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No current histological or cytological indices can distinguish reliably malignant from benign tumors in neuroendocrine tumors, including pheochromocytomas, pancreatic endocrine tumors, and carcinoid tumors. We investigated immunohistochemically the expression of Ki-67 in 52 neuroendocrine tumors, including 17 pheochromocytomas, 9 pancreatic endocrine tumors, 23 carcinoid tumors, 2 neuroendocrine carcinomas (NEC), and 1 neuroblastoma with liver metastasis. Of the 52 tumors, distant metastasis was observed in 4 pheochromocytomas, 2 pancreatic endocrine tumors, 4 carcinoids, 2 NEC, and 1 neuroblastoma. We classified these tumors into 3 groups; Groups A, B, and C, depending on the number of Ki-67-positive cells counted under a 200 x magnified field. Expression of Ki-67 was extremely high in group A (> 50 labeled nuclei/field), moderately high in group B (20-50 labeled nuclei), and very low in group C (< 10 labeled nuclei). There was a significant correlation between expression of Ki-67 and tumor progression. The tumors in group A progressed rapidly with the worst outcome; the tumors in group B progressed slowly but with a bad outcome; and the tumors in group C had no metastasis and a good prognosis. Ki-67 is an excellent indicator to assess progression of neuroendocrine tumors.

Pheochromocytoma usually shows prominent nuclear atypia, but the presence of such atypical cells is known to be an unreliable predictor of malignancy. DNA ploidy of pheochromocytomas has been analyzed by flow cytometry or photospectrometry on paraffinem-bedded tissue, but the results were controversial. We performed DNA analysis on cytology specimens of 11 pheochromocytomas using an image analysis system. All tumors had a mixed pattern of a large population of diploid cells and a small population of polyploid cells. DNA content correlated with nuclear size, and larger cells had more DNA content. Such larger tumor cells had polyploid nuclei, such as 4 C, 8 C, 16 C, and 32 C, in both malignant and benign pheochromocytomas. The larger polyploid nuclei may result from difficulty of duplication at the mitotic phase of the cell cycle.

Although hypertension is a well known risk factor for microalbuminuria, it is unclear whether blood pressure less than 140/90 mmHg could be a risk for microalbuminuria. We assessed the relationship between baseline blood pressure and the future onset of microalbuminuria in the general population.We studied 2603 town inhabitants of Watari, located in the southeastern part of Miyagi prefecture, Japan. Demographic data, medical history, sitting blood pressure, fasting blood chemistry, and urinary albumin-creatinine ratio were measured at baseline and were followed annually during the next 3 years.Among 2338 individuals who were normoalbuminuric at baseline (albumin-creatinine ratio30 mg/g Cr), 161 developed microalbuminuria (albumin-creatinine ratio 30-299 mg/g Cr) during a mean follow-up period of 2.4 years. Incident microalbuminuria patients were older (63.7 ± 8.6 vs. 61.4 ± 10.5 years; P0.01), included fewer men (31.1 vs. 40.1%; P0.05), had a greater BMI (23.8 ± 3.6 vs. 23.1 ± 3.1 kg/m²; P0.01), higher blood pressures (133.5 ± 18.1/75.8 ± 11.9 vs. 127.6 ± 18.1/73.4 ± 11.0 mmHg; P0.01 for both systolic and diastolic), higher triglycerides (median 1.18 vs. 1.02 mmol/l; P0.01), higher fasting blood glucose (median 5.05 vs. 4.94 mmol/l; P0.01), higher urinary albumin excretion (median 13.0 vs. 5.9 mg/g Cr; P0.001), and lower serum creatinine concentrations (59.2 ± 12.8 vs. 61.4 ± 13.2 μmol/l; P0.05) compared to persistent normoalbuminuric individuals. Multivariate Cox proportional hazards analysis including all covariates revealed that only baseline urinary albumin excretion was an independent predictor for future microalbuminuria, whereas high-normal DBP, triglyceride, and fasting blood glucose concentrations were all significant predictors in the model excluding urinary albumin excretion.High-normal DBP associated with metabolic disorders could initiate glomerular damage, leading to future microalbuminuria.

Objective : This study investigated whether the angiotensin II type-1 receptor blocker (ARB) candesartan affects markers of oxidative stress in type 2 diabetes mellitus (DM) patients with essential hypertension (EH). Methods : Urinary excretion of pyrraline (PR), pentosidine (PT), acrolein (AC), and 8-hydroxy-2'- deoxyguanosine (8-OH-dG) and microalbuminuria were assessed in patients with DM complicated by EH who were treated with candesartan 4 mg/day for 3 months. Results : In a total of 25 patients urinary excretion of PR (nmol/g・cr), PT (pmol/g・cr), and 8-OH- dG (ng/mg・cr) was significantly (all P < 0.05) decreased from (mean ± SEM) 11.9 ± 1.9, 30.6 ± 2.4, and 7.9 ± 0.6, respectively, at baseline to 8.4 ± 1.4, 27.1 ± 2.0, and 6.9 ± 0.6, respectively, at 3 months. Meanwhile, excretion of AC was unaltered from 209.6 ± 40.0 to 189 ± 24.8 nmol/mgcr (P = NS). Urinary albumin excretion was significantly (P < 0.05) reduced from 27.7 ± 4.6 to 14.1 ± 1.1 mg/g・cr. There were weak but statistically significant positive correlations between the change of urinary 8-OH-dG excretion and that of albumin (r = 0.414 ; P < 0.05) and change of hemoglobin (Hb) A1c (r = 0.45 ; P < 0.05). Conclusion : Candesartan exerts protective effect(s) on the cardiovascular system by suppression of oxidative stress ─ mainly through inhibiting production of advanced glycation end products (AGEs) rather than of advanced lipoxidation end products (ALEs) ─ in type 2 DM patients with EH.

Brachial-ankle pulse wave velocity (baPWV) is a new tool for measuring arterial stiffness. The prognostic significance of this measure, however, is not fully established. We initiated a multicenter cohort study to examine the prognostic significance of baPWV in patients with essential hypertension in 2002. After baseline measurements were obtained, 662 previously untreated patients (mean age 60±12 years, mean blood pressure 156±19/94±12 mm Hg, 45% men) underwent long-term follow-up according to the current hypertension treatment guidelines. During the follow-up period (mean: 3 years, range: 3 months-8 years), 24 cardiovascular events were observed. The subjects were divided into high and low baPWV groups according to the median value (1750, cm s(-1)). Patients in the high baPWV group were older and had a lower body mass index, higher blood pressure, faster heart rate and higher fasting glucose and plasma creatinine concentrations compared with those in the low baPWV group. Cardiovascular morbidities per 1000 person-years for the high and low baPWV groups were 17.48 and 6.38, respectively (P0.05), and the 8-year cardiovascular event-free survival rates were 78.2% and 93.5%, respectively (log-rank test, P=0.01). A multivariate Cox proportional hazard analysis showed that high baPWV compared with low baPWV was associated with a significantly poorer outcome (hazard ratio (HR) 2.97; 95% CI: 1.006-9.380). In conclusion, baPWV is an independent risk factor for future cardiovascular events in patients with essential hypertension.

