N-terminal pro-brain natriuretic peptide levels in monochorionic diamniotic twins with selective intrauterine growth restriction.

OBJECTIVE: To compare serum N-terminal pro-brain natriuretic peptide levels at birth between monochorionic diamniotic twins with and without selective intrauterine growth restriction. STUDY DESIGN: Blood samples were collected from 73 monochorionic diamniotic twins without twin-to-twin transfusion syndrome. Two groups were studied on the basis of fetal ultrasonographic findings: 16 twins with and 57 twins without selective intrauterine growth restriction. Selective intrauterine growth restriction was defined as an estimated fetal weight below the 10th percentile in one twin at 18 to 26 weeks of gestation. Serum N-terminal pro-brain natriuretic peptide levels were measured. RESULT: Serum N-terminal pro-brain natriuretic peptide levels in monochorionic diamniotic twins with selective intrauterine growth restriction were significantly higher than in those without selective intrauterine growth restriction. Selective intrauterine growth restriction was independently associated with increased N-terminal pro-brain natriuretic peptide levels. CONCLUSION: N-terminal pro-brain natriuretic peptide levels at birth are elevated in monochorionic diamniotic twins with selective intrauterine growth restriction.

Differential effects of vitamin D receptor activators on vascular calcification in uremic rats.

Vascular calcification is associated with cardiovascular disease, the most common cause of death in chronic kidney disease (CKD). Patients with CKD are treated with vitamin D receptor activators (VDRAs); therefore, we determined if this treatment affects vascular calcification. Uremic rats were given vehicle, calcitriol, paricalcitol, or doxercalciferol three times a week for 1 month. Calcitriol significantly increased the serum calcium-phosphate product and aortic calcium content. Paricalcitol had no effect but the same dose of doxercalciferol significantly increased the calcium-phosphate product and the aortic calcium content, the latter being confirmed by von Kossa staining. To see if the increased aortic calcium was due to an increased serum calcium-phosphate product or to a differential effect of the two VDRAs, we lowered the dose of doxercalciferol and increased the dose of paricalcitol. A lower doxercalciferol did not increase the calcium-phosphate product but increased the aortic calcium content. A higher dose of paricalcitol still had no effect. Doxercalciferol treatment increased the mRNA and protein expression of the bone-related markers Runx2 and osteocalcin in the aorta, whereas paricalcitol did not. Hence, different VDRAs have different effects on vascular calcification in uremic rats. The effects are independent of the serum calcium-phosphate product suggesting independent mechanisms.

An Asian variant of intravascular lymphoma: unique clinical and pathological manifestation in the gallbladder.

We here present a rare case of intravascular lymphoma (IVL) in a Japanese man. 4 months after cholecystectomy due to cholecystitis, a diagnosis of intravascular lymphoma (IVL) was strongly suspected. Lymphoma cells were diffusely observed in the bone marrow parenchyma, but were absent in the vascular spaces. The patient died of respiratory failure and at autopsy a small number of lymphoma cells in the extravascular parenchyma of the adrenal gland and bone marrow were seen. Serial sections of the surgically resected gallbladder retrospectively confirmed the diagnosis of IVL. In addition, congestion and edema were observed in the connective tissue layer. It is possible that edema or ischemia in the gallbladder wall or at other anatomic sites due to the circulation disturbance induced by the intravascular obstruction of lymphoma cells may have caused the initial symptoms. In conclusion, clinicians and pathologists should keep in mind that the gallbladder may be initially involved in IVL.

Bridging necrosis and reticulin bridging fibrosis induced by intrahepatic involvement of acute biphenotypic leukemia.

A 47-year-old Japanese woman was diagnosed as having acute biphenotypic leukemia with association of t(9;22)(q34;q11). Cholestatic liver dysfunction arose, and she died of cachexia and intracranial hemorrhage. Autopsy showed unusual hepatic fibrosis. In the liver, bridging infiltration, bridging necrosis and bridging fibrosis by leukemic cells were seen. It seemed that the degree of fibrosis was associated with the number of aggregates of infiltrating leukemic cells. The fibrotic foci were predominantly composed of reticulin and collagen fibers, and distortion of the lobules was observed. Immunohistochemically, dense bundles of alpha-smooth muscle actin (ASMA)-positive stromal cells, namely activated hepatic stellate cells (HSCs), were observed in the immature fibrotic foci as well as along the sinusoids densely infiltrated by leukemic cells. No cells positive for TGF-beta1 or PDGF-BB were identified. In conclusion, extensive intrahepatic involvement by neoplastic cells in adult acute biphenotypic leukemia may cause the unusual "disorganized" hepatic fibrosis.

