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Biomedical subjects

M Minagawa

Publications and source records attributed to M Minagawa.

At least 55 records · Page 3Linked to original sources

Participation of NK1.1+ T cells in the rejection of lpr alphabetaT cells when bone marrow cells of lpr mice are transplanted into B6 mice.

When C57BL/6 (B6) mice were irradiated (9 Gy) and received bone marrow (BM) cells of B6-lpr/lpr mouse origin (i.e., lpr-->B6), all mice died within 6 days. In the irradiated B6 mice, radioresistant CD3 IL-2Rbeta+ NK cells and IL-2Rbeta+ CD3int cells (i.e., CD3int cells of extrathymic origin) remained, especially in the liver. There were two subsets, NK1.1+ and NK1.1-, among the IL-2Rbeta+ CD3int cells. However, the NK1.1+ subset (i.e., NK1.1- T cells) was much more radioresistant, and the majority of CD3int cells belonged to this subset in irradiated mice. The expansion of lymphocytes from injected BM cells did not occur in the irradiated B6 mice. However, such expansion did take place in irradiated B6-lpr/lpr mice injected with both BM cells of B6-lpr/lpr and B6 origin. As a result, the mice subjected to BM cells survived. Irradiated B6 mice were treated in vivo with anti-NK1.1 mAb or anti-asialoGM1 antibody to eliminate NK cells alone or both NK cells and NK1.1+ T cells. When irradiated B6 mice were pretreated with anti-NK1.1 mAb, the mice could survive. These results suggest that intact NK1.1+ T cells of extrathymic origin may recognize abnormal BM cells with the lpr gene and inhibit the expansion of lymphocytes, including abnormal double-negative CD4 8 cells, in B6-lpr/lpr mice. To inhibit the expansion of lymphocytes, mechanisms other than Fas ligand/Fas molecules on extrathymic T cells may be responsible.

Animals↗

Serous cystadenoma of the pancreas with invasive growth: benign or malignant?

We describe a case of serous cystadenoma, that invaded a lymph node and adipose tissue. Preoperatively, the cystic lesion of the pancreas was diagnosed as a serous cystadenoma and subsequently the patient, a 71-yr-old woman, underwent distal pancreatectomy with splenectomy. Macroscopically, a greyish white, externally lobulated and partly ovoid tumor, measuring 12 x 8.5 x 5 cm, occupied the pancreatic body and tail extensively. In cross-section, multiple nodules were observed, which measured from 0.5 to 3 cm in diameter, were separated by hyalinized fibrous septa and were filled with numerous microcysts. Light microscopic findings were consistent with those for serous cystadenoma. At the splenic hilus, the tumor was found to have invaded the lymph node and adipose tissue. Based on the clinicopathological features of the six reported cases, including the present case (which behaved in a malignant fashion in terms of pathological findings of invasion or metastasis), serous cystadenoma should be regarded as having the potential for malignant growth.

Adipose Tissue↗

Difference in height associated with a translation start site polymorphism in the vitamin D receptor gene.

The function of 1,25-dihydroxyvitamin D3 in bone development is to regulate the differentiation or proliferation of osteoblastic, osteoclastic, and chondrocytic lineage, affecting bone mineralization and linear bone growth. An A(T/C)G substitution exists in the first of the two putative translation initiation sites in exon 2 of the vitamin D receptor (VDR) gene. We studied the relationship between exon 2 polymorphism and height in 90 healthy Japanese female subjects aged 18-20 y, who had attained final height, in 159 healthy Japanese aged 13 y, and 24 children with constitutional short stature aged 6-10 y less than -1.5 SD in height, mostly with parents of normal height. Exon 2 polymorphism was analyzed by PCR-single strand conformation polymorphism, PCR-direct sequencing, and PCR-restriction fragment length polymorphism. The frequency of the exon 2 polymorphism was genotype CC (ACG/ACG), 0.37; genotype CT (ACG/ATG), 0.51; and genotype TT (ATG/ATG), 0.12 in 249 normal subjects. The mean height of female subjects aged 18-20 y with the genotype CT was 160.3 +/- 4.3 cm (mean +/- SD), whereas that with CC was 4.4 cm lower (p < 0.0001), and that with TT was 2.7 cm lower (p = 0.0302). At age 13 y, this trend was observed, and the mean height SD score of subjects with the genotype CT was taller than homozygotes (CC/CT; p = 0.0363 and CT/TT; p = 0.0208) in 159 subjects. Genotype CT in 24 children with constitutional short stature was less frequent than other genotypes (CC, 0.62; CT, 0.21; TT. 0.17) (chi 2 p value, 0.0171). In conclusion, the exon 2 polymorphism affecting the VDR mRNA and protein is one of the major determinants of adult height at least in female Japanese, which was noted at the age of 13 y examined in both sexes.