VnfA is a transcriptional activator that is required for the expression of the structural genes encoding nitrogenase-2 in Azotobacter vinelandii. VnfA consists of three domains: an N-terminal regulatory domain termed GAF, including a Cys-rich motif; a central domain from the AAA+ family; and a C-terminal domain for DNA binding. Previously, we reported that transcriptionally active VnfA harboring an Fe-S cluster (presumably of the 3Fe-4S type) as a prosthetic group and the Cys-rich motif were possibly associated with coordination of the Fe-S cluster. In the present study, we have investigated the roles of the GAF and central domains in the regulatory function of VnfA using truncated variants: ΔN15VnfA and ΔGAFVnfA that lack the N-terminal 15 residues and whole GAF domain, respectively, and GAFVnfA consisting of only the GAF domain. ΔN15VnfA and ΔGAFVnfA lost the ability to bind the Fe-S cluster, whereas GAFVnfA was still able to bind to the cluster, consistent with the hypothesis that the Cys-rich motif is essential for Fe-S cluster binding. The GAF domain showed an inhibitory effect on the transcriptional activity of VnfA, which was reversed in the presence of the Fe-S cluster, and reactivated upon disassembly of the cluster. The inhibitory activity of the GAF domain acts on the NTPase activity of the central domain, whereas the binding ability of VnfA to DNA was not significantly affected, when VnfA retains its tetrameric conformation. The results imply that a major pathway, by which VnfA function is regulated, operates via the control of NTPase activity by the GAF domain. Structured digital abstract • VnfA binds to VnfA by molecular sieving (View Interaction 1, 2) Database VnfA has been submitted to the Swiss-Prot database under accession number: C1DI41.

Microalbuminuria, for which hypertension and diabetes are well-known risk factors, has recently been used to detect individuals at risk for cardiovascular and chronic kidney diseases in the general population. We aimed to determine the thresholds of blood pressure or blood glucose concentration at which the odds ratio of having microalbuminuria begins to increase. An annual public health checkup was conducted on 3166 participants aged 29-84 years (mean, 61±11 years; 40% men) living in Watari town, Japan. We studied their demographic data, medical history of hypertension, diabetes, dyslipidemia, sitting blood pressure and fasting blood samples. Urinary albumin excretion was examined in terms of the albumin/creatinine ratio in spot urine samples. Microalbuminuria was defined as 30-299 mg albumin per gram creatinine. Final analyses included 2133 participants under no anti-hypertensive or anti-diabetic medication. Microalbuminuria was detected in 118 subjects (5.5%). We used the adjusted odds ratios for microalbuminuria in different blood pressure and blood glucose groupings as the reference. The adjusted odds ratio increased linearly with increase in systolic blood pressure. A similar trend, although not as linear, was observed with diastolic blood pressure. The odds ratio increased significantly with high-normal levels of both systolic and diastolic blood pressure. For blood glucose, the adjusted odds ratio increased significantly from the impaired fasting glucose level. Therefore, the odds ratio for microalbuminuria begins to increase from high-normal blood pressure and impaired fasting glucose levels in comparison with the reference. Early intervention in such cases may be useful for reducing cardiovascular and renal risks.

Objective Brachial-ankle pulse wave velocity (baPWV) is a new measure of arterial stiffness. We have shown that a higher baPWV is associated with more severe albuminuria in patients with essential hypertension. However, it is still unclear as to whether baPWV predicts the future albuminuria status in patients under standard care. Methods A total of 321 nondiabetic patients with essential hypertension who had normoalbuminuria or microalbuminuria and were receiving treatment under the current hypertension guidelines were followed up for 2 years. Resting BP, fasting blood glucose, urinary albumin excretion and baPWV were measured before treatment, and periodically thereafter for 2 years. Results A 2-year treatment regimen lowered BP from 156/ 93 to 135/81 mmHg (P< 0.0001) and reduced the incidence of microalbuminuria from 25.8 to 14.0%. To determine the predictors for future microalbuminuria status, we compared the baseline data between patients with normoalbuminuria (n = 276) and those with microalbuminuria (n = 45) 2 years after the treatment. The microalbuminuric patients had a significantly higher baPWV and urinary albumin excretion and a significantly lower high-density lipoprotein concentration than the normoalbuminuric patients. Furthermore, the frequency of the use of renin-angiotensin system inhibitors was significantly lower in the microalbuminuric patients than in the normoalbuminuric patients. A multiple logistic regression analysis showed that higher baPWV was an independent risk factor for microalbuminuria 2 years after treatment of hypertension. When we restricted our analysis to a cohort of patients without microalbuminuria at the baseline, we found that higher baPWV was an independent predictor of the development of microalbuminuria after 2 years. Conclusion Higher baPWV could be an independent risk factor for future microalbuminuria in patients with essential hypertension.

The first synthesis of allenylselenonium salts and their reactivities are described. The corresponding allenyl methyl selenides were alkylated with methyl trifluoromethanesulfonate to afford the desired compounds. Their reactions with active methylene carbanions produced furan, dihydrofuran or methylene cyclopropane derivatives via the Michael addition of nucleophiles to the selenonium salts.

This study identifies a role for the gene for the POU transcription factor Brn1 in distal tubule formation and function in the mammalian kidney. Normal development of Henle's loop (HL), the distal convoluted tubule and the macula densa was severely retarded in Brn1-deficient mice. In particular,elongation and differentiation of the developing HL was affected. In the adult kidney, Brn1 was detected only in the thick ascending limb (TAL) of HL. In addition, the expression of a number of TAL-specific genes was reduced in the Brn1+/- kidney, including Umod,Nkcc2/Slc12a1, Bsnd, Kcnj1 and Ptger3. These results suggest that Brn1 is essential for both the development and function of the nephron in the kidney.

The transcriptional activator, VnfA, is necessary for the expression of the structural genes encoding vanadium-dependent nitrogenase in Azotobacter vinelandii. We have previously reported that VnfA harbours a Fe-S cluster as a prosthetic group, presumably a 3Fe-4S type, which is vital for the transcriptionally active VnfA. A plausible effector molecule is a reactive oxygen species (ROS), which disassembles the Fe-S cluster switching the active VnfA to become fully inactive. This finding prompted us to investigate the effect of nitric oxide (NO), another physiologically important radical species on the VnfA activity. Unlike ROS, the VnfA activity was moderately inhibited and converged to 70% of the maximum by NO irrespective of its concentration. The Fe-S cluster of VnfA was found to react with NO to form a dinitrosyl-iron complex, either in the dimeric or monomeric form, dependent on the relative stoichiometry of NO to the Fe-S cluster. The VnfA species harbouring the dinitrosyl-iron complexes in each form exhibited 50% ATPase activity compared to the active VnfA. The findings of this study would open an argument about a biological effect of NO on nitrogenase in light of its transcriptional regulatory system.

