Familial occurrence of differentiated,nonmedullary thyroid carcinoma

Familial occurrence of differentiated, nonmedullary thyroid carcinoma in 23 patients from 11 families is reported. Five patients were male and 18 were female. The familial relationship of patients was parent and child in 12 cases from 6 families, and siblings in 11 cases from 5 families. Carcinoma of other organs was noted in other members in 8 families. Histological examination revealed 18 papillary, 2 follicular, and 2 anaplastic carcinomas (the 2 anaplastic carcinomas were considered to be transformed from preexisting differentiated carcinoma). In 1 case, the histological type was unknown. The average diameter of the primary lesion was 29.9 mm. Cervical lymph node metastasis was found in 77.8% and local recurrence in 28.6% of the patients. Solid and invasive growth was dominant. On HLA typing, phenotypes of B₇ and DR₁ were significantly redominant in familial patients compared with nonfamilial patients and normal Japanese. Moreover, the haplotype of B₇-C_w7-DR₁ was observed in 5 of 13 patients tested. It is suggested from these observations that some types of differentiated, nonmedullary thyroid carcinoma may show familial occurrence and that they may have common factors with regard to the genetic and immunologic basis of the disease.

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Resumen Se informa la ocurrencia familiar de carcinoma bien diferenciado, no medular, de tiroides en 23 pacientes provenientes de 11 familias, 5 hombres y 18 mujeres. La relación familiar fue padre e hijo en 12 casos de 6 familias, y hermanos en 11 casos de 5 familias. Se observé la presencia de carcinoma de otros órganos en otros miembros de 8 familias. El examen histopatológico reveló 18 carcinomas papilares, 2 foliculares, y 2 anaplásicos (los 2 fueron considerados como transformación de carcinomas diferenciados preexistentes). En un caso no fue conocido el tipo histológico. El diámetro promedio de la lesión primaria fue 29.9 mm. Se hallaron metástasis en ganglios cervicales en 77.8% de los pacientes y recurrencia local en 28.6%. El crecimiento sólido e invasivo apareció como característica dominante. En la tipificación HLA aparecieron como significativamente predominantes los fenotipos de B₇ y DR₁ en pacientes familiares en comparación con pacientes no familiares y japoneses normales. Por otra parte, el halotipo de B₇-C_W7-DR₁ fue observado en 5 de 13 pacientes investigados.Como resultado de estas observationes se sugiere que algunos tipos de carcinomas diferenciados, no medulares, pueden demostrar ocurrencia familiar y que pueden poseer factores comunes relacionados con las bases genéticas e inmunológicas de la enfermedad.

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Résumé On a étudié les caratéristiques du cancer de la thyroïde, dans sa variété différenciée non médullaire, survenu chez 23 patients provenant de 11 familles. Cinq patients étaient des hommes, 18 des femmes. La relation familiale était parent/enfant dans 12 cas provenant de 6 familles, et frère/soeur dans 11 cas provenant de 5 familles. Des membres de 8 autres familles présentaient un cancer d'un autre organe. Il y avait 18 cancers papillaires, 2 cancers folliculaires, et 2 cancers anaplasiques (on a considéré que les 2 cancers anaplasiques étaient des transformations à partir de cancers différenciés préexistants). Dans un cas, le type histologique était inconnu. Le diamètre moyen de la lésion primitive était de 29.9 mm. On a retrouvé des métastases ganglionnaires cervicales chez 77.8% des patients et une récidive locale chez 28.6%. Les tumeurs étaient principalement solides et invasives. Par rapport aux cancéreux non familiaux et à la population japonaise normale, il y avait plus de phénotypes B₇ et DR₁ au système HLA. L'haplotype B₇-C_W7-DR₁ était observé chez 5 des 13 patients testés.On suggère que certains types de cancer différenciés, non médullaires, ayant des facteurs communs génétiques et immunologiques, peuvent survenir dans une même famille.

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Presented at the International Association of Endocrine Surgeons in Sydney, Australia, September, 1987.     

Studies on the enhanced effect of acupuncture analgesia and acupuncture anesthesia by D-phenylalanine (first report)--effect on pain threshold and inhibition by naloxone

It has been claimed that the mechanism of acupuncture analgesia can be explained in part by endogenous opioids. If so, it might be possible to enhance the analgesic effect of acupuncture by the administration of endorphins. If D-phenylalanine (DPA), an inhibitor of the endorphin degrading enzyme, is administered, the analgesic effect of acupuncture should be prolonged due to the increased level of endorphins. From the changes of the pain threshold (PT), we investigated whether or not the pre-administration of DPA can enhance the analgesic effect of acupuncture in humans. In addition, we examined the inhibitory effect of naloxone. 1) In all five subjects whose PT was raised after acupuncture anesthesia (respondents), the rise in PT was significantly prolonged by DPA. 2) Out of 10 subjects whose PT remained almost unchanged after acupuncture anesthesia (non-respondents), the PT was increased by DPA in 5 cases. 3) The rise in PT was most prominent when DPA was administered 30 minutes before the start of acupuncture anesthesia. 4) In all 4 respondents in whom the rise in PT persisted after DPA and acupuncture anesthesia, their raised PT dropped after the intravenous injection of naloxone (10 mg). 5) These findings show that DPA enhances the analgesic effect of acupuncture by the "endorphin mechanism."     