Putaminal hyperperfusion in dystonic posturing on subtracted SPECT: a case report.

Dystonic posturing (DP) is one of the most reliable lateralizing symptoms for mesial temporal lobe epilepsy, although the mechanism remains unclear. We demonstrated a hyperperfusion area in the right putamen on subtracted postictal SPECT by using the automatic registration technique in one patient with ictal DP of the left hand. The putamen may play a key role in DP, similar to other diseases with dystonia.

Mouse model of Bell's palsy induced by reactivation of herpes simplex virus type 1.

In order to investigate the mechanism of Bell's palsy, we developed an animal model of facial nerve paralysis induced by the reactivation of herpes simplex virus type 1 (HSV-1). Eight weeks after recovery from facial nerve paralysis caused by inoculation with HSV-1, the mice were treated with auricular skin scratch at the site of the previous inoculation, or with intraperitoneal injection of anti-CD3 monoclonal antibody (mAb), or combination of both procedures. No mice developed facial nerve paralysis when they were treated with either auricular scratch or mAb injection alone. In contrast, 20% of mice developed facial nerve paralysis with the combined treatment. With one exception, no mouse treated with either auricular scratch or mAb injection showed HSV-I DNA in their facial nerve tissue, whereas 4 out of 6 mice receiving both treatments showed HSV-1 DNA on day 10 after treatment. Histopathological findings showed neuronal degeneration in the geniculate ganglion and demyelination of the facial motor nerve in paralyzed mice. These findings suggest that a combination of stimuli, local skin irritation, and general immunosuppression is essential for successfully inducing facial nerve paralysis in mice with latent HSV-1 infection.

Effect of dexamethasone therapy on pulmonary function in chronic lung disease: a comparison of disease types.

BACKGROUND: In the present study, we investigated the effect of dexamethasone (DEX) therapy on extubation and pulmonary function in patients with chronic lung disease (CLD) who required long-term mechanical ventilation. In addition, we compared the effects of DEX therapy among CLD types. METHODS: Twenty-two CLD patients who were ventilator dependent for 28 days or longer received DEX therapy for the purposes of extubation. A tapering dose of DEX, starting from 0.5 mg/kg per day, was administered for 7 days. Pulmonary function was measured at initiation of administration and 4 days after initiation. We evaluated static respiratory system compliance (Crs) and static respiratory system resistance (Rrs) adjusted by bodyweight. Chronic lung disease types were categorized according to the classification of the Ministry of Health and Welfare Research Project. We compared the effect of DEX therapy among CLD types. RESULTS: Dexamethasone therapy was started at a mean (+/-SD) 45 =/- 11 days after birth and 32.1 +/- 1.3 weeks of postconceptional age in infants with a mean bodyweight of 939 +/- 153 g. After DEX therapy, extubation was successful in all 22 patients. Following DEX administration, Crs was significantly increased from 0.69 +/- 0.13 to 1.17 +/- 0.21 mL/cm H2O per kg. In contrast, Rrs did not show any clear changes. Comparing CLD types, no difference was observed for Crs and Rrs in each disease type. CONCLUSIONS: Dexamethasone was administered to CLD patients requiring long-term mechanical ventilation for the purposes of extubation and extubation was successful in all patients. It was found that Crs was increased in all patients following DEX, regardless of CLD type. The increase in Crs following DEX administration may have been related to successful extubation.

[A case report of chronic chyluria probably due to Bancroftian filariasis, which showed hypoproteinemia].

