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Biomedical subjects

K Kawai

Publications and source records attributed to K Kawai.

At least 73 records · Page 4Linked to original sources
PubMed2001

Orexin-A and leptin change inversely in fasting non-obese subjects.

OBJECTIVE: Leptin, neuropeptide-Y (NPY) and orexin are peptides regulating energy metabolism and appetite control. NPY and orexin are mainly found in the central nervous system and they have also recently been found in the peripheral nervous system. We investigated how fasting affects changes in circulating concentrations of these peptides and their association with nutritional and metabolic parameters in humans. DESIGN AND METHODS: Ten non-obese female patients with psychosomatic disorders fasted for 7 or 10 days. Blood samples were collected at 0800 h before fasting, on the 3rd and 7th days during the fast (with an additional sample taken on the 10th day when the fasting continued for 10 days) and on the 3rd and 7th days of refeeding. We measured blood concentrations of orexin-A, NPY, leptin, adrenocorticotropin, cortisol, insulin, C-peptide, glucose, and beta-hydroxybutyrate. RESULTS: Body mass index and plasma leptin concentrations concomitantly and significantly decreased during fasting, whereas serum orexin-A concentrations significantly increased and were negatively correlated with plasma leptin concentrations. Plasma NPY concentrations decreased slightly but were not significantly different from the prefasting values, and no significant relationship with leptin or orexin-A was found. Orexin-A and leptin concentrations showed a significant inverse correlation with serum glucose, insulin, C-peptide, and beta-hydroxybutyrate concentrations. Only changes in plasma leptin concentrations showed a significant negative correlation with serum cortisol concentrations. All the measured indices which changed during fasting returned to the prefasting concentrations by the 7th day of refeeding. CONCLUSION: Peripheral orexin-A and leptin concentrations inversely change during fasting, which is significantly correlated with energy metabolism in humans.

Adolescent↗
PubMed2001

Differential effects of activity and climate on onset of subarachnoid hemorrhage.

Conflicting findings of the effect of climate on onset of subarachnoid hemorrhage (SAH) may result from the influence of strenuous activities which can trigger aneurysmal rupture independent of climatological factors. The effect of climate and patient activities on onset of SAH were analyzed. The clinical records of 786 consecutive patients with aneurysmal SAH admitted to our hospital for 10 years were reviewed. Activities at onset were categorized according to the intensity of strain at onset. Seasonal variation, circannual cyclic trend, and association with 90 meteorological factors were examined in each category and the results were compared between categories. Bimonthly occurrence in the light strain group showed a significant seasonal variation and cyclic trend with two peaks in early spring and fall, whereas no significant trend was detected in the overall patients and in the heavy strain group. The significant meteorological factors were global solar radiation, sunshine hours, changes in mean and minimum temperature and mean vapor pressure from the previous day, and minimum pressure in the previous 7 days. Lower global solar radiation in the light strain group was associated with onset with the lowest p value (p = 0.0046). No factors were significant in the heavy strain group. There is some evidence of the possible influence of climatological factors on onset of SAH without strenuous activity. Strenuous activity seems to affect onset more strongly, which masks any effect of climate.

Adult↗
PubMed2001

Failure of low-dose radiosurgery to control temporal lobe epilepsy.

Radiosurgical treatment of intractable epilepsy has emerged as a noninvasive alternative to resection. Although gamma knife surgery (GKS) reportedly is effective when the radiation dose is sufficient to cause a destructive reaction in the targeted medial temporal lobe, the optimal target area and dose distribution are largely unknown. Some investigators have suggested that focused irradiation from a nondestructive dose is also effective. In this article the authors report two cases of medial temporal lobe epilepsy in which the patients underwent GKS performed using a 50% marginal dose of 18 Gy covering the amygdala. hippocampal head and body, and parahippocampal gyrus. In both cases this procedure failed to control seizures. Both patients became seizure free after undergoing anterior temporal lobectomy 30 and 16 months, respectively, after radiosurgery.

