An LMNA variant is associated with dyslipidemia and insulin resistance in the Japanese

Nuclear lamins A and C are encoded by LMNA and are present in terminally differentiated cells. Rare mutations in LMNA were shown to cause familial partial lipodystrophy, a syndrome characterized by regional loss of adipose tissue, glucose intolerance, and dyslipidemia, making LMNA a candidate gene for insulin-resistant diabetes. The aim of this study was to investigate whether genetic variation in LMNA can influence the risk of type 2 diabetes in a Japanese cohort. First, we performed mutational screening of LMNA by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequence analysis in 8 insulin-resistant males with acanthosis nigricans who were not lipodystrophic. One known single nucleotide polymorphism, 1908C/T, was found in exon 10. We subsequently screened samples of 171 nondiabetic and 164 type 2 diabetic male subjects for the presence of the 1908C/T polymorphism by PCR-restriction fragment length polymorphism (RFLP). The frequency of subjects with the 1908T allele tended to be higher in the diabetic group than in the nondiabetic group; however, the difference was not significant (43.9% v 32.2%) (P =.084). Carriers of the 1908T allele, both among diabetics and nondiabetics, showed significantly higher fasting insulin, triglycerides (TG), total cholesterol (TC), and lower high-density lipoprotein-cholesterol (HDL-C) levels than those of the 1908C/C subjects. These results suggest the LMNA 1908C/T single nucleotide polymorphism (SNP) is not associated with the prevalence of type 2 diabetes, although it may be a factor predisposing to insulin resistance and dyslipidemia in some Japanese.     

Lack of promoting effect of titanium dioxide particles on chemically-induced skin carcinogenesis in rats and mice

Nano-sized titanium dioxide particles (TiO(2)) are widely used in cosmetics, sunscreens and food additives. We previously reported that topical application of non-coated rutile type TiO(2) did not exhibit a promoting effect on ultraviolet B-initiated skin carcinogenesis in rats, and that this was likely due to lack of penetration of TiO(2) into the epidermis. In the present study, we examined the promoting effect of silicone coated TiO(2 )(sTiO(2)) suspended in silicone oil and non-coated TiO(2 )(ncTiO(2)) suspended in Pentalan 408 on a two-stage skin chemical carcinogenesis model: sTiO(2) suspended in silicon oil forms smaller particles than ncTiO(2) suspended in Pentalan because of the smaller sizes of aggregates formed. The model used skin carcinogenesis-sensitive human c-Ha-ras proto-oncogene transgenic mice (rasH2) and rats (Hras128) and their wild-type counterparts and CD-1 mice to test the effects of topical application of TiO(2). Animals were initially treated with a single dose of 7,12-dimethylbenz[a]anthracene (DMBA) and then with 0, 10, or 20 mg sTiO(2) (mice) or 0, 50, or 100 mg ncTiO(2) (rats). The incidence and multiplicity of skin tumors (squamous cell papilloma and carcinoma) did not increase over DMBA alone controls in skin carcinogenesis-sensitive mice or rats or wild-type animals. Analysis of rat skin indicated that sTiO(2) and ncTiO(2) did not penetrate though either healthy or damaged skin. Furthermore sTiO(2) did not penetrate an in vitro human epidermis model. Our results indicate that treatment with sTiO(2) or ncTiO(2) did not promote skin carcinogenesis in mice or rats, probably due to lack of penetration through the epidermis.     

Identification of differentially expressed genes in psoriasis using expression profiling approaches

To identify differentially expressed genes which play causal roles in pathogenesis and maintenance for psoriasis, we used BodyMapping and introduced amplified fragment length polymorphism approaches. From the BodyMap database, we selected 2007 genes which specifically expressed in epithelial tissues. Among 2007 genes, we surveyed genes which differentially expressed in involved or uninvolved psoriatic lesional skin samples compared with atopic dermatitis, mycosis fungoides, and normal skin samples. As a result of surveying 2007 genes, 241 genes were differentially expressed only in involved psoriatic skin but not in the other samples. Hierarchical cluster analysis of gene expression profiles showed that 13 independent psoriatic-involved skin samples clustered tightly together, reflecting highly similar expression profiles. Using the same 2007 gene set, we examined gene expression levels in five serial lesions from distal uninvolved psoriatic skin to involved psoriatic plaque. We identified seven genes such as alpha-1-microglobulin/bikunin precursor, calnexin, claudin 1, leucine zipper down-regulated in cancer 1, tyrosinase-related protein 1, Yes-associated protein 1, and unc-13-like protein (Coleonyx elegans) which show high-expression levels only in uninvolved psoriatic lesions. These seven genes, which were reported to be related to apoptosis or antiproliferation, might have causal roles in pathophysiology in psoriasis.     

CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma and promotes survival of quiescent CML cells

Chronic myelogenous leukemia (CML) is driven by constitutively activated Bcr-Abl tyrosine kinase, which causes the defective adhesion of CML cells to bone marrow stroma. The overexpression of p210Bcr-Abl was reported to down-regulate CXCR4 expression, and this is associated with the cell migration defects in CML. We proposed that tyrosine kinase inhibitors, imatinib or INNO-406, may restore CXCR4 expression and cause the migration of CML cells to bone marrow microenvironment niches, which in turn results in acquisition of stroma-mediated chemoresistance of CML progenitor cells. In KBM5 and K562 cells, imatinib, INNO-406, or IFN-alpha increased CXCR4 expression and migration. This increase in CXCR4 levels on CML progenitor cells was likewise found in samples from CML patients treated with imatinib or IFN-alpha. Imatinib induced G0-G1 cell cycle block in CML cells, which was further enhanced in a mesenchymal stem cell (MSC) coculture system. MSC coculture protected KBM-5 cells from imatinib-induced cell death. These antiapoptotic effects were abrogated by the CXCR4 antagonist AMD3465 or by inhibitor of integrin-linked kinase QLT0267. Altogether, these findings suggest that the up-regulation of CXCR4 by imatinib promotes migration of CML cells to bone marrow stroma, causing the G0-G1 cell cycle arrest and hence ensuring the survival of quiescent CML progenitor cells.     

Biting for attention: A case of dental discomfort manifesting in behavioural problems

There is a dearth of literature describing behaviour that expresses discomfort caused by poor dentition in patients with dementia. In this paper, we report on a patient whose behaviour only abstrusely pointed to his teeth as the source of discomfort. Although changes to his medication over a 2‐year period had little effect, eventual extraction of his caries brought about an almost immediate resolution of all antisocial behaviour. Clinicians must be mindful that poor dental care is easily meliorated but remains endemic in patients suffering from dementia.     

The Usefulness of Endoscopic Color Doppler Ultrasonography (ECDUS) for Endoscopic Injection Sclerotherapy (EIS)

Abstract: We studied 12 patients using endoscopic injection sclerotherapy (EIS) guided by endoscopic color Doppler ultrasonography (ECDUS). The ECDUS was performed with a PENTAX FG-32UA (7.5MH2, convex type) and a HlTACHl EUB 565 as a display machine. The EIS needle, as well as changes in intramural blood flow before and after EIS were clearly observed with the ECDUS. When the sclerosant was injected properly into the esophageal varices, the blood flow in the esophageal varices could not be detected with color Doppler flow imaging nor with fast-Fourier transform (FFT) analysis. Therefore EIS was safely performed with an adequate volume of sclerosant having been accurately injected into the varices. Of the disadvantages of this technique, the forceps channel was found to be a bit narrow, and the anterior view was somewhat oblique. Even so, EIS guided by ECDUS is surely a promising method for the treatment of esophageal varices, especially once the technical difficulties are overcome. (Dig Endosc 1994; 6 : 39–44)     

An Application of Endoscopic Color Doppler Ultrasonography (ECDUS) in the Diagnosis of Hemodynamics of Gastric Varices,and the Therapeutic Effect of Endoscopic Therapy

Abstract: We studied 14 patients using endoscopic color Doppler ultrasonography (ECDUS) to evaluate the hemodynamics of gastric varices, and evaluated the endoscopic therapeutic effects on gastric varices in 8 patients. Three patients had F₃ type gastric varices and eleven had F₂. The ECDUS was performed with a PENTAX FG-32UA (7.5MHz, convex type) and a HITACHI EUB 565 was used as a display machine. The intramural blood flow in the gastric varices and inflows from the extra-gastric wall were clearly observed with the ECDUS in all 14 patients. The extramural blood flow (gastro or spleno-renal shunts) was detected in 9 of 14 patients. The velocity of the intramural flow in tumorous type varices (F₃) was higher than in the nodular or flat elevated type (Fa). Next, we evaluated the therapeutic effects on gastric varices of the ECDUS. The successful disappearance of intramural blood flow was observed in 6 of 8 patients who had this endoscopic therapy. In two of the 8 patients, there was not enough therapeutic effect on the intramural blood flow. The extramural blood flow, however, did not change before or after endoscopic therapy with the ECDUS. Therefore, we concluded that ECDUS is a very useful modality for the diagnosis of hemodynamics and to evaluate the therapeutic effects on gastric varices.