A germline mutation either in exon 10 or 11 of the RET proto-oncogene is found in the majority of patients with multiple endocrine neoplasia type 2A (MEN 2A). A 41-year-old female patient was referred for further evaluation of incidentally discovered right adrenal tumor. She had bilateral adrenal pheochromocytomas and medullary thyroid carcinomas detected by endocrinological and radiological examination, and diagnosed as MEN 2A. Molecular genetic testing of the RET exons 10 and 11 exhibited the identical somatic missense mutation at codon 634 in both tumors but did not confirm germline mutations in the corresponding sites. Possible mechanisms for tumorigenesis in this patient are discussed.

We examined the effects of repeated administration of (S)- α- fluoromethylhistidine (FMH), a specific inhibitor of histidine decarboxylase (HDC), on radial maze performance and brain contents of histamine and amino acids in rats. By daily subcutaneous (s.c.) administration of FMH (100 mg kg ), rats showed significant enhancement of a radial maze performance without changes in locomotion. Six days after FMH treatment, the histamine levels both in the cerebral cortex and diencephalon decreased significantly. However, the glutamate and glycine levels significantly increased in the cerebral cortex and hippocampus. These results suggest that FMH enhances the acquisition phase of radial maze study with the increases in glutamate and glycine levels in the cerebral cortex and hippocampus of rats.

The expression of cerebellin and cerebellin mRNA was studied by radioimmunoassay and Northern blot analysis in the human brain, adrenal gland and the tumour tissues of adrenal tumour, ganglioneuroblastoma and neuroblastoma. Immunoreactive cerebellin was detected in every region of brain studied, with the highest concentrations found in the hemisphere of the cerebellum (424·2 ± 12·6 pmol/g wet weight, n=6, mean ± s.e.m.) and the vermis of the cerebellum (256·8 ± 30·5 pmol/g wet weight). Immuno-reactive cerebellin was also detected in the pituitary (8·2 ± 1·8 pmol/g wet weight), the spinal cord (3·3 ± 0·3 pmol/g wet weight) and the normal parts of adrenal glands (2·98 ± 0·37 pmol/g wet weight, n=9) and some tumour tissues, such as phaeochromocytomas, cortisol-producing adrenocortical adenomas, ganglioneuroblastomas and neuroblastomas. Northern blot analysis showed that cerebellin mRNA was highly expressed in the hemisphere and vermis of the cerebellum. Cerebellin mRNA was also expressed in other regions of the brain and the tumour tissues of phaeochromocytoma, cortisol-producing adrenocortical adenoma, ganglioneuroblastoma and neuroblastoma. Immunocytochemistry of the normal adrenal gland showed that immunoreactive cerebellin was localized in the adrenal medulla. The present study has shown the expression of cerebellin and cerebellin mRNA, not only in the cerebellum but also in other regions of the brain and some tumours, such as cortisol-producing adrenocortical adenoma, phaeochromocytoma and neuroblastoma. These findings suggest possible pathophysiological roles of cerebellin peptides, not only in the cerebellum, but also in the extra-cerebellar tissues. Journal of Endocrinology (1997) 154, 27–34

To investigate changes in systemic and regional hemodynamics during the development of human hypertension, we simultaneously measured cardiac index (CI) by the indocyanine green (ICG) dye dilution method, hepatosplanchnic blood flow (HBF) by the ICG clearance method using a two-compartment model, and renal blood flow (RBF) by the p-aminohippurate clearance method in patients with borderline and essential hypertension. In patients with borderline hypertension (BH, n=27), HBF (435±15 ml/min/m2) and HBF/CI (16±1%) were significantly (p

Factor XI deficiency is a rare hereditary coagulation disorder and mostly its bleeding manifestation is excessive bleeding after surgery and trauma. Hemostasis of a 69-year-old Japanese woman with factor XI deficiency in total hip joint replacement was successfully achieved by plasma replacement therapy. Plasma exchange was took place preoperatively with 2800ml of fresh frozen plasma. Factor XI level of the patient plasma showed 65% of normal immediately after the plasma exchange and 57% at the operation. Subsequently, fresh frozen plasmas were transfused to maintain factor XI level at 40% for 24 hours after surgery then 30% for the next 3 days. Factor XI level and APTT were monitored and no excessive bleeding was observed during and after the operation.

We report a case of hypertension associated with Guillain-Barré syndrome. In this case, the circadian variation of blood pressure was interrupted. Examination of neurohumoral factors revealed a hyperactive sympathetic nervous system and an increase in plasma renin activity. Clonidine, which acts centrally to inhibit sympathetic outflow, did not suppress serum norepinephrine or epinephrine. These observations suggest that autonomous hyperactivity of the efferent pathway of the sympathetic nervous system may cause the sustained hypertension throughout the day in this case.

In patients with cerebral palsy of the tension athetosis type, a number of symptoms may be observed, including not only the fairly constant involuntary athetotic movements but also myotonic disorders of the motor function of all four limbs and trunk, vocalization and motions associated with eating such as mastication and swallowing. Aggravation of involuntary movements and pain in the neck and back are also seen in many cases. Existing conservative treatment methodologies have proved to be more or less ineffective, and limitations in functional training in adults have made treatment extremely difficult. We first employed low reactive-level laser therapy (LLLT) in a case of spastic cerebral palsy in 1994 with good results. In the present study, we applied laser irradiation (830 nm. 60 mW continuous wave) to all myotonic sites around the face and neck region where myotonia was severe in 20 patients with cerebral palsy of the adult tension athetosis type for which there was no effective treatment for their neck and back pain. Improvement of myotonia was seen in 19 patients while improvement of pain in the neck and back was seen in all the 16 patients who had pain in these regions. Suppression of myotonia reduced tonic vocalization making words easily heard; moreover, suppression of myotonia and involuntary movements improved working efficiency enabling the patient to perform fairly complex tasks such as word processing. Insomnia and dysuria also improved. Even in the most severe cases, assisting the patient became easier and breathing improved. LLLT with the 830 nm diode laser provides a new and effective treatment modality in this extremely problematic condition, has no serious side effects, and has the potential to improve these patients’ quality of life.

To investigate the potential modulating influence of angiotensin II (ANG II) on sympathetic activity in response to changes in baroreflex activity, renal and total norepinephrine (NE) spillover rates were examined during sodium nitroprusside (SNP) and phenylephrine (PE) infusions in four groups of conscious rabbits: 1) saline (control); 2) subpressor ANG II (ANG II, 2 ng.kg-1.min-1); 3) enalaprilat (MK-422, 200 micrograms/kg and 3.3 micrograms.kg-1.min-1); and 4) MK plus ANG II (MK+ANG II). Upper plateaus of baroreflex-NE spillover curves for renal and total NE spillover were reduced in the MK group (25 and 81 ng/min) compared with control (38 and 125 ng/min) and MK+ANG II (37 and 155 ng/min). To investigate the interaction of ANG II and sympathetic activity during treadmill exercise, hindlimb NE spillover rate was examined in three groups of rabbits: 1) control, 2) MK, and 3) MK+ANG II. Exercise at 6 and 12 m/min produced similar effort-related hemodynamic responses in the three groups. At maximal exercise, hindlimb NE spillover was reduced in the MK group (29 +/- 3 ng/min) compared with control (62 +/- 17 ng/min, P < 0.05) and MK+ANG II group (51 +/- 10 ng/min). It is concluded that endogenous ANG II enhances sympathetic activity during pharmacological (baroreflex) and physiological stimulation.

