Targeted deletion of the murine corneodesmosin gene delineates its essential role in skin and hair physiology

Controlled proteolytic degradation of specialized junctional structures, corneodesmosomes, by epidermal proteases is an essential process for physiological desquamation of the skin. Corneodesmosin (CDSN) is an extracellular component of corneodesmosomes and, although considerable debate still exists, genetic studies have suggested that the CDSN gene in the major psoriasis-susceptibility locus (PSORS1) may be responsible for susceptibility to psoriasis, a human skin disorder characterized by excessive growth and aberrant differentiation of keratinocytes. CDSN is also expressed in the inner root sheath of hair follicles, and a heterozygous nonsense mutation of the CDSN gene in humans is associated with scalp-specific hair loss of poorly defined etiology. Here, we have investigated the pathogenetic roles of CDSN loss of function in the development of skin diseases by generating a mouse strain with targeted deletion of the Cdsn gene. Cdsn-deficient mouse skin showed detachment of the stratum corneum from the underlying granular layer and/or detachment within the upper granular layers due to the disrupted integrity of the corneodesmosomes. When grafted onto immunodeficient mice, Cdsn-deficient skin showed rapid hair loss together with epidermal abnormalities resembling psoriasis. These results underscore the essential roles of CDSN in hair physiology and suggest functional relevance of CDSN gene polymorphisms to psoriasis susceptibility.     

Pancreatic arteriovenous malformation with pancreatitis involving a pancreatico-venous fistula

An arteriovenous malformation of the pancreas is a very rare disease, but its presentation is distinct and unique. In this report, we describe a patient who presented with this malformation which was localized in the tail of pancreas and demonstrated by abnormal angiography findings. The patient was a 60-year-old male with severe left hypochondralgia. Angiography revealed an increased blood volume in the tail of the pancreas with arteriovenous shunting. Secondary pancreatitis caused by the arteriovenous malformation was suspected by abnormal laboratory data, and confirmed by histology from the resected tail of the pancreas. This is a very rare report in which pancreatic arteriovenous malformation involving a pancreaticovenous fistula was confirmed by endoscopic retrograde cholangiopancreatography (ERCP).     

The effect of insulin sensitizer, troglitazone, on lipoprotein lipase mass in preheparin serum

Lipoprotein lipase mass exists in preheparin serum, even though the activity is scarcely found. The implication of this is unclear. We studied the effect of an insulin sensitizer, troglitazone, on this preheparin serum lipoprotein lipase mass (preheparin LPL mass) in non-insulin-dependent diabetes mellitus (NIDDM) patients as well as on serum lipid levels and low density lipoproteins (LDL) particle size. Thirty-one NIDDM patients with poor control were administered troglitazone 400 mg/day. Hemoglobin A1c had significantly decreased (13%, P < 0.001) 2 months later. Preheparin LPL mass had gradually increased and a 69% increase (P<0.01) was observed 4 months later. Triglyceride significantly decreased (23%, P < 0.01) and high density lipoprotein-cholesterol increased (10%, P < 0.01), whereas total cholesterol and LDL levels did not change 4 months later. The size of LDL increased significantly (P < 0.01). These results were consistent with the idea that preheparin LPL mass might be relating to the insulin sensitivity enhanced by troglitazone, as well as LDL particle size.     

Histological changes of the liver in experimental graft-versus-host disease across minor histocompatibility barriers. VIII. Role of eosinophil infiltration

Abstract: Although eosinophil infiltrate has been recognized in hepatic graft-versus-host disease, its significance in relation to hepatic graft-versus-host disease lesions is unknown. In the present study, we analyzed hepatic eosinophil infiltration in relation to bile duct damage in experimental mouse graft-versus-host disease across minor histocompatibility barriers up to 14 months after transplantation. Portal eosinophil infiltration was found from 1 week after transplantation throughout the entire 14-month observation period. It was most striking during the early chronic stage of hepatic graft-versus-host disease between 2 to 7 months, with a peak at 5 months after transplantation. Microscopic and electron microscopic study revealed eosinophils infiltrated around the bile duct as well as in the bile duct epithelial layer. They were commonly found together with lymphocytes but were also occasionally found singly around the bile duct and in the bile duct epithelial layer. Bile duct epithelial cells in contact with and in the vicinity of eosinophils showed a variety of degenerative changes, occasionally associated with the presence of extracellular eosinophil granules. Bile duct epithelial cells with eosinophil infiltration just beneath the basement membrane frequently showed further characteristic severe degenerative changes with shedding or dropping-off into the lumen, which features were quite similar to those seen in the bronchial epithelium in asthma patients. These results indicate that not only lymphocytes but also eosinophils may be involved in the production of the bile duct injury in hepatic graft-versus-host disease, especially in its early chronic stage.     