Adolescent↗

Familial hypoparathyroidism: identification of a novel gain of function mutation in transmembrane domain 5 of the calcium-sensing receptor.

Activating mutations of the extracellular calcium (Ca2+e)-sensing receptor (CaR) gene, mostly in its extracellular domain, can cause both familial and sporadic hypoparathyroidism. We report a Japanese family with severe hypoparathyroidism with pretreatment serum calcium (Ca) levels of 4.9-5.9 mg/dL. The proband presented with a seizure at 6 days of age. Her older brother and mother, who had also experienced seizures and tetany, respectively, likewise had hypoparathyroidism. A heterozygous missense mutation substituting a cysteine for the phenylalanine normally present at codon 788 (F788C) was identified in the CaR's fifth transmembrane domain and was shown to cosegregate with the disease. The mutation was absent in DNA from 50 control subjects. Analysis of the functional properties of the mutant receptor was carried out in transiently transfected HEK293 cells loaded with fura-2 by assessing Ca2+e-evoked increases in the cytosolic calcium concentration (Ca2+i). There was a leftward shift in the concentration-response curve for the mutant receptor [EC50 (effective concentration of Ca2+e producing half of the maximal Ca2+i response, 2.7 +/- 0.1 vs. 4.1 +/- 0.1 mmol/L for the wild-type receptor]. HEK293 cells cotransfected with both the wild-type and mutant CaRs (to mimic the heterozygous state in affected family members) showed an EC50 (3.0 +/- 0.1 mmol/L) similar to that of the mutant CaR alone. Thus, we confirm that 1) a gain of function mutation in the fifth transmembrane domain of the CaR causes severe familial hypoparathyroidism by rendering the receptor more sensitive than normal to activation by Ca2+e; 2) some patients in the family do not experience seizures despite their severe hypocalcemia; and 3) this condition needs to be differentiated from other causes of hypoparathyroidism.

Blotting, Western↗

Autosomal dominant familial hypoparathyroidism and sensorineural deafness without renal dysplasia.

OBJECTIVE: A family is described which has a unique combination of autosomal dominant hypoparathyroidism and sensorineural deafness without renal dysplasia. CASE REPORT: The proband was a male infant aged 1 month with episodes of seizures for 20 days. He was born at 35 weeks' gestation without asphyxia, weighing 2040 g. His initial calcium, phosphorus and percentage of tubular reabsorption of phosphorus were 6.8 mg/dl (normal range 8.5-10.5 mg/dl), 8.9 mg/dl (normal range 5.5-7.4 mg/dl) and 96.8% (normal range 85-95%) respectively. He had normal values for serum parathyroid hormone (PTH) and 25-hydroxyvitamin D. No abnormalities were found by renal imaging and a routine renal function study. He showed a brisk plasma cAMP increase in response to human PTH-(1-34) infusion. He had normal karyotype 46, XY, without a microdeletion in chromosome 22q11.2 by an in situ hybridization method. Five family members were affected with hypoparathyroidism with sensorineural deafness with autosomal dominant transmission. The study of calcium-sensing receptor and preproPTH gene showed a normal DNA sequence. CONCLUSION: The combination of familial hypoparathyroidism with sensorineural deafness without renal dysplasia is novel and the cause may be distinct from previously reported familial hypoparathyroidism with sensorineural deafness and renal dysplasia.