Bruch''s membrane of the brachymorphic mouse

Bruch's membrane exists between the retinal pigment epithelium and the choriocapillary endothelium. Its structure is very complicated, having five sublayers containing basement membranes of retinal pigment epithelium and choriocapillary endothelium, outer and inner collagenous layers, and a central elastic layer. In the development of Bruch's membrane in normal mice, both basement membranes are created first. Secondarily, collagen fibers are accumulated in the space between these basement membranes and then form a collagenous layer. Finally, the elastic layer elaborated in the collagenous layer separates this into outer and inner collagenous layers. Brachymorphic mice have a disorder in the sulfation pathway, resulting in undersulfation. Consequently, in Bruch's membrane of brachymorphic mice, the expression of decorin, a small proteoglycan containing chondroitin sulfate and an indispensable component in collagen assembly, is at a very low level. It is clear that hypoplasia of the collagenous layer in Bruch's membrane of brachymorphic mice induces a disorder in the following formation of the elastic layer. These findings suggest that the formation of the collagenous layer, regulated with acidic glycoconjugates such as decorin, is important in the development of Bruch's membrane.     

Divergent expression and localization of aquaporin 5, an exocrine-type water channel,in the submandibular gland of Sprague-Dawley rats

By Western blot analysis, the expression level of aquaporin (AQP) 5 in the submandibular gland (SMG) was found to be different among individual rats of the Sprague-Dawley (SD) strain. Such differences were observed for AQP5 but not for AQP1 and consequently the SD strain was divided into two groups, one expressing a high level of AQP5 and the other a low one. The difference in average intensity of expression between the two groups was more than twofold. Immunohistochemical analysis of the SMG demonstrated that the AQP5 protein was localized in the basal and apical/lateral plasma membrane of acinar cells in rats expressing the high level of AQP5. In the rat expressing the low level, however, this channel protein was localized strongly in the apical/lateral plasma membrane, but only very weakly in the basal membrane of the acinar cells. Such a diverse localization of AQP5 was confirmed by Western blotting as well. Breeding between brother and sister was repeated for two times within high expressers and low expressers to obtain the third generation progenies (F2); the AQP5 level of the SMG in the third generation (F2 rats) from high expressers was significantly higher than the F2 from low expressers. Our present study suggests the existence of genetic variation in the expression of a water channel protein, AQP5, in rats.     

Activation of protease-activated receptor 2 stimulates proliferation and interleukin (IL)-6 and IL-8 secretion of endometriotic stromal cells

BACKGROUND: Inflammation has been proposed to play essential roles in the pathophysiology of endometriosis, in which neutrophils and mast cells have been suggested to be involved. We studied whether the protease-activated receptor 2 (PAR2), which is activated by enzymes from neutrophils and mast cells, in endometriotic stromal cells (ESC) has any implication in the development of the disease. METHODS: Cultured ESC were stimulated with various concentrations of a specific PAR2 agonist peptide. Proliferating activity of the cells was determined using immunostaining of proliferating cell nuclear antigen (a cell proliferation marker), 5-bromo-2'-deoxyuridine incorporation into DNA and cell count. The concentrations of interleukin (IL)-6 and IL-8 were measured using specific enzyme-linked immunosorbent assay kits. The phosphorylation of three mitogen-activated protein kinases (MAPK), i.e. p38 MAPK, p42/44 MAPK and stress-activated protein Kinase/c-jun N terminal Kinase, in ESC was examined with Western blot analysis. RESULTS: Activation of PAR2 stimulated the proliferation of ESC and the secretion of IL-6 and IL-8 from ESC in a dose-dependent manner. Activation of PAR2 stimulated the phosphorylation of all three MAPK, and inhibitors of each MAPK suppressed the PAR2 activation-induced proliferation of ESC. CONCLUSIONS: The activation of PAR2 in ESC may be involved in the pathophysiology of endometriosis by inducing the growth and inflammation of endometriotic lesions.     