Isolation and characterization of cDNAs encoding human very low density lipoprotein (VLDL) receptor revealed the presence of two forms of the receptor: one consists of five domains that resemble the low density lipoprotein (LDL) receptor, and a variant form lacks an O-linked sugar domain. More than 96% of amino acids in the human and rabbit VLDL receptors are identical, whereas those in the LDL receptors are less conserved between the two species (76%). The human VLDL receptor gene contains 19 exons spanning approximately 40 kilobases. The exon-intron organization of the gene is almost the same as that of the LDL receptor gene, except for an extra exon that encodes an additional repeat in the ligand binding domain of the VLDL receptor. Analysis of DNA from human-rodent hybrid cells revealed that the gene is located on chromosome 9. Although the 5'-flanking region of the VLDL receptor gene contains two copies of a sterol regulatory element-1 like sequence, the levels of mRNA for the receptor in THP-1 human monocytic leukemia cells were unchanged by sterols. The 5'-untranslated region of the receptor mRNA contains a polymorphic triplet repeat found also in the fragile X syndrome gene.

In rehabilitative training and treatment of patients with cerebral palsy, return and maintenance of good muscle tonicity and suppression of tonic muscle spasm is crucial. However, an effective method that is reliable, simple, painless and noninvasive has yet to be reported. In the present study, 150 cerebral palsy patients were treated on their limbs and trunk with infrared diode low reactive-level laser therapy (LLLT) (810 nm. 60 mW and 100 mW, continuous wave) , The treatment sites were those normally associated with conventional therapies such as nerve block or acupuncture, and where muscular hyperspasm was particularly evident. In the majority of the patients, spasm was successfully suppressed by LLLT, with the notable exception of those patients suffering from severe joint contracture. Compared with conventional methodology, laser therapy has proved to be a simple, reliable and noninvasive method which enabled painless suppression of spasm. Another of the advantages of LLLT is that multiple repeated application is possible on any site selected by the physician, with an almost unlimited choice of treatment sites. The effect of LLLT lasted from one to several hours in patients with severe spasticity. Although it may be argued that this variable length of effect is one of the limitations of LLLT, the authors feel that LLLT is particularly useful as a supplementary or adjunctive therapeutic modality to improve the overall efficacy of physical rehabilitation and functional training in children with cerebral palsy.

VnfA is a transcriptional activator that is required for the expression of the structural genes encoding nitrogenase-2 in Azotobacter vinelandii. VnfA consists of three domains: an N-terminal regulatory domain termed GAF, including a Cys-rich motif; a central domain from the AAA+ family; and a C-terminal domain for DNA binding. Previously, we reported that transcriptionally active VnfA harboring an Fe-S cluster (presumably of the 3Fe-4S type) as a prosthetic group and the Cys-rich motif were possibly associated with coordination of the Fe-S cluster. In the present study, we have investigated the roles of the GAF and central domains in the regulatory function of VnfA using truncated variants: ΔN15(VnfA) and ΔGAF(VnfA) that lack the N-terminal 15 residues and whole GAF domain, respectively, and GAF(VnfA) consisting of only the GAF domain. ΔN15(VnfA) and ΔGAF(VnfA) lost the ability to bind the Fe-S cluster, whereas GAF(VnfA) was still able to bind to the cluster, consistent with the hypothesis that the Cys-rich motif is essential for Fe-S cluster binding. The GAF domain showed an inhibitory effect on the transcriptional activity of VnfA, which was reversed in the presence of the Fe-S cluster, and reactivated upon disassembly of the cluster. The inhibitory activity of the GAF domain acts on the NTPase activity of the central domain, whereas the binding ability of VnfA to DNA was not significantly affected, when VnfA retains its tetrameric conformation. The results imply that a major pathway, by which VnfA function is regulated, operates via the control of NTPase activity by the GAF domain.

SUMMARY 1. The acute effect of an angiotensin converting enzyme inhibitor (ACEI), enalaprilat, on baroreflex-mediated changes in renal and total NA spillover rate in conscious rabbits with doxorubicin-induced cardiomyopathic congestive heart failure (CHF) were investigated under resting conditions and in response to changes in arterial pressure induced by sodium nitroprusside and phenylephrine infusions. 2. Six saline-treated (N group) and 11 doxorubicin-treated rabbits (1 mg/kg administered i.v. twice weekly) were studied after 4 and 6 weeks treatment. Five CHF rabbits received saline (C group) and six enalaprilat infusion (ACEI group). 3. After 4 weeks of doxorubicin, mean arterial pressure (MAP)-renal noradrenaline (NA) spillover and MAP-total NA spillover curves did not change during enalaprilat infusion. 4. After 6 weeks, the C group showed blunted MAP-renal NA spillover and MAP-total NA spillover curves. In the ACEI group, however, both curves returned toward those seen in the N group (slope of MAP-renal NA curve: from 0.27 to 1.80 ng/min per mmHg, MAP-total NA curve: from 1.61 to 3.59 ng/min per mmHg). 5. Results of this study indicate that enalaprilat enhances baroreflex control of renal and total NA spillover in rabbits with CHF and further support the view that activation of the renin-angiotensin system contributes significantly to the attenuated baroreflex responses in CHF.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a novel hypothalamic peptide consisting of 38 amino acids [PACAP(1–38)] with a potent stimulatory action on adenylate cyclase in rat pituitary. The presence of immunoreactive (IR-) PACAP in the tumor tissue of pheochromocytomas was studied by radioimmunoassay and immunocytochemistry. The antibody to PACAP was raised in a rabbit injected with a peptide containing amino acids 28–38 of PACAP. This antibody showed no significant cross-reactivity with either PACAP(1–27) or vasoactive intestinal polypeptide. The tumor tissue concentrations of IR-PACAP(1–38) were 0.5–57.5 pmol/g wet weight ( n = 13 ) ( 24.5 ± 22.4 pmol/g wet weight, mean ± SD), while those in the normal adrenal glands were 3.58 ± 2.02 pmol/g wet weight ( n = 7 ) and those in the adrenal cortical tumors were 5.58 ± 2.02 pmol/g wet weight ( n = 6 ). The IR-PACAP(1–38) concentrations in 7 out of 13 pheochromocytomas exceeded 18 pmol/g wet weight. Sephadex G-50 column chromatography revealed that the IR-PACAP(1–38) in extracts of pheochromocytomas eluted in both the positions of PACAP(1–38) and a larger molecular weight. Reverse-phase high performance liquid chromatography of the tumor extracts revealed a peak in the position of PACAP(1–38) and at least four other peaks. Immunocytochemistry of pheochromocytomas showed numerous immunoreactive cells. The immunostaining was abolished by absorption of the antiserum with synthetic PACAP(1–38). These findings indicate that multiple forms of IR-PACAP(1–38) are present in pheochromocytomas.

