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Biomedical subjects

T Sugimoto

Publications and source records attributed to T Sugimoto.

At least 397 records · Page 22Linked to original sources

Exaggerated C-fiber activation prevents peripheral nerve injury-induced hyperinducibility of c-Fos in partially deafferented spinal dorsal horn.

Dorsal horn neurons chronically deafferented by peripheral nerve injuries acquire hypersensitivity to noxious input from outside the original receptive field. This study examines the effect of electrical nerve stimulation at the time of injury on such injury-induced hypersensitivity. The medial 3/8 of the dorsal horn laminae I/II around the junction of 4th and 5th lumbar segments (the tibial territory) was deafferented by transection of the ipsilateral tibial nerve in rats. At 2 days or 3 weeks postinjury, the hindpaw was injected with formalin to induce c-fos. At 2 days, neurons with induced c-Fos protein-like immunoreactivity (fos-neurons) were largely confined in the lateral 5/8 of laminae I/II (the peroneal and hip, thus P and H territory). At 3 weeks, fos-neurons significantly increased in the deafferented tibial territory. A similar increase was also noted in the P and H territory. Thus the dorsal horn neurons exhibited c-fos hyperinducibility, an indication of hypersensitivity. Electrical stimulation with a train of 150 shocks (10 V, 2 ms) of the proximal nerve stump immediately after transection prevented the c-fos hyperinducibility. The effect was greater with the stimulation frequency of 0.5 Hz than 0.1 Hz or 10 Hz. The stimulation had no effect on the c-fos inducibility at 2 days postinjury.

Animals↗

Trigeminal primary projection to the rat brain stem sensory trigeminal nuclear complex and surrounding structures revealed by anterograde transport of cholera toxin B subunit-conjugated and Bandeiraea simplicifolia isolectin B4-conjugated horseradish peroxidase.

Trigeminal primary afferent neurons were labeled by injecting the rat trigeminal ganglion with either wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP), cholera toxin B subunit (B)-HRP or Bandeiraea simplicifolia isolectin B4 (IB4)-HRP. B-HRP stained medium to large cells (> 600 microm2), while IB4-HRP mostly small cells (< 400 microm2). WGA-HRP labeled trigeminal ganglion neurons of all sizes. Cell bodies in the mesencephalic trigeminal tract nucleus were labeled with WGA-HRP and B-HRP but not IB4-HRP. B-HRP revealed dense projection to the entire brain stem sensory trigeminal nuclear complex (BSTC) except for lamina II of the medullary dorsal horn (MDH). Some contralateral projection was also seen in the caudal part of MDH. Non-trigeminal nuclei receiving B-HRP-labeled terminals included the paratrigeminal nucleus (paraV), solitary tract nucleus, supratrigeminal nucleus, Probst's nucleus and median accessory nucleus. Following IB4-HRP application, terminal label was found in more restricted regions within the BSTC. Modest terminal label was seen in the dorsal part of principal sensory nucleus and at the medial edge of subnucleus interpolaris, while relatively dense terminal fields were seen in the dorsal half of subnucleus oralis. The MDH laminae I and II contained dense terminal label. Non-trigeminal nuclei were almost devoid of the IB4-HRP-labeled terminals excepting the paraV that contained dense terminal label. The terminal areas revealed with WGA-HRP coincided with B-HRP-labeled and IB4-HRP-labeled areas combined.

Animals↗

Microalbuminuria is not associated with cardiovascular death in Japanese NIDDM.