Adult↗

Sibling relationships of Japanese children with diabetes.

Sibling relationships among diabetic children and their sibling are similar to those among healthy children. However, there was more sibling interaction among diabetics and their siblings than among healthy children. The diabetic's siblings are interested in learning about diabetes and in being supportive to their ill brother or sister. However, the feelings are different among the ill children. The ill sibling does not feel that the healthy sibling is supportive of the strict dietary regimen. This is especially true when it comes to eating sweets in front of them. Many parents viewed their healthy children as supportive to the patients, and they wished them to continue to be supportive persons to the patients in the future. Some parents felt guilt and conflict about spending more time with the ill child.

Adaptation, Psychological↗

Numerical and functional characteristics of lymphocyte subsets in centenarians.

The immune system in the aged is a very interesting subject for study. In this study, analysis was extended to extrathymic T cells as well as NK cells and "conventional" T cells (i.e., thymus-derived T cells) in terms of their constitution and function in both healthy and unhealthy centenarians. Middle-aged persons were used as controls. Healthy and unhealthy centenarians showed lower levels in the proportion and absolute number of lymphocytes. The major change in the constitution of lymphocyte subsets was increased levels in the proportion of NK cells (CD56+/CD57+) and extrathymic T cells (CD3+CD57+). Inversely, conventional T cells decreased in proportion and function (i.e., proliferative response to mitogen). Although NK cells increased in centenarians, NK activity by whole lymphocytes and the purified NK fraction decreased. The difference between healthy and unhealthy centenarians was small in all parameters, the only difference being a lower level of expression of CD56 antigens on CD57+ T cells in unhealthy centenarians. These results indicate that there is a major shift in lymphocyte population from conventional T cells to NK cells and extrathymic T cells with aging. Concerning the age-associated increases in CD56+ T and CD57+ T cells, these cells correspond to NK1+ T cells in mice.

Aged↗

Circadian rhythm of leucocytes and lymphocytes subsets and its possible correlation with the function of the autonomic nervous system.

There are physiological variations in the levels of leucocytes. Among these, the circadian rhythm is very important in terms of the magnitude. Since newly identified lymphocyte subsets (i.e. extrathymic T cells) have recently been detected, a comprehensive study of the circadian rhythm was conducted. All leucocytes were found to vary in number or proportion with a circadian rhythm and were classified into two groups. One group--granulocytes, macrophages, natural killer (NK) cells, extrathymic T cells, gammadelta T cells, and CD8+ subset--showed an increase in the daytime (i.e. daytime rhythm). The other group--T cells, B cells, alphabeta T cells, and CD4+ subset--showed an increase at night. Humans are active and show sympathetic nerve dominance in the daytime. Interestingly, granulocytes and lymphocyte subsets with the daytime rhythm were found to carry a high density of adrenergic receptors. On the other hand, lymphocyte subsets with the night rhythm carried a high proportion of cholinergic receptors. Reflecting this situation, exercise prominently increased the number of cells with the daytime rhythm. These results suggest that the levels of leucocytes may be under the regulation of the autonomic nervous system.

Adult↗

Cloning and characterization of the promoter regions of the human parathyroid hormone (PTH)/PTH-related peptide receptor gene: analysis of deoxyribonucleic acid from normal subjects and patients with pseudohypoparathyroidism type 1b.

Expression of the PTH/PTH-related peptide (PTHrP) receptor (PTHR) in the mouse is controlled by at least two promoters. The downstream promoter (P2) is ubiquitously expressed, whereas expression of the upstream promoter (P1) is largely restricted to kidney. These observations may provide a genetic basis for a human PTH resistance syndrome, pseudohypoparathyroidism type 1b (PHP1b), in which renal, but not osseous, signaling by PTH is defective. We, therefore, cloned and characterized the 5'-end of the human PTHR gene and found that its organization is very similar to that of the mouse. Transcription initiation sites of human P1 and P2 promoters are in similar, but not identical, positions to those of the mouse gene. The identification of a human P2 promoter is significant because no P2-specific human PTHR complementary DNAs have been isolated to date. Southern analysis of genomic DNA from seven PHP1b patients did not reveal any rearrangements in proximal promoter regions or exons encoding 5'-untranslated region sequences. No significant sequence differences were found in clones of normal and patient DNAs encompassing proximal promoter sequences, and untranslated region and signal sequence exons. Thus, in the seven PHP1b patients analyzed, no defects were identified that would influence initiation site selection, stability, or splicing of renal PTHR transcripts. These data indicate that the genetic defect(s) in PHP1b in these patients lies in distal enhancer elements of the gene, in an essential transcriptional regulator, or in some as yet unidentified cofactor required for renal PTH signaling.

