Progression of cardiac dysfunction in a case of mitochondrial diabetes: a case report.
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Adult↗
Biomedical subjects
T Saruta
Publications and source records attributed to T Saruta.
NeuroD/beta2 gene G-->A polymorphism may affect onset pattern of type 1 diabetes in Japanese.
OBJECTIVE: The majority of type 1 diabetes is considered to be autoimmune with, for the most part, abrupt development. However, type 1 diabetes with slow onset, or the so-called slowly progressive type 1 diabetes or latent autoimmune diabetes in adults, has been recently recognized and is considered to be autoimmune-related. Although some investigators tried to explain the difference in onset pattern by the genetic background, including HLA type, it has not been established thus far. We hypothesized that the difference in onset pattern may relate to regeneration or differentiation of pancreatic beta-cells, and we therefore focused on the NeuroD/BETA2 gene, which encodes a transcription factor for the insulin gene and beta-cell differentiation. RESEARCH DESIGN AND METHODS: We examined the NeuroD/BETA2 gene polymorphism in 105 Japanese type 1 diabetic patients and in 122 nondiabetic Japanese subjects in a case-control study, and we stratified the patients according to their onset pattern and islet-associated autoantibody positivity. RESULTS: Regardless of the existence of islet-associated autoantibody, we found a significant difference in A allele frequency between type 1 diabetic patients with acute-onset type and control subjects. However, no difference was found between type 1 slow-onset diabetic patients and control subjects. CONCLUSIONS: These results support our hypothesis that NeuroD/BETA2 may affect the ability of regeneration of beta-cells, leading to a difference in the onset pattern and clinical course of type 1 diabetes.
Adolescent↗
Balance of GAD65-specific IL-10 production and polyclonal Th1-type response in type 1 diabetes.
It has been proposed that cytokine responses of memory CD4+ cells change from a T-helper 2 (Th2)-to a T-helper 1 (Th1)-dominant response as the disease progresses in non-obese diabetic (NOD) mice. However, the regulation of Th1/Th2 balance in spontaneous diabetes development in this model is not well understood. In this study, higher glutamic acid decarboxylase 65 (GAD65)-specific IL-10 production was observed at 10-12 weeks in NOD mice, and a marked increase of Th1-type response (IFN-gamma production) upon polyclonal (anti-CD3 antibody) stimulation was observed just before diabetes development along with a decline of GAD65-specific IL-10 production. Moreover, there was a clear negative correlation between IL-10 level upon GAD65 stimulation and log(IFN-gamma) level upon anti-CD3 antibody stimulation (r=-0.999, p<0.001). These results suggest that the balance between GAD65-specific IL-10 production and polyclonal Th1-type response may regulate the onset of hyperglycemia in type 1 diabetes in NOD mice.
Aging↗
[The Japanese new guideline for the management of hypertension--background of its preparation and characteristics of the new guideline].
The Japanese society of hypertension organized guidelines subcommittee for guidelines for the management of hypertension by request of Japanese physicians and people in the Ministry of Health and Welfare in 1998. Professor Masatoshi Fujishima in the School of Medicine, Kyushu University became a chairman in the committee. He had proceeded the preparation smoothly, and in July, 2000 the new guideline for the management of hypertension was published. The Japanese new guideline for the management of hypertension is slightly different from those in other countries, such as JNC-VI or the WHO/ISH guideline. The Japanese new guideline was prepared under the consideration of characteristics of hypertension in Japan, Japanese life style and recent trends in the management of hypertension in Japan. It is desired that Japanese physicians treat hypertensive patients according to this new guideline, and questionable parts in the guideline should be corrected to make it more useful and valuable. Especially the parts peculiar to the Japanese guideline should be ascertained by further studies in Japan.
Antihypertensive Agents↗
Divergent natriuretic action of calcium channel antagonists in mongrel dogs: renal haemodynamics as a determinant of natriuresis.
