Statin exposure and the risk of dementia in individuals with hypercholesterolaemia.

OBJECTIVES: This study aimed to examine the association between statin exposure and dementia risk in individuals with hypercholesterolaemia using data from the NHIS-HEALS database between 2002 and 2015. METHODS: Subjects were classified into statin exposure and statin nonexposure groups according to medication possession ratio. Dementia was defined as those with primary diagnostic dementia codes such as F00-F03, G30, G31.1, G31.9 or G31.82. Cox proportional hazards regression models were adopted after stepwise adjustment for confounders to investigate the prospective association between statin exposure and dementia risk. RESULTS: During the follow-up period (median follow-up 11.7 years), 711 cases of dementia occurred, accounting for 11.5% of the total study population (statin exposure group, 8.2%; statin nonexposure group, 12.9%). Compared to the statin nonexposure group, fully adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) for overall dementia in the statin exposure group were 0.63 (0.43-0.91) and 0.62 (0.50-0.78) in men and women, respectively. Compared to the statin nonexposure group, the HRs (95% CIs) for Alzheimer's disease and related dementia, vascular dementia and other types of dementia in the statin exposure group were 0.54 (0.32-0.91), 2.45 (0.69-8.68) and 0.59 (0.32-1.07), respectively, in men and 0.53 (0.38-0.73), 1.29 (0.42-3.96) and 0.70 (0.51-0.96), respectively, in women. CONCLUSIONS: Hypercholesterolaemic individuals exposed to statin had a lower risk of overall dementia and Alzheimer's disease and related dementia in both sexes, and a lower risk of other types of dementia in women, than subjects who were not exposed to statins.

Increased retinol-binding protein (RBP) 4 and anti-RBP4 antibody in alopecia areata.

BACKGROUND: Neither the underlying pathogenesis of alopecia areata (AA) nor the molecular mechanisms leading to hair loss have been fully elucidated. OBJECTIVES: To compare the protein profiles of sera obtained from patients with AA with those from healthy controls. METHODS: Protein profiles of sera obtained from subjects with AA and healthy controls were compared using proteomics techniques. Serum levels of the identified protein were quantified by specific enzyme-linked immunosorbent assay (ELISA). The relative serum reactivities of the recombinant human protein were compared between patients with AA and healthy controls using Western blots and double indirect immunofluorescence. RESULTS: The upregulated expression of retinol-binding protein (RBP) 4 was identified, and RBP4 ELISA demonstrated significantly increased serum levels of RBP4 among subjects with AA when compared with healthy controls. Western blots using recombinant human RBP4 and the sera from both groups presented serum reactivity of antihuman recombinant RBP4 IgG antibodies in 10/15 subjects with AA (67%) and 2/15 healthy controls (13%). Double indirect immunofluorescence demonstrated merged fluorescence signals of serum anti-RBP4 IgG antibodies and monoclonal antibodies to RBP4 in subjects with AA on the outer root sheath and companion layer. CONCLUSIONS: Our data demonstrate that AA is associated with increased serum levels of RBP4 and positive IgG immunoreactivity against recombinant human RBP4. These results suggest that the major components for the retinoic acid biosynthesis pathway may be crucially involved in the pathogenic process of AA.

Systemic IFN-beta gene therapy results in long-term survival in mice with established colorectal liver metastases.

Most patients succumbing to colorectal cancer fail with liver-predominant metastases. To make a clinical impact in this disease, a systemic or whole-liver therapy may be required, whereas most cancer gene therapy approaches are limited in their ability to treat beyond local disease. As a preclinical model for cancer gene therapy, recombinant adenovirus containing the human IFN-beta (hIFN-beta) cDNA was delivered systemically in nude mouse xenograft models of human colorectal cancer liver metastases. The vector targeted hepatocytes that produced high levels of hIFN-beta in the liver, resulting in a profound apoptotic response in the tumors and significant tumor regression. hIFN-beta gene therapy not only resulted in improved survival and long-term cure in a micrometastatic model, but provided similar benefits in a clinically relevant gross disease model. A similar recombinant adenovirus containing the murine IFN-beta (mIFN-beta) cDNA also resulted in a therapeutic response and improved survival in syngeneic mouse models of colorectal cancer liver metastases. Depletion studies demonstrate a contribution of natural killer cells to this therapeutic response. The toxicity of an adenoviral vector expressing murine IFN-beta in a syngeneic model is also presented. These encouraging results warrant further investigation of the use of cancer gene therapy for targeting metastatic disease.

