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.     

Effects of Sustained‐Release Beraprost in Patients With Primary Glomerular Disease or Nephrosclerosis: CASSIOPEIR Study Results

TRK‐100STP, a sustained‐release preparation of the orally active prostacyclin analogue beraprost sodium, targets renal hypoxia. This study aimed to show the superiority of TRK‐100STP over placebos in patients with chronic kidney disease (with either primary glomerular disease or nephrosclerosis) to determine the recommended dose. CASSIOPEIR (Chronic Renal Failure Asian Study with Oral PGI₂ Derivative for Evaluating Improvement of Renal Function) was a randomized, double‐blind, placebo‐controlled study conducted at 160 sites in seven Asia‐Pacific countries and regions. Eligible patients (n = 892) were randomized to TRK‐100STP 120, 240 μg, or placebo for a treatment period of up to 4 years. The primary efficacy endpoint was time to first occurrence of a renal composite: doubling of serum creatinine or occurrence of end‐stage renal disease. No significant differences were observed in composite endpoints between TRK‐100STP and placebo (P = 0.5674). Hazard ratios (95% CI) in the TRK‐100STP 120 and 240 μg vs. placebo groups were 0.98 (0.78, 1.22) and 0.91 (0.72, 1.14), respectively. The overall incidence of adverse events and adverse drug reactions was comparable between treatment arms.     

Possibility of solving complex problems by recursive thinking

This study examined the ability in recursive thinking to solve problems. To think recursively is one of the most effective ways to break up large and complex problems into smaller ones. This study prepared two problems with the same tail recursion: The "Guess-the-Number game" and the "Hat puzzle (Wise men puzzle)." Because participants (N = 35) were not familiar with recursive thinking, they learned how to think recursively in the Guess-the-Number game. Then, we tested whether they could solve the Hat puzzle recursively. The results show that two-thirds of the participants could solve the problem recursively, even if the size of the problem increased. Furthermore, their solution times had differed between correct and incorrect answers. This suggests that the difference reflected a "saving" of effort for problem solving.     

An N-terminal 80 kDa recombinant fragment of human thrombospondin-2 inhibits vascular endothelial growth factor induced endothelial cell migration in vitro and tumor growth and angiogenesis in vivo

We have previously shown that stable overexpression of the thrombospondin-2 (TSP-2) gene inhibited the tumor growth and angiogenesis of human squamous cell carcinoma xenotransplants. To investigate the potential antitumoral efficacy of systemic TSP-2 therapy, we expressed a recombinant 80 kDa fragment of human TSP-2 (TSP-2/NTF), encompassing the N-terminal globular region through the three type 1 repeats, in human kidney 293 EBNA cells, using a modified pCEP4 expression vector. Daily intraperitoneal injections of TSP-2/NTF resulted in a significant inhibition of the growth of human A431 squamous cell carcinomas in vivo and in reduced tumor vascularization. To further investigate possible mechanisms of the antiangiogenic activity of TSP-2/NTF, several in vitro angiogenesis assays were performed in human dermal microvascular endothelial cells. TSP-2/NTF inhibited vascular endothelial growth factor induced migration of human dermal microvascular endothelial cells and inhibited tube formation on Matrigel in vitro. TSP-2/NTF also inhibited vascular endothelial growth factor induced angiogenesis in an in vivo Matrigel assay. Moreover, TSP-2/NTF potently induced human dermal microvascular endothelial cell apoptosis in vitro but did not affect A431 tumor cell proliferation or apoptosis. These findings identify TSP-2/NTF as a potent systemic inhibitor of tumor growth and angiogenesis, acting by direct inhibition of several endothelial cell functions involved in neovascularization.     

A critical role of placental growth factor in the induction of inflammation and edema formation

Angiogenesis is a prominent feature of a number of inflammatory human diseases, including rheumatoid arthritis, psoriasis, and cutaneous delayed-type hypersensitivity (DTH) reactions. Up-regulation of placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, has been found in several conditions associated with pathologic angiogenesis; however, its distinct role in the control of angiogenesis has remained unclear. To directly investigate the biologic function of PlGF in cutaneous inflammation and angiogenesis, DTH reactions were investigated in the ear skin of wild-type mice, of PlGF-deficient mice, and of transgenic mice with targeted overexpression of human PlGF-2 in epidermal keratinocytes, driven by a keratin 14 promoter expression construct. Chronic transgenic delivery of PlGF-2 to murine epidermis resulted in a significantly increased inflammatory response, associated with more pronounced vascular enlargement, edema, and inflammatory cell infiltration than seen in wild-type mice. Conversely, PlGF deficiency resulted in a diminished and abbreviated inflammatory response, together with a reduction of inflammatory angiogenesis and edema formation. VEGF expression was up-regulated at a comparable level in the inflamed skin of all genotypes. These findings reveal that placental growth factor plays a critical role in the control of cutaneous inflammation, and they suggest inhibition of PlGF bioactivity as a potential new approach for anti-inflammatory therapy.     