Adult↗
PubMed2001

[Platinum compounds in cancer therapy--past, present, and future].

Platinum cytotoxics play an important role globally in the management of solid tumours. Cisplatin sets the standard for efficacy in both regions with careful administration to reduce nephrotoxicity. Carboplatin is associated with neurotoxicity, but has become the leading product in the US due largely to the easier to manage toxicity profile. Both agents have been widely used in both registered and non registered indications and are frequently combined with other cytotoxics. In Japan, cisplatin has been used successfully at low doses in combination with 5-FU based regimens and appears to achieve a synergistic effect, but controlled data are not yet available. More recently oxaliplatin (Europe) and nedaplatin (in Japan) have been introduced, but their clinical roles in therapy have yet to be established. One of the limiting features of the first generation of platinum compounds is that a significant proportion of tumours develop cross resistance to platins due to either changes in uptake or excretion, intracellular detoxification or accelerated DNA repair. The forum discussed the possibility for the development of better new platinum compounds, A new platin agent which had lower toxicity and higher efficacy across a wide range of cancers without the development of resistance would be a significant step forward. If the tolerability profile was suitable, an oral formulation may improve the quality of life for patients but this must not be at the expense of efficacy. Even after the introduction of new target based drugs, platinum cytotoxics are likely to be used to reduce the tumour mass and in some cases can be expected to potentiate the effects of the new agents. In preclinical studies, ZD0473 has been shown to by-pass some major mechanisms of resistance and has the potential to achieve these objectives and is now being evaluated in clinical studies in both Japan and the West.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

[Comparison of management of advanced cancer in various organs].

The management of advanced cancer presents the greatest challenge to physicians involved in oncology. There will usually be a large burden of disease; cure is unlikely; and the needs of the patient in terms of pain control and palliation will also be important over and above the direct treatment of the disease. Different issues will arise depending on the site and pathological type of the cancer. Increasingly over the past few years, treatment protocols and guidelines have been developed for different cancers, but these can only be rough guides rather than definite treatment recommendations. Additionally in most cancers advanced disease offers the opportunity for evaluation of new treatments in Phase II studies and other trials. With the new generation of molecular targeted therapies, such as EGFR inhibitors, striking results are being seen in advanced disease that compare favourably with what has been seen previously. Other agents such as those which attack the tumour vasculature may also have promise in this setting. Palliation is also an important aspect of the management of advanced disease, and pain control in particular is an important component of patient management. In summary, the treatment of advanced disease provides a test bed for new agents, but this need to develop better cancer therapies must be balanced against patient needs for a pain-free and comfortable end to life.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Synthesis of optically active TAN-67, a highly selective delta opioid receptor agonist, and investigation of its pharmacological properties.

We have synthesized the nonpeptidic highly selective delta opioid receptor agonist, (+/-)-TAN-67, (4aS*, 12aR*)-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydropyrido [3,4-b] acridine. In spite of high potent agonist activity for the delta opioid receptor in in vitro assay, (+/-)-TAN-67 afforded no analgesic activity in the mouse warm-plate test. This result led us to separate (+/-)-TAN-67 into optically pure compounds. Each enantiomer of racemic TAN-67 was synthesized from the corresponding optically active 6-oxodecahydroisoquinoline which was obtained by fractional recrystallization of its optically pure di-p-toluoyl tartaric acid salt. In bioassay using mouse vas deferens, (-)-TAN-67 showed full agonist activity (IC50 = 3.65 nM). On the other hand, (+)-TAN-67 showed almost no agonist activity, but interestingly afforded hyperalgesic activity in vivo (i.t. injection).

Analgesics↗
PubMed2001

[Reevaluation of 201Tl-SPECT for patients with solitary pulmonary nodule--comparison study with biopsy method and tumor marker measurement].