Proteinuria is commonly observed in patients with chyluria due to Bancroftian filariasis. However, whether or not hypoalbuminemia is caused by chyluria alone is still a matter of debate. This is because various forms of glomerulonephritis are complicated in such patients. Herein, we report a case we have recently encountered. A 72-year-old male was admitted to our division for further evaluation of nephrotic syndrome. He was from the Southernmost part of Japan, where Bancroftian filariasis has been epidemic, and had developed persistent chyluria over a period of nearly 50 years. There was no other past history of illness except for diabetes mellitus(DM) pointed out 3 months prior to admission. The physical and laboratory examinations on admission fulfilled the diagnostic criteria for nephrotic syndrome. Lymphoscintigraphy showed an intense tracer accumulation in both kidneys. A renal biopsy was performed. At the light microscopic level, the glomeruli looked normal. Edema of the tubulointerstitium was noted. At the electron microscopic level, effacement of podocyte foot processes was not observed. Immunofluorescent study did not show glomerular deposition of immunoglobulins and complements. He also had persistent microscopic hematuria. Automated urinary sediment analysis by real-time confocal scanning laser microscopy revealed red blood cells of the non-glomerular type. Taken together, these findings strongly indicated that hypoalbuminemia of this patient was caused by chyluria alone. In conclusion, a report of the present case provides strong evidence that hypoalbuminemia of a patient with Bancroftian filariasis could be caused by chyluria alone.

[Two cases of idiopathic membranous nephropathy with focal and segmental glomerulosclerotic lesions in which renal function progressively deteriorated].

Previous reports have clarified that focal and segmental glomerulosclerosis(FSGS) appearing in membranous nephropathy(MN) is associated with a poorer prognosis than that of MN without FSGS. However, the etiology and pathogenesis of such FSGS lesions may show substantial individual differences. In some patients, hemodynamic alterations secondary to hypertension and vascular disorders seem to play a crucial role in the development of such FSGS lesions. In such instances, steady regulation of blood pressure might slow down further progression of FSGS lesions. Here we describe two cases of biopsy-proven MN with FSGS. Case I was a 44-year-old man who had shown massive proteinuria with hematuria at the age of 39 years. Renal biopsy specimens obtained at the age of 40 and 41 years showed MN without FSGS and MN with FSGS, respectively. His blood pressure control was fairly good throughout the course. Although he was on a steroid, an immunosuppressant, a low protein diet, and an ACE inhibitor, his renal function declined in 5 years. Case 2 was a 61-year-old woman who showed nephrotic syndrome at the age of 39 years. A renal biopsy specimen obtained at the age of 58 years showed MN with FSGS and remarkable atherosclerotic changes of the interlobular arteries. Her blood pressure control was rather poor throughout the course. Her renal function gradually declined over 22 years. Since parts of the FSGS lesions of the second case may have been caused by hypertension, it is tempting to speculate that day-to-day control of blood pressure could improve the long-term prognosis. We believe that, at least in some patients of MN with FSGS, careful management may lead to a more favorable course of decline in renal function.

[Muscle involvement of Stormorken's syndrome].

We described two patients, a mother and daughter, of Stormorken's syndrome. The syndrome is characterized clinically by autosomal dominant inheritance, congenital miosis, thrombocytopenia, asplenia and muscle weakness. Both patients had bleeding tendency, ichthyosis of arms, and muscle weakness. The daughter additionally had short stature (146 cm), low body weight (32 kg) and muscle cramp. Neurological findings of the patients included migraine-like headache, cognitive dysfunction, limitation of upward and lateral gaze, and amydriasis. Femoral muscle MRI of the daughter demonstrated decreased volume with patchy high intensity areas in the hamstrings. A muscle biopsy from the daughter showed myogenic changes with muscle fiber necrosis and regeneration, variation in fiber size, tubular aggregates in approximately 5% of fibers, and fibrous tissue proliferation. Dystrophin, dystrophin-associated proteins and dysferlin were normally expressed. Although both patients had elevated creatine kinase levels and generalized muscle wasting, muscle weakness was mild with slow progression. A certain membrane defect in the platelet and muscle fiber might be responsible for the pathogenesis of this syndrome.

Unidirectional olfactory hallucination associated with ipsilateral unruptured intracranial aneurysm.

