Immunoglobulin G from anti-glucose-6-phosphate isomerase antibodies positive patient with rheumatoid arthritis induces synovitis in cynomolgus monkeys

Anti-glucose-6-phosphate isomerase (GPI) antibodies (Abs) solely induce arthritis in mice. High titers of anti-GPI Abs are found in some patients with rheumatoid arthritis (RA), but their pathogenic role remains elusive. The aim of this study was to evaluate the pathogenic role of anti-GPI Abs in cynomolgus monkeys. IgG fractions were separated from sera of anti-GPI Abs-positive RA patients and healthy subjects and directly injected into the metacarpophalangeal joints of 4 cynomolgus monkeys. At day 16, the joints were harvested and examined histologically and immunohistochemically. The expression of C5a receptor (C5aR) molecule in the synovium was quantified by real-time PCR using cDNA from monkey joints. In monkey joints, IgG including anti-GPI Abs resulted in recruitment of granulocytes and mononuclear cells, strong deposition of human IgG on the articular surface, and overexpression of C5aR, but no joint swelling. No infiltrated cells or IgG deposition were observed in monkeys injected with IgGs from healthy subjects. Our results suggest that IgG fraction from RA patients including anti-GPI Abs may play a crucial role in the generation of synovitis in monkeys, although the pathogenesis of anti-GPI Abs in RA patients is still uncertain.     

Lung adenocarcinoma with bronchioloalveolar carcinoma component is frequently associated with foci of high-grade atypical adenomatous hyperplasia

We assessed the occurrence of atypical adenomatous hyperplasia (AAH) in whole lung lobes with primary cancer lesions. Following surgical resection, tissue specimens were sliced to a thickness of 4 mm (3,641 specimens from 61 cases; mean = 59.7 specimens per case). A total of 119 AAH foci were found and an association was evident in 25 (57%) of 44 adenocarcinomas, 3 (30%) of 10 squamous cell carcinomas, and 2 (29%) of 7 other lung cancers. Histologic evaluation showed that 108 AAH foci were categorized as low-grade and the other 11 as high-grade AAH. These 11 foci of high-grade AAH were present in 7 patients with adenocarcinoma, and in 1 patient there was a synchronous double primary lung adenocarcinoma. High-grade AAH was closely associated with bronchioloalveolar carcinoma (BAC) type adenocarcinoma, and low-grade AAH with non-BAC adenocarcinoma. The mean +/- SD Ki-67 labeling index in high-grade AAH (3.5%+/-2.9%) was significantly higher than for the low-grade index (1.4%+/-1.6%). We propose that foci of high- but not low-grade AAH may be potential precursor lesions of lung adenocarcinoma, especially with the BAC component.     

HLA class I distribution in Japanese patients with schizophrenia

Several Caucasian studies and one Japanese study have observed associations between human leukocyte antigen (HLA) class I specificities, including A24 (9) and A26 (10) and schizophrenia. Most of those studies were conducted in 1970s and early 1980s, when the typing technique of HLA was not adequately reliable. Also, an operational diagnostic system was not employed in many of the studies. The present study investigated frequencies of HLA-A specificities in schizophrenia patients (ICD-10 and DSM-III-R, n=98) and sex-matched healthy controls (n=392) from population in the southwestern part of Japan. HLA-B and -C specificities were studied in addition. Frequencies of subjects possessing A24 and A26 were not different between the patients and controls (54% and 24% in the patients and 62% and 24% in the controls, respectively). No significant difference was found in frequencies of other class I (A, B, and C) specificities between the patients and the controls. Thus, the present study provided no evidence for an association between the HLA class I specificities, including A24, A26, and others, and schizophrenia in the Japanese population.     