1. We investigated the usefulness of neuropeptide Y as a plasma marker for phaeochromocytoma, ganglioneuroblastoma and neuroblastoma using a simple and highly sensitive r.i.a. for human neuropeptide Y. 2. Plasma immunoreactive neuropeptide Y concentrations were measured without extraction in plasma samples (100 μl) from patients with various diseases. 3. The plasma immunoreactive neuropeptide Y concentration in patients with phaeochromocytoma (172.3 ± 132.4 pmol/l, mean ± sd, n = 23) was significantly higher than that in healthy adult subjects (40.1 ± 10.1 pmol/l, n = 40, P 4. The plasma immunoreactive neuropeptide Y concentration in patients with essential hypertension (34.0 ± 3.7 pmol/l, n = 18) was within the normal range, but in patients with chronic renal failure undergoing maintenance haemodialysis (192.1 ± 68.0 pmol/l, n = 25) and in non-dialysed patients with chronic renal failure (85.1 ± 23.1 pmol/l, n = 7) it was significantly higher than that in healthy adult subjects (P 5. Eighty-seven per cent of the patients with phaeochromocytoma, 67% of the patients with ganglioneuroblastoma and 80% of the patients with neuroblastoma showed plasma immunoreactive neuropeptide Y concentrations higher than the upper limits in the control subjects [62 pmol/l (adult) and 160 pmol/l (children)]. 6. These results suggest that neuropeptide Y is a useful plasma marker for these tumours in addition to other factors unless the patients have renal failure.

Immunohistochemical localization of the catecholamine synthesizing enzymes, tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), dopamine-beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT), was investigated in 70 cases of functioning and non-functioning phaeochromocytomas comprising 52 of adrenal and 18 of extra-adrenal origin. Of 59 functioning tumours, 30 were mixed epinephrine and norepinephrine-producing (mixed type) and 29 were norepinephrine-producing tumours. TH, AADC and DBH were detected in all functioning phaeochromocytomas, but PNMT was limited to the mixed-type phaeochromocytomas. Non-functioning phaeochromocytomas were divided into two groups, comprising a complete type, which induced neither elevated plasma catecholamines nor their metabolites in urine, and an incomplete type which exhibited no elevated plasma catecholamines, but showed a slightly high urinary vanillylmandelic acid level. In the non-functioning complete-type tumours, immunoreactive TH was negative, but the incomplete tumours of the adrenal medulla had all four enzymes, and corresponded to a mixed-type phaeochromocytoma. AADC and DBH were present universally in all functioning and non-functioning tumours, including TH-negative tumours. TH is a rate-limiting enzyme of catecholamine biosynthesis and deficiency of TH is an important feature of extra-adrenal non-functioning phaeochromocytomas.

Four cases of mixed neuroendocrine-neural tumors composed of pheochromocytoma and neuroblastoma elements (including ganglioneuroma and ganglioneuroblastoma) were studied for the presence of catecholamine-synthesizing enzymes, neuroendocrine markers, and peptide hormones with clinicopathological correlations. Paroxysmal hypertension with hypercatech olaminemia was observed in 3 patients. One patient had an extremely elevated level of dopamine. The location of the tumor was in the adrenal glands in 2 patients and in the retroperitoneum in the other 2. Numerous electron-dense granules in the cytoplasm and neural processes with abundant neurotubules were characteristic of mixed neuroendocrine-neural tumors. Immunohistochemical study revealed that catecholamine-synthesizing enzymes were present in both components of the pheochromocytoma and neuroblastoma group, but phenylethanolamine N-methyltransferase was detectable only in epinephrine-producing tumors. Chromogranin and neurofilament immunoreactivities were present in both components; however, the intensity of chromogranin immunoreactivity was stronger in pheochromocytoma than in the other components. In contrast, neurofilament positivity was stronger in the neuroblastoma group than it was in pheochromocytoma. Multiple peptide hormones were immunoreactive in both components. Neuropeptide Y and met-enkephalin-positive cells were numerous in both; cells containing vasoactive intestinal peptide and somatostatin were less common but were comparatively more frequently found in ganglion cells than in pheochromocytoma cells.

Doxazosin was administered once daily to 26 patients with renal hypertension or hypertension associated with renal dysfunction. Doxazosin produced a significant reduction in blood pressure that was stable throughout the treatment period. A significant change was not observed in heart rate. Blood pressure was “markedly decreased” or “decreased” in 80% of patients receiving doxazosin monotherapy, 78.6% of patients receiving combined therapy, and 79.2% of all the patients. The cumulative efficacy ratio according to final daily dose was 62.5% with 1 to 4 mg/day and 75.0% to 79.2% with 8 to 16 mg/day. Side effects were observed in three patients (12.0%), none of them severe, and all side effects disappeared with continued administration of doxazosin. Abnormal laboratory values in six items were observed in four patients. Serum crealinine and blood urea nitrogen values, which were regarded as renal function parameters, did not show significant changes, and no negative influence was observed with respect to doxazosin therapy. Overall clinical usefuiness was considered “very useful” or “useful” in 80% of patients receiving doxazosin monotherapy, 78.6% of patients receiving combination therapy, and 79.2% of all patients. In conclusion, once-daily administration of doxazosin was considered a useful antihypertensive therapy for renal hypertension and hypertension associated with renal dysfunction.

We report a case of an autopsy of unusual retroperitoneal sympathetic paraganglioma (SPG) that directly invaded the duodenum and showed expansive growth mimicking a submucosal tumor. The tumor was clinically suspected to be a gastrointestinal stromal tumor (GIST) of the duodenum because of its location and extension to the retroperitoneum without catecholamine-associated symptoms. However, a small biopsy specimen of the tumor showed diffuse proliferation of large basophilic cells that were negative for C-kit and CD34, ruling out GIST and indicating an epithelial malignancy. An autopsy revealed that the tumor was mainly in the retroperitoneum, measuring 7.5 x 9.5 cm, weighing 600 g and extending into the duodenum, adjacent to the pancreas but free of the adrenal glands. On cut section, the tumor involved the entire wall of the duodenum. There were no metastases in any organs. For differential diagnosis, endocrine tumors of the duodenum or pancreas and extra-adrenal SPG were considered. The tumor cells were immunohistochemically strongly positive for chromogranin A and were surrounded by cells positive for S100 protein. The Ki67-labeling index was under 1%. The four catecholamine-synthesizing enzymes were detected in the tumor cells. We report this case of SPG with emphasis on differential diagnosis and the significance of its local invasion.