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<0.05) and glomerular filtration rate (GFR) (25+/-5%; P<0.05) (all values are means+/-S.E.M., n=7). Efonidipine (0.33 microgram .min(-1).kg(-1)) also elevated RPF (18+/-6%; P<0.05), and tended to increase GFR (17+/-8%; P=0.08). These antagonists exerted contrasting actions on the filtration fraction (FF), with an increase being elicited by nifedipine, whereas efonidipine had no effect. Furthermore, mibefradil (0.01-1 microgram.min(-1).kg(-1)) slightly elevated RPF (between 5+/-3% and 8+/-3%), but failed to alter GFR, resulting in a decrease in FF. Nifedipine slightly increased urinary sodium excretion (U(Na)V) (29+/-16% increase at 1 microgram .min(-1).kg(-1)) and fractional sodium excretion (FE(Na)) (18+/-14%), whereas efonidipine (0.33 microgram .min(-1).kg(-1)) elicited marked elevations in U(Na)V (110+/-38%; P<0.05) and FE(Na) (102+/-44%; P<0.05). Mibefradil (1 microgram .min(-1).kg(-1)) exerted a moderate natriuretic action [U(Na)V, +60+/-32% (P=0.1); FE(Na), +67+/-20% (P<0.05)]. Furthermore, although a positive correlation was observed between U(Na)V and urinary nitrate/nitrite excretion, no differences were noted between the various calcium channel antagonists. Collectively, this study demonstrates that the glomerular haemodynamic and natriuretic actions of these calcium channel antagonists, which possess diverse blocking activities on L/T-type channels, vary. Based on the divergent actions on FF (i.e. increase, no change and decrease by nifedipine, efonidipine and mibefradil respectively), the natriuretic action of calcium channel antagonists is possibly attributed to the inhibition of tubular sodium reabsorption associated with increased post-glomerular blood flow, rather than increased GFR.
Animals↗
Analysis of Galpha protein recognition profiles of angiotensin II receptors using chimeric Galpha proteins.
Receptors with a heptahelical structure initiate signal transduction by interacting with specific Galpha proteins. The aim of this study was to analyze the ability of type 1 (AT1) and type 2 (AT2) angiotensin receptors to recognize the receptor coupling regions of Galpha proteins using our previously described technique (Ikezu, T., Okamoto, T., Komatsuzaki, K., Matsui, T., Martyn, J.A.J., Nishimoto, I., 1996. Negative transactivation of cAMP response element by familial Alzheimer's mutants of APP. EMBO J. 15, 2468-2475; Komatsuzaki, K., Murayama, Y., Giambarella, U., Ogata, E., Seino, S., Nishimoto, I., 1996. A novel system that reports the G-proteins linked to a given receptor: a study of the type 3 somatostatin receptor. FEBS Lett. 406, 165-170). Chimeric Galphas protein constructs, whose receptor binding regions contained sequences from the four major families of Galpha proteins (Galphaq, Galphai, Galpha12, Galphas), were cotransfected with AT1 or AT2 receptors in COS cells, then stimulated with angiotensin II (Ang II). Changes in cellular cAMP were assayed on cell lysates by enzyme immunoassay. In the case of the Galphaq family, cotransfection of AT1 with Galpha11/Galphas, Galpha14/Galphas, Galpha16/Galphas, elicited significant increases in cAMP after agonist stimulation. Confirmatory results were found using an independent [35S]GTPgammaS binding assay. Further examination using chimeric G proteins for Galpha12 proteins and Galphai family proteins provided evidence that the AT1 receptor can recognize sequences from Galpha12, Galphai1/i2, Galphaz, Galphao, while both receptors interacted with Galphai3. These results provide a Galpha protein recognition database for both AT1 and AT2 receptors, which may be important for understanding the full spectrum of cellular responses mediated by the hormone Ang II.
3T3 Cells↗
A new member of the HCO3(-) transporter superfamily is an apical anion exchanger of beta-intercalated cells in the kidney.
