In patients with pemphigus vulgaris (PV), autoantibodies against desmoglein 3 (Dsg3) cause loss of cell–cell adhesion of keratinocytes in the basal and immediate suprabasal layers of stratified squamous epithelia. The pathology, at least partially, may depend on protease release from keratinocytes, but might also result from antibodies interfering with an adhesion function of Dsg3. However, a direct role of desmogleins in cell adhesion has not been shown. To test whether Dsg3 mediates adhesion, we genetically engineered mice with a targeted disruption of the DSG3 gene. DSG3 −/− mice had no DSG3 mRNA by RNase protection assay and no Dsg3 protein by immunofluorescence (IF) and immunoblots. These mice were normal at birth, but by 8–10 d weighed less than DSG3 +/− or +/+ littermates, and at around day 18 were grossly runted. We speculated that oral lesions (typical in PV patients) might be inhibiting food intake, causing this runting. Indeed, oropharyngeal biopsies showed erosions with histology typical of PV, including suprabasilar acantholysis and “tombstoning” of basal cells. EM showed separation of desmosomes. Traumatized skin also had crusting and suprabasilar acantholysis. Runted mice showed hair loss at weaning. The runting and hair loss phenotype of DSG3 −/− mice is identical to that of a previously reported mouse mutant, balding (bal). Breeding indicated that bal is coallelic with the targeted mutation. We also showed that bal mice lack Dsg3 by IF, have typical PV oral lesions, and have a DSG3 gene mutation. These results demonstrate the critical importance of Dsg3 for adhesion in deep stratified squamous epithelia and suggest that pemphigus autoantibodies might interfere directly with such a function.

Background: Several studies have reported that the prevalence of idiopathic normal-pressure hydrocephalus (iNPH) was between 0 and 5%. However, the precise prevalence in a community-based elderly population remains unclear. We investigated the prevalence of possible iNPH retrospectively using an age- and gender-stratified random sample database. Methods: Five hundred and sixty-seven participants were randomly selected from among the 1,654 members of the population aged 65 years and older in Tajiri, Japan, and 497 underwent MRI. We classified participants as having possible iNPH if they had: (1) ventricular enlargement, as shown by an Evans index of ≥0.3, with closing sulci at the high convexity with dilation of the sylvian fissure on MRI, (2) at least one of the iNPH clinical triad (gait disturbance, urinary incontinence and cognitive impairment), and (3) no identifiable potential secondary cause of hydrocephalus. Results: We found 7 participants who met the criteria mentioned above. Cognitive impairments were the most common symptoms (n = 6) followed by gait disturbances (n = 3); however, urinary incontinence was not observed. No full clinical triad was present in the patients and only 3 participants had 2 of the triad. Conclusions: We considered the prevalence of possible iNPH in elderly adults to be 1.4% (95% confidence interval = 0.6–2.9%).

Background: There have been no reports on the prevalence of dementia among the old-old people in Japan. Methods: We studied the old-old population in Kurihara, northern Japan. Analysis 1 of Participants 1 (n = 590) was performed to evaluate the prevalence of dementia and dementing diseases by intensive evaluation including MRI. Analysis 2 aimed to determine a good indicator for detecting 'suspected dementia condition' based on the Long-Term Care Insurance index. Analysis 3 of Participants 2 (n = 3915) aimed to estimate the prevalence of 'suspected dementia condition'. Results: In Analysis 1, 73 people (12.4%) were diagnosed with dementia. The most common cause was Alzheimer's disease with cerebrovascular disease. In Analysis 2, level I of the Impairment Level of Dementia was found to be a good indicator of 'suspected dementia condition'. In Analysis 3, the overall estimated prevalence of 'suspected dementia condition' was 23.6%. In men, the ratio increased gradually from 75 to 87 years old to about 20%, increased to 40% at the age of 88 and became stable thereafter. In contrast, in women, the ratio increased from 75 to 95+ years old, reaching about 70%. Conclusions: The prevalence was higher than that reported previously. There was a difference between the sexes: an 'age-related' increase occurred in men and an 'ageing-related' increase in women. Alzheimer's disease with cerebrovascular disease was the most common cause, which coincided with the previous findings of individuals aged 65 years and older; however, the ratio of mixed dementia was greater.

Prevalence, magnetic resonance imaging (MRI) findings, cognitive function and depression are four major aspects of vascular cognitive impairment no dementia (vascular CIND). We performed a community-based study to examine these using 497 community-residents aged 65 years or older. Vascular CIND was defined as a clinical dementia rating (CDR) 0.5 with cerebrovascular disease. Several neuropsychological tests were performed, including MMSE, Geriatric Depression Scale (GDS), and Trail Making Test (TMT). Cerebrovascular disease and white matter lesions were visually assessed using MRI. Prevalence of vascular CIND, localization of cerebrovascular disease, and the relationships amongst MRI findings, white matter lesions, cognitive impairment and depression were analyzed. The prevalence of vascular CIND was 8.5% amongst the total population, corresponding to the rate being 37.2% amongst the CDR 0.5 participants. Compared with the CDR 0, the CDR 0.5 group had more subjects with strategic cerebrovascular disease in the thalamus, etc. No effects of cerebrovascular disease on MMSE and GDS scores were found, but the CDR 0.5/strategic cerebrovascular disease group showed impaired TMT-B scores. In the CDR 0 group, only anterior periventricular hyperintensity was associated with TMT-A score independent of cerebrovascular disease. A vascular CIND population was identified, and executive dysfunction in this population is probably based on an impaired fronto-subcortical circuit.

