WT1 immunoenzyme staining using SurePath(™) processed urine cytology helps to detect kidney disease.

OBJECTIVES: Damage and detachment of podocytes and loss into the urine have been implicated in the progression of kidney diseases. The purpose of this study was to investigate the potential role of urine cytology based on SurePath(™) combined with immunoenzyme staining using Wilms' tumour 1 (WT1) antibody as a podocyte marker in the discrimination of normality and non-renal urinary tract disease from kidney disease. METHODS: Sixty-six patients with kidney disease, 45 patients with lower urinary tract disease and 30 healthy volunteers were examined. Urine cytology slides were prepared using the SurePath method and immunoenzyme stained with WT1 antibody, and the number of WT1-positive cells was counted. RESULTS: In kidney disease, WT1-positive cells were found in 33 (50%) of 66 samples. No WT1-positive cells were found in 45 patients with lower urinary tract disease or in 30 healthy volunteers. The positive rates for WT1 varied with disease type, but not significantly: immunoglobulin A (IgA) nephropathy, (14/23); membranous glomerulonephritis, (4/10); Henoch-Schönlein purpura nephritis, (3/5); diabetic glomerulopathy, (5/5); minor glomerular abnormality/minimal change nephrotic syndrome (0/4). CONCLUSIONS: The results suggest that WT1 immunoenzyme staining of urine cytology can be used to detect some types of kidney disease.

Prognostic significance of lymphovascular invasion for patients with stage I non-small cell lung cancer.

AIMS: This study retrospectively investigated the clinical significance of lymphovascular invasion (LVI) following a complete resection for stage I non-small cell lung cancer (NSCLC). METHODS: A total of 226 patients who underwent a complete resection for pathological stage I NSCLC were examined. RESULTS: Lymphatic invasion was pathologically diagnosed as ly0 in 156 patients, ly1 in 65, and ly2 in 5 patients. The pathological vascular invasion was diagnosed as v0 in 178 patients, v1 in 35, v2 in 10, and v3 in 3 patients. The 5-year survival rate after surgery of the patients with and without lymphatic invasion was 76.8 and 90.6%, respectively. There was a significantly more unfavorable prognosis in patients with lymphatic invasion (p = 0.042). The 5-year survival rate of the patients with vascular invasion was also significantly more unfavorable (67.8%) than that of patients without vascular invasion (90.4%; p = 0.004). LVI was found to significantly correlate with tumor size and the presence of pleural invasion. CONCLUSION: The LVI of NSCLC is a significant prognostic factor in patients with stage I tumors. In future clinical trials, it is necessary to evaluate the efficacy of adjuvant therapy for the selection of patients according to this criterion.

Purification of an acidic alpha-D-mannosidase from Aspergillus saitoi and specific cleavage of 1,2-alpha-D-mannosidic linkage in yeast mannan.

An acidic alpha-D-mannosidase (alpha-D-mannoside mannohydrolase, EC 3.2.1.24) has been isolated from culture filtrate of Aspergillus saitoi. The extracellular alpha-mannosidase was homogeneous in polyacrylamide gel electrophoresis. The molecular weight of the enzyme was 51 000 and the isoelectric point pH 4.5. The purified enzyme has a pH optimum of 5.0, a Km of 0.45 mM with baker's yeast mannan and has no activity towards p-nitrophenyl-alpha-D-mannoside. The mode of action of the enzyme has been studied with baker's yeast mannan and saké yeast mannan. The enzyme cleaves specifically the 1,2-alpha-linked side chain, producing free mannose.

Thermolabile phenotype of carnitine palmitoyltransferase II variations as a predisposing factor for influenza-associated encephalopathy.

To assess the etiology of influenza-associated encephalopathy (IAE), a surveillance effort was conducted during 2000-2003 in South-West Japan. All fatal and handicapped patients except one (4/34 patients) exhibited a disorder of mitochondrial beta-oxidation evoked by the inactivated carnitine palmitoyltransferase II (CPT II) with transiently elevated serum acylcarnitine ratios (C(16:0) + C(18:1))/C(2) > 0.09 during high-grade fever. Analyses of genotypes and allele compositions of CPT II revealed a thermolabile phenotype of compound heterozygotes for [1055T > G/F352C] and [1102G > A/V368I], which shows a higher frequency in IAE patients than healthy volunteers (P < 0.025). The thermolabile phenotype of CPT II variations may be a principal genetic background of IAE in Japanese.

Effect of beta-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy.