Adolescent↗

Jansen-type metaphyseal chondrodysplasia: analysis of PTH/PTH-related protein receptor messenger RNA by the reverse transcriptase-polymerase chain method.

Jansen-type metaphyseal chondrodysplasia (JMC) has both delayed ossification in long bones and usually hypercalcemia. We report a Japanese male patient with JMC who presented with rachitic signs on radiographs, hypercalcemia (13 mg/dl) and low %TRP at age 3 months (mo). Hypercalcemia was treated from age 3 mo to 11 yr. Progressive widening, splaying and fragmentation of the metaphyses have been recognized on radiographs which resulted in shortened tubular bones and consequent short stature [107 cm (-6.5 SD)] at age 13 yr. Hypercalcemia tended to normalize, and %TRP became normal at age 13 yr. Repeated measurements of serum PTH and PTH-related protein (PTHrP) levels showed that they were low or normal in the face of hypercalcemia and high urine cAMP excretion, which led us to suspect constitutive activation of the PTH/PTHrP receptor. Direct sequencing of PTH/PTHrP receptor complementary DNA from skin fibroblast cells revealed a CAC to CGC transversion yielding a strictly conserved His223 to Arg substitution found in 90% of DNA fragment in the second transmembrane domain of the receptor. This mutation created a restriction site Sphl (G/CATG/C). Direct sequencing of genomic DNA and also restriction enzyme digestion revealed heterozygous transition. The mutation was absent in the parents with normal phenotype. We conclude that both dysplastic bone lesions and calcium homeostasis are age-dependent in JMC, and that the His223-Arg substitution is the same as that found in four Caucasian patients with a similar phenotype irrespective of the ethnic difference, and that the preferential expression of an abnormal allele of the PTH/PTHrP receptor mRNA in skin fibroblast despite heterogygotic transversion in the genomic DNA suggests the importance of allele expression.

Dwarfism↗

[Female autopsy case of Seitelberger's connatal form of Pelizaeus-Merzbacher disease].

We report here an autopsy case of connatal Pelizaeus-Merzbacher disease, the second from Japan. Her clinico-pathological findings were essentially the same as those of the first case that we reported previously. The clinical course of this patient was 19 years in duration. Pathologically myelin had disappeared from the entire central nervous system, whereas that of the peripheral nervous system was preserved. Axons appeared also intact except for torpedo formation in the cerebellum. Demyelinated areas showed isomorphic gliosis. Recent studies have revealed impairment of proteolipid protein synthesis in classical Pelizaeus-Merzbacher disease, the causative gene of which being located on the X chromosome. Thus, this disease is inherited as an X-linked recessive trait. However we report herein a sporadic female case in a non-consanguineous family. Therefore, we propose that this disease might have another causative gene and/or another mode of inheritance.

Adult↗

Stable carbon and nitrogen isotopic composition of diet and hair of Gidra-speaking Papuans.

