10 years younger in Indian compared with Chinese and Japanese subjects. Diabetes and IGR will be underestimated in Asians based on the fasting glucose testing alone.

Although available evidence demonstrates that obesity manifests insulin resistance and causes glomerular sclerosis, it has not been determined whether insulin resistance alters the renal microvascular reactivity. This study examined whether insulin- and acetylcholine (ACH)-induced vasodilation was impaired in Zucker obese rats, and attempted to clarify the change in myogenic afferent arteriolar constriction, a determinant of glomerular pressure. Isolated perfused hydronephrotic rat kidneys were used to visualize the renal microcirculation. In Zucker lean rats, insulin (10 to 300 [mu ]U/mL) inhibited norepinephrine (NE)-induced afferent and efferent arteriolar constriction in a dose-dependent manner, with 112 % [plusmn] 8% and 98% [plusmn] 8% reversal at 300 [mu ]U/mL Similarly, ACH elicited dose-dependent dilation of these vessels. In Zucker obese rats, by contrast, afferent and efferent arterioles failed to dilate in response to insulin, and manifested diminished vasodilator responses to acetylcholine In the presence of nitro- L -arginine methylester (LNAME; 100 [mu ]mol/L), ACH (10 [mu ]mol/L) induced transient afferent arteriolar dilation (121% [plusmn] 9% reversal) in Zucker lean rats, whereas this response was blunted in obese rats (72% [plusmn] 8% reversal) Furthermore, myogenic afferent arteriolar constriction by elevating renal arterial pressure to 180 mm Hg was diminished in Zucker obese rats ([minus ]14% [plusmn] 3% decrement in diameter), compared with that in lean rats ([minus ]23% [plusmn] 2% decrement) Finally, the impairment in these vasodilator and vasoconstrictor responses was partially prevented by troglitazone, an insulin-sensitizing agent. Collectively, in insulin resistance, renal microvessels are refractory to the vasodilator action of insulin. Furthermore, [ldquo ]renal insulin resistance[rdquo ] is associated with the impaired vasodilator responses to ACH-induced nitric oxide (NO) and the diminished vasoconstrictor responses to pressure. The blunted myogenic afferent arteriolar constriction would allow glomerular hypertension, and in concert with the impaired endothelium-dependent vasodilation, could be responsible for the development of glomerular injury in obesity.

The present study was undertaken to clarify the role of intrarenal angiotensin (Ang) II and its generating pathways in clipped and nonclipped kidneys of 4-week unilateral renal artery stenosis in anesthetized dogs. After 4 weeks, renal plasma flow (RPF) decreased in clipped and nonclipped kidneys (baseline, 59±3; clipped, 16±1; nonclipped, 44±2 mL/min; P P P 11 - d -Ala 12 ]Ang I (an inactive precursor that yields Ang II by chymase but not by ACE; 1 to 50 nmol/kg) markedly elevated intrarenal Ang II in clipped, but not in nonclipped, kidneys. In conclusion, renal Ang II contents were elevated in both clipped and nonclipped kidneys, which contributed to the altered renal hemodynamics and microvascular tone. Furthermore, the mechanisms for intrarenal Ang II generation differ, and chymase activity is enhanced in clipped kidneys, whereas ACE-mediated Ang II generation is possibly responsible for elevated Ang II contents in nonclipped kidneys.

The role of nitric oxide (NO) and prostaglandins (PG) in modifying renal hemodynamics was examined in clipped and nonclipped kidneys of unilateral renal artery stenosis. Chronic unilateral renal ischemia was established by 4-wk-clipping the left renal artery of canine kidneys, and renal interstitial nitrate+nitrite and PGE2contents were evaluated by the microdialysis technique. Unilateral renal artery stenosis caused 45 ± 1 and 73 ± 1% decrements in renal plasma flow (RPF) in moderately and severely clipped kidneys and 21 ± 3% decrements in nonclipped kidneys with severe stenosis. Renal nitrate+nitrite decreased in moderately (−31 ± 1%) and severely clipped kidneys (−63 ± 4%). Nω-nitro-l-arginine methyl ester reduced RPF (−56 ± 3%) and glomerular filtration rate (GFR; −54 ± 3%) in moderately clipped kidneys, whereas this inhibitory effect was abolished in severely clipped kidneys. In contrast, renal PGE2contents increased modestly in moderate clipping and were markedly elevated in severely clipped kidneys (from 111 ± 7 to 377 ± 22 pg/ml); sulpyrine impaired renal hemodynamics only in severely clipped kidneys. In contralateral nonclipped kidneys, although renal PGE2was not increased, sulpyrine reduced RPF (−32 ± 1%) and GFR (−33 ± 3%) in severe stenosis. Collectively, NO plays a substantial role in maintaining renal hemodynamics both under basal condition and in moderate renal artery stenosis, whereas the contributory role shifts from NO to PG as renal artery stenosis progresses. Furthermore, because intrarenal angiotensin II is reported to increase in nonclipped kidneys, unilateral severe ischemia may render the nonclipped kidney susceptible to PG inhibition.