We have demonstrated a compact and inexpensive frequency stabilization technique for commercially available 1mW, 850nm vertical cavity surface emitting laser (VCSEL) using a Fabry-Perrot cavity as frequency standard. Recently VCSEL has been widely prevailed for uses of low cost and small sized sensors, since it may afford low power operations and manufacturing costs in comparison with edge emitting type Fabry-Perrot laser diodes. Therefore, a highly versatile and inexpensive frequency stabilized coherent light source which can be mass producible will be available if the frequency stabilization for this type of VCSEL's is carried out. Generally, it has been commonly accepted that a satisfactory degree of coherence may be easily obtained from VCSEL's without any additional frequency stabilization technique since highly reflective coatings are to be put on their laser cavity edges. Nevertheless, some VCSEL devices, especially inexpensive type commercial products show multi-mode behaviors along with polarization instabilities. In the present work, as a simple and inexpensive approach to commercially available VCSEL devices, we have demonstrated a frequency stabilization scheme using a Fabry-Perrot cavity. The error signal was derived by phase sensitive detection for the transmitted light from the Fabry-Perrot resonator. Thus, the lasing frequency of the VCSEL was locked to the zero-crossing of the error signal by negative feedback for injection current via a PID controller. As a result, we have successfully suppressed the amount of frequency fluctuations in the free-running VCSEL of as much as 2GHz to be within 500MHz at measuring time of 30sec, that is, the attained Allan variance is 4.1×10E-8.

In the present work, we have developed an efficient and well stablized hyper coherent diode laser light source as compact as even portable using commercially available visible 400 nm band laser diodes. The attained coherence of the present system can always be controlled at the best condition indifferent to changes in its settled environmental conditions by applying Pound-Drever-Hall technique in which the frequency of a 160mW type 405nm GaN violet laser diode is locked to a reference Fabry-Perot cavity by negative electrical feedback for the injection current of the laser diode based on FM sideband technique. In addition to this frequency stabilization system, we have also realized a stability evaluation system that can measure the Allan variance of the frequency fluctuations of our frequency stabilized laser source in real-time basis by using simple devices of a portable computer and a digital signal processing unit. As a result, we have accomplished a compact and efficient hyper coherent laser system which can always perform its optimum conditions even if the environmental conditions around the laser are to be dynamically changed when used in a field basis. The attained values of power spectral density (PSD) of FM noise calculated from the error signals of our system under controlled condition were better by about 1~2 orders than typical values of free-running conditions in the fourier frequency domain from 100Hz to 300kHz. The best achieved value of PSD was about 2.56×10 7 [Hz 2 /Hz] in the fourier frequency domain from 100Hz to 1kHz, while as for the Allan variance as another measure of frequency stability, the achieved value of the minimum square root of Allan variance was 3.46×10 -11 in a 400nm type violet laser diode at integration time of 10 ms, which has been well comparable to the hyper coherent condition for the laser diode light sources.

The Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP) Study is the first large-scale intervention trial in Japan using a PROBE design to determine an optimal target blood pressure (BP) level on the basis of self-measured BP at home and optimal initial antihypertensive medication. The registered patients are randomized to one of two different BP levels and to initial antihypertensive regimens (i.e., calcium antagonist [Ca-A], angiotensin-converting enzyme inhibitor [ACE-I], or angiotensin II receptor antagonist [ARB]). At the end of February 2004, 2729, 1687, and 971 patients were recruited, randomized, and followed-up for 12 months or more. Among the 971 patients, mean systolic/diastolic BP levels at randomization in the Ca-A, ACE-I, and ARB groups were 150/90, 152/89, and 151/89 mmHg, respectively. These values reduced after six months of Ca-A-, ACE-I-, and ARB-based treatment (133/81 mmHg, 135/80 mmHg, and 134/79 mmHg, respectively) and further reduced after 12 months (131/80 mmHg, 134/79 mmHg, and 132/79 mmHg, respectively) without any significant differences among groups. In more intensive and less intensive BP-lowering groups, mean systolic/diastolic BP levels at randomization were 151/90 and 150/89 mmHg, respectively. Although BP levels reduced after 6-month (135/80 mmHg and 133/80 mmHg, respectively) and 12-month treatment (133/79 mmHg and 132/80 mmHg, respectively) in each target group, no significant difference in BP values was observed between groups. These results indicate the necessity of additional interventional strategies to improve the achievement of target BP levels, especially in the more intensive BP-lowering group.

We have demonstrated for the first time the analysis of noise properties in a 65mW, 405nm violet laser diode and also stabilized its frequency fluctuations as low as hyper coherent level. We measured the longitudinal mode behavior in some operation conditions, including the ambient temperature and optical feedback amount and so on. With some optical feedback amounts usually seen in typical optical pick-up systems, we have confirmed that the average relative intensity noise (RIN) value measures up to about -125dB/Hz, while the external cavity length dependences of the RIN show maximal and minimal spikes repeatedly at certain points where the external cavity length coincides with integral multiples of the effective internal cavity length of our sample LD. Under such circumstances, we have achieved the suppression of the optical feedback noise to about - 132dB/Hz by selecting the polarization of the feedback light. Moreover, we have proved the measured 65mW, 405nm violet laser diode sample tends to oscillate in multiple modes, so that we should carry out the single longitudinal mode operation by controlling the ambient temperature about 15°C. Thus, we have finally attained the frequency stabilization of the violet laser diode using a reference Fabry-Perot cavity based on the Pound-Drever- Hall method. As a result, we have achieved for the first time the frequency stability of 1.71×10 -10 of the minimum square root of Allan variance in a 400nm type violet laser diode.

Pheochromocytomas and extra-adrenal sympathetic paragangliomas show varied histological patterns, and it is difficult to diagnose malignancy or predict the clinical course using current histological criteria. In the present study, we reviewed 146 sympathetic paragangliomas including 116 adrenal (102 unilateral, 14 bilateral) and 30 extra-adrenal tumors including 38 metastatic tumors. We developed a scoring scale according to the following six factors: histological pattern, cellularity, coagulation necrosis, vascular/capsular invasion, Ki-67 immunoreactivity, and types of catecholamine produced. The tumors were classified as well (WD), moderately (MD), and poorly differentiated (PD) types according to their scores. The frequency of these tumor types were 113 WD (77%), 27 MD (19%), and 6 PD (4%). Metastasis was observed in 15 of 113 WD (13%), 17 of 27 MD (63%), and all 6 PD (100%). Five-year survivals of patients with metastases were 92% with WD, 69% with MD, 0% with PD. Respective 10-yr survivals were 83%, 38%, and 0%. Differences between groups were statistically significant. The data show that using this grading scoring system for sympathetic paragangliomas correlates with both metastatic potential and patient survival.

The Hypertension Objective treatment based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP) study is a large-scale intervention trial to determine both optimal target blood pressure (BP) on the basis of self-measured BP at home, and optimal initial antihypertensive medication.To investigate the quality of randomization at the end of March 2003, and BP-controlled conditions during initial 6 months.We evaluated the number of patients randomized by the end of March 2003, and BP changes during the initial 6 months based on intention-to-treat analysis.By the end of March 2003, a total of 1086 patients (12% of a planned randomization of 9000 patients) had been randomized. Among 653 patients who had been followed foror =6 months after randomization, mean systolic/diastolic BPs at randomization in the calcium antagonist, angiotensin-converting enzyme and angiotensin II receptor blocker groups were 149/89, 150/89 and 149/88 mmHg, respectively. Blood pressures were reduced after 3 months (137/83, 139/82 and 136/82 mmHg, respectively), and further reduced after 6 months (134/81, 135/80 and 133/80 mmHg, respectively), with no significant differences identified between groups. In more- and less-intensive BP-lowering groups, mean systolic/diastolic BPs at randomization were 149/88 and 150/89 mmHg, respectively. Although BPs were reduced after treatment for 3 months (137/83 and 137/82 mmHg, respectively) and 6 months (134/80 and 135/80 mmHg, respectively) in each target group, significant differences were still not observed between groups.Good quality of randomization was observed at the end of March 2003, but rate of achievement for target BPs was insufficient.

