Restriction fragment length polymorphisms of the CYP11B1 gene in the Japanese population

Summary Restriction fragment length polymorphisms (RFLPs) of the CYP11B1 gene were studied in Japanese using cDNA clone P450c11 as a probe. Genomic DNAs from 60 unrelated Japanese individuals were digested with 8 different restriction enzymes and analyzed by Southern blot hybridization. Two RFLPs were detected inMspI digests of the DNA. One(A) was characterized by polymorphic bands at 3.4 and 2.5 kilobasepairs (kb) and the other (B) by polymorphic bands at 1.7 and 1.2 kb. The third RFLP was observed inPvuII-digested samples and was polymorphic at 5.8 and 4.0 kb bands. Two of the three RFLPs found, RFLP (A) and (C), have not been described in the only previous report which was based on Caucasian samples. We also examined the RFLPs of a 3 generation family of 11-hydroxylase deficiency caused by an abnormality of the CYP11B1 gene. All the family members were homozygous in all three RFLPs and was thus not informative.     

Blepharophimosis sequence and de novo balanced autosomal translocation [46, XY,t(3;4)(q23;p15.2)]: Possible assignment of the trait to 3q23

We report on a boy with the blepharophimosis sequence and de novo, apparently balanced reciprocal translocation between 3q23 and 4p15.2 [46, XY,t(3;4)(q23;p15.2)de novo]. Possible assignment of this autosomal dominant disorder is discussed. A 3q23 band is a more preferable gene locus of the blepharophi mosis sequence, based on the comparison of clinical manifestations between 4p- and 3q-syndromes.     

Concurrent visual task effects on evoked and emitted auditory p300 in adolescents

Using an oddball stimulus presentation paradigm, the effects of divided attention on auditory P300s were studied. Auditory attention was either divided or focused, depending on the demands placed on subjects during the performance of a concomitantly presented visual task. Two types of auditory tasks were performed under each of the two auditory attention conditions. In one, subjects responded to infrequently presented high pitched tones (oddball stimuli). In the other they responded to the occasional omission of a stimulus in an otherwise rhythmically presented chain of stimuli. P300s and reaction times were recorded to both the rare tones and the omissions. The Sternberg visual memory task was used to manipulate the subject's auditory attention state. Subjects actively performed the Sternberg task during the divided auditory attention condition, whereas during the focused attention condition they were not required to respond to the visual stimuli. During focused auditory attention, evoked auditory P300s were both larger and faster than their emitted counterparts. During divided attention, auditory P300s were reduced in amplitude but latency was unaffected. Evoked auditory P300s showed evidence of containing P300a as well as P300b components, particularly when attention was shared with the visual task.     

Abscess-forming granulomatous lymphadenitis: Histological typing of suppurative granulomas and clinicopathological findings with special reference to cat scratch disease

In order to clarify the histological and immunohistochemical characteristics of suppurative granuloma in abscess-forming granulomatous lymphadenitis (AGL), and the relation between AGL and cat scratch disease (CSD), 36 cases of AGL were studied. The combined results showed that there were two types of suppurative granulomas. The suppurative granulomas histologically revealed small lymphocytes of predominantly T cell phenotype distributed among the epithelioid histiocytes bordering central necrotic areas in the suppurative granulomas. These suppurative granulomas could be further subdivided into two groups, mainly those with and without the intermingling of large transformed cells of B-cell phenotypes: Type B granuloma with large transformed B cells and Type A without large transformed B cells. Both types of granulomas were observed in a varying degree in most cases. According to the predominant type of granulomas, 36 patients with AGL were further classified into two groups: Group I of Type A dominance and Group II of Type B dominance. Warthin-Starry (WS) silver stain positive bacteria, which are said to be a causative agent of CSD, were present in about 50% of both groups. No Brown-Hopps' Gram-positive bacteria, fungus, toxoplasma, Chlamydia or Bacillus Calmette-Guerin antigen were found in any case. Clinically, there was no significant difference between these two groups. On the other hand, the detection of WS-positive bacteria seemed to have some relationship with the duration of disease and the history of exposure to cats, and 70% of AGL cases occurred in autumn without a single concurrent epidemic.     

Beta-catenin mutations are frequent in calcifying odontogenic cysts, but rare in ameloblastomas

We have reported previously that alterations to beta-catenin occur frequently in adamantinomatous craniopharyngioma. Based on its histological resemblance to some odontogenic tumors, we suspected the presence of common genetic alterations among these tumors. To address this issue, 11 cases of calcifying odontogenic cyst (COC) and 20 cases of ameloblastoma were investigated for the presence of beta-catenin mutations and beta-catenin expression. Ten COCs were successfully analyzed by direct sequencing, and nine of them were found to harbor somatic beta-catenin mutations. Immunohistochemically, all of the COCs showed nuclear and cytoplasmic expression of beta-catenin with a heterogeneous pattern. No beta-catenin mutations were found in ameloblastomas, except for one case of the follicular type. All follicular ameloblastomas exhibited moderate nuclear and cytoplasmic accumulation of beta-catenin, in contrast to the predominantly membranous expression seen in the plexiform type. beta-Catenin mutation is considered to be a characteristic genetic feature of COC, and may play a critical role in its histogenesis. Although ameloblastoma closely resembles COC histologically, the two have genetically distinctive features.     