We compared the differential diagnostic capabilities of 201Tl-SPECT and biopsy methods and serum tumor marker in 125 patients with solitary pulmonary lesions composed of 87 lung cancer and 38 benign lesions. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of 201Tl-SPECT were 76%, 95%, 97%, 63%, and 82%, respectively. These parameters are similar in biopsy methods. Although sensitivity improved to be 85% by the combination with tumor marker methods, both specificity and accuracy deteriorated to be 55% and 76%. Using combination method with 201Tl-SPECT and biopsy, sensitivity, NPV and accuracy improved to be 84%, 70% and 85%. Based on its high PPV value, 201Tl-SPECT could be useful when biopsy method could not prove lung cancer or in case whose biopsy is considered to be invasive. Because of the lower NPV value owing to false negative cases in some adenocarcinoma, negative 201Tl-SPECT case should be followed up carefully.

Biomarkers, Tumor↗
PubMed2001

Effect of diabetic retinopathy on redox state of aqueous humor and serum albumin in patients with senile cataract.

PURPOSE: To investigate the oxidative status of albumin in the aqueous humor and serum of senile cataract patients with diabetes in order to clarify the pathogenesis of this condition. METHODS: High-performance liquid chromatography (HPLC) was employed to measure the reduced form of albumin (mercaptalbumin) and the oxidized form of albumin (nonmercaptalbumin) in serum and aqueous humor. The mercaptalbumin, nonmercaptalbumin-1, and nonmercaptalbumin-2 fractions in aqueous humor obtained at the start of cataract surgery and in serum obtained intraoperatively were analyzed by HPLC in 7 senile cataract patients with diabetic retinopathy (2 men and 5 women aged 70+/-9.8 years). RESULTS: The mean content (%) of mercaptalbumin, nonmercaptalbumin-1, and nonmercaptalbumin-2 in serum albumin from the diabetic patients was 60.3+/-7.8, 36.9+/-6.6, and 2.7+/-1.7%, respectively, while the corresponding values for aqueous humor albumin were 40.0+/-14.1, 52.4+/-12.6, and 7.5+/-3.6%. When the mercaptalbumin content (%) of aqueous humor albumin was compared between patients with active and inactive diabetic retinopathy, the respective values were 47.0+/-9.1% and 22.8+/-5.7%. A significant correlation mercaptalbumin content (%) of aqueous humor albumin did not show with the HbA1c level, but there was still a relationship (Y = 5.0 x - 2.7, r = 0.80, and p < 0.052). CONCLUSION: The increase of mercaptalbumin (the reduced form of albumin) in the aqueous humor of patients with diabetic retinopathy probably resulted from an increase of retinal vascular permeability.

Aged↗
PubMed2000

Characterization of the protease-activated receptor-1-mediated contraction and relaxation in the rat duodenal smooth muscle.

Activation of protease-activated receptor-1 (PAR-1) produces a dual action, apamin-sensitive relaxation followed by contraction, in the rat duodenal smooth muscle, which is partially dependent on activation of L-type Ca2+ channels, protein kinase C (PKC) or tyrosine kinase (TK), and resistant to tetrodotoxin. The present study further characterized the PAR-1-mediated duodenal responses. Removal of extracellular Ca2+ as well as SK&F96365 reduced the contraction due to the PAR-1 agonist TFLLR-NH2 (TFp-NH2) by 60-80% that was similar to the extent of the inhibition by nifedipine. Lowering of the extracellular Na+ concentration, but not IAA-94, a Cl- channel inhibitor, reduced both the PAR-1-mediated contraction and relaxation by about 50%. U73122, a phospholipase C (PLC) inhibitor, or wortmannin, a phosphatidyl inositol 3'-kinase (PI3K) inhibitor, significantly reduced the PAR-1-mediated contraction, but not the relaxation, by itself, as the PKC inhibitor GF109203X and the TK inhibitor genistein did. U73122 or wortmannin, like GF109203X, when applied in combination with genistein, significantly reduced the PAR-1-mediated relaxation. The relaxation was resistant to antagonists of PACAP receptors, VIP receptors and P2 purinoceptors. Thus, the PAR-1-mediated contraction is considered to be dependent on intracellular and extracellular Ca2+, the influx of the latter being induced through activation of L-type Ca2+ channels triggered by the enhanced Na+ permeability, and that PLC and PI3K, in addition to PKC and TK, are involved in the PAR-1-mediated dual responses. Furthermore, non-adrenergic, non-cholinergic nerve neurotransmitter candidates that may modulate K+ channels do not appear to contribute to the relaxation by PAR-1 activation.