OBJECTIVES: This study was designed to evaluate the beneficial effect of beta-blockers on circulating cytokine levels in patients with dilated cardiomyopathy (DCM). BACKGROUND: Elevated circulating levels of inflammatory cytokines have been reported in patients with DCM. However, alterations of the levels of inflammatory and anti-inflammatory cytokines in association with beta-blocker therapy are unknown. METHODS: We studied 32 patients with idiopathic DCM who had been treated with digitalis, diuretics and angiotensin-converting enzyme inhibitors. In addition to this combination therapy, beta-blockers were started in all patients. Serum levels of interleukin (IL)-10, tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptors (sTNF-R1 and R2) were measured at baseline and 12 weeks after the initiation of beta-blocker therapy. We also measured plasma levels of neurohumoral factors, as well as left ventricular (LV) size and function. Ten age-matched subjects with no cardiac disease served as the control group. RESULTS: Baseline levels of IL-10, TNF-alpha and sTNF-R2 were significantly higher in patients with DCM than in control subjects (p < 0.05). There was a significant positive correlation between IL-10 and TNF-alpha levels (r = 0.545, p = 0.029). The TNF-alpha/IL-10 ratio correlated well with plasma epinephrine levels (r = 0.677, p = 0.025), and the level of sTNF-R2 was closely related to LV size. Serum levels of IL-10, TNF-alpha and sTNF-R2 were significantly decreased during beta-blocker therapy (p < 0.005). CONCLUSIONS: Our findings indicate that beta-blockers have an important immunoregulatory role in modifying the dysregulated cytokine network in DCM. This effect of beta-blockers may be partly responsible for the efficacy of therapeutic drugs for heart failure.

Myocardial scintigraphic characteristics in patients with primary aldosteronism.

To evaluate the difference in myocardial damage between primary aldosteronism and untreated essential hypertension, we performed thallium-201 myocardial single-photon emission computed tomography in 10 patients with primary aldosteronism and 10 patients with essential hypertension who were matched for age, sex, blood pressure, and the severity of left ventricular hypertrophy for primary aldosteronism. From the analysis of thallium-201 myocardial scintigraphy, extent score was calculated. Extent score was significantly higher in primary aldosteronism than in essential hypertension (45.8 +/- 23.5% versus 9.5 +/- 7.3%, P < .01). After operation, blood pressure significantly decreased, and the precordial voltages (SV1 + RV5) and left ventricular mass indexes were significantly reduced in patients with primary aldosteronism. Extent score was also significantly improved. These results suggest that despite the same severity of myocardial hypertrophy between primary aldosteronism and essential hypertension, the myocardial damage estimated by thallium-201 myocardial scintigraphy is more severe in primary aldosteronism than in essential hypertension. Extent score was useful for evaluation of the severity of myocardial damage in hypertensive patients.

Blood pressure response to the Valsalva maneuver in pheochromocytoma and pseudopheochromocytoma.

To elucidate whether a difference in blood pressure reactivity exists between patients with pheochromocytoma (n = 8) and pseudopheochromocytoma (n = 22), we evaluated blood pressure changes during a Valsalva maneuver and baroreceptor reflex sensitivity. We also examined the effects of propranolol and prazosin on blood pressure reactivity during a Valsalva maneuver in patients with pseudopheochromocytoma. Pseudopheochromocytoma was defined as a paroxysmal rise in blood pressure accompanying pheochromocytoma-like symptoms and normal catecholamine values. The difference in systolic blood pressure between phase IV of the Valsalva maneuver and baseline (delta SBP) was markedly smaller in the pheochromocytoma patients (8.4 +/- 18.4 mm Hg) than in the essential hypertension patients (n = 30, 30.9 +/- 19.4 mm Hg) and normotensive control subjects (n = 10, 31.3 +/- 11.4 mm Hg), whereas delta SBP in the pseudopheochromocytoma patients (77.8 +/- 11.2 mm Hg) was markedly greater than in the other three groups. delta SBP was markedly suppressed by the administration of both propranolol and prazosin. Baroreceptor reflex sensitivity index was lower in the pheochromocytoma group than in the other three groups. In conclusion, blood pressure reactivity responses to a Valsalva maneuver are disparate between pheochromocytoma and pseudopheochromocytoma. The high blood pressure reactivity to a Valsalva maneuver in pseudopheochromocytoma is due to hyperactivity in both beta- and alpha 1-adrenergic receptor functions, and the low blood pressure reactivity to a Valsalva maneuver in pheochromocytoma seems to be mainly due to the desensitization of both adrenergic systems associated with chronic catecholamine excess. In addition, the impaired baroreceptor function in pheochromocytoma is partially responsible for it.

