Yoshio Yoshimoto

Qualitative and quantitative analyses of human chorionic gonadotropin and its subunits produced by malignant tumors

Human chorionic gonadotropin (hCG) and its subunits in plasma, urine, ascites, and tumor extracts from four patients with hCG‐producing tumors (undifferentiated cell carcinoma and choriocarcinoma of the bladder, malignant teratoma of the retroperitoneum, and pancreatic carcinoma) were measured by the radioimmunoassays specific to each component. While both free α and β subunits as well as the whole molecule of hCG were found in all these samples, the proportion of β subunit was much higher in these tumor extracts than in the placental extracts. Since the α and β subunits are known to be translated from separate mRNAs, such increase of subunit is probably due to the predominant increase of mRNA encoding β subunit of hCG in the hCG‐producing tumors. Gel filtration of the extracts of these four tumors on Sephadex G‐100 and G‐150 columns demonstrated a heterogeneity of hCG, α, and β subunits in these tumor extracts, and the elution profiles of plasma, urine and tumor extracts were slightly different. Lower molecular weight forms of hCG and its β subunit were present in all urine samples. The significance of these heterogeneities remains to be elucidated.

αvβ3 Integrin ligands enhance volume-sensitive calcium influx in mechanically stretched osteocytes

We propose that specific osteocyte–matrix interactions regulate the volume-sensitive calcium influx pathway, which we have shown is mediated by stretch-activated cation channels (SA-Cat) and is essential for the stretch-activated anabolic response in bone. The current study measured the hypotonic swelling-induced increase in cytosolic calcium concentration, [Ca2+]i, in rat osteocytes, and found that cells adherent to different matrices behave differently. Osteopontin and vitronectin, matrix molecules that bind the αVβ3 integrin, induced larger responses to the hypotonic swelling than other matrix molecules that bind other integrins. Addition of echistatin, which is a soluble αVβ3 ligand, significantly enhanced the hypotonic [Ca2+]i increase in addition to inducing an immediate increase in [Ca2+]i by itself. These results strongly support the contention that αVβ3 integrin signaling in osteocytes interacts with that in mechanotransduction, which is downstream of SA-Cat.

Quantitative computed tomography of lumbar vertebrae in Japanese patients with osteoporosis

Vertebral trabecular bone mineral density of both healthy Japanese subjects and Japanese patients with osteoporosis was measured by quantitative computed tomography (QCT) technique. The age-related reduction rate in vertebral trabecular bone mineral density of control females averaged 1.1% per year, from age 20 to 80, with an accelerated loss demonstrated after age 40. In the male controls, trabecular bone mineral density declined by an average of 0.9% per year. These values were found to be similar to the University of California at San Francisco (UCSF) QCT data (US Caucasians: 1.2% for female, 0.72% for male). Therefore, it appears that age-related rates of trabecular bone loss in the lumbar vertebrae may be similar for both Japanese and Caucasians. However, when compared to average values in UCSF QCT data of comparable age and sex, the mean values in Japanese appear to be approximately 10-20 mg/cm3 lower than Caucasian counterparts. All female patients with osteoporosis as evidenced by atraumatic vertebral fracture had QCT values below 50 mg/cm3. It is suggested that the Japanese may have lower trabecular bone mineral density than Caucasians but may also have a lower threshold for fracture of the vertebrae. Further studies are needed to establish the possible racial differences in vertebral trabecular bone mineral density, and to determine whether these possible disparities are related to genetic differences, or to differences in body size, dietary intake, physical activity or other lifestyle/environmental factors.

Multiple-hormone producing lung carcinoma

Endocrine and immunohistochemical studies were performed in a patient with lung cancer associated with gynecomastia. Elevated level of human chorionic gonadotropin (hCG) in plasma and mild hyperadrenocorticism were demonstrated by hormone assays. Postmortem examination proved the existence of anaplastic small cell carcinoma of the lung mixed with a feature of chorioepithelioma. The presence of significant amounts of adrenocorticotropic hormone (ACTH), β‐melanocyte stimulating hormone (β‐MSH), calcitonin, gastrin, hCG, hCG‐α, hCG‐β and human chorionic somatomammotropin (hCS) in tumor tissues was demonstrated by radioimmunoassays, bioassay and immunohistochemical techniques. We present here a unique case of multiple hormones producing tumor elaborating both hormones of amine precursor uptake and decarboxylation (APUD) series (ACTH, β‐MSH, calcitonin and gastrin) and of placentral origin (hCG, hCG‐α, hCG‐β and hCS).

Blunted TSH and unaltered PRL responses to TRH following repeated administration of TRH in neurologic patients: A replication of neuroendocrine features of major depression

A blunted thyrotropin (TSH) and an unaltered prolactin (PRL) responses to thyrotropin-releasing hormone (TRH) are widely recognized in neuroendocrinology of depression. We studied effects of repeated TRH administration of 1 mg/day for 10 days on the pituitary-thyroid axis function and PRL secretion in 16 euthyroid patients with neurological disorders. Although levels of serum thyroid hormones and of nonstimulated PRL were not affected by the treatment, baseline TSH levels were markedly inhibited. A blunted response of TSH to TRH was found without a significant effect on a PRL response to TRH after long-term treatment with TRH in four patients in whom a TRH test was performed. These changes are similar to those in depressed patients. TRH administration in this manner replicates a lowered sensitivity of thyrotrophs of the pituitary with a normal responsibility of lactotrophs in depression.