Androstadienes↗
PubMed2000

Leptin as a modulator of sweet taste sensitivities in mice.

Leptin acts as a potent inhibitory factor against obesity by regulating energy expenditure, food intake, and adiposity. The obese diabetic db/db mouse, which has defects in leptin receptor, displays enhanced neural responses and elevated behavioral preference to sweet stimuli. Here, we show the effects of leptin on the peripheral taste system. An administration of leptin into lean mice suppressed responses of peripheral taste nerves (chorda tympani and glossopharyngeal) to sweet substances (sucrose and saccharin) without affecting responses to sour, salty, and bitter substances. Whole-cell patch-clamp recordings of activities of taste receptor cells isolated from circumvallate papillae (innervated by the glossopharyngeal nerve) demonstrated that leptin activated outward K(+) currents, which resulted in hyperpolarization of taste cells. The db/db mouse with impaired leptin receptors showed no such leptin suppression. Taste tissue (circumvallate papilla) of lean mice expressed leptin-receptor mRNA and some of the taste cells exhibited immunoreactivities to antibodies of the leptin receptor. Taken together, these observations suggest that the taste organ is a peripheral target for leptin, and that leptin may be a sweet-sensing modulator (suppressor) that may take part in regulation of food intake. Defects in this leptin suppression system in db/db mice may lead to their enhanced peripheral neural responses and enhanced behavioral preferences for sweet substances.

Animals↗
PubMed2000

Tissue-specific carcinogenesis in transgenic mice expressing the RET proto-oncogene with a multiple endocrine neoplasia type 2A mutation.

Germ line mutations of the RET proto-oncogene are responsible for the development of multiple endocrine neoplasia type 2A (MEN 2A), an inherited cancer syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia. To study the mechanism of tissue-specific tumor development by RET with a MEN2A (cysteine 634-->arginine) mutation, we generated transgenic mice by introducing the RET-MEN2A gene fused to Moloney murine leukemia virus long terminal repeat. Expression of the transgene and its product was detected at variable levels in a variety of tissues including thyroid, heart, liver, colon, parotid gland, and brain. All of 29 mice analyzed developed thyroid C-cell hyperplasia or medullary carcinoma, accompanying high levels of serum calcitonin. In addition, development of mammary or parotid gland adenocarcinoma was observed in one-half of the transgenic mice. RET dimerization and its complex formation with Shc and Grb2 adaptor proteins were detected in tumor tissues. Unexpectedly, no tumor formation was found in other tissues despite RET-MEN2A expression where RET dimerization was undetectable. Because these tissues but not tumors expressed glial cell line-derived neurotrophic factor family receptor alpha (GFR alpha) at high levels, this suggested that GFR alpha expression may interfere in the dimerization of the RET-MEN2A mutant proteins, leading to tissue-specific tumor development in vivo.

3T3 Cells↗
PubMed2000

Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor.