To evaluate whether the presence of microalbuminuria can predict cardiovascular death in Japanese subjects with non-insulin-dependent diabetes mellitus (NIDDM), we investigated 297 Japanese NIDDM patients with Albustix-negative urine. Patients were divided into two groups, normoalbuminuric (n = 201) and microalbuminuric (n = 96) and followed until death or the end of 1994 (the mean follow-up period was 6.4 years). During the follow-up period, 28 deaths (14 normoalbuminuric and 14 microalbuminuric patients) were confirmed and only 10 deaths were attributed to cardiovascular disease (6 normoalbuminuric and 4 microalbuminuric patients). Although the age- and sex-adjusted mortality rate from all-causes in the microalbuminuric group was significantly higher than that in the normoalbuminuric group (13.5 vs. 8.2 per 1000 person-years: P < 0.05), the mortality rate from cardiovascular disease was not significantly different between two groups (3.4 vs. 3.3 per 1000 person-years). On age-adjusted Cox proportional hazards analysis. HbA1c and triglyceride were independent risk factors in mortality from cardiovascular disease, while microalbuminuria was not associated with cardiovascular death. These results indicate that, unlike Caucasians, the presence of microalbuminuria can not predict cardiovascular death in Japanese subjects with NIDDM.

Aged↗

Continuous transoesophageal echocardiography monitoring during weaning from cardiopulmonary bypass in children.

The purpose of this study was to evaluate the effectiveness of transoesophageal echocardiography monitoring during weaning from cardiopulmonary bypass after intracardiac repair in children. The left ventricular ejection fraction, left ventricular end-diastolic volume and left ventricle wall motion were monitored continuously by transoesophageal echocardiography in controls weaned easily from cardiopulmonary bypass (group A, n = 25), and those weaned with difficulty from cardiopulmonary bypass after mechanically assisted circulation (group B, n = 16). In group A, left ventricular ejection fraction and left ventricle wall motion were within normal range, and did not change significantly during weaning after cardiopulmonary bypass when compared with pre-bypass data. In contrast, left ventricular ejection fraction, left ventricular end-diastolic volume and left ventricle wall motion in group B during the first trial of weaning from bypass were significantly worsened. Hence, assisted circulation was performed until the data obtained via transoesophageal echocardiography improved with regard to maintenance of fluid balance, catecholamine dosage and assisted pump flow. All cases in group B were weaned safely from cardiopulmonary bypass despite their critical condition. In conclusion, continuous transoesophageal echocardiography monitoring may be a useful tool in children with severe heart failure for safe weaning from cardiopulmonary bypass after intracardiac repair.

Adolescent↗

In vivo transfection of cis element "decoy" against nuclear factor-kappaB binding site prevents myocardial infarction.

The transcriptional factor nuclear factor-kappaB (NFkappaB) plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes that might be involved in myocardial damage after ischemia and reperfusion. Therefore, we hypothesized that synthetic double-stranded DNA with high affinity for NFkappaB could be introduced in vivo as "decoy" cis elements to bind the transcriptional factor and to block the activation of genes mediating myocardial infarction, thus providing effective therapy for myocardial infarction. Treatment before and after infarction by transfection of NFkappaB decoy, but not scrambled decoy, oligodeoxynucleotides before coronary artery occlusion or immediately after reperfusion had a significant inhibitory effect on the area of infarction. Here, we report the first successful in vivo transfer of NFkappaB decoy oligodeoxynucleotides to reduce the extent of myocardial infarction following reperfusion, providing a new therapeutic strategy for myocardial infarction.

Animals↗

Characterization of nociceptin hyperalgesia and allodynia in conscious mice.