PURPOSE: We describe a patient with complex partial seizure with unidirectional olfactory aura associated with ipsilateral unruptured aneurysm. METHODS AND RESULTS: The patient felt a sweet pleasant smell coming from behind her right side every time before the attack. Cranial magnetic resonance imaging (MRI) and three-dimensional computed tomography (CT) angiography revealed a large aneurysm at the bifurcation of the right middle cerebral artery and compression of the right orbitofrontal cortex. Small spikes were recorded from the right orbitofrontal and superior temporal gyri and from the uncus by the cortical electrodes during clipping of the aneurysm. CONCLUSIONS: The orbitofrontal cortex may have a function related to the ipsilateral directional olfactory sensation.

Distribution and excretion of boron after intravenous administration of disodium mercaptoundecahydro-closo-dodecaborate to rats.

Disodium mercaptoundecahydro-closo-dodecaborate (BSH) is an important compound for boron neutron capture therapy. The pharmacokinetics of boron by BSH were studied in normal rats after rapid intravenous injection at three doses (30, 100, 300 mg/kg) or continuous infusion (100 mg/kg/30 min). The boron concentration in biological samples was measured by inductively coupled plasma atomic emission spectroscopy. The blood half-lives of boron in the elimination phase (t1/2 beta) after rapid injection of BSH at doses of 30, 100 and 300 mg/kg were 1.7, 17 and 19 hr, respectively. AUC (32, 219 and 4030 micrograms.hr/ml) increased with the dose, but there was no proportionality among the values. Total clearance decreased drastically from 233 ml/hr/kg (100 mg/kg) to 38 ml/hr/kg (300 mg/kg). As boron was excreted mainly into urine, these results suggest that renal function failure might occur with dosing of 300 mg/kg. In the case of continuous infusion of 100 mg/kg of BSH for 30 min, the pharmacokinetic parameters were similar to those of rapid injection of 100 mg/kg. The highest boron concentration was observed in the kidney and the lowest in the brain. After multiple dosing of BSH at 100 mg/kg/day x 14 days, the boron concentrations in blood, liver, lung and kidney at 24 hr after the last dosing were higher than those after single dosing and were similar to those of simulated values calculated from the single dosing parameters. These results clearly indicated that boron does not accumulate unexpectedly in any tissue with multiple dosing of 100 mg/kg of BSH for two weeks.

Disposition and metabolism of the new hypocholesterolemic compound S-8921 in rats and dogs.

S-8921 (methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimeth oxy-2- naphthoate, CAS 151165-96-7) is a novel hypocholesterolemic agent which was found to inhibit ileal Na+/bile acid cotransporter. In this report, the pharmacokinetic profile of S-8921 was studied in rats and dogs. After dosing of 14C-S-8921 to rats at 1 to 25 mg/kg as 0.5% methylcellulose (MC) suspension, tmax was observed during 5-6 h, and AUCs increased with the dose, but not proportionally. The elimination half-lives were around 38-41 h for the doses examined. The apparent absorption ratio of 5 mg/kg of 14C-S-8921 as MC suspension was about 14%. Most of the radioactivity (98% of dose) was excreted into the feces and only 1-2% into the urine. Biliary excretion of radioactivity after dosing of 1, 5 or 25 mg/kg was 22, 20, 15%, respectively. Saturation of the absorption process was suggested. Even in case of intravenous dosing, about 88% was excreted into the bile. Enterohepatic circulation of biliary metabolites was also observed in rat. Its extent was small (6%), but, it may be contribute to the slow elimination of S-8921 from rat. The highest radioactivity was observed in the liver, with other tissues showing similar radioactivity profiles to that of plasma. The elimination half-lives of radioactivity from tissues were very long, e.g. 68 h for the liver and 58 h for the kidney. After 14 days multiple dosing, most tissues showed about two times higher radioactivity than that after a single dose. The simulation curves of liver and plasma showed a good fit with those of the observed values. These results suggested that there is no serious accumulation of radioactivity in tissues by multiple dosing of 14C-S-8921 in rats. The plasma radioactivity after oral dosing of 5 mg/kg of 14C-S-8921 to dogs as an MC suspension reached maximum concentration (c.a. 33 ng/ml) at 2 h, then decreased very slowly with a half-life of 169 h. The apparent absorption ratio was 4.6% for MC suspension. The excretion of radioactivity into bile, feces and urine after oral dosing of 14C-S-8921 at 5 mg/kg as an MC suspension were 3.0%, 94.6% and 0.3%, respectively. Even in the case of intravenous dosing, urinary excretion was very small (2.2%) and most of the radioactivity was excreted very slowly into the feces. The major metabolite of S-8921 in rat bile was its glucuronide. Other minor metabolites identified were the demethylated forms of 7-methoxy and 4'-methoxy moieties of S-8921. They were also excreted into bile as their glucuronides.