Matrix metalloproteases (MMP) constitute a family of proteolytic enzymes degrading extracellular matrix components. Their activity is inhibited by tissue inhibitors of metalloproteases (TIMP). Previous studies have demonstrated that various cytokines can modulate MMP and TIMP gene expression. In this study, we demonstrate that interferon-gamma coordinately upregulates MMP-1 (interstitial collagenase) and MMP-3 (stromelysin-1) gene expression in cultured keratinocytes, as determined at the mRNA steady-state levels, and this effect is dependent on on-going protein synthesis. In contrast, there was no effect on TIMP-1 gene expression. Enhanced MMP-1 expression by IFN-gamma was also demonstrated at the protein level by Western analysis. Transient transfections with MMP-1 and MMP-3 promoter/reporter gene constructs revealed no response to IFN-gamma, whereas incubation of keratinocytes with this cytokine appeared to stabilize the MMP-1 mRNA, resulting in reduced turnover of the transcript. These data suggest that IFN-gamma enhances MMP gene expression at the post-transcriptional level. The altered MMP expression by IFN-gamma without concomitant effect on TIMP gene expression potentially leads to imbalance between these proteases and their inhibitors, and enhanced proteolytic activity may play a role in the remodeling of cutaneous tissue involving inflammatory processes, such as wound healing.

Normal myocardial perfusion imaging by stress thallium-201 SPECT using high-dose ATP performed within 1 month after the beginning of haemodialysis treatment is a powerful predictor of cardiac event-free survival in patients with ESRD.

Effort-Reward Imbalance and Depression in Japanese Medical Residents: Yumi SAKATA, et al. Department of Occupational Mental Health, Graduate School of Medical Sciences, Kitasato University-The effort-reward imbalance is an important psychosocial factor which is related to poor health among employees. However, there are few studies that have evaluated effort-reward imbalance among medical residents. The present study was done to determine the association between psychosocial factors at work as defined by the effort-reward imbalance model and depression among Japanese medical residents. We distributed a questionnaire to 227 medical residents at 16 teaching hospitals in Japan at the end of August 2005. We asked participants to answer questions which included demographic information, depressive symptoms, effort-reward imbalance, overcommitment and social support. Depression was evaluated using the Japanese version of the Center for Epidemiologic Studies-Depression (CES-D) scale. The effort-reward imbalance and overcommitment were assessed by the Effort-Reward Imbalance (ERI) questionnaire which Siegrist developed. Social support was determined on a visual analog scale. Logistic regression analysis was performed to determine the associations between effort-reward imbalance and depressive symptoms. Depressive symptoms were found in 35 (29.2%) 1st-year residents and 21 (27.6%) 2nd-year residents. The effort-reward ratio >1 (OR, 8.83; 95% CI, and low social support score (OR, 2.77, 95% CI, 1.36-5.64) were associated with depressive symptoms among medical residents. Effort-reward imbalance was independently related to depression among Japanese medical residents. The present study suggests that balancing between effort and reward at work is important for medical residents' mental health. (J Occup Health 2008; 50: 498-504)

The hemagglutinating virus of Japan (HVJ)-liposome method involves the entrapment of DNA and nuclear protein within liposomes and the use of HVJ to enhance liposome fusion with cell membranes. This method has been used successfully for in vivo gene transfer to various types of tissue. In this study, we investigated whether this method transfers genes effectively to normal and malignantly transformed keratinocytes in vivo. We applied HVJ-liposome complex (HLC) containing the beta-galactosidase gene to the tape-stripped skin of hairless rats and detected the enzyme activity in the keratinocytes of the treated skin. Comparison of this method with the naked DNA injection method, which was shown recently to be useful for in vivo gene transfer to keratinocytes, demonstrated that the transfer efficiency of the latter was about 5 times higher than that of the former. We assessed the efficacy of the HVJ-liposome method for gene transfer to transformed keratinocytes by examining the effect of HLC containing the herpes simplex virus thymidine kinase gene on the growth of mouse squamous cell carcinomas. Local injection of HLC into the tumors followed by administration of ganciclovir to mice resulted in tumor growth inhibition. These results indicate that the HVJ-liposome method is suitable for in vivo gene transfer to keratinocytes; also that this method may prove a good tool for basic research into keratinocyte biology and future keratinocyte gene therapy.