The carbon and nitrogen stable isotopic composition of the scalp hair and diet of Gidra-speaking people in four villages in Papua New Guinea is presented. The isotopic composition of hair was measured, while that of the diet was estimated from food consumption survey data and the measured isotopic composition and protein and carbohydrate contents of food items. The average isotopic ratios of the hair samples and of the diet varied among the four study villages, which were selected because of their diverse ecological settings. Comparison was made between hair and calculated dietary isotopic compositions. Two of the four diet-hair enrichment values obtained for 13C (+1.8 and 2.2%) were similar to those previously reported (1.4-2.0%), but the other two values (3.7 and 4.8%) were greater than in earlier reports. 15N enrichment was systematically greater (by 1.0%) than reported values (4.3%) except for one village, where a much greater enrichment (6.9%) was found. The factors potentially relevant to these deviations are discussed. Possible errors in estimating the dietary isotopic composition and minor modifications of dietary habits revealed by food consumption surveys could explain most of the discrepancies. However, the great enrichment of 15N found in one of the villages remains unexplained.

Adult↗

Management of new hepatic nodules detected by intraoperative ultrasonography during hepatic resection for hepatocellular carcinoma.

BACKGROUND: During hepatic resection for hepatocellular carcinomas (HCCs) it is not uncommon that intraoperative ultrasonography detects "new nodules" that were not found by preoperative examinations. Because the operative procedure may have to be changed if the new nodule is another HCC lesion, differential diagnosis of such nodule is critical. This study examines ultrasonographic findings and clinical features of new nodules and discusses how to cope with such nodules in the operating room. METHODS: Fifty-one new nodules detected in 92 liver resections were analyzed. Intraoperative ultrasonography was performed by using 5.0 or 7.5 MHz probes after mobilization of the liver. Histologic diagnosis of the new nodules was made by means of enucleation, resection with the primary lesions, thick-needle biopsy, or additional partial resection of the liver. RESULTS: New nodules were detected in 27 (29.3%) of 92 resected cases. Internal echoic pattern of the nodules were type I, hypoechoic (29 nodules); type II, hyperechoic (19); and type III, mosaic (3). Ten HCC nodules (17.9%) were included, and chance of being malignant for each type was 24.1%, 0%, and 100%, respectively. Of the seven patients with malignant new nodules, three underwent additional systematic resection and all were alive without recurrence 49, 13, and 11 months after the operation. Others were treated by use of enucleation (two cases), intraoperative ethanol injection (one case), and intraarterial chemotherapy (one case). CONCLUSIONS: Although most of the new nodules lacked specific findings for HCC, hypoechoic nodules, 24.1% of which were HCCs, should not be overlooked. Histologic confirmation of the new nodules is necessary especially when the number of lesions detected before operation is multiple or the interval between lipiodol computed tomography and the operation is longer than 2 months. Once the diagnosis of HCC has been made for the new nodule, systematic additional resection to remove the new lesion is recommended.

Adult↗

H1-receptor-mediated excitation and facilitation of the heat response by histamine in canine visceral polymodal receptors studied in vitro.

1. We examined excitation and the facilitatory effect on the heat responses induced by histamine in visceral polymodal receptors with the use of the canine testis-spermatic nerve preparation in vitro. 2. The proportion of units that showed excitation (> 10 impulses 1 min after application of histamine was initiated) increased roughly with higher concentrations of histamine: 7% at 1 microM, 26% at 10 microM, 79% at 100 microM, and 61% at 1,000 microM. The discharge rate also increased with the concentration. 3. Histamine (100 and 1,000 microM) responses > 0.5 imp/s were observed only in units with conduction velocities (CVs) of < or = 10 m/s, but not in those with CVs faster than 10 m/s. On average, histamine-induced discharges were significantly greater in units with CVs of < or = 10 m/s at all concentrations > or = 10 microM. Thus units studied in this experiment were empirically divided into slow-CV (< or = m/s) and fast-CV (> 10 m/s) groups. 4. Histamine significantly facilitated the heat responses of the slow-CV group from 10 microM, and also facilitated the fast-CV group from 100 microM. This sensitizing effect was observed irrespective of the precedent histamine-induced excitation. The magnitude of sensitization tended to increase with an increase in histamine concentration. 5. For studying the histamine receptor subtype involved in excitation and facilitation, we used D-chlorpheniramine maleate (5 microM) (an H1 receptor antagonist), famotidine (20 microM) (an H2 receptor antagonist), and thioperamide maleate (20 microM) (an H3 receptor antagonist). The magnitude of histamine-induced excitation of the slow-CV group was significantly suppressed by the H1 receptor antagonist but not by other antagonists. 6. The facilitatory effect of histamine on the heat response was also suppressed by the H1 receptor antagonist in both slow- and fast-CV groups. 7. These results strongly suggested that both excitation and facilitation of the heat response induced by histamine are mediated through the H1 receptor.