Rapid diagnosis of varicella zoster virus infection in acute facial palsy.

Patients with zoster sine herpete and Ramsay Hunt syndrome without pathognomonic vesicles at the initial visit are often misdiagnosed with Bell's palsy and treated without antiviral agents. With PCR, we found that varicella zoster virus genomes were frequently detectable in auricular skin exudate from patients with zoster sine herpete or Ramsay Hunt syndrome before the appearance of vesicles.

Varicella-zoster virus distribution in Ramsay Hunt syndrome revealed by polymerase chain reaction.

The pathogenesis of facial nerve paralysis and vestibulo-cochlear dysfunction of Ramsay Hunt syndrome remains unclear as varicella-zoster virus (VZV) has not been demonstrated in the lesions. Using the polymerase chain reaction, we detected VZV genomes not only in the vesicles on the auricles or oral cavity but also in the facial nerve sheath, middle ear mucosa and cerebrospinal fluid from patients with Ramsay Hunt syndrome. The VZV genome was undetectable in the same kinds of clinical samples obtained from control patients with facial nerve paralysis of other etiologies. The results indicated that VZV spreads widely in the neural components, mucocutaneous tissue and cerebrospinal fluid. The present study will facilitate better understanding of the pathogenesis of facial nerve paralysis, vertigo, hearing impairment and other cranial nerve dysfunction of Ramsay Hunt syndrome.

Suppression of acute experimental allergic encephalomyelitis in Lewis rats with a mycophenolic acid derivative.

Oral administration of ethyl O-[N-(p-carboxyphenyl-carbamoyl]-mycophenolate (CAM), a derivative of mycophenolic acid (MPA) and an inosine monophosphate dehydrogenase inhibitor, dose-dependently suppressed acute experimental allergic encephalomyelitis in Lewis rats without exerting any serious adverse effects. A daily dose of 50 mg/kg of CAM almost completely abolished both the clinical disease and the inflammation in the CNS. In the CAM-treated rats, a weight loss and fluctuations of peripheral lymphocyte subsets were minimized. The CAM treatment was effective when started at the time of sensitization but ineffective when deferred till day 10. Furthermore, CAM reduced the percentage of CD4+CD45RC- cells in the peripheral blood. The only detectable adverse effect was moderate anemia but it was rapidly improved after withdrawal of the drug. This drug could be a useful adjunct for the long-term immunosuppressive therapy for inflammatory diseases of the CNS.

Somatostatin release as measured by in vivo microdialysis: circadian variation and effect of prolonged food deprivation.

In vivo microdialysis was used to determine SRIF release from the hypothalamus in unanesthetized male rats over a period of 24 h and in rats deprived of food for 72 h, in relation to changes in plasma GH levels. Before the experiment, a microdialysis probe was inserted into the anterior pituitary gland of the rats with an indwelling right atrial cannula. Dialysates and blood samples were collected serially, after normal feeding or 72-h deprivation of food. Normal rats implanted with the microdialysis probe showed an episodical pattern of GH secretion at intervals of 3 h. SRIF was secreted in a pulsatile fashion in the dark period in a similar manner to the light period. Mean SRIF pulse amplitude and mean SRIF level were significantly increased in the dark period. There was no significant correlation between the SRIF and GH pulses in the light period. SRIF levels in dialysates obtained from fed rats and food-deprived rats showed a pulsatile pattern. Food deprivation resulted in significant increases in mean SRIF level and mean SRIF pulse amplitude. These results suggest that the existence of circadian rhythm in SRIF release and the increase in SRIF release play an important role in suppressing GH secretion during prolonged food deprivation.

Thyrotropin-releasing hormone release in normal and hyperthyroid rats as measured by microdialysis.

