Biomedical subjects
Publications and source records attributed to Y Miki.
We report a case of achondroplasia with downward displacement of the brain stem. Although upward displacement and anterior angulation deformity of the brain stem are common findings in achondroplasia, they were not observed in this case, because of a coexistent Chiari malformation.
An encapsulated fluid epidural haematoma in a 9-year-old boy was successfully evacuated by a simple burr hole procedure 5 months after a minor head injury. Clinicopathological findings suggested that chronic expansion of an initially unsuspected epidural haematoma occurred as a result of repeated haemorrhages from the haematoma membrane, resulting in an unusually long delayed appearance of clinical evidence. This case demonstrates that a chronic expanding process similar to that seen in chronic subdural haematoma needs to be considered as a possible complication of epidural haematoma and indicates an important role for the haematoma membrane in the chronic expansion of epidural haematoma.
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A critical step in positional cloning is the identification of candidate genes from a large, genetically defined region. Candidate gene isolation by hybrid selection, genomic sequencing, and direct cDNA library screening identified 45 candidate gene fragments (CGFs) from a 600 kb genomic region that contains the BRCA1 gene. These CGFs define a minimum of 15 genes, six of which are newly localized to the BRCA1 region. We present an analysis of the efficiency and the sequences generated for each of these methods. We also compare our CGF set to those reported for the BRCA1 region by three other groups, revealing a surprising lack of overlap among the sets.
An 89-year-old woman presented a rapidly growing red nodule of 5 years' duration on her left eyelid. Histologically, the entire dermis was occupied by multiple lobules of atypical tumor cell nests surrounded by inflammatory cells and fibrous stroma. The tumor cell nests were connected with the overlying epidermis and extended into the subcutaneous fat and muscles. There were no tendencies towards squamous or glandular differentiation of the tumor cells. Immunohistochemistry showed the tumor cells to be positive for keratin/cytokeratin and epithelial membrane antigen, but negative for neuron specific enolase and vasoactive intestinal polypeptide. S-100 protein-positive Langerhans cells were also found within the tumor nests. There was no apparent evidence of a primary lesion elsewhere.
The clinical characteristics of vertebrobasilar dissecting aneurysms occurring with subarachnoid hemorrhage (SAH) were reviewed in 42 patients, with particular focus on the time, incidence, and outcome in association with subsequent rupture. Twenty-nine patients underwent 31 surgical procedures, and the remaining 13 patients were managed without surgery. Surgical details included 19 proximal vertebral artery obliterations (including 1 case of endovascular surgery using balloon occlusion), 9 trappings, 1 wrapping, 1 bleb clipping, and 1 bleb clipping combined with wrapping. Surprisingly, subsequent rupture occurred in 30 (71.4%) of the 42 patients. Excluding one patient with postoperative rupture, 29 patients suffered a subsequent rupture in the unsecured stage. Of these 29 patients, 19 were operated on after the subsequent rupture and 10 were not operated on because of deteriorated clinical condition (9 patients) or anatomic considerations (1 patient). Of the 30 patients that suffered a subsequent rupture, 14 died. Twelve of the deaths were directly related to the second episode of rupture. Of the 12 patients who did not suffer a subsequent rupture, 10 underwent operations and there were no operative deaths. Only one patient died as the result of the initial critical SAH. The mortality (46.7%) of the patients with subsequent rupture was significantly higher (P < 0.05) than that (8.3%) of the patients without subsequent rupture. Seventeen (56.7%) of the 30 subsequent ruptures occurred within 24 hours after the first SAH, and 24 (80%) occurred within the first week. Six (66.7%) of the 9 patients operated on within 24 hours after the first SAH and 11 (68.8%) of the 16 patients operated on within a week suffered preoperative subsequent ruptures.(ABSTRACT TRUNCATED AT 250 WORDS)
Monoclonal antibodies were used to demonstrate proliferating cell nuclear antigen (PCNA) and Ki-67 antigen of dermal fibroblasts in formalin-fixed, paraffin-embedded tissue sections of keloids, hypertrophic scars and normal skin. PCNA-stained fibroblasts were more pronounced than Ki-67, which showed only scanty Ki-67-positive fibroblasts. The mean density of dermal fibroblasts was significantly higher in keloids and hypertrophic scars than in normal skin (p < 0.01). The proliferating activity of fibroblasts detected by PCNA was significantly higher in keloids than in hypertrophic scars or normal skin (p < 0.01). The mean densities and the proliferating activities were apparently not correlated with the age of the patient. This indicates that keloids, with higher density and proliferating activity of dermal fibroblasts, continue to increase their volume and invade the surrounding tissue, while hypertrophic scars, with higher density and lower proliferating activity, show a tendency towards spontaneous regression.