Glial cell line derived neurotrophic factor (GDNF) signals through a multicomponent receptor complex consisting of RET receptor tyrosine kinase and a member of GDNF family receptor alpha (GFRalpha). Recently, it was shown that tyrosine 1062 in RET represents a binding site for SHC adaptor proteins and is crucial for both RAS/mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K)/AKT signaling pathways. In the present study, we characterized how these two pathways diverge from tyrosine 1062, using human neuroblastoma and primitive neuroectodermal tumor cell lines expressing RET at high levels. In response to GDNF stimulation, SHC bound to GAB1 and GRB2 adaptor proteins as well as RET, and SHC and GAB1 were highly phosphorylated on tyrosine. The complex formation consisting of SHC, GAB1 and GRB2 was almost abolished by replacement of tyrosine 1062 in RET with phenylalanine. Tyrosine-phosphorylated GAB1 was also associated with p85 subunit of PI3-K, resulting in PI3-K and AKT activation, whereas SHC-GRB2-SOS complex was responsible for the RAS/ERK signaling pathway. These results suggested that the RAS and PI3-K pathways activated by GDNF bifurcate mainly through SHC bound to tyrosine 1062 in RET. Furthermore, using luciferase reporter-gene assays, we found that the RAS/ERK and PI3-K signaling pathways are important for activation of CREB and NF-kappaB in GDNF-treated cells, respectively. Oncogene (2000) 19, 4469 - 4475.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Phospholipid signaling in apoptosis: peroxidation and externalization of phosphatidylserine.

The role of phospholipids in apoptosis signaling and the relationship between oxidation of phosphatidylserine and its redistribution in the plasma membrane were studied. A novel method for detection of site-specific phospholipid peroxidation based on the use of cis-parinaric acid as a reporter molecule metabolically integrated into membrane phospholipids in living cells was employed. When several tissue culture cell lines and different exogenous oxidants were used, the relationship between the oxidation of phosphatidylserine and apoptosis has been revealed. The plasma membrane was the preferred site of phosphatidylserine oxidation in cells. It was shown that selective oxidation of phosphatidylserine precedes its translocation from the inside to the outside surface of the plasma membrane during apoptosis. A model is proposed in which cytochrome c released from mitochondria by oxidative stress binds to phosphatidylserine located at the cytoplasmic surface of the plasma membrane and induces its oxidation. Interaction of peroxidized phosphatidylserine with aminophospholipid translocase causes inhibition of the enzyme relevant to phosphatidylserine externalization.

Animals↗
PubMed2000

Tau pathology in diffuse neurofibrillary tangles with calcification (DNTC): biochemical and immunohistochemical investigation.

Diffuse neurofibrillary tangles with calcification (DNTC) represents a primary and sporadic presenile dementia that is characterized by temporal or fronto-temporal atrophy with diffuse neurofibrillary tangles (NFTs), neuropil threads and Fahr-type calcification without senile plaques. We examined the tau pathology in five autopsy cases of DNTC by immunoblotting and immunohistochemistry using phosphorylation-dependent and -independent anti-tau antibodies. The pattern of staining for different epitopes of beta-amyloid (A beta) was also investigated. NFTs were immunopositive with all the anti-tau antibodies used in this study. On the immunoblots, sarkosyl-insoluble tau appeared as three major bands of 60, 64 and 68 kDa, and as a minor band at 72 kDa. The majority of extracellular NFTs were weakly immunopositive only with the antibody recognizing the 40 carboxyl-terminal of A beta in DNTC. These results suggest that Alzheimer's disease-like tau pathology could exist independently of A beta deposits in DNTC.

Aged↗
PubMed2000

Relationship between flow cytometric DNA ploidy and nuclear grade with endocrine dysfunction in adrenal cortical adenomas.