Left ventricular hypertrophy precedes other target-organ damage in primary aldosteronism.

To elucidate whether there is a difference in the progression of target-organ damage between primary aldosteronism and essential hypertension, we compared left ventricular hypertrophy and extracardiac target-organ damage in 23 patients with primary aldosteronism and 116 patients with essential hypertension. The severity of hypertensive retinopathy and the renal involvement in primary aldosteronism were subclinical and similar to those in essential hypertension without left ventricular hypertrophy but significantly milder than those in essential hypertension with left ventricular hypertrophy. There was a strongly significant correlation between the degree of left ventricular mass index and the severity of hypertensive retinopathy and renal involvement independent of office blood pressure in essential hypertension. In contrast, left ventricular hypertrophy markedly progressed despite the mild extracardiac target-organ damage in primary aldosteronism. Left ventricular end-diastolic dimension index in primary aldosteronism (3.16+/-0.50 cm/m2) was significantly larger than in essential hypertension without (2.87+/-0.23) and with (2.88+/-0.22) left ventricular hypertrophy. On the other hand, there was no difference in extracardiac target-organ damage between 13 primary aldosteronism patients with eccentric left ventricular hypertrophy and the 26 essential hypertensive patients with eccentric left ventricular hypertrophy. The results suggest that predominantly volume load, be it due to aldosteronism or other mechanisms, resulting in eccentric left ventricular hypertrophy is less likely to cause extracardiac target-organ damage than hemodynamic or nonhemodynamic mechanisms resulting in concentric left ventricular hypertrophy.

Treatment of carcinoma of the uterine cervix by remotely controlled afterloading intracavitary radiotherapy with high-dose rate: a comparative study with a low-dose rate system.

From September, 1974 through December, 1979, a total of 249 patients with carcinoma of the cervix uteri Stage IIb and III were randomly allocated to either remotely controlled high-dose-rate intracavitary radiotherapy or manual afterloading low-dose-rate therapy, with radiotherapy of 20 Gy in 2 weeks to Point A to whole pelvis and 40 Gy in 4 weeks to the parametria. The dose to Point A by intracavitary radiotherapy was 40-60 Gy with one or two fractions in the low-dose-rate group and 30 Gy for the high-dose-rate group by 3 fractions with a once a week schedule. The purpose of this paper is to compare the results between the groups and to clarify the problems in the high-dose-rate group clinically. The local control rate was higher in the high-dose-rate group; however, the complication rate was also higher in this group than in the low-dose-rate group. The dose schedule and the place of rectal dose measurement is discussed. The overall cumulative survival rate was nearly the same in both groups (55% at 5 years), although some difference was noted in each stage. The most common cause of death was distant metastasis outside the pelvis and the second most common was intercurrent disease in Stage IIb and local failure in Stage III.

Clinical evidence for an association between left ventricular geometric adaptation and extracardiac target organ damage in essential hypertension.

OBJECTIVES: To elucidate an association between left ventricular geometric adaptation to sustained hypertension and preclinical extracardiac target organ damage in essential hypertension. We also studied the clinical significance of neurohumoral factors for cardiovascular structural changes. DESIGN: One hundred and forty patients with essential hypertension were divided into four subgroups, based on left ventricular mass index and relative wall thickness. With respect to extracardiac target organ damage, we measured the funduscopic grade of retinal changes and serum creatinine levels. RESULTS: Among the hypertensive patients, only 19 (14%) had a typical concentric hypertrophy (increase in left ventricular mass index and relative wall thickness). Hypertensive patients with concentric hypertrophy had the most advanced funduscopic abnormalities and the greatest renal involvement, and hypertensive patients without left ventricular hypertrophy had the least extracardiac target organ damage. Plasma renin activity and plasma aldosterone concentration were higher in hypertensive patients with than in those without concentric hypertrophy. In a multiple regression model there was a strongly significant correlation between the degree of left ventricular mass index and the severity of hypertensive retinopathy and renal involvement, independent of office blood pressure. CONCLUSIONS: These results clearly demonstrate that echocardiographically determined left ventricular mass and geometry stratify extracardiac target organ damage in patients with essential hypertension more closely than office blood pressure. The present study also suggests that, in addition to blood pressure load, the renin-angiotensin-aldosterone system appears to play an important role in myocardial hypertrophy and peripheral vascular damage in hypertension.

