Dermoscopic features of pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a disease characterized by aberrant mineralization of soft tissue and fragmentation of elastic fibres. It is often difficult to distinguish PXE clinically from pseudoxanthoma elasticum-like papillary dermal elastolysis (PXE-like PDE). However, we have identified that the dermoscopic findings in PXE include coalescing and reticulated yellow-white clods on a light purple-red background, whereas the dermoscopic findings in PXE-like PDE lack such a coloured background. To our knowledge, this is the first detailed description of dermoscopic differences between PXE and PXE-like PDE.

NLRP3 activation induces ASC-dependent programmed necrotic cell death, which leads to neutrophilic inflammation.

NLR family pyrin domain containing 3 (NLRP3) is a cytoplasmic pattern recognition receptor that regulates innate immune responses by forming a protein complex, the inflammasome. It leads to production of proinflammatory cytokine productions such as interleukin 1ß (IL-1ß). We and others demonstrated that an induction of activated NLRP3 also induced cell death. However, little is known about the characteristics and mechanisms of the cell death and its involvement in the pathogenesis of inflammatory conditions. In this study, we established cell lines in which NLRP3 was induced by doxycycline using a tetracycline-inducible expression (Tet-on) system. Using this system, the expression of NLRP3 mutants in cryopyrin-associated periodic syndrome (CAPS) patients was sufficient for the induction of necrotic cell death without lipopolysaccharide stimulation or generation of mature IL-1ß. We also found that CA074-Me, a cathepsin B inhibitor, blocked cell death before oligomerization of apoptosis-associated speck-like protein containing a CARD (ASC), whereas Z-VAD-fmk, a pan-caspase inhibitor, blocked the cell death after the oligomerization. Silencing of the ASC gene (Pycard) by small hairpin RNA treatment inhibited the NLRP3 mutant-induced cell death, but silencing of the caspase-1 gene (Casp1) did not. Taken together, these results indicated that ASC was indispensable for NLRP3-mediated programmed necrotic cell death, and that this type of cell death was distinct from 'pyroptosis', which requires caspase-1. Finally, we demonstrated in an in vivo model that the programmed necrotic cell death induced by activated NLRP3 could cause neutrophil infiltration, indicating a possible role of cell death in neutrophil infiltration of skin lesions in CAPS patients.

Dramatic Clinical Response of Relapsed Metastatic Extramammary Paget's Disease to Trastuzumab Monotherapy.

We report the first case of 68-year-old Japanese woman with metastatic HER2-positive extramammary Paget's disease that showed the validity of trastuzumab monotherapy. We administered trastuzumab at a loading dose of 8 mg/kg i.v., followed by a 6 mg/kg maintenance dose every three weeks according to a protocol for HER2-positive metastatic breast cancers and a near-complete response was achieved after the tenth infusion. The patient experienced a moderate headache and flushing during the first infusion, but had no advanced effects during subsequent infusions with ibuprofen and d-chlorpheniramine maleate. Given the dramatic response, the patient has had 17 infusions of trastuzumab with no disease progression. Thus, trastuzumab has few side effects and is well tolerated for elderly patients. It may become a new choice of the adjubant therapy of this disease.

Melanoma in association with acquired melanocytic nevus in Japan: a review of cases in the literature.

BACKGROUND: Malignant melanomas clinically and/or histologically associated with melanocytic nevi have been reported worldwide. Approximately 20% of malignant melanomas in Caucasians, most of which are found on the trunk and proximal extremities, develop in association with pre-existing melanocytic nevi. In Japan, however, over half of all melanomas are acral lentiginous melanomas (ALMs) on the hands and feet; melanomas on sun-exposed areas are seen less frequently in Japanese people than in Caucasians. As ALMs are not usually accompanied by melanocytic nevi and there have been no reviews of the literature or statistical data regarding Japanese cases of melanomas with melanocytic nevi, dermatologists in Japan have few opportunities to see melanomas associated with pre-existing melanocytic nevi. METHODS: Here we report a case of a superficial spreading melanoma that was formed on a melanocytic nevus on the trunk, and we review for the first time the case reports from the Japanese literature. RESULTS AND CONCLUSIONS: With regard to the reported cases, melanomas associated with melanocytic nevi were mainly superficial spreading melanomas and nodular melanomas on the trunk or extremities; ALMs were rarely associated with nevi, indicating a trend similar to that observed in Caucasians. These findings suggest that the low frequency of associations between melanomas and melanocytic nevi in Japan reflects racial differences in the frequencies of each type of melanoma.

A clinical study of Henoch-Schönlein Purpura associated with malignancy.

