Nationwide survey of nevoid basal cell carcinoma syndrome in Japan revealing the low frequency of basal cell carcinoma

Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by developmental defects and tumorigenesis. The clinical manifestations of NBCCS have been reported in large epidemiological studies from the United States, the United Kingdom, and Australia, but not from an Asian country. We conducted a nationwide survey and identified 311 NBCCS patients in Japan. We investigated the detailed clinical manifestations of 157 patients ranging in age from 9 months to 77 years old (mean: 33.1 years). We then compared the frequency and age of onset for various tumors developed in Japanese NBCCS patients with patients from the three countries listed above in which NBCCS studies were previously conducted. Our most significant finding was the low frequency of basal cell carcinoma (BCC) in Japanese patients. Frequency of BCC in patients over 20 years of age was 51.4%, a much lower rate compared to the United States, Australia, and the United Kingdom (91%, 85%, and 73%, respectively). The mean age of BCC onset was 37.4 years of age, a much older age compared to the above-mentioned countries. These findings suggest that differences in ethnicity and/or environmental factors affect the incidence of BCC. Because the age of BCC onset is generally higher in Japanese NBCCS patients, careful skin examination over a prolonged period of time is warranted.     

Enhanced estradiol-induced vasorelaxation in aortas from type 2 diabetic mice may reflect a compensatory role of p38 MAPK-mediated eNOS activation

Cardiovascular problems are a major cause of morbidity and mortality, mainly due to coronary artery disease and atherosclerosis, in type 2 diabetes mellitus. However, female gender is a protective factor in the development of, for example, atherosclerosis and hypertension. One of the female hormones, 17??-estradiol (E2), is known to protect against the cardiovascular injury resulting from endothelial dysfunction, but the mechanism by which it does so remains unknown. Our hypothesis was that E2-mediated activation of Akt and mitogen-activated protein kinase (MAPK), and the subsequent endothelial NO synthase (eNOS) phosphorylation, might protect the aorta in diabetic mellitus. The experimental type 2 diabetic model we employed to test that hypothesis (female mice given streptozotocin and nicotinamide) is here termed fDM. In fDM aortas, we examined the E2-induced relaxation response and the associated protein activities. In control (age-matched, nondiabetic) aortas, E2 induced a vascular relaxation response that was mediated via Akt/eNOS and mitogen-activated/ERK-activating kinase (MEK)/eNOS pathways. In fDM aortas (vs. control aortas), (a) the E2-induced relaxation was enhanced, (b) the mediation of the response was different (via Akt/eNOS and p38 MAPK/eNOS pathways), and (c) E2 stimulation increased p38 MAPK and eNOS phosphorylations, decreased MEK phosphorylation, but did not alter estrogen receptor activity. We infer that at least in fDM aortas, E2 has beneficial effects (enhanced vascular relaxation and protection) that are mediated through Akt activation and (compensating for reduced MEK activation) p38 MAPK activation, leading to enhanced eNOS phosphorylation.     

Changes of sleep patterns in rats with chronic constriction injury under aversive conditions

In the present study, we investigated the changes of sleep parameters in rats with chronic constriction injury (CCI) under aversive conditions. The electroencephalogram (EEG) in the frontal cortex of CCI rats and electromyogram (EMG) were measured over 6 h by placing rats on sandpaper as an aversive condition, to compare with rats placed on sawdust. Six days after CCI surgery, the rats exhibited significant mechanical allodynia, and also had neuropathic pain. When rats were placed on sawdust, no significant difference was observed between the CCI group and sham-operated control group in sleep latency, total waking time, total non-REM sleep time and total REM sleep time. On the other hand, when CCI rats were placed on sandpaper, a significant increase was observed in sleep latency and total waking time compared with the sham group; however, no significant difference was observed in the total non-REM sleep time and total REM sleep time between these two groups. These results indicate that an important factor of sleep disturbance in CCI rats is not only damage to the nerves but also being under aversive conditions. In addition, it was found that CCI rats placed on sandpaper as an aversive condition can serve as a new sleep disturbance model.     

Role of lysophosphatidylcholine (LPC) in atherosclerosis

Lysophosphatidylcholine (LPC) is a bioactive proinflammatory lipid generated by pathological activities. LPC is also a major phospholipid component of oxidized low-density lipoprotein (Ox-LDL) and is implicated as a critical factor in the atherogenic activity of Ox-LDL. LPC is believed to play an important role in atherosclerosis and inflammatory diseases by altering various functions in a number of cell-types, including endothelial cells, smooth muscle cells, monocytes, macrophages, and T-cells. LPC activates several second messengers -- including protein kinase C, extracellular-signal-regulated kinases, protein tyrosine kinases, and Ca(2+) -- implicating the engagement of transduction mechanisms in its observed actions. Moreover, recent evidence suggests that in several cell-types, cloned orphan G-protein-coupled receptors may serve as the specific receptors via which LPC modulates second messenger pathways (although LPC may not be a direct ligand of such receptors). In addition, current evidence suggests that LPC impairs the endothelium-dependent relaxations mediated by endothelium-derived relaxing factors and directly modulates contractile responses in vascular smooth muscle. However, despite all this, and although elevated levels of LPC have been linked to the cardiovascular complications associated with atherosclerosis, ischemia, and diabetes, the precise pathophysiological roles played by LPC in several states remain to be established. In this review, we focus in some detail on the entirety of the signal-transduction system for LPC, its pathophysiological implications, and the vascular abnormalities associated with it.     