1. Intrathecal (i.t.) administration of nociceptin and high doses of morphine induced allodynia in response to innocuous tactile stimuli, and i.t. nociceptin evoked hyperalgesia in response to noxious thermal stimuli in conscious mice. Here we have characterized the nociceptin-induced allodynia and compared it with the morphine-induced allodynia and the nociceptin-evoked hyperalgesia. 2. Nociceptin-induced allodynia was evoked by the first stimulus 5 min after i.t. injection, reached a maximum at 10 min, and continued for a 50 min experimental period. Dose-dependency of the allodynia showed a bell-shaped pattern from 50 pg to 5 ng kg-1, and the maximum effect was observed at 2.5 ng kg-1. 3. Morphine-induced allodynia reached the maximum effect at 15 min and declined progressively until cessation by 40-50 min. The dose-response curve showed a bell-shaped pattern, similar to that induced by nociceptin, with a maximum effect at 0.5 mg kg-1, five orders of magnitude higher than that of nociceptin. 4. The allodynia evoked by nociceptin and morphine were dose-dependently blocked by glycine, D(-)-2-amino-5-phosphonovaleric acid (D-AP5, an N-methyl-D-aspartate (NMDA) receptor antagonist), gamma-D-glutamylaminomethyl sulphonic acid (GAMS, a non-NMDA receptor antagonist) and methylene blue (a soluble guanylate cyclase inhibitor), but were not affected by muscimol (a gamma-aminobutyric acidA (GABAA) receptor agonist) and baclofen (a GABAB receptor agonist). 5. Morphine did not inhibit forskolin-stimulated cyclicAMP formation in cultured cells expressing the nociceptin receptor. 6. Nociceptin-induced hyperalgesia was evoked 10-15 min after i.t. injection. Nociceptin produced a monophasic hyperalgesic action over a wide range of doses from 5 fg to 50 ng kg-1. The nociceptin-induced hyperalgesia was blocked by glycine only among the agents examined. 7. None of the pain responses evoked by nociceptin and morphine were blocked by naloxone. 8. These results demonstrate that, whereas the mechanisms of the nociceptin-induced allodynia and hyperalgesia are evidently distinct, they involve a common neurochemical event beginning with the disinhibition of the inhibitory glycinergic response. Morphine may induce allodynia through a pathway common to nociceptin, but the nociceptin receptor does not mediate the action of high doses of morphine.

Animals↗

Endosonography-guided endoscopic resection of duodenal carcinoid tumor.

Endoscopic resection techniques using snare polypectomy with or without submucosal saline injection have also been applied to resect smaller duodenal carcinoid tumors. We report on two patients where endoluminal ultrasound using a small diameter probe was used to visualize the adherence of the carcinoids to the underlying wall layers and the separating effect of subtumoril saline injection. One patient, in whom a clear separation between the tumor and the underlying tissue after saline injection was visualized, underwent successful endoscopic resection. In the other patient no clear separation could be achieved after saline injection and the patient underwent surgical removal of his tumor; both tumors were 1 cm or less in their maximal diameter.

Aged↗

Dietary soybean protein increases insulin receptor gene expression in Wistar fatty rats when dietary polyunsaturated fatty acid level is low.

To investigate the effects of different dietary fatty acids and proteins on glucose tolerance and insulin receptor gene expression, Wistar fatty rats (genetically obese, noninsulin-dependent diabetes mellitus) and their lean littermates (8 wk old) were fed a casein or soybean protein diet containing 9% partially saturated beef tallow (plus 1% corn oil), 10% corn oil or 10% fish oil for 3 wk. In glucose tolerance tests, plasma insulin concentrations were significantly higher in obese rats fed corn oil or fish oil than in those fed partially saturated beef tallow, particularly in the soybean protein groups. However, plasma glucose concentrations were not significantly affected by dietary protein or fat. The insulin receptor mRNA concentrations in livers and adipose tissues were higher in rats fed soybean protein/partially saturated beef tallow than in those fed any other protein/fat combination. Dietary soybean protein may help to reduce the insulin resistance, but only when a diet low in polyunsaturated fatty acids is consumed. On the other hand, the insulin receptor mRNA concentrations in adipose tissue were generally lower in the obese rats of all dietary groups than in the lean rats, suggesting that insulin resistance may be due to a defect of insulin receptor gene expression.

Animals↗

Changes in cerebral blood flow and vasoreactivity in response to acetazolamide in patients with transient global amnesia.