Bioavailability of Oyster Shell Electrolysate

Balance studies were conducted on 4 normal elderly subjects, 2 males and 2 females, ranging in age between 66 and 86 years in order to compare the bioavailability of oyster shell electrolysate with that of calcium carbonate and calcium lactate, in a crossover design. In each subject, 600 mg oyster shell electrolysate was more effective than calcium carbonate or calcium lactate containing the same 600 mg calcium to restore the negative calcium balance found on 600 mg/day calcium intake, suggesting a better bioavailability of oyster shell electrolysate than the two kinds of calcium salts.

Quantitative computed tomography: Comparison of two calibration phantoms

Vertebral trabecular mineral density of healthy Japanese (91 females and 67 males) was measured using the quantitative computed tomography (QCT) technique in a cross-sectional study. We compared estimates of vertebral bone density using two calibration phantoms: the Genant K2HPO4 phantom developed by Genant and a solid CaCO3 phantom developed by Chugai Pharmaceutical. Using the CaCO3 phantom, the rate of decrease of spinal trabecular mineral with age in control females averaged 1.1% per year from age 20 to 80, with an accelerated loss demonstrated at menopause (1.8%). Trabecular bone mass in male controls declined an average 0.9% per year. There was a highly significant correlation between the results obtained with each phantom (r=0.980, p<0.001). This relation was linear over the range of bone mass (60 –172 mg K2HPO4/cm3), and was expressed by the equation y(CaCO3)=1.26×(K2HPO4)+12.3 There was, however, some dispersion of the data around the regression. The calibration phantom used for the measurement of the vertebral trabecular bone should need to be more consistent in longitudinal studies. Apart from this consideration, a solid Chugai phantom can be said to be useful having practical advantages in its flexibility.

Basic and clinical evaluation of the measurement of bone resonant frequency

SummaryA new computerized apparatus was constructed to measure the resonant frequency of human ulnain vivo with high sensitivity and reproducibility. Experimental studies using aluminum bar and dried human bone revealed the importance of the ulna being positioned parallel to the radius, approximately 90 degree flexion of the elbow joint, and minimal muscle activity in order to demonstrate maximum resonant frequency of ulna. Measurement of bone resonance in monkeysin vivo and after removal of the bonein vitro showed good agreement. Product of F (maximum resonant frequency in Hz) and L (ulnar length in cm), FL, indicating the speed of propagation of sound wave through the ulna, showed a significant positive correlation with bone mineral content/bone width (BM/BW) measured by Norland-Cameron apparatus and age-bound decline in both sexes. Patients with osteomalacia and primary hyperparathyroid bone disease tended to have higher FL values than expected from BM/BW. Two-dimensional display of FL and BM/BW thus appears to be useful in distinguishing osteoporosis from osteomalacia better than the use of BM/BW alone.

Intracranial Human Chorionic Gonadotropin Producing Tumors

We are reporting 4 cases of the intracranial human chorionic gonadotropin (HCG) producing tumors. Case 1 was a 21-year-old female with visual disturbance, diabetes incipidus, and hypogonadism. Case 2 was an 11-year-old male with visual disturbance, diabetes incipidus and precocious puberty. Case 3 and 4 were 10-year-old males who had progressive left hemiparesis and precocious puberty. According to the endocrinological examination of hypothalamic pituitary function by radioimmunoassay, serum luteinizing hormone (LH) levels were abnormally high, and serum follicle stimulating hormone (FSH) levels were scanty in all cases. As the result of radioimmunoassay using antibody to native HCG and β-subunit of HCG, native HCG as well as α and/or β-subunit of HCG were identified in sera of all cases, in CSF of 2 cases, in tumor tissue of 1 case and in urine of 1 case. Tumors were confirmed to be located in suprasellar, hypothalamic and thalamic region by neuro-radiological examinations. Two out of four cases were operated and were diagnosed to be choriocarcinoma and two-cell-pattern pinealoma (germinoma). Following LINEAC irradiation in all cases, HCG levels in the serum and in the CSF became negligible. Serum LH and FSH levels in all cases and plasma testosterone concentration in 3 males who were diagnosed as precocious puberty fell into normal range. Histologically, a part of intracranial human chorionic gonadotropin producing tumors seemed to be germ cell origin. Endocrinological examinations by radioimmunoassay are very useful to make diagnosis and therapy as well as to predict prognosis.

Somatostatin inhibits duodenal calcium transport mediated by 1,25-dihydroxyvitamin D3 in perfused duodena from normal chicks

We have reported that physiological dose (30pM-650pM) of 1,25-dihydroxyvitamin D3[1,25(OH)2D3] increased the unidirectional movement of45Ca2+ from the lumen to the venous effluent within a few minutes in perfused duodena from normal chicks, and hypercalcemia inhibited this rapid stimulatory effect on calcium transport mediated by 1,25(OH)2 D3. The purpose of the present study was to determine the effect of somatostatin on calcium transport in chicks. The basal Ca2+ transport, in the absence of 1,25(OH)2 D3, did not change when 10−8M to 10−6M of somatostatin was added to the perfusate. The effect of 1,25(OH)2D3 on calcium transport, however, was completely abolished on addtion of 10−6M somatostatin in the perfusate, and partially blocked on addition of 10−7M somatostatin and 10−8M somatostatin had no effect on 1,25(OH)2 D3 mediated calcium transport. These results suggest that somatostatin may decrease intestinal calcium transport mediated by the rapid direct action of 1,25(OH)2 D3.