Improvement of bone disease with increased dose of glucocerebrosidase in a Gaucher disease patient who had a bone lesion presenting during low-dose enzyme replacement therapy

In recent years, enzyme replacement therapy has been shown to be useful for the treatment of Gaucher disease. A 10 year old Japanese boy with Gaucher disease underwent splenectomy at the age of 5 years and received enzyme replacement therapy from the age of 6 years. He had avascular necrosis of the bilateral femoral heads, which was not seen at the beginning of the therapy, without deterioration of hematological variables during maintenance therapy. The enzyme dosage was increased from 20 to 120 IU/kg per month resulting in an improvement of the clinical symptoms and bone lesion. In enzyme replacement therapy, dose increase is considered to be essential for improvement in bone disease; however, it is important to watch for the development of bone lesion.     

PERIPHERAL K CELLS IN GRAVES''DISEASE AND HASHIMOTO''S THYROIDITIS IN RELATION TO CIRCULATING IMMUNE COMPLEXES

A plaque assay was employed to quantify the number of peripheral K cells in autoimmune thyroid diseases. The percentages of peripheral K cells determined were 3.1 +/- 2.2% and 3.3 +/- 1.3% (mean +/- SD) in forty-one patients with Graves' disease and twenty-two patients with Hashimoto's thyroiditis, respectively, which were significantly lower than 5.3 +/- 2.5% in 22 normal subjects. Circulating immune complexes (ICs) were measured by three different methods. The positivity of these ICs was investigated in relation to the level of peripheral K cells. The percentage of peripheral K cells in the patients positive for ICs was found to be lower than that in the patients negative for any ICs. Moreover, it was observed that the number of detectable K cells from a normal subject was significantly decreased by incubating the K cells with sera of patients positive for ICs. These results suggest that the decrease of peripheral K cells in the patients with autoimmune thyroid diseases may be due to saturation of K cell Fc receptors by binding ICs.     

Transplacentally-Administered Enalapril Inhibits the Spontaneous Constriction of the Ductus Arteriosus in the Newborn Rat

ABSTRACT Pregnant Wistar rats were given orally enalapril maleate (EM), an angiotensin-converting enzyme (ACE) inhibitor, 15–60 min prior to Caesarean operation and the diameter of the ductus arteriosus (DA) in the newborn rats was calibrated at intervals after delivery. The caliber of the DA in control newborn rats gradually decreased to less than 10% of the initial value by 90 rnin after delivery. The DA calibers of the newborn rats treated with 50 or 200 mg/kg EM in utero were larger than the controls at any time interval up to 90 rnin and the difference from the control value was significant for at least 30 rnin after delivery when the drug was given to the dam 30 rnin prior to Caesarean section. The present study has demonstrated that transplacentally-administered enalapril inhibits the spontaneous constriction of the neonatal rat DA and supports the view that ACE inhibitors should not be used late in pregnancy.     

Maternal adrenocortical hormones maintain the early development of pancreatic B cells in the fetal rat

To investigate the effect of maternal adrenocortical hormones on the development of fetal pancreatic islet cells, pregnant rats were adrenalectomised on d 6 of gestation. On d 12–16 the growth patterns of fetal insulin-producing B cells, glucagon-producing A cells, and somatostatin-producing D cells were observed histometrically. Maternal adrenalectomy resulted in growth retardation of fetal B cells on d 12–15. Maternal corticosterone therapy prevented this retardation. Maternal adrenalectomy, however, did not affect the developmental patterns of A and D cells. By Western blotting and immunohistochemistry, glucocorticoid receptors were demonstrated to be present in the islet cells from d 12 to d 15. These results suggest that maternal adrenocortical hormones, glucocorticoids in particular, maintain the early development of fetal pancreatic B cells through their specific intracellular glucocorticoid receptor.     

Effects of Different Absorption Enhancers on the Permeation of Ebiratide,an ACTH Analogue,across Intestinal Membranes

The permeation of ebiratide (H-Met(O₂)-Glu-His-Phe-d -Lys-Phe-NH(CH₂)₈NH₂), a novel ACTH analogue, across the intestinal mucosae has been examined by use of isolated intestinal membranes from rats in a modified Ussing chamber. Regional differences were observed in the permeation of ebiratide across intestinal membranes; the order of membrane permeability was jejunum > ileum > duodenum > colon. Overall, the permeation of ebiratide was relatively poor. The effects of various absorption enhancers were examined to increase the intestinal permeability to ebiratide. Sodium glycocholate and sodium caprate had no significant enhancing effect on the permeability of the jejunal membrane, but significantly enhanced the permeation of ebiratide through the colonic membrane. On the other hand, N-dodecyl-β-d -maltopyramoside (LM) significantly enhanced the permeation of ebiratide through both jejunal and colonic membranes. In general, the absorption-enhancing effects of these agents were more predominant in the colon than in the jejunum. Membrane damage by the absorption enhancers was evaluated by measuring the amount of protein released from the intestinal membrane. It was found that all the absorption enhancers slightly increased the amount of protein released, but that the amounts of protein released in the presence of these enhancers were much less than in the presence of ethylenediaminetetraacetic acid (EDTA), used as a positive control. These findings suggest that the absorption enhancers, especially LM might be useful adjuvants for improving the intestinal absorption of peptide and protein drugs, including ebiratide.     