OBJECTIVE: Previous reports about changes in cerebral blood flow (CBF) in transient global amnesia disclosed decreased flow in some parts of the brain. However, CBF analyses in most reports were qualitative but not quantitative. The purpose of this study was to determine changes in CBF in transient global amnesia. METHODS: The CBF was measured and the vasoreactive response to acetazolamide was evaluated in six patients with transient global amnesia using technetium-99m hexamethylpropylene amine oxime single-photon emission computed tomography (SPECT). The CBF was measured during an attack in two patients and soon after an attack in the other four. About one month later, CBF was re-evaluated in each patient. RESULTS: Two patients examined during an attack and one patient examined five hours after an attack had increased blood flow in the occipital cortex and cerebellum. Three patients examined at six to 10 hours after an attack had decreased blood flow in the thalamus, cerebellum, or putamen. These abnormalities of blood flow almost disappeared in all patients one month after onset. The vasodilatory response to acetazolamide, which was evaluated initially using SPECT, was poor in areas of increased blood flow. By the second evaluation of CBF with acetazolamide, the vasodilatory response had returned to normal. CONCLUSIONS: In a patient with transient global amnesia, CBF increased in the vertebrobasilar territory during the attack and decreased afterwards. The vasodilatory response to acetazolamide may be impaired in the parts of the brain with increased blood flow. It is suggested that transient global amnesia is distinct from migraine but may share the same underlying mechanism.

Acetazolamide↗

The action of GH/IGF-I/IGFBP in osteoblasts and osteoclasts.

Bone remodelling is a cyclical phenomenon consisting of osteoclastic bone resorption followed by osteoblastic bone formation. Although recent evidence suggests that GH participates in bone remodelling, the exact mechanism remains unclear. The present series of in vitro studies aimed to clarify how GH affects bone formation and resorption. GH binding sites were found to be present in osteoblastic MC3T3-E1 cells. Bovine GH (bGH) increased DNA synthesis, stimulated alkaline phosphatase activity and enhanced both type I procollagen mRNA expression and collagen synthesis. GH also increased the expression of both IGF-I and IGF-binding protein-5 mRNA as well as the release of IGF-I from these cells. The addition of IGF-I or recombinant IGFBP-5 alone significantly increased ALP activity and type I procollagen mRNA expression. These findings indicate that GH acts directly on osteoblasts to stimulate bone formation and that IGF-I and IGFBP-5 are involved in GH-stimulated bone formation. GH also stimulated pit formation on dentine slices and osteoclast differentiation in stromal cell-containing mouse bone cell cultures, whereas it did not affect the bone-resorbing activity of isolated rabbit osteoclasts. The addition of IGF-I or rIGFBP-5 alone exhibited similar effects. These stimulatory effects of GH on pit formation and osteoclast differentiation were significantly blocked in the presence of neutralizing anti-IGF-I antibody. PCR products corresponding in size to the mouse GH receptor were detected in osteoclast precursor cells. GH stimulated osteoclast-like cell formation from these cells in the absence of stromal cells, and these osteoclast-like cells formed pits on dentine slices in the presence of MC3T3-G2/PA-6 stromal cells. These findings indicate that GH stimulates osteoclastic bone resorption through both its direct and indirect action on the maturation of osteoclast precursor cells and through its indirect activation of mature osteoclasts, possibly via stromal cells. In conclusion, GH stimulates osteoclastic bone resorption as well as osteoblastic bone formation in vitro, and locally produced IGF-I and/or IGFBP-5 are involved in the stimulation of bone remodelling by GH.

Animals↗

Leriche syndrome. Surgical procedures and early and late results.

During the past thirteen years, 29 patients underwent surgical intervention for Leriche syndrome. Fifteen patients (aged forty-two to seventy-two years, average 60.7 years) underwent anatomical bypass, and 9 of them whose thrombus was confined to the infrarenal aorta received a routine graft insertion. In the other 6 whose thrombus extended to the level of the renal arteries, an open thrombectomy of the juxtarenal aorta was first performed through a transection of the infrarenal aorta under renal ischemia (4-14 minutes, average 7). Twelve elderly or high-risk patients (aged sixty-eight to eighty-four years, average 75.3 years) underwent an axillobifemoral bypass, and another 2 (fifty-eight and sixty years old, respectively) who had been operated on at an earlier time received an ascending aortobifemoral bypass. In cases of anatomical bypass, no graft has occluded and all patients but 1, who died of cerebral infarction, have an active life now. In cases of extraanatomical bypass, 5 of the 28 grafts occluded and only 6 patients have survived. The other 8 patients died of malignancy, atherosclerotic complications, or unknown causes. The 10-year survival rate was 92.9% and 29.5% in the anatomical bypass and extraanatomical bypass group, respectively. In Leriche syndrome, anatomical bypass is preferred to extraanatomical bypass if conditions permit. In the juxtarenal type, an open thrombectomy under renal ischemia is mandatory for anatomical bypass, and a transection of the infrarenal aorta facilitates this procedure. Because the patients with Leriche syndrome are elderly and harbor arteriosclerotic lesions, a careful follow-up is mandatory.