Contractile properties of left ventricular myocytes isolated from spontaneously hypertensive rats: effect of angiotensin II.

OBJECTIVE: This study was undertaken to clarify whether the myocardial dysfunction observed in the hypertensive heart is an intrinsic property of the myocyte or not. MATERIALS AND METHODS: We investigated left ventricular function and contractile function of myocytes from 30-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). We also evaluated the effect of angiotensin II on contractile function of myocytes from both rats. RESULTS: The time constant of isovolumic pressure fall was significantly greater in SHR (13.2 +/- 0.6 ms) than in WKY (10.3 +/- 0.5 ms). The extent of shortening in isolated myocytes was significantly higher in SHR (11.3 +/- 0.4%) than in WKY (9.8 +/- 0.4%, P<0.01). Both the normalized maximal velocity of shortening and the normalized maximal velocity of relengthening were significantly greater in SHR (2.12 +/- 0.08 and 2.10 +/- 0.08 s-1; both P<0.01) than in WKY (1.76 +/- 0.06 and 1.75 +/- 0.07 s-1). Angiotensin II caused significant decreases in the extent of shortening, the normalized maximal velocity of shortening and the normalized maximal velocity of relengthening in isolated myocytes from SHR, but these parameters were unchanged in WKY. CONCLUSIONS: These results suggest that left ventricular diastolic dysfunction in SHR is not due to an intrinsic abnormality of the cardiac myocytes, and that angiotensin II suppresses the function of myocytes from hypertrophied hearts.

Effect of age on left ventricular geometric patterns in hypertensive patients.

OBJECTIVES: To investigate the effect of age on left ventricular structure and geometry in hypertensive patients, we studied the relationship between age and echocardiographic variables in patients with uncomplicated essential hypertension. PATIENTS AND METHODS: We divided 168 patients with hypertension into three groups according to age: young (<40 years), middle-aged (40-59 years) and an elderly group (> or = 60 years). They were further categorized according to relative wall thickness and the left ventricular mass index. We then evaluated the prevalence of left ventricular geometric patterns in these patients according to age. RESULTS: The left ventricular end-diastolic dimension decreased with age, both in normotensive control subjects and in hypertensive patients. The magnitude of this decrease was similar for both. The relative wall thickness and left ventricular mass index were greater in the hypertensive patients than in the normotensive control subjects, and these increased with age both in the controls and the hypertensives. The differences between normotensives and hypertensives in these variables remained unchanged with age. The prevalence of a normal left ventricle (normal relative wall thickness and left ventricular mass index) in the hypertensive patients decreased with age. Conversely, the prevalence of concentric remodeling (increased relative wall thickness with normal left ventricular mass index) and concentric hypertrophy (increased relative wall thickness and left ventricular mass index) increased with age. CONCLUSIONS: These results demonstrate that age significantly affects left ventricular structure both in normotensive control subjects and in hypertensive patients. Thus, the differences in left ventricular geometric patterns with age may have important implications in assessing left ventricular structure and geometric patterns in hypertensive patients.

Alterations in expression of sarcoplasmic reticulum gene in Dahl rats during the transition from compensatory myocardial hypertrophy to heart failure.

OBJECTIVES: To clarify whether the functional changes during the transition from compensatory myocardial hypertrophy to failure are associated with changes in sarcoplasmic reticulum gene expression. METHODS: We examined the gene expression of sarcoplasmic reticulum proteins [sarcoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban, calsequestrin and ryanodine receptor] in Dahl salt-sensitive (Dahl-S) rats fed a high-salt (8%) diet from the age of 6 weeks. In-vivo contractile functioning was evaluated using echocardiography, and gene expression of sarcoplasmic reticulum proteins in the left ventricle was analyzed by Northern blotting for each stage of left ventricular hypertrophy. RESULTS: SERCA messenger RNA (mRNA) levels in Dahl-S rats with compensatory hypertrophy did not change significantly, whereas phospholamban mRNA levels were increased by 61% (P < 0.01), and calsequestrin mRNA levels were increased by 130% (P < 0.01) compared with those in Dahl salt-resistant (Dahl-R) rats. SERCA mRNA levels in Dahl-S rats with decompensated dilatation were decreased by 32% (P< 0.05), whereas levels of phospholamban and calsequestrin mRNA remained unchanged. Ryanodine receptor mRNA levels did not change either with compensatory hypertrophy or with decompensated dilatation. CONCLUSIONS: Alterations in expression of sarcoplasmic reticulum gene may be related to changes in systolic and diastolic properties in compensatory hypertrophy and heart failure.