Magnetic resonance imaging (MRI) of articular cartilage of the knee using ultrashort echo time (uTE) sequences with spiral acquisition

The objective of this study was to evaluate the sensitivity of ultrashort echo time (uTE) sequence for visualisation of calcified deep layers of articular cartilage. MRI with a uTE sequence was performed on five healthy volunteers. Signals from the calcified deep layers of the articular knee cartilage were evaluated on uTE subtraction images and computed tomography images. The calcified deep layers of the articular cartilage changed from having a low to a high signal when imaged with a uTE sequence. The reported uTE sequence was effective in imaging the deep layers of the knee cartilage.     

Keratinocytes can differentiate into eccrine sweat ducts in vitro: involvement of epidermal growth factor and fetal bovine serum

BACKGROUND: in addition to formation of an epidermal sheet and dermal substitution, reconstruction of skin that possesses functionality is an important goal for dermatologists. OBJECTIVE: we attempted to regenerate eccrine sweat glands in vitro. METHODS: we constructed skin equivalent models with various combination of normal human keratinocytes and fibroblasts and also examined the effect of various growth factors. RESULTS: we found that keratinocytes invaded the collagen gels and formed eccrine duct-like structures, only when (i) the culture media contained at least 15 ng/ml of epidermal growth factor (EGF) and fetal bovine serum (FBS), (ii) the keratinocytes were derived from young donors, and (iii) fibroblasts were present in the gel. Interestingly, when cultured under the same conditions eccrine gland duct cells were unable to invade the gel. Immunohistochemical analyses revealed induction of carcinoembryonic antigen by EGF at the inner part of the eccrine duct-like structures. Proliferating cell nuclear antigen was expressed mainly in basal layers of the epithelia but was not observed in the deeply invaded part. Cytokeratin profiles of the reconstructed epithelia were consistent with those of the regenerating epidermis and partly with the eccrine sweat duct. CONCLUSIONS: although not perfect model, these results indicate that 'young' keratinocytes could differentiate into/toward eccrine sweat ducts in vitro in the presence of EGF and FBS in cooperation with dermal fibroblasts.     

Equol,a Metabolite of Daidzein,Is More Efficient than Daidzein for Bone Formation in Growing Female Rats

Few studies have examined the effects of isoflavones and particularly equol, a metabolite of the isoflavone daidzein, on bone formation during the growth period in animals. The present study investigated the effects of orally administered daidzein or equol on bone formation and bone mineral density in growing female rats. Female Sprague‐Dawley rats, aged 3 weeks, were divided into four groups (n = 8 per group) as follows: rats were orally administered a corn oil, 8 mg/day of daidzein, 4 mg/day of equol or 8 mg/day of equol in corn oil for 4 weeks. Daidzein and equol increased the bone mineral density of growing female rats by stimulating bone formation without exhibiting a substantial effect on the weight of their reproductive organs. Bone growth caused by increased bone mineralizing surface and bone formation rate in rats administered with equol was approximately twice that of rats administered with daidzein. These results suggest that equol might be more efficient than daidzein for bone formation in growing female rats. Copyright © 2015 John Wiley & Sons, Ltd.     

ANGIOGRAPHIC, HISTOMETRIC AND HISTOPATHOLOGICAL STUDIES ON THE INTRAMURAL CORONARY ARTERIES IN THE INFARCTED HEART

Arterial changes of the intramural branches of the coronary arteries were studied angiographically, histometrically and histopathologically in the heart obtained at autopsy from 50 cases with myocardial infarction and 21 control subjects. Stenosis was observed in 14.4% of the intramural coronary arteries in the infarction group, 3.0% in the aged and 0% in the young control group. Hypertrophy of the media was observed in 18.9% of the intramural coronary arteries in the infarction group and 10.7% in the control group. Proliferation of the internal elastic lamina was observed in 6.9% of the intramural coronary arteries in the infarction group and 0.9% in the control group. Stenosis of the intramural branches was the most frequent in those less than 300 p in diameter and was caused by muscular hypertrophy of the media. Histological changes in the vascular wall of the intramural coronary artery was less frequent in the distal to the epicardial branches with marked stenosis than distal to the epicardial branches without stenosis. ACTA PATH. JAP. 27: 511˜526, 1977.