BACKGROUND: Malignancy has been reported as a causative factor of cutaneous vasculitis, although only two retrospective epidemiological studies have analysed the association between Henoch-Schönlein purpura (HSP) and malignancy to date. OBJECTIVE: To analyse the association between adult HSP and malignancy. METHODS: We retrospectively reviewed the medical records of patients and found 103 cases of HSP over the past 20 years. Fifty-three cases (aged > or = 41 years) were categorized to two groups including 'with malignancy' or 'without malignancy', so that we could analyse the differences of clinical features between them. We also compared our study to previous reports. RESULTS: Twenty-three cases out of 53 patients exhibited underlying malignant tumours. We focused on nine patients in which malignant tumours were thought to be strongly associated. Seven of nine patients exhibited new metastatic lesions or died due to underlying cancer within 1-32 months. CONCLUSIONS: An association between HSP and malignant disease might have important diagnostic and pathophysiologic implications.

CD4+CD25high regulatory T cells are markedly decreased in blood of patients with pemphigus vulgaris.

BACKGROUND: It remains to be determined whether pemphigus vulgaris (PV), an autoimmune blistering disease, has a reduction and/or dysfunction of CD4(+)CD25(high) regulatory T (Treg) cells. OBJECTIVES: To evaluate the frequency and phenotypes of Treg cells in blood of patients with PV. METHODS: Peripheral blood mononuclear cells were prepared from PV patients as well as normal and disease control volunteers, and the frequency and phenotypes of Treg cells were determined by flow cytometry. CD4(+)CD25(+) and CD4(+)CD25(-) T cells isolated from peripheral blood mononuclear cells of PV patients and normal controls were subjected to real-time semiquantitative RT-PCR for the expression of Foxp3 gene. RESULTS: The proportion of Treg cells in all PV patients was severely reduced, approximately ten times less than controls. These observations were further confirmed by both diminished gene and protein expression of Foxp3 in the CD4(+)CD25(+) T cell population in PV patients. CONCLUSIONS: Numerical impairment of Treg cells may be involved in the pathogenesis of PV.

Immunosuppressive properties of CD95L-transduced "killer" hybrids created by fusing donor- and recipient-derived dendritic cells.

Allogeneic immune responses, which are initiated by dendritic cells (DCs) of both donor and host origins, remain a major obstacle in organ transplantation. Presentation of intact major histocompatibility complex (MHC) molecules by allogeneic DCs and allogeneic peptides by syngeneic DCs leads to complex allogeneic immune responses. This study reports a novel strategy designed to suppress both pathways. A stable DC line XS106 (A/J mouse origin) was transfected with CD95L cDNA and fused with splenic DCs purified from allogeneic BALB/c mice. The resulting "killer" DC-DC hybrids: (1) expressed CD95L and MHC class I and class II molecules of both A/J and BALB/c origins, while maintaining otherwise characteristic surface phenotypes of mature DCs; (2) inhibited MHC class I- and class II-restricted mixed leukocyte reactions between the parental strains by triggering apoptosis of alloreactive T cells; and (3) abolished delayed-type hypersensitivity responses of A/J (and BALB/c) mice to BALB/c-associated (and A/J-associated) alloantigens when injected intravenously into A/J (and BALB/c) mice. The onset of graft-versus-host disease in (BALB/c x A/J) F1 hosts receiving A/J-derived hematopoietic cell transplantation was suppressed significantly (P <.001) by killer DC-DC hybrid treatment. These results form both technical and conceptual frameworks for clinical applications of CD95L-transduced killer hybrids created between donor DCs and recipient DCs in the prevention of allogeneic immune responses following organ transplantation.

Antioxidant activity and inhibitory effect of Gamazumi (Viburnum dilatatum THUNB.) on oxidative damage induced by water immersion restraint stress in rats.

The antioxidant activity and antiulcer effects of Gamazumi (Viburnum dilatatum THUNB.) fruit squeezing solution (GSS) were investigated. GSS including no antioxidant additive showed strong antioxidant activity by the XYZ-dish method and the electron spin resonance (ESR) method. GSS showed to have no negative effect on growth of rats for 2 weeks of feeding with free access to GSS. After feeding, the GSS group showed a significant inhibitory effect on gastric ulcer formation by water immersion restraint stress for 6 hours compared with the Water group. Plasma, liver and stomach concentrations of lipid peroxide in the GSS group were reduced rather than the water group. Furthermore, the activities of plasma lactic dehydrogenase, amylase and creatine phosphokinase are ordinarily increased by stress; however these activities in the GSS group decreased to the level in the Control group having no stress. The physiological effects of GSS were similar to, or higher than, those of 0.1% (-)-epigallocatechin gallate (EGCg) solution. These effects of EGCg and GSS were similar to the order of antioxidant activity against hydroxyl radical found by both the XYZ-dish and the ESR methods. It was concluded that after ingestion of GSS, during the period of strong antioxidant activity in the body, it could prevent stress-induced oxidative damage.

[Is routine application of off-pump coronary artery bypass grafting warranted?].