Corrosion casts were made from angiosarcoma of the scalp of an elderly person, Klippel-Trenaunay syndrome, pseudo-Kaposi's sarcoma, diffuse neonatal hemangiomatosis, cavernous hemangioma and arteriovenous malformation and were examined by scanning electron microscopy (SEM). The normal scalp from a cadaver was studied as a control for the angiosarcoma of the scalp. the SEM of the vascular corrosion casts clearly demonstrated the fine three-dimensional (3-D) architectures of malignant and benign cutaneous vascular lesions; the superficial fine and medium-sized vascular networks of the skin were replaced by abnormal balloon-like dilatations, extravasated fringes, glomerular structures, sinusoidal vessels or localized bulla-like structures of the capillary loops, depending on the nature of the cutaneous vascular lesions. The corrosion cast technique is helpful for understanding the 3-D patterns of various vascular lesions.
The authors present the case of a 17-year old man with slit ventricle syndrome, presenting as progressive neurological deterioration after head trauma. Serial computed tomography scans revealed slight ventricular enlargement, suggesting shunt malfunction. Communication between the lumbar subarachnoid space and the lateral ventricles was confirmed by computed tomography cisternography. He underwent a lumboperitoneal shunt, resulting in complete resolution of the symptoms. A lumboperitoneal shunt is considered to be a promising option for the treatment of slit ventricle syndrome.
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Though it is proposed that osteocytes have several functions in bone metabolism, only limited definite information including results of calcium regulation has been forthcoming. We demonstrate here for the first time that the concentration of divalent cations, such as calcium, nickel and cadmium, directly regulates the cytosolic calcium concentration in osteocytes.
A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.
Loss of heterozygosity data from familial tumors suggest that BRCA1, a gene that confers susceptibility to ovarian and early-onset breast cancer, encodes a tumor suppressor. The BRCA1 region is also subject to allelic loss in sporadic breast and ovarian cancers, an indication that BRCA1 mutations may occur somatically in these tumors. The BRCA1 coding region was examined for mutations in primary breast and ovarian tumors that show allele loss at the BRCA1 locus. Mutations were detected in 3 of 32 breast and 1 of 12 ovarian carcinomas; all four mutations were germline alterations and occurred in early-onset cancers. These results suggest that mutation of BRCA1 may not be critical in the development of the majority of breast and ovarian cancers that arise in the absence of a mutant germline allele.
We have examined molecular mechanisms of the PMA-inducible HA binding ability of human lymphocytes. Newly established OS/6 and OS/37, specific for human CD44, specifically inhibited PMA-induced HA binding of several human cell lines, suggesting that both mAb detect HA binding epitope(s) on CD44. Sequential staining revealed that these mAb cross-blocked each other's binding to Molt-4, T lymphoblast lines, and that neither of them interfered with staining of Molt-4 by other anti-CD44 mAb which induced significant homotypic cell aggregation. Biochemical and PCR analyses did not provide any evidence that PMA stimulation induced dramatic changes in molecular weight or molecular isoforms of CD44. Interestingly, HA binding was not affected and rather slightly increased by cytochalasin B which disrupts F-actin microfilament integrity. This suggests that the ability of CD44 to bind to HA does not correlate with the association of CD44 with the cytoskeleton. On the other hand, protein synthesis inhibitors, cycloheximide and anisomycin clearly inhibited the induction of HA binding of PMA-activated Molt-4 without affecting the expression of CD44 at the same time after stimulation. The same treatment had no effect on PMA-induced FN binding of the cells, which was mediated by VLA integrins. These results suggest that the adhesion functions of CD44 and integrins are differently regulated despite the fact that both are induced by PMA stimulation, and that new protein synthesis is essential for the PMA-induced HA binding by CD44.