OBJECTIVE To assess the in-vivo action on the renal microvasculature of the calcium antagonists nifedipine (L-type blocker), efonidipine (L/T-type blocker), and mibefradil (predominant T-type blocker). DESIGN An intravital needle-type charge-coupled device (CCD) camera videomicroscope was introduced to visualize the renal microcirculation directly in vivo. METHODS In anesthetized mongrel dogs, nifedipine (0.01-1 mg/kg per min), efonidipine (0.033-0.33 mg/kg per min), or mibefradil (0.01-1 mg/kg per min) was infused intravenously after the insertion of a CCD probe into the kidney. Renal microvascular responses to calcium antagonists were directly evaluated, with concomitant observation of renal clearance. RESULTS Each calcium antagonist caused modest vasodepressor action without affecting heart rate. Nifedipine (1 mg/kg per min, n = 9) increased renal plasma flow (RPF) (14 +/- 4%, P < 0.05) and glomerular filtration rate (GFR) (19 +/- 5%, P < 0.05), and tended to increase the filtration fraction (5 +/- 2% increment, P = 0.07). Efonidipine (0.33 mg/kg per min, n = 9), however, had no effect on filtration fraction, with 14 +/- 6% increments in RPF (P < 0.05) and 14 +/- 7% increments in GFR (P = 0.08). Rather, mibefradil (1 mg/kg per min, n = 9) elicited 6 +/- 2% decreases in filtration fraction (P < 0.05), with slight increments in RPF (6 +/- 3%) and no changes in GFR. In direct in-vivo microvasculature observations, nifedipine caused predominant (22 +/- 2%) dilatation of afferent arterioles (from 15.5 +/- 0.4 to 18.9 +/- 0.4 microm, n = 5), compared with that of efferent arterioles (10 +/- 2%; from 11.0 +/- 0.4 to 12.1 +/- 0.3 microm). In contrast, efonidipine caused a similar magnitude of vasodilatation (16 +/- 4%) compared with 18 +/- 2%; n = 6), and mibefradil caused greater dilatation of efferent arterioles (20 +/- 4%, n = 7) than that of afferent arterioles (13 +/- 4%). CONCLUSIONS There exists marked heterogeneity in action of nifedipine, efonidipine and mibefradil on the renal microvascular in canine kidneys in vivo. Furthermore, our current observations suggest an important contribution of T-type calcium channel activity to efferent arteriolar tone in vivo.

Haemorrhagic diathesis develops in chronic renal failure, in which calcium antagonists are used widely as antihypertensive agents. Although calcium antagonists are reported to impair platelet function, it has not been examined whether calcium antagonists alter bleeding time. The present study was conducted to clarify whether calcium antagonists affect bleeding time in chronic renal failure. Patients with chronic renal failure without and with calcium antagonists were enrolled (n = 156), and bleeding time (Ivy's method) as well as blood parameters (BUN, creatinine, platelet counts, and haemoglobin) were compared in patients with normal and prolonged bleeding time. Among patients not taking calcium antagonists (n = 34), three cases manifested prolonged bleeding time, whereas abnormal bleeding time was observed in 31 patients out of 122. Positive correlations were observed between bleeding time and BUN in both calcium antagonist-untreated (r = 0.46) and -treated groups (r = 0.25). The odds ratio for prolongation of bleeding time in patients taking calcium antagonists was 3.52 (95% CI, 1.01-12.33). In 12 calcium antagonist-treated patients with prolonged bleeding time, the withdrawal of calcium antagonists markedly shortened bleeding time (from 11.3 +/- 0.8 to 5.4 +/- 0.8 min, P < 0.05, n = 12). In contrast, in the additional group (n = 9), the continued treatment with calcium antagonists had no effect on bleeding time (from 11.7 +/- 0.9 to 10.0 +/- 1.0 min). Despite the inhibitory effect of calcium antagonists on bleeding time, no clinically serious events associated with haemorrhagic diathesis developed. In conclusion, calcium antagonists prolong bleeding time in patients with chronic renal failure. The subclinical (laboratory) effect of calcium antagonists however is not necessarily associated with haemorrhagic events of clinical significance.

A 58-year-old male experienced a sudden stroke-like onset of right hemiplegia and numbness of his right upper limb while engaged in his desk-work on April 7, 1997. He had a past history of diabetes mellitus and hyperlipidemia. On admission, he had no fever and the blood pressure was 140/70 mmHg. General physical examination was unremarkable. Neurological examination showed 4/5 strength of his right unilateral extremities and numbness of his right upper limb. Clinical features and computed tomography (CT) without contrast medium at the onset of hemiplegia suggested a stroke. Seven days after admission, his consciousness worsened and body temperature fluctuated between 37 and 38 degrees C. Subsequent Gd-enhanced magnetic resonance (MR) which demonstrated an irregular shaped ring-enhancement lesion and lumbar puncture 9 days after admission was compatible with the diagnosis of brain abscess. Surgical drainage confirmed the presence of brain abscess due to alpha-streptococcus. It improved following surgical drainage and antibiotic therapy with PAPM.BP 2 g/day and PIPC 4 g/day. An afebrile patient of sudden stroke-like onset may be a rarity to be added to the differential diagnosis of brain abscess.