The kidneys play pivotal roles in acid-base homeostasis, and the acid-secreting (alpha-type) and bicarbonate-secreting (beta-type) intercalated cells in the collecting ducts are major sites for the final modulation of urinary acid secretion. Since the H(+)-ATPase and anion exchanger activities in these two types of intercalated cells exhibit opposite polarities, it has been suggested that the alpha- and beta-intercalated cells are interchangeable via a cell polarity change. Immunohistological studies, however, have failed to confirm that the apical anion exchanger of beta-intercalated cells is the band 3 protein localized to the basolateral membrane of alpha-intercalated cells. In the present study, we show the evidence that a novel member of the anion exchanger and sodium bicarbonate cotransporter superfamily is an apical anion exchanger of beta-intercalated cells. Cloned cDNA from the beta-intercalated cells shows about 30% homology with anion exchanger types 1-3, and functional expression of this protein in COS-7 cells and Xenopus oocytes showed sodium-independent and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid-insensitive anion exchanger activity. Furthermore, immunohistological studies revealed that this novel anion exchanger is present on the apical membrane of beta-intercalated cells, although some beta-intercalated cells were negative for AE4 staining. We conclude that our newly cloned transporter is an apical anion exchanger of the beta-intercalated cells, whereas our data do not exclude the possibility that there may be another form of anion exchanger in these cells.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Three types of putative presympathetic neurons in the rostral ventrolateral medulla studied with rat brainstem-spinal cord preparation.
To study the electrophysiological properties of presympathetic neurons in the rostral ventrolateral medulla (RVLM), intracellular recordings were performed by the whole-cell patch-clamp technique. We utilized the neonatal rat brainstem-spinal cord preparation, in which the sympathetic neuronal network is thought to be preserved, unlike in slice preparation. In response to stimulation in the ipsilateral Th2 spinal segment including intermediolateral cell column (IML), 33 of 151 non-respiratory RVLM neurons showed antidromic action potentials with a constant latency of 45 ms, and can be considered as presympathetic neurons. We classified and characterized the RVLM presympathetic neurons into three types: 'regularly firing neurons (n=7)', which showed ramp depolarization and frequent action potentials (4.2+/-0.9 spikes/s) with rare excitatory postsynaptic potentials (EPSPs); 'irregularly firing neurons (n=21)', which exhibited many EPSPs that modulated the firing rate; and 'silent-type neurons (n=5)', which discharged action potentials only during current-induced depolarization. Lucifer-Yellow staining showed that the irregularly firing neurons were significantly larger and had more dendrites than the regularly firing neurons. All regularly firing neurons retained their discharges during low-Ca2+ -high-Mg2+ superfusion that blocks synaptic input, whereas the discharges in 11 of 16 irregularly firing neurons were abolished, suggesting that the regularly firing neurons discharged independently of synaptic input. Seven of 31 RVLM neurons were hyperpolarized by stimulation of vagal afferent nerves. In summary, three types of RVLM presympathetic neurons were characterized by the patch-clamp technique in the brainstem-spinal cord preparation, in which the connection was preserved from vagal afferent to the Th2 spinal segment through the RVLM. Since antidromic action potentials were demonstrated by stimulation in the Th2 spinal segment in 33 neurons of all three types, all types of RVLM neurons constitute a part of the sympathetic neuronal network.
Action Potentials↗
Association between diabetic retinopathy and genetic variations in alpha2beta1 integrin, a platelet receptor for collagen.
Platelets might be involved in the pathogenesis of diabetic microangiopathy. Wide interindividual variations in the density of a platelet collagen receptor (alpha2beta1 integrin or glycoprotein Ia/IIa) are reportedly associated with polymorphism(s) in the gene encoding the alpha subunit of the receptor, including a Bgl II polymorphism in intron 7. The aim of the present study was to determine the relationship between the Bgl II polymorphism and the susceptibility to diabetic microangiopathy. A case-control study comparing 227 patients with type II diabetes mellitus (119 with versus 108 without diabetic retinopathy) as well as 169 nondiabetic subjects demonstrated that genotypes with Bgl II (+) allele had a significant increase in the risk for retinopathy. The odds ratio for Bgl II (+/+) to Bgl II (-/-) was 3.41 (95% CI, 1.49-7.78, P =.0036) when analysis was confined to those with a disease duration of diabetes of 10 years or more. The present study suggests that the presence of a Bg II (+) allele is a genetic risk factor for diabetic retinopathy. (Blood. 2000;95:1560-1564)
Alleles↗
Targeted expression of baculovirus p35 caspase inhibitor in oligodendrocytes protects mice against autoimmune-mediated demyelination.