Overexpression of heme oxygenase-1 in coronary atherosclerosis of Japanese autopsies with diabetes mellitus: Hisayama study

Few studies regarding the topographical expression of heme oxygenase-1 (HO-1) and its pathophysiological role in human coronary atherosclerotic lesions, particularly in relation to type 2 diabetes mellitus (DM) and intimal angiogenesis, have been reported. HO-1 expression was immunohistochemically examined in 312 tissue blocks of coronary arteries obtained from 53 Japanese autopsy cases in Hisayama cohort study that included 19 diabetic subjects and 34 age- and sex-matched non-diabetic subjects (56-93 years old, mean+/-S.D.: 73+/-10). The HO-1 was ubiquitously distributed in atherosclerotic intima, and was mainly expressed by macrophages and endothelial cells, and partly by smooth muscle cells. The prevalence of HO-1 expression increased as the lesion type (as classified by the American Heart Association (AHA) Committee) and stenotic grade progressed (p<0.0001), and was significantly higher in diabetic than in non-diabetic subjects (p<0.01). This HO-1 overexpression was associated with greater CD-68-positive macrophage infiltration (p=0.005). Interestingly, the distribution of HO-1-positive cells was accentuated in coronary atherosclerotic lesions with intimal microvessels in diabetic subjects (p<0.05), particularly those with hypercholesterolemia (p<0.05), and was preferentially distributed in the shoulder region of atherosclerotic lesion type IV in the AHA classification (p<0.01). In conclusion, HO-1 expression was distributed in overall human coronary atherosclerotic lesions, particularly in diabetic subjects, indicating that HO-1 expression is intimately associated with atherogenesis and may play an important role as an adaptive molecule in the inflammatory-repair process. The association of HO-1 overexpression with a greater extent of intraplaque angiogenesis suggests a multi-faceted role for HO-1 in modulating the progression of atherosclerosis.     

Immunohistochemical alpha- and beta-catenin and E-cadherin expression and their clinicopathological significance in human lung adenocarcinoma

The E-cadherin/catenin complex (alpha-catenin, beta-catenin, and E-cadherin) plays a crucial role in cell-cell adhesion and tissue remodeling, and abnormalities in these molecules have been suggested to participate in the proliferation and invasive and metastatic potentials of several human carcinomas. However, in human lung adenocarcinomas, its importance has not yet been sufficiently investigated. We immunohistochemically examined the expressions of E-cadherin/catenin complex in 35 primary lung adenocarinomas, and evaluated their expressions in a semiquantitative manner. Correlations between these expression levels, MIB-1 and nuclear p53 indices, and clinicopathological factors were analyzed by subdividing the cases into high- and low-expression groups for each protein. The reduction in membranous E-cadherin/catenin complex expression correlated significantly with low-grade histological differentiation and with high MIB-1 index. Survival analyses were also performed to clarify which factors potentially affected the prognosis of lung adenocarcinoma patients. The low expression of beta-catenin and the high MIB-1 index had a significantly unfavorable influence on the patients' survival. Moreover, the immunohistochemical expression of beta-catenin by cancer cells and MIB-1 index are considered useful prognostic factors for lung adenocarcinoma.     

Biodegradation and bioabsorption innovation of the functionally graded bovine bone-originated apatite with blood permeability

Bioabsorbable and functionally graded apatite (fg-HAp) ceramics were designed using bovine bone by the calcination and partial dissolution-precipitation methods. The fg-HAp ceramics that were developed had gradual distributions of the degree of crystallinity and the grain size of single-phase hydroxyapatite from the surface layer of the pore wall to the bulk structure region. Calcination at 1073 K gave a specific surface area of 30 m2 x g-1 and porosities of 60-80%. The pore structure of the fg-HAp was classified into two regions: a macro-pore region (100-600 microm) originating from spongy bone and a micro-pore region (10-160 nm) related to body fluid permeation and blood permeability. By implantation in subcutaneous tissue of rat, it was confirmed that body fluid permeated the bulk region of the fg-HAp ceramics through the micro-pores. The volumetric populations occupied by body fluid were 60% at 4 weeks and 68% at 8 weeks in the ceramics explants, indicating drastic bioabsorption, although the body fluid was found to be immunopositive for an albumin as the main serum protein in blood. On the fg-HAp ceramics developed here, the bioabsorption rate could be controlled by careful selection of the calcination temperature. These ceramics can be applied as new biomimetic ceramics exhibiting surface and bulk degradations and cellular absorption by giant cells.