Maltose binding protein (MBP) fusion proteins with low or no affinity to amylose resins can be single-step purified using a novel anti-MBP monoclonal antibody.

The maltose binding protein (MBP) fusion protein expression system is a powerful tool to produce and isolate recombinant proteins in E. coli. Whereas the conventional isolation technique for MBP-fusion proteins takes advantage of the binding affinity of MBP to maltose, this method is limited insofar as the biological activity of MBP has to be fully conserved for a successful purification. In this study, a novel monoclonal antibody (mAb) specific for MBP, termed HAM-19, was generated and its application in the purification and detection of MBP-fusion proteins determined. Using anti-MBP immunoaffinity columns, even recombinant MBP fusion products with lowered or impaired binding affinity to maltose were purified in a single step procedure. In comparison to amylose resins, HAM-19 immunoaffinity columns showed a higher binding capacity and affinity to MBP-fusion proteins. Furthermore, the mAb HAM-19 also provides a technical improvement over polyclonal antisera for the detection and analysis of MBP-fusion proteins which are under use in various forms in the fields of molecular and cellular biology.

Gene therapy of metastatic disease: progress and prospects.

Gene therapy remains a new and exciting therapy that holds the potential to impact the care of many diseases. Cancer gene therapy strategies encompass a major part of this developing field. Initial preclinical and phase I clinical trials have demonstrated the ability to transfer genetic material to cells in vitro and in vivo with resultant expression of biologically active protein. Most of these studies have involved direct injection or local installation of vector. A majority of patients succumbing to cancer do so because of metastatic disease. Clearly, to broaden the impact of cancer gene therapy on these patients' outcome, new strategies for targeting regional or systemic disease are required. This article offers a review of current vectors and therapeutic strategies along with the application of these in human cancers.

Depression in vascular dementia is quantitatively and qualitatively different from depression in Alzheimer's disease.

BACKGROUND/AIMS: To compare the prevalence and characteristics of depression in vascular dementia (VaD) and Alzheimer's disease (AD) after adjusting for dementia severity and gender. METHODS: One hundred and eight pairs of VaD and AD patients matched for dementia severity and gender were assessed. RESULTS: Major depressive disorder (MDD) was more prevalent in the VaD group than in the AD group (20.4% in VaD, 10.2% in AD, p = 0.04, Cochran-Mantel-Haenszel, CMH, test) regardless of the dementia severity and gender. The odds ratio for developing MDD in the VaD group versus the AD group was estimated to be 2.20 (95% confidence interval = 1.02-4.74). Neurovegetative symptoms such as 'felt tired and weak all the time' (30.6% in VaD, 13.9% in AD, p = 0.003, CMH test) and 'changed weight without trying' (16.7% in VaD, 6.5% in AD, p = 0.02, CMH test) were more prevalent in the VaD group than in the AD group. CONCLUSION: Depression in VaD was quantitatively and qualitatively different from that in AD regardless of the severity of dementia and gender; depression was more prevalent, severer and more retarded and vegetative in VaD than in AD.

A normative study of the Revised Hasegawa Dementia Scale: comparison of demographic influences between the Revised Hasegawa Dementia Scale and the Mini-Mental Status Examination.