The mechanisms underlying oligodendrocyte (OLG) loss and the precise roles played by OLG death in human demyelinating diseases such as multiple sclerosis (MS), and in the rodent model of MS, experimental autoimmune encephalomyelitis (EAE), remain to be elucidated. To clarify the involvement of OLG death in EAE, we have generated transgenic mice that express the baculovirus anti-apoptotic protein p35 in OLGs through the Cre-loxP system. OLGs from cre/p35 transgenic mice were resistant to tumor necrosis factor-alpha-, anti-Fas antibody- and interferon-gamma-induced cell death. cre/p35 transgenic mice were resistant to EAE induction by immunization with the myelin oligodendrocyte glycoprotein. The numbers of infiltrating T cells and macrophages/microglia in the EAE lesions were significantly reduced, as were the numbers of apoptotic OLGs expressing the activated form of caspase-3. Thus, inhibition of apoptosis in OLGs by p35 expression alleviated the severity of the neurological manifestations observed in autoimmune demyelinating diseases.
Animals↗
Age of onset, not type of onset, affects the positivity and evanescence of IA-2 antibody.
Autoantibody against IA-2 (IA-2A) was found to be discordant with autoantibody against glutamic acid decarboxylase (GADA) with respect to both positivity and titer in Japanese, the same as in Caucasians. In this study, 247 type 1 diabetic patients were tested in order to clarify how the type of onset, age of onset, and duration of diabetes affect the frequency and evanescence of IA-2A. Among the young onset patients, the frequency of IA-2A was higher (52.2%), but evanescent (54.5, 66.7 and 36.7% in the insulin therapy duration < or =1, 2-5 years, and > or =6 years groups, respectively), whereas among adult onset patients, the frequency was lower (19.3%) but persistent (19.6, 13.3 and 23.5%, respectively). In addition, in the follow-up study, two of three IA-2A-positive young onset patients converted to negative in only three years, while all five adult onset patients remained positive for over 5 years. Among the adult onset patients, IA-2A frequency was similar in the slowly progressive type and the abrupt onset type. In view of the above findings, IA-2A positivity and evanescence in type 1 diabetic patients appear to be affected by age of onset, not type of onset.
Adolescent↗
Effect of 22-oxacalcitriol on bone histology of hemodialyzed patients with severe secondary hyperparathyroidism.
To examine the effectiveness of 22-oxacalcitriol (OCT) injection on the improvement of severe osteitis fibrosa, we studied 10 hemodialyzed patients (age, 59 +/- 12 years). The initial OCT dose was 5 microg and was administered three times weekly at the end of each hemodialysis session. OCT doses (1, 3, 5, 10, 15, and 20 microg) were changed in subsequent weeks to maintain serum calcium levels at less than 11.5 mg/dL. Administration of OCT significantly suppressed serum intact parathyroid hormone (PTH) from an initial level of 1,193 +/- 584 to 775 +/- 552 pg/mL in the 24th week (n = 10). OCT increased PTH levels again to 857 +/- 635 pg/mL in the 48th week (n = 7). Among the 10 patients, 5 patients (high responders) showed more than a 50% suppression of serum intact PTH levels at the end of the study. The rest of the patients had hypercalcemia and did not receive increased OCT doses (low responders). At the start of the treatment, the only difference between high and low responders was serum calcium level. Serum calcium levels (adjusted for serum albumin level) increased from 9.7 +/- 0.7 mg/dL (n = 10) at the beginning to 10.5 +/- 0.6 mg/dL (n = 10) in the 24th week and to 11. 1 +/- 0.7 mg/dL (n = 7) in the 48th week. Six patients (1 to 6) agreed to undergo a second bone biopsy in the 24th week of OCT administration. In bone histomorphometric measurements, OCT significantly changed bone marrow fibrosis, mineralization (labeled mineralizing surface and bone formation rate), and osteoid formation (osteoid volume and thickness). In conclusion, intravenous OCT effectively suppressed PTH secretion and improved the bone histological characteristics of severe osteitis fibrosa, especially in patients with initial serum calcium levels less than 10 mg/dL. With concerns about OCT causing adynamic bone, additional bone histological data are needed to ensure the long-term safety of OCT.
Adult↗
Urinary steroid profile in adrenocortical tumors.