To measure the thyrotropin-releasing hormone (TRH) release from the hypothalamus in euthyroid and hyperthyroid states, we investigated the changes in TRH levels in the anterior pituitary of conscious male rats using an in vivo microdialysis technique. In the euthyroid rats (n = 18), TRH levels in the extracellular dialysates of the anterior pituitary varied from 1.0 to 101.0 pg/ml in a pulsatile fashion: 15.9 +/- 13.9 (mean +/- SD) pg/ml with 5.8 +/- 1.5 pulses/24 h. In the hyperthyroid rats (n = 5) who received L-thyroxine at 10 micrograms/100 g body weight for 7 days, TRH levels in the dialysates during 6 h was 3.6 +/- 1.7 pg/ml, and significantly lower (P < 0.05) than those of the control rats (15.5 +/- 14.1 pg/ml); the pulse frequency was unchanged. These findings demonstrated for the first time the existence of pulsatile TRH release from the hypothalamus, and showed that thyroid hormone inhibits TRH release by the reduction of pulse amplitude, but not of pulse frequency.

Effects of thyroidectomy on thyrotropin-releasing hormone (TRH) and somatotropin release-inhibiting factor (SRIF) patterns in intrahypophysial microdialysates in rats.

The effects of thyroidectomy on patterns of TRH and somatotropin release-inhibiting factor (SRIF) release from the hypothalamus were investigated by using a microdialysis technique. Thyroidectomized and sham-operated rats underwent placement of a guide cannula into the anterior pituitary gland to obtain dialysates, or implantation of an intravenous cannula into the right atrium for blood sampling. Seven days postoperatively dialysates were collected at a flow rate of 2 microliters/min every 1 h. TRH concentrations in dialysates from thyroidectomized rats (0.43 +/- 0.2 pg/h) were significantly higher than those from control rats (0.17 +/- 0.02 pg/h). In contrast, SRIF concentrations in dialysates from thyroidectomized rats (2.45 +/- 0.05 pg/h) were significantly lower than those from control rats (3.80 +/- 0.22 pg/h). In addition, plasma TSH concentrations in thyroidectomized rats (24.8 +/- 0.5 ng/ml) were increased compared with those in control rats (2.5 +/- 0.1 ng/ml), and plasma GH concentrations were decreased from 68.6 +/- 6.4 ng/ml in control rats to 21.2 +/- 0.6 ng/ml in thyroidectomized rats. These findings indicate that TRH and SRIF releases from the hypothalamus are detectable by microdialysis method, and directly show the increase in TRH secretion and the decrease in SRIF secretion from hypothalamus in the hypothyroid state.

Radioimmunoassay and gas chromatography/mass spectrometry for a novel antiglaucoma medication of a prostaglandin derivative, S-1033, in plasma.

A radioimmunoassay (RIA) and a gas chromatographic/mass spectrometric (GC/MS) method for a new antiglaucoma medicament, the prostaglandin derivative sodium (5Z, 9 alpha, 11 alpha, 13E)-9,11-dihydroxyprosta-5, 13-dienoate (S-1033), in human and rabbit plasma were investigated. For a competitive RIA, antisera from rabbit and radioiodine-labeled S-1033 were prepared by immunizing a conjugate of S-1033 with bovine serum albumin and by the Bolton and Hunter method, respectively. Pretreatment by C18 solid-phase extraction (SPE) for rabbit plasma sample and further purification by high-performance liquid chromatography (HPLC) for human plasma samples followed by the RIA (SPE/RIA and HPLC/RIA, respectively) were developed. The assay recoveries of SPE/RIA and HPLC/RIA were both excellent and the limits of quantitation were 320 and 10 pg ml-1, respectively. GC/MS for plasma samples after solid-phase extraction and thin-layer chromatographic purification was also developed using deuterium-labeled S-1033 as internal standard. The limit of quantitation was 100 pg ml-1 in human or rabbit plasma. Rabbit plasma samples after administration of this drug were measured by SPE/RIA and GC/MS and the assay results from both methods agreed well. The SPE/RIA, HPLC/RIA and GC/MS assay methods were suitable for measuring samples from preclinical studies, clinical studies and cross-validation, respectively.