BACKGROUND/AIMS: We investigated the demographic influence on the performance of the Revised Hasegawa Dementia Scale (HDS-R) and provided normative data of the HDS-R in the elderly. METHODS: The HDS-R was administered to 803 community-dwelling cognitively normal elderly subjects aged 55 years or over. Cognitive disorders and psychiatric disorders were strictly excluded using the CERAD-K assessment packet and the Mini-International Neuropsychiatric Interview. The demographic influence on the performance of the HDS-R was examined using multiple linear regression analyses, and compared with that on the performance of the Mini-Mental Status Examination (MMSE) using the Chow test and t statistics. Overlapping strata were used in developing age-, education- and gender-specific normative data of the HDS-R. RESULTS: Age, education, and gender influenced significantly the performance of the HDS-R, and explained 22.5% of the total score variance. Older age, lower education, and male gender were associated with lower performance of the HDS-R. However, the demographic influence on the HDS-R was much weaker than that on the MMSE (t = 5.578, d.f. = 800, p < 0.001). The normative data of the HDS-R stratified by age (60-69, 70-79, > or =80), education (0-6, 7-12, > or =13), and gender were presented. CONCLUSIONS: The HDS-R was more robust to demographic influences than the MMSE, and normative data may contribute to improving further its diagnostic accuracy for dementia.

Intraductal papillary mucinous neoplasms of the pancreas.

The introduction of the exocrine pancreatic classification by the World Health Organization and improvements in pancreatic imaging have led to an improved understanding of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. As a result, IPMNs of the pancreas are increasingly being recognized as a separate disease entity. IPMNs are characterized by the cystic dilatation of the pancreatic duct and its branches, with papillary projections. There are three histological subtypes of IPMNs: main duct, branch duct, and mixed. The degree of atypia ranges from adenoma to frank invasive carcinoma. The lymph nodes are involved considerably less frequently than they are in pancreatic adenocarcinoma. Most patients are symptomatic at diagnosis and require a diagnostic workup similar to that for patients with pancreatic adenocarcinoma. Although some investigators continue to advocate total pancreatectomy, the evidence in support of this is decreasing. Partial pancreatectomy remains the treatment option. Intraoperative assessment of the resection surgical margins is an important component of surgical resection. Additionally, controversy also exists regarding the nature of the follow-up and the need for adjuvant chemoradiation therapy in the patient. Unlike ductal adenocarcinomas, IPMNs follow a relatively indolent course; the 5-year survival rate in patients with invasive IPMNs is 57%. A mural nodule and a main pancreatic duct diameter greater than 5 mm have been found to be predictors of malignancy.

The expression and tyrosine phosphorylation of E-cadherin/catenin adhesion complex, and focal adhesion kinase in invasive cervical carcinomas.

The present study aimed to confirm the hypothesis that the expression and phosphorylation status of the E-cadherin/catenin adhesion complex is related to cervical carcinogenesis and cervical cancer invasion, and to investigate the expression and the tyrosine phosphorylation of focal adhesion kinase (FAK) and its relation with E-cadherin/catenin adhesion complex. The expression of E-cadherin, alpha- and beta-catenin, and FAK were studied by a western blot analysis with 26 cervical carcinomas, nine normal cervices, and five carcinomas in situ of cervix. The tyrosine phosphorylation of alpha- and beta-catenin and FAK were examined by an immunoprecipitation. The expressions of alpha- and beta-catenin and E-cadherin were reduced in cervical carcinoma, and the tyrosine phosphorylation of alpha- and beta-catenin in cervical carcinoma was higher than in normal cervix and carcinoma in situ of cervix. Tyrosine phosphorylation of FAK was elevated in cervical carcinoma although the expression of FAK was not significantly different. Moreover, alpha- and beta-catenin were coimmunoprecipitated with FAK. We conclude that the loss of E-cadherin/catenin proteins and the tyrosine phosphorylation of E-cadherin/catenin are involved in cervical carcinogenesis and cancer invasion. Tyrosine phosphorylation of focal adhesion kinase is also related to the cervical cancer invasion. The E-cadherin/catenin complex and FAK may be related functionally and structurally.

Presence of circulating autoantibodies against bronchial epithelia cell in patients with nonatopic asthma.