Accumulation of filamentous tau in the cerebral cortex of human tau R406W transgenic mice

Missense mutations of the tau gene cause autosomal dominant frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), an illness characterized by progressive personality changes, dementia, and parkinsonism. There is prominent frontotemporal lobe atrophy of the brain accompanied by abundant tau accumulation with neurofibrillary tangles and neuronal cell loss. Using a hamster prion protein gene expression vector, we generated several independent lines of transgenic (Tg) mice expressing the longest form of the human four-repeat tau with the R406W mutation associated with FTDP-17. The TgTauR406W 21807 line showed tau accumulation beginning in the hippocampus and amygdala at 6 months of age, which subsequently spread to the cortices and subcortical areas. The accumulated tau was phosphorylated, ubiquitinated, conformationally changed, argyrophilic, and sarcosyl-insoluble. Activation of GSK-3beta and astrocytic induction of mouse tau were observed. Astrogliosis and microgliosis correlated with prominent tau accumulation. Electron microscopic examination revealed the presence of straight filaments. Behavioral tests showed motor disturbances and progressive acquired memory loss between 10 to 12 months of age. These findings suggested that TgTauR406W mice would be a useful model in the study of frontotemporal dementia and other tauopathies such as Alzheimer's disease (AD).     

The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis

PTEN is an important tumor suppressor gene. Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePten(flox/+) mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85alpha and p110gamma. In vitro, Tie2CrePten(flox/+) endothelial cells showed enhanced proliferation/migration. Tie2CrePten(flox/flox) mice died before embryonic day 11.5 (E11.5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes depend strongly on p110gamma rather than on p85alpha and were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2. Pten is thus indispensable for normal cardiovascular morphogenesis and post-natal angiogenesis, including tumor angiogenesis.     

Dedifferentiated adenoid cystic carcinoma: a clinicopathologic study of 6 cases.

Dedifferentiated adenoid cystic carcinomas are a recently defined, rare variant of adenoid cystic carcinomas characterized histologically by two components: conventional low-grade adenoid cystic carcinoma and high-grade "dedifferentiated" carcinoma. We examined six cases and analyzed their clinicopathologic profiles, including immunohistochemical features and p53 gene alterations. The 6 patients (3 men and 3 women) had a mean age of 46.8 years (range, 34-70 y). The mean size of the tumors was 3.5 cm (range, 1.7-6 cm). The submandibular gland, maxillary sinus, and nasal cavity were involved in 2 cases each. Postoperatively, 5 patients had local recurrence and 5 developed metastatic disease. Five patients died of disease at a mean of 33.7 months after diagnosis (range, 6-69 mo), and one other was alive with disease at 60 months. Histologically, the conventional low-grade adenoid cystic carcinoma component of the tumors consisted of a mixture of cribriform and tubular patterns with scant solid areas. The high-grade dedifferentiated carcinoma component was either a poorly differentiated adenocarcinoma (4 cases) or undifferentiated carcinoma (2 cases). Three tumors were studied immunohistochemically. Myoepithelial markers were expressed in low-grade adenoid cystic carcinoma but not in the dedifferentiated component. In 2 cases, diffusely positive p53 immunoreactivity together with HER-2/neu overexpression was restricted to the dedifferentiated component. Loss of pRb expression was demonstrated only in the dedifferentiated component of the 1 other case. The Ki-67-labeling index was higher in the dedifferentiated component than in the low-grade adenoid cystic carcinoma component. Furthermore, molecular analysis of 2 cases demonstrated the loss of heterozygosity at p53 microsatellite loci, accompanied by p53 gene point mutation, only in the dedifferentiated carcinoma component of 1 case, which was positive for p53 immunostaining. These results indicate that dedifferentiated adenoid cystic carcinoma is a highly aggressive tumor. Because of frequent recurrence and metastasis, the clinical course is short, similar to that of adenoid cystic carcinomas with a predominant solid growth pattern. Limited evidence suggests that p53 abnormalities in combination with HER-2/neu overexpression or loss of pRb expression may have a role in dedifferentiation of adenoid cystic carcinoma.     

Epstein-Barr virus association with early cancers found together with gastric medullary carcinomas demonstrating lymphoid infiltration

Seven early gastric cancers obtained from patients also demonstrating Epstein-Barr virus (EBV)-positive gastric medullary carcinoma with lymphoid infiltration were investigated using a combined polymerase chain reaction (PCR) and in situ hybridization (ISH) approach. Sharing the same background mucosa as gastric medullary cancers, they comprised four intramucosal carcinomas, predominantly well-differentiated adenocarcinomas, and three submucosal carcinomas, histologically showing mixtures of well and poorly differentiated adenocarcinoma. In the three cases of submucosal carcinoma, the presence of EBV was proven by means of both PCR and ISH. However, not all cancer cells were positive for EBV on the basis of ISH examination, in contrast to the large series of gastric carcinoma with lymphoid infiltration previously investigated. All four mucosal carcinomas were EBV-negative. Lymphocyte-determined membrane antigen (LYDMA) monoclonality, performed by PCR, and latent membrane protein-1 (LMP-1) and Epstein-Barr virus (EBNA2) expression, assessed immunohistochemically, were negative in all seven cases. The results suggest that EBV becomes associated with gastric medullary carcinoma with lymphoid infiltration (GMCL) at a relatively early stage of the disease, shortly after the tumour has initially progressed to an invasive form, and plays some role in the manifestation as GMCL.