Enhanced blood pressure response to isometric handgrip exercise in patients with essential hypertension: effects of propranolol and prazosin.

To elucidate whether a difference exists in blood pressure (BP) elevation during isometric handgrip exercise (IHG) between essential hypertensives (EHT) and normotensives (NT), IHG was carried out in 12 NT and 46 EHT under constant sodium intake using a new instrument. The acute effects of propranolol and prazosin on IHG were also examined in EHT. The change in systolic BP (delta SBP) during IHG in EHT, delta SBP = 61 +/- 21 mmHg, was markedly greater than that in NT, delta SBP = 28 +/- 4 mmHg. Among EHT, delta BP increased with increasing severity of hypertension. Neither the changes in plasma norepinephrine nor in epinephrine during IHG showed significant differences between EHT and NT. The pressor response during IHG could not be suppressed by propranolol, but about 30% suppression of BP was observed during IHG with prazosin. It is concluded from these findings that EHT have an exaggerated BP response to IHG that is due to increased post-junctional alpha 1-adrenoceptors.

The effect of coronary vasospasm on the direction of ST-segment deviation in patients with both hypertrophic cardiomyopathy and vasospastic angina.

BACKGROUND: There has been no report of ECG changes during anginal attacks in patients with coexistent hypertrophic cardiomyopathy (HCM) and vasospastic angina. STUDY OBJECTIVES: To elucidate the change in ST-segment during anginal attacks in patients with coexistent HCM and vasospastic angina (the HCM group) in comparison with that of patients with vasospastic angina and no left ventricular hypertrophy (the non-HCM group). DESIGN: Retrospective study. PATIENTS: Twelve patients in the HCM group, and 28 patients in the non-HCM group. MEASUREMENTS: The direction of ST segment shift, either ST-segment elevation or depression, on the ECGs recorded during vasospastic anginal attacks with severe vasoconstriction in the epicardial coronary artery after intracoronary injection of acetylcholine. RESULTS: Age, male gender, and distribution of coronary arteries in which the vasospasm occurred were similar between the two groups. Collateral circulation to the affected arteries was absent in all the study patients. The prevalence of anginal attacks associated with ST-segment elevation was 2.7 times higher in the non-HCM group than in the HCM group (51. 5% [17 of 33 attacks] vs 18.8% [3 of 16 attacks], respectively; p = 0.03). CONCLUSIONS: In the HCM group, myocardial ischemia associated with a transmural injury pattern seen on the ECG, which is represented as ST-segment elevation, seldom develops during vasospastic anginal attacks because of marked left ventricular hypertrophy.

Left ventricular mass and atrial volume determined by cine magnetic resonance imaging in essential hypertension.

To evaluate the relationship between left atrial volume determined by cine magnetic resonance imaging and progression of left ventricular hypertrophy (LVH), left atrial volume and echocardiographic left ventricular mass (LVM) were measured in 30 hypertensive patients (15 without LVH and 15 with LVH) and 10 normotensive control subjects. We also evaluated the effects of antihypertensive therapy on the cardiac chamber volumes and LVM in hypertensive patients. The cardiac chamber volumes and LVM were indexed by body surface area. Although there were no significant differences in left ventricular chamber volumes among the three groups, both maximum and minimum left atrial volume indexes, and the LVM index were greater in hypertensive patients with LVH than in the other two groups. The LVM index was correlated with maximum left atrial volume index (r = 0.74, P < .0001), and minimum left atrial volume index (r = 0.76, P < .0001), respectively. Furthermore, in multivariate models, the LVM index was significantly correlated with maximum left atrial volume index. In hypertensive patients with LVH, both maximum and minimum left atrial volume indexes, and the LVM index significantly reduced after treatment. The percent of changes in maximum left atrial volume index after treatment was significantly correlated with the percent of changes in LVM index after treatment. In conclusion, our data indicate that LVH is an independent determinant of left atrial enlargement, and both LVH and left atrial enlargement may be reversed by some effective therapeutic interventions.

Increased contraction of myocytes isolated from the young spontaneously hypertensive rat: relationship between systolic and diastolic function.