Adult↗

Synthesis of glycosyl-trehaloses by cyclomaltodextrin glucanotransferase through the transglycosylation reaction.

Cyclomaltodextrin glucanotransferase from Bacillus stearothermophilus produced a series of glycosyl-trehaloses through the transglycosylation reaction with cyclomaltohexaose as the glycosyl donor and trehalose as its acceptor. After beta-amylase treatment, five species of glycosyl-trehaloses were isolated by column chromatography. After chemical and enzymatic analyses, it was concluded that these oligosaccharides were alpha-maltosyl alpha-D-glucopyranoside, alpha-maltotriosyl alpha-D-glucopyranoside, alpha-maltosyl alpha-maltoside, alpha-maltotriosyl alpha-maltoside, and alpha-maltotriosyl alpha-maltotrioside. These were not hydrolyzed by salivary amylase, artificial gastric juice, or pancreatic amylase, however they were hydrolyzed by enzymes of the small intestine.

Carbohydrate Sequence↗

Dexamethasone stimulates osteoclast-like cell formation by directly acting on hemopoietic blast cells and enhances osteoclast-like cell formation stimulated by parathyroid hormone and prostaglandin E2.

Although an excess of glucocorticoid induces secondary osteoporosis, the mechanism still remains unclear, particularly in regard to glucocorticoid-stimulated bone resorption. We examined the effects of dexamethasone (Dex) on osteoclast-like cell formation and bone-resorbing activity by employing mouse bone and spleen cell cultures and further investigated whether Dex would modulate osteoclast-like cell formation stimulated by several bone-resorbing factors. Dex stimulated osteoclast-like cell formation in stromal cell-containing mouse bone cell cultures in a concentration-dependent manner. Also, Dex significantly stimulated osteoclast-like cell formation from hemopoietic blast cells in spleen cell cultures derived from 5-fluorouracil-pretreated mice. In contrast, Dex (10(-8) M) did not affect the bone-resorbing activity of mature osteoclasts. Pretreatment with 10(-8) M Dex significantly enhanced osteoclast-like cell formation in unfractionated mouse bone cell cultures stimulated by 10(-8) M human (h) parathyroid hormone (PTH) (1-34), 10(-8) M hPTH-related protein (1-34) and 10(-6) M prostaglandin E2, but not by 10(-8) M 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Moreover, pretreatment with 10(-8) M Dex significantly enhanced osteoclast-like cell formation stimulated by both forskolin and dbcAMP. In contrast, pretreatment with 10(-8) M Dex significantly inhibited osteoclast-like cell formation in mouse spleen cell cultures stimulated by both 10(-8) M hPTH(1-34) and 10(-8) M 1,25(OH)2D3. These findings suggest that Dex stimulates osteoclast-like cell formation, at least in part by directly acting on hemopoietic blast cells. They further suggest that Dex enhances osteoclast-like cell formation stimulated by PTH and prostaglandin E2 through an indirect pathway via cells other than hemopoietic blast cells.

Animals↗

Serum levels of insulin-like growth factor (IGF) I, IGF-binding protein (IGFBP)-2, and IGFBP-3 in osteoporotic patients with and without spinal fractures.