Determination of the urinary steroid profile has been proposed as a sensitive tool for diagnosing adrenocortical tumors. The urinary steroid profiles were determined for patients with adrenocortical tumors. Urinary steroids were extracted, derivatized to form methyloxime-trimethylsilyl ether and analyzed by gas chromatography/mass spectrometry. Patients with adrenal adenomas from primary hyperaldosteronism had increased metabolites of 18-hydroxycorticosterone and aldosterone, and those with Cushing's syndrome had elevated excretion of 11 -deoxycortisol, cortisol, 18-hydroxycortisol, and cortisone metabolites. In patients with adrenocortical carcinomas, increased levels of metabolites of 11-deoxycortisol or 33-hydroxy-5-ene steroids were observed. The urinary steroid profiles of adrenal adenomas and adrenocortical carcinomas were quite different, suggesting the diagnostic validity for discriminating malignant from benign diseases.
Adenoma↗
Amlodipine is comparable to angiotensin-converting enzyme inhibitor for long-term renoprotection in hypertensive patients with renal dysfunction: a one-year, prospective, randomized study.
Unlike angiotensin converting enzyme inhibitors (ACEI), few long-term studies have shown calcium antagonists to retard the progression of renal dysfunction. Our aim was to prospectively compare the effects of amlodipine and ACEI (enalapril) on renal function in hypertensive patients with renal impairment due to chronic glomerulonephritis and essential hypertension. A total of 72 hypertensive patients with serum creatinine (Cr) > 1.5 mg/dL were randomly allocated to treatment with either drug. During a 1-year period, 33% of the patients treated with ACEI dropped out due to adverse events, whereas 9% of patients with amlodipine dropped out. Data of 28 patients were available for analysis of more than 1-year follow-up. Reductions in blood pressure were comparable between the amlodipine (from 165/101 to 138/81 mm Hg) and ACEI groups. Serum Cr increased from 2.1+/-0.8 (SD) to 2.6+/-1.0 mg/dL with amlodipine (n = 16), but the difference was equivalent to that with ACEI (n = 12). Creatinine clearance (Ccr) in the moderate dysfunction group (basal Cr, 1.5 to 2.0 mg/dL) changed from 36+/-10 to 33+/-11 mL/min (not significant) with amlodipine, and the change was similar to that noted with ACEI. Annual declines in Ccr with amlodipine (-3.7 mL/min/year) and ACEI (-2.6 mL/min/year) were comparable, and both tended to be smaller than the annual decline in glomerular filtration rate reported in the Modification of Diet in Renal Disease study (-6 mL/min/year). Serum potassium was increased significantly (P < .01), from 4.5+/-0.4 to 5.3+/-0.8 mEq/L, only in the ACEI group. This 1-year prospective study demonstrated the effect of amlodipine on renal function to be likely the same as that of ACEI. Furthermore, amlodipine was better tolerated than ACEI for hypertensive patients with renal dysfunction.
Aged↗
Conditional expression of anti-apoptotic protein p35 by Cre-mediated DNA recombination in cardiomyocytes from loxP-p35-transgenic mice.
p35, a viral inhibitor of caspase, prevents cell death induced by various stimuli. We established an experimental system to study the involvement of caspases in cell death, using primary cultured cells from p35 transgenic mice in which the p35 open reading frame (ORF) had been disrupted by the insertion of a DNA segment flanked by loxP sites, the Cre recognition sites. In this system, p35 expression can be initiated by Cre recombinase. Cardiomyocytes, which are highly sensitive to hypoxic stress, were infected with an adenovirus carrying the cre gene (AxCANCre). Expression of p35 by infection with AxCANCre resulted in inhibition of caspase-3 activation and resistance to hypoxia-induced cell death. Hypoxia-induced cytochrome c release was also attenuated in p35-expressing cardiomyocytes. Our transgenic mice can be used as an experimental model for studying the involvement of caspases in various degenerative diseases as well as programmed cell death both in vitro and in vivo.
Animals↗
Identification of 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression in macrophages.