1. This study was designed to investigate the effects of isotonic saline loading on renal tubular and neurogenic dopamine (DA) in conscious rabbits. 2. Isotonic saline loading did not affect mean arterial pressure, heart rate or renal blood flow but markedly increased urine volume, sodium excretion and DA excretion. 3. Renal DA spillover was not affected by venous emptying, while renal noradrenaline (NA) spillover tended to decrease during saline loading. The ratio of % renal DA spillover to % renal NA spillover increased to 2.3 +/- 0.6 (P < 0.05) 3 h after saline loading. 4. Isotonic saline loading increased renal tubular DA production but had little effect on neurogenic DA release.

Adrenomedullin is a potent vasodilator peptide that was isolated from human pheochromocytoma. But the presence of adrenomedullin in the brain has not been clarified. We studied the presence of adrenomedullin in the human brain obtained at autopsy from 6 subjects by radioimmunoassay, as well as in the human adrenal glands and tumor tissues of pheochromocytoma, ganglioneuroblastoma and neuroblastoma. Immunoreactive adrenomedullin was detected in every region of human brain examined (0.26-1.4 pmol/g wet weight) with the highest concentrations found in thalamus (1.40 +/- 0.39 pmol/g wet weight, mean +/- SEM) and hypothalamus (1.28 +/- 0.48 pmol/g wet weight). Reverse phase high performance liquid chromatography showed that the immunoreactive adrenomedullin in the human brain was eluted in the position of synthetic human adrenomedullin 1-52. High concentrations of immunoreactive adrenomedullin were found in human adrenal glands (12.6 +/- 1.0 pmol/g wet weight, n = 7), pheochromocytoma (4.5 +/- 1.5 pmol/g wet weight, n = 11), ganglioneuroblastoma (2.0 +/- 1.3 pmol/g wet weight, n = 4) and neuroblastoma (0.55 +/- 0.21 pmol/g wet weight, n = 3). The present study has shown that adrenomedullin is present in the human brain in high concentrations, suggesting that adrenomedullin acts as a neurotransmitter, neuromodulator or neurohormone in man.

Stanniocalcin (STC) is a calcium (Ca)-regulating hormone that was originally discovered in the fish Stannius body, which is a unique endocrine organ. Hypercalcemia increases STC secretion, which inhibits Ca uptake by the gills and normalizes serum Ca level. In this study we investigated the STC expression in human normal and abnormal adrenal cells. Immunohistochemistry using monoclonal antibody against STC revealed specific staining in zona glomerulosa and medulla of normal human adrenal glands. STC was also detected in human adrenal tumors, such as pheochromocytoma, differentiated neuroblastoma, and aldosterone-producing adenoma, and cultured adrenal tumor cells (rat pheochromocytoma PC-12 cells and human neuroblastoma NB-1 cells). However, undifferentiated human adrenal neuroblastoma was negative for STC staining. Reverse transcription polymerase chain reaction demonstrated STC mRNA expression in cultured PC-12 cells and NB-1 cells. Following several studies indicating that zona glomerulosa cells of adrenal glands express neuroendocrine properties, STC expression in normal and abnormal adrenal cells provides additional evidence to support the neuroendocrine differentiation of these cells. In conclusion, STC may be useful as a new cell marker of adrenal glands under physiological and pathological conditions.

Two women who first had the clinical features of primary aldosteronism in the postpartum period are described. Their gestations were virtually uneventful. After delivery, however, progressively severe hypertension (Joint National Committee VI, stage 3) with hypokalemia developed. Pregnancy may conceal the clinical symptoms of primary aldosteronism that causes unexpected severe hypertension in the postpartum period.

To investigate changes in preoperative clinical features and the long-term outcome of tumor recurrence, mortality, and morbidity in patients with pheochromocytoma, we retrospectively examined changes in the clinical features by comparing 49 patients from 1957 to 1985 (group I) with 46 patients from 1986 to December 1995 (group II). In addition in these 95 patients (excluding 2 who had died before operation), we evaluated long-term postoperative outcome from the initial operation to August 1996 (909 patient-years). The mean age in group II was older than that of group I. The percentage of patients having proteinuria or hypertensive retinopathy in group II was less than that in group I. Of 20 patients with incidentally discovered pheochromocytoma, 7 (35%) were ≥60 years old, 7 asymptomatic, and 11 (55%) normotensive. Plasma and urinary catecholamines in these patients were significantly (P < .01) lower than in patients with pheochromocytoma having typical clinical features. Long-term cohort study showed 14 deaths. Relative survival rates were 91% at 5 years and 83% at 10 years and unchanged thereafter. The Kaplan-Meier estimate of pheochromocytoma-free survival was shorter in patients with a larger-than-median (60 g) tumor weight. Six patients had malignant recurrence 3 to 101 months (median, 45 months) after the initial operation. Of 65 patients confirmed alive at follow-up, 11 were hypertensive. In the Cox model, hypertension-free survival was not associated with age, a family history of hypertension, duration of hypertension, or creatinine clearance. Pheochromocytoma should be diagnosed from a wide spectrum of clinical features including those that are not generally suspected of resulting from excess catecholamines or hypertension, and after surgery, patients with this disease should be followed-up carefully for a long period (at least 10 years) because of the risk of tumor recurrence and the high prevalence of disease.

The lumbo-sacral region has anatomical lordosis and two-dimensional magnetic resonance imaging (2D-MRI) cannot therefore show spinal roots including the dorsal root ganglions in one picture. This makes it difficult to present the lateral part of spinal root lesions. We have recently described a new three-dimensional magnetic resonance imaging (3D-MRI) method which allows a stereoscopic view of the spinal cord and spinal nerve roots. In the present study, we evaluated three 3D-MRI techniques, rapid imaging spin echo (RISE) small tip angle gradient echo (STAGE), and short TI inversion recovery (STIR), for detecting disc tissue degeneration, and spinal cord and nerve root compression for identification of nerve roots and detecting signal changes indicative of thickening of the nerve root, and for evaluation of the extent of herniation in 30 patients with lumbar disc herniation. The RISE method was superior for detecting signal changes in disc degeneration, (in 100% of patients) compared with the STAGE method (in 56.1% of patients). All methods poorly identified L4 roots compared with L5 or S1 roots. The STIR method was the best for identifying nerve roots (L4, 62.5%; L5, 87. 5%; S1, 91.7%). STAGE and STIR were useful for detecting injuries of the nerve roots. RISE showed disc extrusion better than the other techniques (in 64.7% of patients). The presurgical diagnosis on 3D-MRI agreed with the pathology findings at surgery in 71.4% of STIR, 55.6% of RISE, and 33.3% of STAGE MR images. Our results indicate that 3D-MRI is most useful for the diagnosis of lumbar disc herniation and spinal cord and nerve root compression. The STIR method is best for identifying abnormalities of the spinal cord, roots, and intervertebral discs.