The present study was performed to investigate the role of insulin-like growth factor I (IGF-I), IGF-binding protein-2 (IGFBP-2), and IGFBP-3 in age-dependent bone loss in postmenopausal Japanese women. One hundred and sixty-five Japanese women aged 43-88 years (mean age, 62) were enrolled in the cross-sectional study. Bone mineral density (BMD) was measured at the lumbar spine, femoral neck, and midradius by dual-energy X-ray absorptiometry or single-photon absorptiometry. Serum levels of IGF-I, IGFBP-2, and IGFBP-3 were measured by radioimmunoassay. BMD at all sites as well as serum levels of IGF-I and IGFBP-3 declined with age, while the serum IGFBP-2 level increased with age. Serum IGFBP-3 and -2 levels were positively and negatively correlated with the serum IGF-I level, respectively. Serum IGF-I and IGFBP-3 levels showed positive correlationship with BMD at any site, particularly at the midradius, while the serum IGFBP-2 level showed negative correlation with BMD. Multiple regression analyses showed age-independent positive correlation between the serum IGF-I level and BMD at all sites as well as age-independent positive correlation between the serum IGFBP-3 level and midradius BMD. The relationship between susceptibility to osteoporotic spinal fracture and serum IGF-I, IGFBP-3, or -2 levels was examined by decade to exclude the influence of aging. Serum levels of IGF-I and IGFBP-3 were significantly lower in subjects with spinal fractures than those without fractures at any decade. No significant difference of serum IGFBP-2 level was observed between subjects with and without fractures. The present findings suggest that IGF-I and IGFBP-3 are important to maintaining bone mass quantitatively as well as qualitatively, and that the determination of serum IGF-I and IGFBP-3 levels could be clinically useful to predict the severity of osteoporosis, particularly the risk of bone fracture associated with osteoporosis.

Absorptiometry, Photon↗

Clinical and biochemical presentation of primary hyperparathyroidism in Kansai district of Japan.

Although the number of patients with primary hyperparathyroidism (pHPT) has increased since biochemical screening came to be widely employed, few data are available concerning the clinical analysis of Japanese patients. We therefore tried to determine the recent clinical and biochemical state of Japanese patients with pHPT. Clinical and biochemical data were analyzed in a series of 103 pHPT patients who had been hospitalized in Kobe University Hospital during a 17 year period from 1979 to 1995. The data were obtained from the hospital records and additionally from information through questionnaires performed in 1995. Patients were 29 males and 74 females. The average ages at diagnosis were 53.4 +/- 16.0 (SD) year-old and 53.9 +/- 15.2 year-old, respectively. The major clinical symptoms were nephrolithiasis (35.9%), thirst/polyuria (33.0%), easy fatigability (20.4%) and back pain/lumbago (16.5%), but 19.4% of the patients were asymptomatic. Out of 87 cases who received parathyroidectomy, 10 (11.5%) were diagnosed with parathyroid carcinoma. Age- and sex-corrected bone mineral density (BMD) of the radius was significantly lower in the group with back pain/lumbago than in the group without the symptom. Similarly, radial BMD was lower in the group with a high serum alkaline phosphatase value. Patients with nephrolithiasis had a lower urinary calcium/creatinine ratio (UCa/ UCr; 0.305 +/- 0.188 mg/mg) than the patients without nephrolithiasis (0.400 +/- 0.160 mg/mg). This inconsistent result suggests that some important factors except urinary calcium would contribute to urinary stone formation in pHPT. Our data mostly agreed with previous reports on a Caucasian population except for a relatively high prevalence of parathyroid carcinoma, but the negative correlation between nephrolithiasis and urinary calcium was not easily explicable. This finding should be confirmed by analyzing a larger number of cases.

Adolescent↗

Effect of natural menopause on serum levels of IGF-I and IGF-binding proteins: relationship with bone mineral density and lipid metabolism in perimenopausal women.