Animals↗

Spinal and femoral bone mass accumulation during normal adolescence: comparison with female patients with sexual precocity and with hypogonadism.

Since the attainment of higher bone mineral density (BMD) is a crucial strategy in preventing age-related bone loss and consequent fracture, we determined when bone mass of the lumbar spine (L2-L4) (g/cm2) and femoral neck (g/cm2) reaches its peak in healthy Japanese subjects and examined the influence of early exposure to estrogen and estrogen deficiency on BMD. We also determined the volumetric BMD, termed bone mineral apparent density (BMAD), of the lumbar spine and femoral neck. Using dual-energy x-ray absorptiometry (DXA) (Hologic QDR-1000), we measured BMD of both the lumbar spine and the femoral neck in 31 healthy children aged 2-11 yr, 269 children (138 males and 131 females) aged 13-19 yr, 12 men and 12 women aged 20-34 yr as adult controls, 11 patients with female central sexual precocity, and 3 patients with female primary hypogonadism. Because the densitometric data obtained from DXA are strongly influenced by the size of the bone in growing subjects, the volumetric BMAD (g/cm3) of the vertebral cube (L2-L4) and femoral neck were determined: BMAD (g/cm3) = BMD (g/cm2)/square root of scanned area (cm2) for the lumbar spine and by BMAD = BMD/width for the femoral neck. The BMD, both lumbar spine and femoral neck, nearly reached its peak at age 14.5-15 yr in girls and 16.5-17 yr in boys when compared with adult normal values. The difference in this age between sexes is identical to the difference in age at sexual maturation. BMD in patients with sexual precocity was high compared to age-matched controls, whereas patients with primary hypogonadism showed lower lumbar apparent BMD, and the increase in lumbar BMAD (g/cm3) was noted after the progression of puberty in healthy children, probably suggesting the importance of sex steroids in the increase of BMD and lumbar BMAD in both sexes. The girls with earlier menarche showed higher lumbar BMD at age 18 and 19 yr. For the femoral BMAD, there was no significant relationship between this value and age in girls. We conclude that peak bone mass is mainly achieved by late adolescence in Japanese as in Caucasians and that pubertal progression and probably estrogen itself play a crucial role in accumulation of bone mass in females.

Adolescent↗

Early detection of infants with hypophosphatemic vitamin D resistant rickets (HDRR).

The onset of physical signs in infants with hypophosphatemic vitamin D resistant rickets (HDRR) has generally been considered to be at the age of 12 months, but the time of appearance of hypophosphatemia and rachitic signs on radiographs remains unclear. We report a prospective study in three neonates whose mothers were HDRR. At birth, despite a low maternal serum inorganic phosphorus (Pi) level, the serum Pi level was normal together with a negligible renal Pi leak in one neonate. At age 3 months, their serum Pi levels, percentages of tubular reabsorption of Pi, and renal tubular maximal rates of Pi reabsorption in relation to the glomerular filtration rate were low except for one infant. Radiographically, their rickets were not apparent at birth but at age 3 months in all. A premature born infant, born at 28 weeks' gestation weighing 1240 g, was diagnosed as HDRR based on hypophosphatemia due to low renal tubular maximal rate of phosphorus reabsorption in relation to the glomerular filtration rate (TmP/GFR) and normal urine Ca excretion at age 5 months. They were initially treated with 1 alpha-hydroxyvitamin D3 (1 alpha OHD3) and later with 1 alpha OHD3 in combination with Pi, which results in healing of the rickets and a normal increase in height. Thus, early detection and treatment of patients born from mothers with HDRR before physical signs of bow-leg and short stature is possible, but the outcome of early treatment requires further study.

Age of Onset↗