Patients with ossification of the posterior longitudinal ligament (OPLL) exhibit severe paralysis of the spinal cord, and such cases are classified as a recalcitrant disease by the Japanese Ministry of Health and Welfare. However, the etiology of this condition has not yet been clarified. The first report in Japan was made by Tsukimoto [1] in 1960, and in 1975 the Japanese Ministry of Health and Welfare research group was formed. Initially, investigations centered on cases of OPLL, but when it was discovered that ossification develops in various spinal ligaments, the concept of ossification of the spinal ligaments (OSL) became established.

Totsune K, Takahashi K, Murakami O, Satoh F, Sone M, Ohneda M. Miura Y. Mouri T. Immunoreactive brain natriuretic peptide in human adrenal glands and adrenal tumors. Eur J Endocrinol 1996;135:352–6. ISSN 0804–4643 The presence of brain natriuretic peptide (BNP) in tissues of human adrenal glands and adrenal tumors was investigated by radioimmunoassay. Immunoreactive BNP concentrations were 0.203 ± 0.061 pmol/g wet tissue (mean ± sem) in normal parts of adrenal glands (cortex and medulla. N = 8), 0.205 ± 0.037 pmol/g wet tissue in pheochromocytomas (N = 8), 0.230 ± 0.062 pmol/g wet tissue in aldosteronomas (N = 11) and 0.180 ± 0.054 pmol/g wet tissue in adrenocortical adenomas with Cushing's syndrome (N = 4). Sephadex G-50 superfine column chromatography and reverse-phase high-performance liquid chromatography showed that most (> 70%) of the immunoreactive BNP in the normal part of adrenal glands was eluted in the position of human BNP-32. Sephadex G-50 superfine column chromatography of immunoreactive BNP in the pheochromocytoma and aldosteronoma showed four peaks: one in the position ofγ-BNP, one in the position of BNP-32, one between γ-BNP and BNP-32 and one in the smaller molecular weight region. The present study has shown that immunoreactive BNP is present both in normal human adrenal glands and in adrenal tumors. Multiple molecular forms of BNP were found to be present in the tumor tissues of pheochromocytoma and aldosteronoma. Kazuhiro Takahashi. Department of Applied Physiology and Molecular Biology, Tohoku University School of Medicine, 2–1 Seiryo-machi, Aoba-ku. Sendai 980–77, Japan

We examined the long-term effects of administration of ( S )-α-fluoromethylhistidine (FMH), a specific inhibitor of histidine decarboxylase, on the spontaneous locomotor activity, food intake and brain contents of histamine, catecholamines, serotonin and amino acids of ICR mice. The distance of ambulation and number of rearings significantly increased from 8 to 15 h (20.00-03.00 h) after treatment with FMH (100 mg/kg, i.p.) and the 24-h food intake also increased significantly. On FMH treatment, the locomotor activity in movements of 3–15 cm/0.5 s was greater than that of control mice, whereas the number of slight movements (0–1 cm/0.5 s) decreased, suggesting that once a mouse treated with FMH is in motion, it moves a longer distance than a control mouse. We sacrificed mice 12 or 24 h after FMH treatment to measure the brain contents of histamine, monoamines and amino acids. Decrease of the brain histamine content to 35% of the control level was observed until 24 h after FMH treatment, but no significant changes in the brain catecholamine and serotonin contents were detected. However, the brain GABA content of ICR mice decreased to 85% of control 12 h after FMH treatment. Moreover, decrease of the brain GABA content after FMH treatment was greater in mast cell-deficient W W v mice, being 70 and 62% of the control level 12 and 24 h after treatment, respectively. The present experiments support the idea that the locomotor activity is affected by the central histaminergic system, directly and/or indirectly.

We treated two rare cases of pheochromocytoma which were histopathologically diagnosed as mixed neuroendocrine-neural tumor (MNNT): a 35-year-old male patient associated with ganglioneuroblastoma and cutaneous neurofibromatosis and a 42-year-old male patient with ganglioneuroma. Both patients showed typical clinical manifestations of pheochromocytoma without any familial traits. Although each of the diseases has its own entity and clinical features, these tumors are all derived from the neural crest tissues. The tumorigenesis of MNNT is still unknown. Here, a brief review of the recent literature on this subject is discussed.

Renal and total dopamine (DA) spillover rates at rest were measured in 25 conscious rabbits with chronically implanted renal vein catheters. Renal DA spillover rate was calculated from veno-arterial difference in plasma free DA concentrations across the kidney corrected by the fractional extraction of infused 3H-DA. Plasma free DA concentrations were 11.0 +/- 2.7 pg/ml in the artery and 14.3 +/- 3.6 in the renal vein. Renal and total DA spillover rates were 0.51 +/- 0.08, 2.61 +/- 0.30 ng/min, respectively, both of which were significantly (p < 0.001) lower than the respective norepinephrine (NE) spillover rates (renal: 16.3 +/- 1.4, total: 39.6 +/- 1.7). The fractional extraction of 3H-DA across the kidney (55 +/- 3%) and the total DA clearance (285 +/- 31 ml/min) were both significantly (p < 0.05) higher than that of 3H-NE (45 +/- 3) and the total NE clearance (198 +/- 9), respectively. The ratio of renal to the total spillover rate of DA (0.23 +/- 0.05) was significantly (p < 0.05) lower than that of NE (0.41 +/- 0.04). These results demonstrate that DA is released into plasma within the kidney and suggest that the measurement of renal DA spillover rate using 3H-DA radiotracer technique is useful to detect resting renal dopaminergic nerve activity.

To investigate the peripheral dopaminergic modulation in the pathogenesis of human hypertension, we examined the responses of plasma free dopamine (DA) to dexamethasone (Dx) administration, which is suggested to activate dopaminergic activity. We administered Dx 2mg intravenously to patients with primary aldosteronism (PA), essential hypertension (EH), and normotensive controls (NT). Plasma free DA was increased significantly in all groups and the responses were more remarkable in PA than in EH and NT. Plasma epinephrine (E) showed a gradual increase while plasma norepinephrine (NE) tended to decrease in all groups. The responses of both plasma DA and E were completely blocked by 250mg of α-methyl-p-tyrosine, a tyrosine hydroxylase (TH) inhibitor, suggesting that Dx may stimulate peripheral dopaminergic activity by increasing catecholamine synthesizing enzyme (probably TH) activities. These data suggest that DA itself plays an inherent role in the sympathoadrenal regulation rather than only as a precursor of NE and that dopaminergic hyperresponses may be involved in the pathophysiology of PA. (Hypertens Res 1995; 18 Suppl. I: S197-S198)