The present study was performed to examine the effect of natural menopause on serum levels of IGF-I, IGF-binding protein (IGFBP)-2 and -3 as well as on bone mass and lipid metabolism in perimenopausal women. One hundred and twenty-one healthy Japanese women, who were 45-55 years old, were studied (71 premenopausal and 50 postmenopausal women 1-9 years after menopause). Bone mineral density (BMD) was measured at the middle third of the radius by using dual energy X-ray absorptiometry. Serum levels of IGF-I, but not those of IGFBP-2 or -3, were significantly reduced in the postmenopausal group compared with the premenopausal group. One year after menopause, serum IGF-I levels were significantly lower, and the biochemical markers of bone turnover, such as serum total alkaline phosphatase level and urinary calcium to creatinine ratio, were significantly higher than the premenopausal levels. Serum levels of IGF-I, but not those of IGFBP-2 or -3, were positively correlated with BMD. Serum levels of IGFBP-2, but not those of IGF-I or IGFBP-3, were negatively correlated with body mass index and body weight. Finally, serum levels of IGFBP-3, but not those of IGF-I, were positively correlated with serum levels of total cholesterol and triglyceride. The present findings suggest that a rapid decrease in serum IGF-I levels after menopause might be partly involved in bone loss following gonadal failure and that IGFBP-2 and -3 might be related to the regulation of body mass and lipid metabolism during perimenopause respectively, although the mechanisms remain unknown.

Bone Density↗

Mitogen-activated protein kinase cascade is activated in glomeruli of diabetic rats and glomerular mesangial cells cultured under high glucose conditions.

The activation of protein kinase C (PKC) found in diabetic glomeruli and glomerular mesangial cells cultured under high glucose conditions has been proposed to contribute to the development of diabetic nephropathy. However, the abnormalities distal to PKC have not been fully elucidated yet. Herein, we provide the evidence that mitogen-activated protein kinase (MAPK) cascade, an important kinase cascade downstream to PKC and an activator of cytosolic phospholipase A2 (cPLA2) by direct phosphorylation, is activated in glomeruli isolated from streptozotocin-induced diabetic rats. MAPK cascade was also activated in glomerular mesangial cells cultured under high glucose (27.8 mmol/l) conditions for 5 days, and the activation of MAPK cascade was inhibited by treating the cells with calphostin C, an inhibitor of PKC. Furthermore, the activities of cPLA2 also increased in cells cultured under the same conditions and this activation was inhibited by both calphostin C and PD 098059, an inhibitor of MEK (MAPK or extracellular signal-regulated kinase [ERK] kinase). These results indicate that MAPK cascade is activated in glomeruli and mesangial cells under the diabetic state possibly through the activation of PKC. Activated MAPK, in turn, may induce various functional changes of mesangial cells at least through the activation of cPLA2 and contribute to the development of diabetic nephropathy.

Animals↗

Endothelin-1 in the gastric mucosa in stress ulcers of critically ill patients.

OBJECTIVE: Gastric microcirculatory disturbances are involved in the pathogenesis of stress ulcers; however, vasomodulators causing this process are not fully understood. This study was conducted to investigate the role of endothelin 1 (ET-1), a potent vasoconstrictive peptide, in stress ulcers in critically ill patients. METHODS: Using sandwich enzyme immunoassay, we measured ET-1 content in plasma and the gastric mucosa of 16 critically ill patients with traumatic head injury on admission and of 11 healthy subjects. Gastric mucosal samples were obtained endoscopically. When gastric drainage contained occult blood, endoscopic examination was performed again, and ET-1 concentrations in injured and adjacent normal mucosa were compared. RESULTS: Plasma and mucosal ET-1 concentrations were significantly higher in critically ill patients on admission (6.1 +/- 0.6 pg/ml and 13.8 +/- 1.6 ng/g, respectively) compared with values in control subjects (2.7 +/- 0.4 pg/ml and 8.2 +/- 0.5 ng/g, respectively) (p < 0.01). The mucosal ET-1 concentration tended to be elevated in patients who had experienced hypoxia compared with those who had not (p = 0.07). In five patients who were again examined endoscopically, the ET-1 concentration in the injured mucosa was significantly higher than that in adjacent mucosa (19.2 +/- 3.2 and 10.1 +/- 1.6 ng/g, respectively; p < 0.05). CONCLUSIONS: These results suggest that endogenous ET-1 plays an important role in the local pathogenesis of stress ulcers, especially those caused by hypoxia.

Adult↗