Association of natural tooth loss with genetic variation at the human matrix Gla protein locus in elderly women

Natural tooth loss represents a major medical issue within the elderly population, since it impairs masticatory function critical for oral intake of essential nutrition. Contribution of genetic factors has been implicated in the determination of natural tooth loss; degree of reduction in number of natural teeth remaining intact (NTI) varies among individuals; thus, heterogeneity in NTI might reflect genetic variation within the population. One candidate gene, the matrix Gla protein gene (MGP), has been implicated in the pathogenesis of bone loss through a repression of bone/tooth formation. We have investigated a possible association between the CA repeat polymorphism at the human MGP gene locus and the NTI in 458 elderly Japanese women. In 916 chromosomes tested, ten alleles of the polymorphic nucleotide repeat were observed (designated A1–A10), among which five alleles were regarded as major alleles to be tested for the association. Twenty-seven women who possessed an A6 allele (164 bp) had significantly higher NTI than the remaining participants (n=431), who did not carry an allele of that size (mean: 10.0 teeth vs 5.6 teeth; P=0.007, Mann-Whitney test). An eight-year longitudinal follow-up study of NTI suggested that the genetic variations at the MGP locus did not affect the rate of tooth loss in the elderly period. These results suggest that genetic variation at the MGP gene locus is associated with some determinants for tooth loss in elderly women.     

Axis development in avian embryos: the ability of Hensen's node to self-differentiate,as analyzed with heterochronic grafting experiments

A series of experiments consisting of transplantation of Hensen's nodes has been conducted to examine axis development in avian embryos. In the first group of experiments, Hensen's nodes from quail embryos were transplanted homotopically and either isochronically or heterochronically to chick embryos, and the structures derived form the grafted nodes were assessed. The grafted Hensen's nodes typically self-differentiated structures appropriate for their stages, and the host embryos developed normally; the structures formed from grafted tissue usually merged caudally with the comparable host structures. Thus, even when the stages of the donor and host tissues were significantly mismatched (e.g., stage 3 donors and stage 9 hosts or vice versa), the graft was unable to repattern the host's neuraxis, and the host was unable to respecify the types of structures derived from the graft. In the second group of experiments, Hensen's nodes from quail embryos were transplanted to sites located just lateral to Hensen's nodes of host chick embryos, thereby providing the potential for development of additional axes. A single axis always resulted in each case in which further development occurred, with the graft self-differentiating its typical stage-specific structures, all of which merged caudally with comparable host structures. A final group of experiments served principally as a control and tested the ability of a part of Hensen's node, when it was transplanted to the extraembryonic germ cell crescent, to organize an ectopic embryo. In these experiments, the entire thickness and length of each Hensen's node, but only the central one-third to one-half of its width, was transplanted to host blastoderms, yet ectopic embryos, complete with induced neuraxes, were formed. Therefore, a part of Hensen's node has the ability to function fully as an organizer when placed in a conducive environment. Collectively, these results provide further documentation of the strong ability of Hensen's node to self-differentiate, and they suggest that once morphogenetic movements are under way, neuraxial structures can form, and characteristic rostrocaudal patterning of the neuraxis can occur, without sustained influence from Hensen's node.     

Lattices of Type I Collagen Select Invasive Variants of K-ras Oncogene-Transfected NIH3T3 with Less Cellular fibronectin

A clone of NIH3T3 transformant (H3) can yield subcutaneous tumors and experimental pulmonary metastasis in nude mice. Compared to H3 in culture, the cells after in vivo tumor growth (H3-N) acquired enhanced tumorigenicity and metastatic ability. Also, indirect immunofluorescence revealed that cellular fibronectin (c-FN) of H3-N was decreased remarkably. We have studied the interactions between H3 and extracellular matrices to elucidate these phenomena. In the present study, we observed the effect of NIH3T3, H3, and H3-N cultured in type I collagen gel. Morphologically in the collagen gel, NIH3T3 assumed an extensive elongated fiber-like shape, H3 assumed a moderately elongated shape, and H3-N assumed a round or spindle shape with short pseudopodia. Compared to conventional cultures on dishes, cell proliferation of all three types was suppressed in collagen gel, but the degree of the suppression was least in H3-N. As a result, H3-N grew fastest in collagen gel. The variants which acquired growth advantage in the subcutaneum of mice also kept it in collagen gel. H3 cells were cultured in type I collagen gel for 4 weeks, a period comparable to that of tumor formation in nude mice. The cells after this long-term culture (H3-C) acquired enhanced tumorigenicity and metastatic ability nearly equal to that of H3-N. FACS analysis revealed that the c-FN of H3-C had decreased to a value comparable to that of H3-N. This means that type I collagen gel as well as subcutaneous tissues could select variants of H3 with less c-FN through proliferation. Moreover, it is suspected that lattices of type I collagen regulate cell proliferation of fibroblast via c-FN. This revised version was published online in August 2006 with corrections to the Cover Date.     