Immunohistochemical localization of calmodulin in the testes of patients with idiopathic male infertility

The localization of calmodulin in testes of patients with idiopathic male infertility was studied using the indirect immunoperoxidase method. Specimens were obtained by testicular biopsy from 55 patients. They were divided into 26 cases of hypospermatogenesis, 11 cases of maturation arrest (8 of primary spermatocyte arrest and 3 of spermatid arrest) and 18 cases of Sertoli cell-only syndrome. Regardless of the type of testicular pathology, the types of immuno-reactive cell and the intensities of staining were the same as those in the normal testis. That is, staining for calmodulin was first found to be positive in early pachytene primary spermatocytes. It became intense in late pachytene primary spermatocytes and round spermatids. By contrast, elongated spermatids and spermatozoa were not stained. Sertoli cells were stained slightly or not at all. A calmodulin-staining index (CaM-S index) was defined as the proportion of primary spermatocytes that were stained intensely for calmodulin relative to the total number of primary spermatocytes. The indices for the testes of men with complete spermatocyte maturation arrest were significantly lower than those for the testes of normal controls and of men with hypospermatogenesis.
Degenerating late pachytene spermatocytes observed in the testes of men with spermatocyte arrest showed low calmodulin-specific immunoreactivity. Such a decrease in numbers of normal late pachytene spermatocytes might be responsible for the low CaM-S index in cases of complete spermatocyte arrest.     

Effects of Grinding and Humidification on the Transformation of Conglomerate to Racemic Compound in Optically Active Drugs

The effects of grinding and humidification on the transformation of conglomerate to racemic compound have been investigated by X-ray powder diffraction (XPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy for leucine, norleucine, valine, serine, tartaric acid and malic acid. Racemic physical mixtures were prepared by physical mixing of equimolar quantities of d and l crystals using a mortar and pestle. Ground mixtures were obtained by grinding the physical mixtures with a vibrational mill. Humidification was performed by storing the physical mixtures and the ground mixtures in a desiccator containing saturated aqueous salt solutions at 40°C. When physical mixtures of malic acid, tartaric acid and serine were ground, the XPD peaks of the racemic compounds were observed. The XPD patterns of humidified physical mixtures of these compounds also showed the formation of the racemic compounds. This indicated that grinding or humidification of malic acid, tartaric acid and serine induced the transformation of conglomerate to racemic compound crystals. When, on the other hand, the physical mixtures of valine, leucine and norleucine were ground, peaks of racemic compounds were not detected in the XPD pattern. After humidification of the ground mixtures of valine, leucine and norleucine, however, the XPD peaks of racemic compounds were observed. DSC and IR studies revealed consistent results. We concluded that grinding or humidification of malic acid, tartaric acid and serine could induce the transformation of a conglomerate to racemic compound. In contrast, humidifying after grinding was needed to bring about the transformation in leucine, norleucine and valine.     

Incidence of hypocomplementemia in elementary and junior high school children with urinary abnormalities

Abnormalities were detected in 2669 of 326 257 elementary and junior high school children (169 856 males and 156 401 females) who were screened at school for urinary abnormalities. Serum complement (C3) level was measured in all 2669 children having urinary abnormalities (811 males, 1856 females). Three had a serum C3 level that was more than three standard deviations below the mean value. Type I membranoproliferative glomerulonephritis (MPGN) was diagnosed on histological examination in one of these three children, while the other two did not undergo renal biopsy because they had serum C3 levels of 40 and 44 mg/dL, respectively, and because their urinary abnormalities were transient. It was considered that there is not much significance in testing the serum complement in the urine screening done at school and the cost/benefit ratio is low. The results appeared to reflect the frequency of persistent hypocomplementemic MPGN in Japan in recent years.     

Six Cases of So-Called Carcinosarcoma of the Esophagus -- Histological and Ultrastructural Study on its Histogenesis --

Histopathological aspects of six cases of so-called carcinosarcomaof the esophagus are reported. Four of the patients had polypoidtumors and the other two had ulcerated lesions. Histologically,every tumor in the six cases was composed of both carcinomatousand "sarcoma-like" elements. The carcinomatous element was squamouscell carcinoma in five cases and anaplastic carcinoma in thesixth. The "sarcoma-like" element was "sarcomatous" proliferationof spindle cells. Histologically transitional features betweencarcinomatous and "sarcoma-like" components were observed inevery tumor. Electron microscopic study of semi-serial sectionsadjacent to toluidine blue-stained histological sections revealedthat the spindle-shaped cells in the "sarcoma-like" tissue wereof squamous epithelial cell origin. Therefore, these findingsled to a conclusion that so-called carcinosarcoma of the esophagusof the six cases was carcinoma associated with "sarcomatous"proliferation of carcinoma cells.