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Biomedical subjects

S Nakanishi

Publications and source records attributed to S Nakanishi.

At least 19 recordsLinked to original sources
PubMed2006

Basic and clinical aspects of parathyroid hyperplasia in chronic kidney disease.

Marked parathyroid hyperplasia develops in patients with chronic kidney disease, especially those with long dialysis vintage. Although progression of hyperplasia is associated with downregulation of vitamin D receptor and calcium-sensing receptor, initial abnormality that triggers and maintains parathyroid cell proliferation, as well the critical abnormality for the progression of diffuse hyperplasia to nodular hyperplasia, still remains to be elucidated. It is quite important for the optimal management of renal osteodystrophy to recognize the development of nodular hyperplasia, because the cells in nodular hyperplasia are usually resistant to medical therapy and further treatment of such patients often leads to vascular calcification. For this purpose, size and blood supply of enlarged parathyroid glands have been used as good clinical markers. Furthermore, we have recently shown that the serum fibroblast growth factor 23 level can be used for predicting refractory hyperparathyroidism. Once nodular hyperplasia develops in any of the enlarged parathyroid glands, such patients need to be treated by parathyroid intervention including percutaneous ethanol injection therapy. In addition, as direct vitamin D injection therapy has been shown to induce regression of hyperplasia, it may become possible to reverse or normalize established nodular hyperplasia if we can develop new agents with such effects in the near future.

Anti-Infective Agents, Local↗
PubMed2005

Relationship between HbA(1)c and mortality in a Japanese population.

AIM/HYPOTHESIS: HbA(1)c concentrations are known to be associated with all-cause excess mortality risk in Caucasians. However, the relationship has not been clarified well in the Japanese. In addition, studies of the relationship between HbA(1)c and mortality from malignant neoplasms are scarce. METHODS: HbA(1)c was measured for 3,710 people of a cohort composed of A-bomb survivors and controls. At baseline they were divided into five groups: a normal HbA(1)c group of 1,143 individuals with HbA(1)c of <5.5%, a slightly high but normal HbA(1)c group of 1,341 individuals with HbA(1)c > or =5.5% to <6.0%, a slightly high HbA(1)c group of 589 individuals with HbA(1)c > or =6.0% to <6.5%, a high HbA(1)c group of 259 individuals with HbA(1)c > or =6.5%, and a group of 378 individuals known to have type 2 diabetes. Using a Cox proportional hazards model, hazard ratios based on comparisons with the normal HbA(1)c group were obtained. RESULTS: During the observation period there were 754 deaths. For all-cause and cardiovascular disease mortality, a significant increase of the hazard ratio was observed for the slightly high HbA(1)c group. A similar increase in malignant neoplasm-related mortality was observed for both the high HbA(1)c group and the diabetes group. CONCLUSIONS/INTERPRETATION: Our results suggest that individuals in the Japanese population with HbA(1)c levels of 6% or more might have increased mortality risk. The results indicate that HbA(1)c measurements should be sought even for people who have not been diagnosed with diabetes.

Aged↗
PubMed2004

A comparison between Japanese-Americans living in Hawaii and Los Angeles and native Japanese: the impact of lifestyle westernization on diabetes mellitus.

We have been conducting the Hawaii-Los Angeles-Hiroshima Study since 1970, mainly to determine the effects of environmental changes on various diseases by comparing Japanese-Americans with native Japanese subjects. Japanese-Americans living in Hawaii and Los Angeles are originated mainly from Hiroshima, Japan and are genetically identical with native Japanese. Through this study, we made several clear observations about Japanese-Americans. First, Japanese-Americans were highly exposed to a westernized lifestyle ; in other words, a relatively high fat and simple carbohydrate diet with low physical activity as compared to native Japanese. Second, the prevalence of type 2 diabetes among Japanese-Americans and death from ischemic heart disease among Japanese-American diabetic patients were higher. Third, the serum fasting insulin level as well as the insulin level after a glucose load, was higher among Japanese-Americans, even when the serum glucose levels were not statistically different as compared to native Japanese. Accordingly, Japanese-Americans were thought to have a high insulin resistance status. However, the initial insulin response after a glucose load was low, which was more similar to Japanese people than to Caucasians. Fourth, the total cholesterol and triglyceride levels were higher among Japanese-Americans. These results are supposed to be derived from the insulin resistant status by the westernization of lifestyle, as well as from the weakness of pancreatic beta cell function that is supposed to be genetically regulated among Japanese. In conclusion, it appears that for genetically Japanese people, environmental factors are important for the development of metabolic diseases such as diabetes mellitus and cardiovascular disease.