Aberrant insulinoma of the duodenal bulb

A rare insulin-immunoreactive neuroendocrine tumor of the duodenum in a 54 year old male is reported. The incidentally identified tumor was located on the anterior free wall of the duodenal bulb and measured approximately 6 mm in diameter. Uncomplicated endoscopic resection of the tumor was carried out. The lesion exhibited classic histologic features of insulinoma of the β-islet cell type with stromal amyloid deposition. In addition to positive reactivities of chromogranin A, neuron-specific enolase, synaptophysin, Leu 7 (CD57), cystatin C, CA15–3 and cytokeratin, the non-argyrophilic tumor cells were strongly immunoreactive for insulin and C-peptide. The stromal amyloid was clearly labeled for amylin. A few cells were stained for somato-statin, whereas other hormones were negative. Interestingly, a few isolated insulin-positive cells were identiii in the non-neoplastic duodenal mucosa in the proximity of the tumor. lmmunoelectron microscopy using paraffin sections disclosed insulin-immunoreactive secretory granules in the cytoplasm. The patient exhibited no signs or symptoms of hypoglycemia. Serum insulin levels were not measured prior to resection. No tumors were demonstrated in the pancreas. Magnetic resonance imaging revealed a 1 cm asymptomatic pituitary mass, in association with moderately elevated serum prolactin levels. The patient is currently being followed up in the outpatient clinic.     

Receptor autoradiographic evidence of specific brain natriuretic peptide binding sites in the porcine subfornical organ

Specific binding sites of brain natriuretic peptide (BNP), a newly discovered peptide in the subfornical organ (SFO) of porcine brain were investigated, following incubation of related tissue sections with 125I-BNP, then using autoradiography and an image analysis coupled with computer-assisted microdensitometry. Specific 125I-BNP binding sites were found to be localized in the SFO, an area densely labeled by 125I-alpha-rat atrial natriuretic peptide and 125I-(Sar1,Ile8)-angiotensin II. Specific 125I-BNP binding to the SFO was displaced by unlabeled BNP, with a high affinity, and was calculated to be Ka = 0.385 x 10(-9) M and Bmax = 40.1 fmol/mg using a LIGAND computer program. Acquisition of these present findings enhances our knowledge of the physiology of BNP, atrial natriuretic peptides and angiotensin II system in the SFO.     

ISOLATED ADRENOCORTICOTROPIC HORMONE (ACTH) DEFICIENCY

The case to be reported is that of a 72-year-old woman with isolated adrenocorticotropic hormone (ACTH) deficiency, who complained of anorexia and generalized malaise. The secretions of human growth hormone(HGH), prolactin (PRL), luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH) were all within normal limit. In spite of the extremely low level of Cortisol, the plasma level of AGTH would not rise sufficiently, but a marked response of Cortisol to AGTH stimulation was recognizaed. The postmortem examination revealed a decrease In basophilic or PAS-positive cells of the anterior pituitary gland which also showed a selective loss of AGTH-secreting cells over immunohistochemical study. Electron microscope could easily visualize somatotroph, mammotroph, thyrotroph, FSH- and LH-gonadtroph, but corticotroph was difficult to be discerned. Adrenocortical cells demonstrated atrophy and degeneration, for which the zona fasciculata and zona reticularis were narrowed. The zona glomerulosa was slightly enlarged In width.