Late-night salivary cortisol as a screening test for the diagnosis of Cushing's syndrome in Japan

Measurement of late-night and/or midnight salivary cortisol currently used in US and European countries is a simple and convenient screening test for the initial diagnosis of Cushing's syndrome (CS). Unfortunately, this test has not been widely used in Japan. The purpose of this study was to evaluate the usefulness of the measurement of late-night salivary cortisol as a screening test for the diagnosis of CS in Japan. We studied 27 patients with various causes of CS, consisting of ACTH-dependent Cushing's disease [5] and ectopic ACTH syndrome [4] and ACTH-independent adrenal CS [11] and subclinical CS [7]. Eleven patients with type 2 diabetes and obesity and 16 normal subjects served as control group. Saliva samples were collected at late-night (23:00) in a commercially available device and assayed for cortisol by radioimmunoassay. There were highly significant correlations (P<0.0001) between late-night serum and salivary cortisol levels in normal subjects (r = 0.861) and in patients with CS (r = 0.788). Late-night salivary cortisol levels in CS patients (0.975 +/- 1.56 microg/dl) were significantly higher than those in normal subjects (0.124 +/- 0.031 microg/dl) and in obese diabetic patients (0.146 +/- 0.043 microg/dl), respectively. Twenty-five out of 27 CS patients had late-night salivary cortisol concentrations greater than 0.21 microg/dl, whereas those in control group were less than 0.2 microg/dl. Receiver operating characteristic curve (ROC) analysis showed that the cut-off point of 0.21 microg/dl provides a sensitivity of 93% and a specificity of 100%. Therefore, it is concluded that the measurement of late-night salivary cortisol is an easy and reliable noninvasive screening test for the initial diagnosis of CS, especially useful for large high-risk populations, such as diabetes and obesity.     

Case of multiple intrapulmonary lymph nodes]

A 45-year-old man who had hypertension, hyperthyroidism, and bronchial asthma was admitted to our hospital because of a low-grade fever and chest pain. The physical findings and laboratory data were almost all within normal limits except for evidence of mild inflammation and liver dysfunction. The chest X-ray findings seemed normal, but a computed tomography (CT) scan showed multiple nodules in both lower lung fields. We suspected the cryptococcosis or lung cancer. Biopsy by video-assisted thoracoscopic surgery (VATS) yielded a diagnosis of multiple intrapulmonary lymph nodes. In cases with the above radiologic findings, careful attention should be paid to making the differential diagnosis between intrapulmonary lymph nodes and primary lung cancer. The promotion of diagnostic imaging and advances in techniques have made it easier to identify small peripheral nodules in the lungs, and we now know of their existence. Solitary intrapulmonary lymph nodes are encountered frequently, but multiple or increasing numbers of nodes, as in our case, are very rare. Moreover, because cases with elevated CEA levels have been reported, differentiation from lung cancer appears to be important.     

Prevalence of total knee arthroplasty and its predictive factors in Japanese patients with rheumatoid arthritis: Analysis using the NinJa cohort

Objectives. The aim of this study was to clarify the prevalence and the predictive factors for undergoing total knee arthroplasty (TKA) among patients with rheumatoid arthritis (RA).

Methods. The data of 1,134 patients with RA who were enrolled in the Japanese nationwide cohort database NinJa in 2003 and consecutively followed up until 2009 were analyzed.

Results. Seventy-six patients underwent TKA during the observation period. The yearly progression of the modified Health Assessment Questionnaire or mHAQ score from 2003 to 2004, but not the yearly progression of the Disease Activity Score in 28 Joints or DAS28 or patient visual analog scale (VAS) score, was significantly higher in the patients who underwent TKA than those who did not.

Multivariate analysis showed that knee involvement in the disease, high Steinbrocker stage (III or IV), and high patient VAS score at the time of enrollment were powerful predictive factors, with hazard ratios of 4.01, 3.71, and 1.20, respectively.

According to survival analysis with TKA as an endpoint, patients with knee involvement in the disease at the time of enrollment had a significantly worse 5-year survival rate than did those without knee involvement (83.5% vs. 97.0%, respectively).

Conclusion. Several factors were elucidated as predictive factors for undergoing TKA among patients with RA.     

Genetic polymorphisms in the tumour necrosis factor locus in childhood acute lymphoblastic leukaemia

Genetic polymorphisms in the tumour necrosis factor (TNF) locus influence the outcome of non-Hodgkin's lymphoma (NHL). We investigated whether these polymorphisms might contribute to the clinical course of childhood acute lymphoblastic leukaemia (ALL). Genomic DNA from 214 childhood ALL patients was analysed. Patients with a high-risk haplotype were older than patients with low-risk haplotype (P = 0.024). No statistically significant associations were found between TNF haplotype and sex, WBC counts, central nervous system involvement, immunophenotype, response to chemotherapy, and event-free survival. These data suggest that genetic polymorphisms in the TNF locus have a limited effect on the outcome of childhood ALL.     

Genetic and environmental effects on fasting and postchallenge plasma glucose and serum insulin values in Finnish twins

The aim of this study was to evaluate genetic and environmental effects on plasma glucose, insulin secretion, and resistance in Finnish twins. Altogether 151 randomly selected twin pairs were examined by the oral glucose tolerance test; 66 twin pairs were monozygotic and 85 like-sexed dizygotic. We estimated the intraclass correlation coefficients and variance components of genetic and environmental effects on waist circumference, plasma glucose, and serum insulin. For fasting insulin, the proportion of total variation accounted for by additive genetic effects (A) and nonshared environmental effects (E) were 43 and 57%, respectively. As to postchallenge insulin and waist circumference, A effects were stronger in female twins (51 and 70%, respectively) than male twins in whom no significant evidence for genetic variance was found. Of the variation in fasting glucose, A and E effects accounted for 45 and 55%, respectively. Of the variation in postchallenge glucose, E effects had a greater role (65%), compared with A effects (35%); A effects on pre- and postchallenge insulin levels were highly correlated (genetic correlation coefficient = 0.81). In conclusion, additive genetic effects are important for the insulin secretion, whereas nonshared environmental effects contribute strongly to peripheral insulin resistance.