Allergic response to common environmental agents has been regarded as a main pathogenetic mechanism of bronchial asthma. However, allergic sensitization (atopy) can not be detected in a siginificant number of adult asthmatic patients. The etiology of nonatopic asthma has not yet been defined. To evaluate the possible involvement of autoimmune response against bronchial mucosa in the pathogenesis of nonatopic asthma, we performed indirect immunofluorescence staining of fresh frozen human bronchial mucosa tissue using serum samples from patients with atopic and nonatopic asthma, healthy controls, and patients with systemic lupus erythematosus. On immunostaining, circulating IgG autoantibodies against bronchial mucosa were detected in 2 (9.1%) of 22 patients with nonatopic asthma and in none of 22 patients with atopic asthma and of 22 healthy controls. IgG autoantibodies from the two patients with nonatopic asthma predominantly stained the cytoplasmic membrane of basal cells in bronchial epithelium. Serum samples from 10 patients with systemic lupus erythematosus immunostained the nucleus of epithelial cells in whole layer of bronchial epithelium. This study showed the presence of circulating IgG autoantibodies against the bronchial epithelial cell in a small portion of patients with nonatopic asthma. Further studies may be necessary to evaluate the possible involvement of autoimmune mechanism in the pathogenesis of nonatopic asthma.

Expression and tyrosine phosphorylation of E-cadherin, beta- and gamma-catenin, and epidermal growth factor receptor in cervical cancer cells.

OBJECTIVES: The cadherin/catenin adhesion complex is fundamentally involved in epithelial cancer invasion and metastasis. Much evidence suggesting that epidermal growth factor (EGF) induced the scattering and invasion of cancer cells, probably by affecting E-cadherin function, has been reported. The present study aimed to confirm the hypothesis that EGF/epidermal growth factor receptor (EGFR) was related with the E-cadherin adhesion system in cervical cancer cells and that EGF might induce tyrosine phosphorylation of beta- and gamma-catenin. METHODS: Cervical cancer cells were treated for different time durations with 30 ng/ml of EGF. Alteration of the cell morphology was examined by light microscopy and the expression of E-cadherin, beta-catenin, gamma-catenin, EGFR, and activated EGFR was assayed using Western blotting. Tyrosine phosphorylation of beta- and gamma-catenin was also examined using immunoprecipitation. RESULTS: E-cadherin and EGFR were expressed in CaSki, HT-3, and ME-180 cell lines, which showed epithelial contact growth. The expression of E-cadherin and beta- and gamma-catenin did not change after treatment with EGF. The expression of EGFR decreased and activated EGFR expression increased in 30 min and then decreased subsequently. The simultaneous expression of activated EGFR and tyrosine phosphorylation of beta- and gamma-catenin was found. CONCLUSIONS: EGF-induced scattering of the E-cadherin-positive cervical cancer cells might be the result of tyrosine phosphorylation of the beta- and gamma-catenin. Phosphorylation of the beta- and gamma-catenin may hamper the adhesive function of the E-cadherin-catenin complex.

Detection of cellular receptors specific for the hepatitis B virus preS surface protein on cell lines of extrahepatic origin.

Hepatitis B virus infection is primarily mediated by the interaction of the preS region of the viral envelope protein with its still unknown cellular receptor. Using recombinantly expressed preS proteins, the distribution of preS-binding receptors on cell lines from extrahepatic origins was determined by immunofluorescence and flow cytometry. In contrast to human liver cell lines, most cell lines from extrahepatic origins did not bind preS proteins. Nevertheless, exceptions were found in the bone marrow-derived cell line, KG-1, and the osteogenic sarcoma cell line SaOS-2, as well as in the previously reported EBV-transformed B-cell line, Wa. To determine the biochemical nature of these receptors, Wa-cells were cell surface biotinylated and the preS-binding receptors were isolated by immunoprecipitation. A specific band with a molecular weight of approximately 30 kDa was identified in a SDS-polyacrylamide gel, which further characterization is expected to provide clues regarding the infection mechanism of HBV in hepatic- and extra-hepatic cells.