Disease associations and altered immune function in CD45 138G variant carriers

The CD45 antigen is a haemopoietic cell specific tyrosine phosphatase essential for antigen receptor mediated signalling in lymphocytes. Expression of different patterns of alternatively spliced CD45 isoforms is associated with distinct functions. We recently identified a polymorphism in exon 6 (A138G) of the gene encoding CD45 (PTPRC) that results in altered CD45 splicing. The 138G allele is present at a high frequency among Japanese (23.7%), with 5.1% individuals homozygous for the G allele. In this study we show that the A138G polymorphism is the cause of altered CD45 isoform expression, promoting splicing towards low molecular weight CD45 isoforms. We further report that the frequency of A138G heterozygotes is significantly reduced in number in cohorts of patients with autoimmune Graves' disease or hepatitis B infection, whereas G138G homozygotes are absent from a cohort of Hashimoto's thyroiditis patients. We also show that 138G individuals exhibit altered cytokine production in vitro and an increased proportion of memory T cells. These data suggest that the 138G variant allele strongly influences these diseases by modulation of immune mechanisms and may have achieved its high frequency as a result of a natural selection probably related to pathogen resistance.     

A new method of perfusion fixation for the rabbit femur

We report a new method of perfusion fixation for the proximal one-third of the femur of the Japanese white rabbit. Fluids to flush the blood and fix the marrow were injected into the abdominal aorta and drained from the stump of the femur. The oozing of the fluids from the stumps guaranteed complete flushing and fixation. The new method facilitated fixation and decreased the volume of necessary fluids. Scanning electron microscopy (SEM) images of bone marrow fixed using the new method and using the conventional method did not differ. Large fat globules were not observed in the SEM specimens produced using either the new or the conventional method.     

Case of minocycline-induced pneumonitis with bilateral pleural effusion]

A 51-year-old man was admitted to our hospital with fever, dry cough and dyspnea. He had taken minocycline for 11 days because of urinary tract infection. Chest X-ray on admission showed diffuse reticular shadows in bilateral lung fields with bilateral pleural effusion. Cessation of minocycline led to spontaneous improvement of symptoms and radiographic findings. The lymphocyte stimulation test for minocycline with peripheral blood and pleural effusion were negative. After provocation test with minocycline, he developed fever and dry cough and bilateral ground glass opacity appeared on his chest X-ray. He was diagnosed as minocycline-induced pneumonitis and recovered rapidly following corticosteroid therapy.     

Role of NMDA receptors in the increase of glucose metabolism in the rat brain induced by fluorocitrate

The effect of inhibition of glial metabolism by infusion of fluorocitrate (FC, 1 nmol/μl, 2 μl) into the right striatum of the rat brain on the glucose metabolism was studied. Significant increases in [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) uptake (45 min) in the right cerebral cortex and striatum were observed 4 h after the infusion of FC, both as determined by the tissue dissection method and autoradiography. No significant increase in the initial uptake of [¹⁸F]FDG (1 min) was seen in the striatum. Pretreatment with dizocilpine (MK-801), an N-methyl-d-aspartate (NMDA) receptor antagonist, reduced [¹⁸F]FDG uptake in not only FC infused hemisphere but also in the contralateral hemisphere (saline-infused side). The radioactivity concentrations in plasma at 1, 5 and 45 min after the [¹⁸F]FDG injection were not altered by MK-801. This effect of MK-801 on glucose metabolism observed in the rat brain infused with FC was different from previous reports which indicated an increase in glucose metabolism in some areas of normal rat brain. In addition, the enhancement of glucose metabolism in the striatum induced by FC was almost completely abolished by pretreatment with MK-801. In the cerebral cortex, the relative ratio of radioactivity concentration in the right hemisphere to that in the left hemisphere still remained 1.37 (tissue dissection method) or 1.55 (autoradiography), which indicated that MK-801 partially blocked the effect of FC of enhancing glucose metabolism in this region. These results indicate an important role of NMDA-mediated signal transmission on the increase of glucose utilization induced by inhibition of glial metabolism.     

Cell type-specific involvement of RIG-I in antiviral response

Toll-like receptors (TLRs) play an important role in antiviral response by recognizing viral components. Recently, a RNA helicase, RIG-I, was also suggested to recognize viral double-stranded RNA. However, how these molecules contribute to viral recognition in vivo is poorly understood. We show by gene targeting that RIG-I is essential for induction of type I interferons (IFNs) after infection with RNA viruses in fibroblasts and conventional dendritic cells (DCs). RIG-I induces type I IFNs by activating IRF3 via IkappaB kinase-related kinases. In contrast, plasmacytoid DCs, which produce large amounts of IFN-alpha, use the TLR system rather than RIG-I for viral detection. Taken together, RIG-I and the TLR system exert antiviral responses in a cell type-specific manner.