This study was designed to assess heart performance in young (10-week-old) spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, in terms of whole heart function in vivo and mechanics of isolated ventricular myocytes in vitro. The data suggest that left ventricular pressure (LVP) generation is greater, and the maximal velocities of LVP generation and decline are faster in SHR than in WKY. Two-dimensional morphologic measurements show that SHR myocytes are hypertrophied and that augmented contractile function is also present in isolated cells as determined by the extent of shortening and velocity of shortening. Relaxation is also faster at the myocyte level as determined by velocity of relengthening. However, the slope of the relationship between myocyte peak shortening and velocity of relaxation was similar in both groups. These results suggest that hyperdynamic myocyte relengthening may reflect changes in elastic recoil from increased shortening rather than intrinsic changes in cellular mechanisms, which are independent of shortening.

Left ventricular geometry as an independent predictor for extracardiac target organ damage in essential hypertension.

Left ventricular hypertrophy (LVH) is an independent cardiovascular risk factor. It has not been established, however, whether left ventricular geometry is an independent predictor of extracardiac target organ damage in essential hypertension. Study groups were classified according to relative wall thickness: 27 patients with concentric LVH and 50 patients with eccentric LVH. Age and left ventricular mass indexes of two groups were matched. As indexes of extracardiac target organ damage, retinal funduscopic grade, and serum creatinine level were measured. The severity of hypertensive retinopathy and the renal involvement were more severe in patients with concentric LVH than in patients with eccentric LVH. Extracardiac target organ damage was consistently higher in patients with concentric LVH than in those with eccentric LVH. Systemic hemodynamics paralleled ventricular geometric patterns, with higher peripheral resistance and lower aortic compliance in patients with concentric LVH, whereas end-diastolic volumes and stroke volumes were higher in patients with eccentric LVH than in patients with concentric LVH. In addition, total peripheral resistance was related to retinal fundoscopic grade (r = 0.41, P < .01), and serum creatinine level (r = 0.28, P < .05). Even in the presence of an identical degree of LVH, echocardiographically determined left ventricular geometry may provide a further independent stratification of extracardiac target organ damage in essential hypertension.

Identification of a response element for vitamin D3 and retinoic acid in the promoter region of the human fructose-1,6-bisphosphatase gene.

Fructose-1,6-bisphosphatase (FBPase) is a key gluconeogenic enzyme. The data herein show that both the enzyme activity and mRNA level of the human FBPase gene are enhanced by 9-cis retinoic acid (9cRA) and all-trans retinoic acid (atRA) as well as by 1,25-dihydroxyvitamin D3 (VD3) in human promyelocytic HL60 cells and normal monocytes in peripheral blood, which were used as an alternative source to liver for the DNA diagnosis of FBPase deficiency. To understand the molecular mechanism of this enhancing action, the 2.4 kb 5'-regulatory region of the human FBPase gene was isolated and sequenced. Using luciferase reporter gene assays, a 0.5 kb FBPase basal promoter fragment was found to confer induction by VD3, 9cRA, and atRA that was mediated by the vitamin D3 receptor (VDR), retinoid X receptor (RXR), and retinoic acid receptor (RAR). Within this region, a direct repeat sequence, 5'-TAACCTttcTGAACT-3' (-340 to -326), which functions as a common response element for VD3, 9cRA, and atRA, was identified. The results of electrophoretic mobility shift assays indicated that VDR-RXR and RAR-RXR heterodimers bind this response element. Collectively, these observations indicate that VD3 and RA are important modulators of the expression of the human FBPase gene in monocytic cells.

The effects of biotin deficiency on organic acid metabolism: increase in propionyl coenzyme A-related organic acids in biotin-deficient rats.

Volatile organic acid levels in plasma and tissues and nonvolatile organic acid levels in urine of biotin-deficient (BD) rats were measured and compared with other factors of biotin deficiency. Biotin levels and the activities of propionyl coenzyme A (CoA) carboxylase (PCC) in the livers of these rats were decreased, respectively, to 22% +/- 3% and 3.6% +/- 0.3% of the average values of pair-fed controls. Plasma concentrations of propionate were higher (15 to 223 micrograms/mL) than those of controls (5 to 7 micrograms/mL), whereas plasma levels of 3-methylcrotonate were only minimally increased as compared with those of controls. Concentrations of these volatile acids in the tissues were similarly increased, although those in brain showed less remarkable increases as compared with levels in other tissues. In the urine of BD rats, large amounts of organic acids derived from propionyl CoA, as well as those from 3-methylcrotonyl CoA, were excreted. Plasma propionate levels were not apparently related to the severity of clinical symptoms, biotin levels, or carboxylase activities, but were related to the amounts of urinary ketone bodies, lactate, and some of the organic acids derived from branched-chain amino acids, including those from propionyl CoA.