A locus for familial melanoma, MLM, has been mapped within the same interval on chromosome 9p21 as the gene for a putative cell cycle regulator, p16INK4 (CDKN2) MTS1. This gene is homozygously deleted from many tumour cell lines including melanomas, suggesting that CDKN2 is a good candidate for MLM. We have analysed CDKN2 coding sequences in pedigrees segregating 9p melanoma susceptibility and 38 other melanoma-prone families. In only two families were potential predisposing mutations identified. No evidence was found for heterozygous deletions of CDKN2 in the germline of melanoma-prone individuals. The low frequency of potential predisposing mutations detected suggests that either the majority of mutations fall outside the CDKN2 coding sequence or that CDKN2 is not MLM.
BRCA1, a breast and ovarian cancer susceptibility locus, has been isolated and maps to 17q21. A physical map of the BRCA1 region which extended from the proximal boundary at D17S776 to the distal boundary at D17S78 was constructed and consists of 51 sequence tagged sites (STSs) from P1 and YAC ends, nine new short-tandem repeat (STR) polymorphic markers, and eight identified genes. The contig, which spans the estimated 2.3 Mb region, contains 29 P1s, 11 YACs, two BACs, and one cosmid. Based on key recombinants in two linked families, BRCA1 was further localized to a region bounded by D17S1321 on the proximal side and D17S1325 on the distal side. Within this estimated 600 kb region, the contig was composed completely of P1s and BACs ordered by STS-content mapping and confirmed by DNA restriction fragment fingerprinting.
Using the technique of solution hybridization coupled with magnetic bead capture, we have isolated a novel homeobox-containing gene from the BRCA1 region of 17q21. This gene is the human homologue of the mouse Mox1 gene previously localized to a syntenic region of mouse chromosome 11. Multiple overlapping cDNAs of human MOX1 were identified using both a cosmid and a P1 genomic clone containing the microsatellite markers D17S750 and D17S858 which map within the BRCA1 region defined by D17S776 and D17S78. MOX1 expression was observed in a variety of normal tissues examined, including breast and ovary. Given that the gene contains a homeobox domain and has the potential to regulate growth and differentiation, MOX1 represents an attractive candidate for the BRCA1 gene. This possibility was investigated in a series of BRCA1 kindreds and primary sporadic breast tumors. No evidence for mutation was found in the coding sequence, making it unlikely that MOX1 is the BRCA1 gene. However, the widespread expression of MOX1 in non-embryonal tissues suggests a role in normal cell biology which warrants further study.
Fas antigen, which belongs to a nerve growth factor/tumor necrosis factor receptor superfamily, is a membrane protein that induces apoptosis. In humans, distribution of Fas antigen has been reported on cell lines and lymphocytes. Immunohistochemical studies revealed Fas antigen on the keratinocytes of lesional epidermis in lichenoid drug eruption, erythema multiforme, contact dermatitis, bullous pemphigoid, pemphigus vulgaris, and herpes zoster; it is co-expressed with intercellular adhesion molecule-1. Cultured keratinocytes expressing Fas antigen increased from 8.4% to 34.6% after stimulation with interferon gamma for 24 h. Treatment of interferon-gamma-stimulated keratinocytes with anti-Fas for 48 h resulted in DNA fragmentation and death of 32% of cells, suggesting that Fas antigen may mediate apoptosis. The expression of Fas antigen on keratinocytes in lesional skin suggests that death via Fas antigen may play an important role in the pathogenesis of keratinocyte cytotoxicity.