Adult↗
PubMed2004

Erectile dysfunction is strongly linked with decreased libido in diabetic men.

Erectile dysfunction frequently occurs with diabetes mellitus. A survey of diabetic men was conducted by anonymous questionnaire to investigate the associations of erectile dysfunction with various predictive factors. A total of 112 diabetic males without an obvious history of erectile dysfunction were available for analyses. The mean age and duration of diabetes were 53.7 +/- 12.2 years and 10.2 +/- 8.6 years (mean +/- standard deviation), respectively. The questionnaire included questions on the presence or absence of smoking, hypertension, libido and subjective symptoms of diabetic neuropathy that may be associated with erectile dysfunction. Analysis of the answers to the questionnaire revealed that 40% of the patients complained of erectile dysfunction (erection 'always insufficient'). Erectile dysfunction was significantly correlated with age (p = 0.005), but not with duration of diabetes (p = 0.25), adjusted for age. Erectile dysfunction was also associated with sensory neuropathy and reduced libido, independently of age. The logistic regression analysis revealed that erectile dysfunction was positively associated with reduced libido and age. The odds ratio of erectile dysfunction for reduced compared to unreduced libido was 18.21, suggesting that psychogenic factors have a marked influence on erectile dysfunction. It is concluded that the presence of erectile dysfunction should be considered when symptoms related to diabetic neuropathy are observed; psychological approaches, such as sexual counseling, could be applied for the treatment of erectile dysfunction.

Adult↗
PubMed2004

The effect of polymorphism in the intestinal fatty acid-binding protein 2 gene on fat metabolism is associated with gender and obesity amongst non-diabetic Japanese-Americans.

AIM: The role of the codon 54 polymorphism of the fatty acid-binding protein 2 (FABP2) gene on fat metabolism has been controversial. Assuming that the effects of the polymorphism were modulated by gender and obesity which were related to lipid and glucose metabolism, we investigated this polymorphism and its effect on fat metabolism according to such factors. METHODS: Subjects were Japanese-Americans (123 men and 126 women) who were diagnosed as non-diabetic by a 75 g oral glucose tolerance test at the baseline. RESULTS: During approximately 7.8 years, 49 (24 men and 25 women) were diagnosed with type 2 diabetes. In a Cox proportional hazards model, this polymorphism was not a significant variable in the incidence of diabetes in either gender. Amongst non-obese men with the Thr54 allele, there was a significant elevation of triglycerides (TGs) (p=0.033) compared with alanine (Ala) homozygotes. Women with the Thr54 allele had significantly elevated total cholesterol (p=0.033) and low-density lipoprotein-cholesterol (LDL-C) (p=0.023) compared with Ala54 homozygotes. CONCLUSIONS: These results therefore suggested that the effects of the FABP2 polymorphism on TG, LDL-C and body mass index were associated with gender difference and obesity amongst non-diabetic Japanese-American subjects.

Aged↗
PubMed2001

Increased sensitivity to cocaine by cholinergic cell ablation in nucleus accumbens.

Chronic exposure to cocaine causes long-lasting behavioral changes associated with cocaine reinforcement and addiction. An important neural substrate for cocaine addiction is the nucleus accumbens (NAc), which receives dopaminergic input from the ventral tegmental area. Although the neural circuit of the NAc is controlled by several other neurotransmitters, their involvement in cocaine addiction remains elusive. In this investigation, we ablated cholinergic interneurons from the adult NAc with immunotoxin-mediated cell targeting and examined the role of acetylcholine transmitter in adaptive behavioral changes associated with cocaine reinforcement and addiction. Acute exposure to cocaine induced abnormal rotation in unilaterally cholinergic cell-eliminated mice. This abnormal turning was enhanced by repeated exposure of cocaine. In bilaterally cholinergic cell-eliminated mice, chronic cocaine administration induced a prominent and progressive increase in locomotor activity. Moreover, these mice showed robust conditioned place preference with a lower dose of cocaine, compared with wild-type littermates. This investigation demonstrates that acetylcholine in the NAc plays a key role in both acute and chronic actions of cocaine.

Acetylcholine↗
PubMed2001

Age-related changes in muscarinic cholinergic receptors in the living brain: a PET study using N-[11C]methyl-4-piperidyl benzilate combined with cerebral blood flow measurement in conscious monkeys.