OBJECTIVES: To determine the relationship among the DNA ploidy, histopathologic features, and clinical syndrome in adrenal cortical adenomas, because the cells often show variability in nuclear size and configuration. METHODS: Our study included 44 adenomas associated with primary aldosteronism and 23 adenomas associated with Cushing syndrome. Normal adrenal glands from patients with renal carcinoma served as the controls. Paraffin-embedded tissues were examined for DNA content by flow cytometry. The mean percentage of G(2)/M (4C%) of the control samples was 3.8%. Tetraploid was represented by a histogram with both a 4C peak greater than 9% (mean + 2.4 SD of control samples) and a small 8C peak. RESULTS: Flow cytometric analysis revealed diploidy in 30, tetraploidy in 27, and aneuploidy in 8 of the 67 adenomas; 2 adenomas could not be classified. All 17 normal adrenal glands showed diploidy. A significant relationship was noted between DNA ploidy and the clinical syndrome (ie, a larger proportion of adenomas with primary aldosteronism had a tetraploid DNA histogram compared with adenomas with Cushing syndrome, P <0. 0001). Adenomas with primary aldosteronism had a significantly higher nuclear grade (III or IV) than did tumors with Cushing syndrome (P = 0.033). A significant relationship was also observed between DNA ploidy and nuclear grade in 57 euploid tumors, with tetraploid tumors often showing the highest nuclear grade (P = 0. 037). CONCLUSIONS: Our results have demonstrated that adrenal cortical adenomas associated with primary aldosteronism often reveal severe nuclear pleomorphism, indicating that nuclear pleomorphism might be due to a tetraploid stemline.

Adenoma↗
PubMed2000

Oxidative signaling pathway for externalization of plasma membrane phosphatidylserine during apoptosis.

Active maintenance of membrane phospholipid asymmetry is universal in normal cell membranes and its disruption with subsequent externalization of phosphatidylserine is a hallmark of apoptosis. Externalized phosphatidylserine appears to serve as an important signal for targeting recognition and elimination of apoptotic cells by macrophages, however, the molecular mechanisms responsible for phosphatidylserine translocation during apoptosis remain unresolved. Studies have focused on the function of aminophospholipid translocase and phospholipid scramblase as mediators of this process. Here we present evidence that unique oxidative events, represented by selective oxidation of phosphatidylserine, occur during apoptosis that could promote phosphatidylserine externalization. We speculate that selective phosphatidylserine oxidation could affect phosphatidylserine recognition by aminophospholipid translocase and/or directly result in enzyme inhibition. The potential interactions between the anionic phospholipid phosphatidylserine and the redox-active cationic protein effector of apoptosis, cytochrome c, are presented as a potential mechanism to account for selective oxidation of phosphatidylserine during apoptosis. Thus, cytochrome c-mediated phosphatidylserine oxidation may represent an important component of the apoptotic pathway.

Animals↗
PubMed2000

The hepatic vagal reception of intraportal GLP-1 is via receptor different from the pancreatic GLP-1 receptor.

Glucagon-like peptide-1 (7-36)amide (tGLP-1), a representative humoral incretin, released into the portal circulation in response to a meal ingestion, exerts insulinotropic action through binding to the tGLP-1 receptor known to be a single molecular form thus far. We previously reported that the hepatic vagal nerve is receptive to intraportal tGLP-1, but not to non-insulinotropic full-length GLP-1-(1-37), through a mechanism mediated by specific receptor to the hormone. In the present study, we aimed to examine how modification of the receptor function alters this neural reception of tGLP-1, by using the specific agonist, exendin-4, and the specific antagonist, exendin (9-39)amide, of the receptor at doses known to exert their effects on the insulinotropic action of tGLP-1. Intraportal injection of 0.2 or 4.0 pmol tGLP-1, a periphysiological and pharmacological dose, respectively, facilitated significantly the afferent impulse discharge rate of the hepatic vagus in anesthetized rats, as reported previously. However, unexpectedly, intraportal injection of exendin-4 at a dose of 0.2 or 4.0 pmol, or of even 40.0 pmol, did not facilitate the afferents at all. Moreover, intraportal injection of exendin (9-39)amide at 100 times or more molar dose to that of tGLP-1, either 5 min before or 10 min after injection of 0.2 or 4.0 pmol tGLP-1, failed to modify the tGLP-1-induced facilitation of the afferents. The present results suggest that the neural reception of tGLP-1 involves a receptor mechanism distinct from that in the well-known humoral insulinotropic action.

Animals↗