BACKGROUND: The 25-hydroxyvitamin D3 1alpha-hydroxylase (1alpha-hydroxylase) is almost exclusively expressed in the kidney. However, 1alpha-hydroxylase activities have been observed in some extrarenal tissues, including inflammatory cells of the monocyte/macrophage lineage. In sarcoidosis, macrophage 1alpha-hydroxylase causes overproduction of 1,25-(OH)2D3, resulting in hypercalcemia. In this study, we investigated the regulation of macrophage 1alpha-hydroxylase at a molecular level. METHODS: We used the human monocytic cell line THP-1, which can be differentiated into macrophage-like cells by treatment with phorbol ester. The expression of 1alpha-hydroxylase in THP-1 cells was examined by Northern blotting and immunoblotting using an antibody raised against a synthetic peptide corresponding to the 14 C-terminal amino acids of 1alpha-hydroxylase. We investigated the regulation of 1alpha-hydroxylase mRNA expression by RNase protection assay. RESULTS: Northern blot and immunoblot analyses confirmed the expression of 1alpha-hydroxylase in THP-1 cells at the mRNA and protein levels. Although parathyroid hormone and calcitonin, known stimulators of renal 1alpha-hydroxylase, did not affect the expression of 1alpha-hydroxylase mRNA, 8-Br-cAMP (5 x 10-4 mol/L) increased the expression of 1alpha-hydroxylase mRNA in THP-1 cells (198 +/- 9%). 1,25-(OH)2D3, known as a suppressor of renal 1alpha-hydroxylase, did not affect the expression of 1alpha-hydroxylase mRNA. By contrast, 1,25-(OH)2D3 markedly increased the expression of 25-hydroxyvitamin D3 24-hydroxylase mRNA. Interferon-gamma (2000 IU/mL) increased the expression of 1alpha-hydroxylase mRNA in differentiated THP-1 cells (922 +/- 25%). CONCLUSIONS: The present results suggest that 1alpha-hydroxylase activity in macrophages is mediated by the same enzyme as in kidney. Interferon-gamma treatment increases macrophage 1alpha-hydroxylase levels via directly increasing gene expression of this enzyme.
Antibodies↗
Role of protein kinase C in angiotensin II-induced constriction of renal microvessels.
UNLABELLED: Role of protein kinase C in angiotensin II-induced constriction of renal microvessels. BACKGROUND: Although angiotensin II (Ang II) exerts its action through multiple vasomotor mechanisms, the contribution of phosphoinositol hydrolysis products to Ang II-induced renal vasoconstriction remains undetermined. METHODS: The role of protein kinase C (PKC) in Ang II-induced afferent (AFF) and efferent (EFF) arteriolar constriction was examined using the isolated perfused hydronephrotic rat kidney. RESULTS: Ang II (0.3 nmol/L)-induced EFF constriction was refractory to inhibition of voltage-dependent calcium channels by pranidipine (1 micromol/L, 19 +/- 2% reversal) but was completely reversed by a PKC inhibitor, chelerythrine (1 micromol/L, 96 +/- 2% reversal). Furthermore, direct PKC activation by phorbol myristate acetate (PMA; 1 micromol/L) caused prominent EFF constriction, and this constriction was inhibited by manganese and free calcium medium. In contrast, Ang II-induced AFF constriction was completely abolished by pranidipine (98 +/- 4% reversal) and was partially inhibited by chelerythrine (55 +/- 3% reversal). Although PMA elicited marked AFF constriction, this constriction was insensitive to the calcium antagonist, but was totally inhibited by manganese or free calcium medium. CONCLUSIONS: PKC plays an obligatory role in Ang II-induced EFF constriction that requires extracellular calcium entry through nonselective cation channels. In contrast, in concert with our recent findings demonstrating a complete dilation by thapsigargin, Ang II-induced AFF constriction is mainly mediated by inositol trisphosphate (IP3) and voltage-dependent calcium channel pathways, but could not be attributed to the PKC-activated calcium entry pathway (for example, nonselective cation channels). Rather, Ang II-stimulated PKC may cross-talk to the IP3/voltage-dependent calcium channel pathway and could modulate the vasoconstrictor mechanism of the AFF. Thus, the role of PKC during Ang II stimulation differs in AFF and EFF, which may constitute segmental heterogeneity in the renal microvasculature.
Angiotensin II↗