The effects of changes in regional cerebral blood flow (rCBF) with aging on muscarinic cholinergic receptor binding were evaluated with [15O]H(2)O and N-[11C]methyl-4-piperidyl benzilate (4-MPB) in the living brains of young (5.9+/-1.8 years old) and aged (19.0+/-3.3 years old) monkeys (Macaca mulatta) in the conscious state using high-resolution positron emission tomography (PET). For quantitative analysis of receptor binding in vivo with [11C]4-MPB, metabolite-corrected arterial plasma radioactivity curves were obtained as an input function into the brain, and graphical Patlak plot analysis was applied. In addition, two-compartment model analysis using the radioactivity curve in the cerebellum as an input function (reference analysis) was also applied to determine the distribution volume (DV=K(1)/k(2)') for [11C]4-MPB. With metabolite-corrected arterial input, Patlak plot analysis of [11C]4-MPB indicated a regionally specific decrease in muscarinic cholinergic receptor binding in vivo in the frontal and temporal cortices as well as the striatum in aged compared with young animals, showing no correlation with the degree of reduced rCBF. In contrast, on the reference analysis with cerebellar input of [11C]4-MPB, all regions assayed except the pons showed a significant age-related decrease of DV, and the degree of reduction of DV was correlated with that of rCBF. These results demonstrated the usefulness of kinetic analysis of [11C]4-MPB with metabolite-corrected arterial input, not with reference region's input, as an indicator of the aging process of cortical muscarinic cholinergic receptors in vivo measured by PET with less blood flow dependency.

Acetylcholine↗
PubMed2001

Quantum loop current in a C(60) molecular bridge.

The existence of a quantum loop current in a C(60) molecular bridge is predicted using the Green's function method. The model for the molecular bridge consists of a C(60) molecule attached to one-dimensional conductive electrodes. It is shown that the loop current is related to the degeneracy of the energy levels of the C(60) molecule. Specific to this loop current is its magnitude which is much larger than that of the source-drain current. The associated magnetic moment also shows certain remarkable features such as its inversion with the energy across the molecular levels and the restriction of its direction onto a single plane.

Journal Article↗
PubMed2001

Evaluation of the general suitability of the rat for the micronucleus assay: the effect of cyclophosphamide in 14 strains.

To evaluate the general suitability of the rat for the micronucleus assay, we conducted the assay in males of 14 different strains, 13 inbred (ACI, BN, BUF, COP, DRH, F344, IS, LEW, RCS, SHR, WAG, WKYO, WTC) and 1 outbred (SD), using cyclophosphamide as the test chemical. Cyclophosphamide at 0 (vehicle), 5, 10, or 20mg/kg per day was administered orally twice, 24h apart, to five rats per dosage group. Bone marrow and peripheral blood were collected 24h after the second treatment. All 14 strains showed a positive response to cyclophosphamide, with slight differences in sensitivity. We concluded that the rat is suitable for the micronucleus assay regardless of strain.

Administration, Oral↗
PubMed2001

NMDA receptor stimulation and brain-derived neurotrophic factor upregulate homer 1a mRNA via the mitogen-activated protein kinase cascade in cultured cerebellar granule cells.

In three alternative splice variants of Homer 1 transcripts, Homer 1a mRNA has been shown to be upregulated selectively and rapidly by neural stimulation and represents a member of the immediate early gene (IEG) family. We investigated the mechanism underlying Homer 1a mRNA induction in cerebellar granule cell culture. All Homer 1 variants were expressed in cultured granule cells as analyzed by RNA blotting and immunochemical characterization. Glutamate stimulation of granule cells selectively upregulated Homer 1a mRNA via NMDA receptor-mediated influx of extracellular calcium. The induction of Homer 1a mRNA was much slower (peaked at 4 hr) and sustained longer than that of the typical IEG c-fos mRNA. Actinomycin D and cycloheximide experiments have revealed that, despite the presence of the mRNA-destabilizing AU-rich motif, transcriptional activation is a main determinant for selective Homer 1a mRNA induction. Inhibitor analysis as well as immunochemical characterization has indicated that the MEK (MAPK/ERK kinase)-ERK (extracellular signal-regulated kinase) cascade plays an indispensable role in glutamate-stimulated induction of Homer 1a mRNA. Consistent with this observation, brain-derived neurotrophic factor, which is known to activate the ERK cascade, similarly upregulated Homer 1a mRNA. These results demonstrate that MAPK (mitogen-activated protein kinase) is a key mediator that links distinct extracellular stimuli to the transcriptional activation of Homer 1a mRNA.

Animals↗
PubMed2001

Regulation of mglu(7) receptors by proteins that interact with the intracellular C-terminus.

The metabotropic glutamate type 7 (mglu(7)) receptor is a widely distributed, mainly presynaptic Group III mglu receptor that can regulate glutamate release. Recently, largely as a result of the identification of specific proteins that interact with the C-terminal domain of this receptor, considerable progress has been made towards understanding some of the mechanisms that underlie the regulation, signal transduction pathways and targeting of mglu(7) receptors. This has led to the proposal that there are three distinct functionally relevant domains present in the intracellular C-terminus of this receptor: (1) a proximal intracellular signalling domain that interacts with G-protein betagamma-subunits and the Ca(2+) sensor Ca(2+)-calmodulin, and is phosphorylated by protein kinase; (2) a central domain thought to provide a signal for axonal targeting; and (3) an extreme PDZ-binding motif that interacts with the protein kinase C interacting protein, PICK1.

Animals↗
PubMed2001

A key role of starburst amacrine cells in originating retinal directional selectivity and optokinetic eye movement.

The directional selectivity of retinal ganglion cell responses represents a primitive pattern recognition that operates within a retinal neural circuit. The cellular origin and mechanism of directional selectivity were investigated by selectively eliminating retinal starburst amacrine cells, using immunotoxin-mediated cell targeting techniques. Starburst cell ablation in the adult retina abolished not only directional selectivity of ganglion cell responses but also an optokinetic eye reflex derived by stimulus movement. Starburst cells therefore serve as the key element that discriminates the direction of stimulus movement through integrative synaptic transmission and play a pivotal role in information processing that stabilizes image motion.

Acetylcholine↗
PubMed2001

Glutamate induces focal adhesion kinase tyrosine phosphorylation and actin rearrangement in heterologous mGluR1-expressing CHO cells via calcium/calmodulin signaling.

Group 1 metabotropic glutamate receptors (mGluR1 and mGluR5) stimulate phospholipase C (PLC) and lead to mobilization of intracellular Ca(2+) and activation of protein kinase C (PKC). In this investigation, using heterologous receptor-expressing Chinese hamster ovary (CHO) cells, we showed that stimulation of mGluR1 or mGluR5 with glutamate rapidly increases tyrosine phosphorylation of focal adhesion kinase (FAK) (maximum at 1-3 min) in a dose-dependent manner (half-maximal responses at approximately 2 microM). In mGluR1-expressing cells, the glutamate-induced increase of FAK tyrosine phosphorylation was blocked by not only the PLC inhibitor, U73122, but also depletion of intracellular Ca(2+) and effectively abrogated by calmodulin (CaM) inhibitors, calmidazolium and fluphenazine. However, neither the PKC inhibitor, GF109203X, nor the CaM kinase II inhibitor, KN-62, inhibited glutamate-stimulated FAK tyrosine phosphorylation. Stimulation of mGluR1 caused a marked increase in actin stress fiber formation. Importantly, this actin rearrangement was prevented by the CaM inhibitor, but not by the PKC inhibitor and is thus in a good agreement with the signaling cascade of the mGluR1-FAK pathway. These results suggest that the Ca(2+)/CaM signaling and its downstream FAK tyrosine phosphorylation play an important role in cellular function of mGluR1.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2001

Comparison of intact PTH assay and whole PTH assay in long-term dialysis patients.

Adynamic bone disease has become a major problem in long-term dialysis patients. It has been suggested that higher levels of parathyroid hormone (PTH) are needed to maintain normal bone turnover in uremia. PTH levels currently are evaluated routinely by intact PTH assay, which may detect inactive 7-84 PTH fragments as well as 1-84 PTH. We examined the efficacy of whole PTH assay, which detects 1-84 PTH exclusively, in 99 nondiabetic patients on maintenance dialysis for more than 10 years, without any residual renal function. PTH levels determined by whole PTH assay were lower than those determined by intact PTH assay in all cases. Serum markers of bone metabolism, such as serum activity of bone alkaline phosphatase, correlated well with whole PTH levels. Because 7-84 PTH has been shown to inhibit the effects of 1-84 PTH, the biologic activity of circulating PTH in uremic patients may be much lower than the values assayed by conventional intact PTH assay. Despite an attempt to correlate 1-84 PTH/7-84 PTH ratio with bone histology, we could find only 1 patient out of 99 with 1-84 PTH/7-84 PTH ratio less than 1, which has been suggested to be indicative of low turnover bone. A cutoff value of this ratio should be set in the future for patients with a long hemodialysis history, with various modes of medical therapy.

Alkaline Phosphatase↗