The limitation and indication of off-pump coronary artery bypass grafting (OPCAB) remain controversial. Since May 1999, we have applied OPCAB for all isolated coronary bypass cases routinely. Intraoperative conversion to CCAB occurred in 8 patients (10.8%). The main reasons for conversion were intramyocardial coronary arteries and arythmia-induced hemodynamic instability in the acute phase of myocardial infarction. We evaluated the results of OPCAB as compared to conventional coronary artery bypass (CCAB) as a historical control. The operative mortality was 1.6% in both groups. Postoperative complications including renal failure and requirements of circulatory support were significantly less in OPCAB. Postoperative max CPK-MB value, the amount of postoperative bleeding and the requirement of transfusion were also significantly less in OPCAB. Only neurological complication in OPCAB was temporary delirium in a high-aged patient, whereas three patients developed neurological complications including permanent stroke in CCAB. Right heart bypass was effectively utilized to maintain hemodynamics and expose the posterior vessels in patients with severely dilated and poorly functioning left ventricle (EF: 24-31%) and a patient with multiple severe stenosis in cerebral arteries. Coronary angiogram performed after the operation demonstrated 94% of graft patency. These results warrant the further application of OPCAB for multivessel surgical revascularization.

Three-dimensional flow velocity quantification of Freestyle aortic stentless bioprosthesis by magnetic resonance imaging: surgical consideration.

The characteristics in flow dynamics of stentless bioprosthetic valve implanted in aortic position has been reported using Doppler echocardiography and beneficial results have been demonstrated in patients. Because some disturbed flow characteristics were seen clinically with existence of pressure gradient, the nature of flow-velocity characteristics was evaluated in patients receiving Freestyle stentless aortic bioprosthesis using new three-dimensional MRI method. In 19 patients after AVR with Freestyle bioprosthesis, flow-velocity study was conducted using velocity-encoding phase-contrast magnetic resonance imaging (MRI). Three-dimensional flow profiles were reconstructed. The implantation techniques were subcoronary (SC) in 10, root inclusion (Incl) in 6, and full root (FR) in 3 patients. These results were compared to 4 pts with stented bioprosthesis and 4 healthy volunteers. In 3-D flow velocity profiles, there were variations from almost normal pattern to some disturbed flow pattern. All patients of FR showed the parabolic flow pattern nearly equal to normal subjects. Over half of the patients with SC and Incl showed disturbed flow pattern with increased pressure gradient. Although hemodynamically acceptable, Freestyle aortic bioprosthesis showed some degree of flow disturbance in subcoronary or inclusion method with increased transvalvular velocity that may cause late problems, and these findings evaluated by 3-D method should be implicated in surgical consideration.

New technologies to prevent and treat contact hypersensitivity responses.

Allergic contact dermatitis is a common inflammatory skin disease caused by T cells that recognize environmental and industrial allergens (i.e., haptens). Langerhans' cells (LC), which are skin-specific and "immature" members of the dendritic cell (DC) family of antigen-presenting cells, play crucial roles in the induction of contact hypersensitivity (CH) responses. Upon exposure to haptens, LC migrate from the epidermis to draining lymph nodes, mature into T cell-stimulatory DC, and activate hapten-reactive T cells. Therefore, CH responses should be preventable at the sensitization phase by interfering with one of these changes that occur in LC. Our objective is to develop new technologies for the prevention and treatment of allergic contact dermatitis. In this article, we will introduce three technologies that we have recently developed. First, using a phage display strategy, we have identified a 12-mer peptide (termed "peptide 1") that binds and blocks the function of hyaluronan (HA), which is known to serve as an adhesive substrate for LC migration. Local injection of peptide 1 in mice before topical application of DNFB blocked almost completely the emigration of LC from the epidermis to the draining lymph node, where antigen presentation takes place. Peptide 1 represents a new strategy that is designed to inhibit the initial event of CH. Second, we have established an in vitro experimental system to study the terminal maturation of LC during antigen-specific interaction with T cells. This experimental system, which employs a long-term LC line and T cell clones, should provide a unique tool for the identification of new immunosuppressive agents that block LC terminal maturation selectively. Finally, under the hypothesis that LC, which are engineered to overexpress a death ligand, would deliver apoptotic signals instead of activation signals to T cells, we created a "killer" LC clone by introducing CD95L cDNA into our long-term LC line XS106. In vivo administration of DNFB-pulsed killer LC into mice, either before or after sensitization, resulted in marked suppression of CH responses to DNFB. The killer LC technology represents an entirely new immunosuppressive therapy that is designed to eliminate only the pathogenic T cells.

Induction of antigen-specific immunosuppression by CD95L cDNA-transfected 'killer' dendritic cells.

Dendritic cells (DCs) are special subsets of antigen-presenting cells characterized by their highly potent capacity to activate immunologically naive T cells. Here we report that DCs that are transfected with CD95 ligand (CD95L) cDNA, called 'killer' DCs, deliver death signals, instead of activation signals, to T cells after antigen-specific interaction. Injection of antigen-pulsed killer DCs into mice before sensitization induced antigen-specific immunosuppression. When administered after sensitization, killer DCs suppressed immune responses almost completely after subsequent challenge. Thus, killer DCs represent an entirely new immunomodulatory protocol, which may become directly applicable in preventing and even treating T cell-mediated inflammatory diseases.

Apoptosis in dendritic cell biology.

Apoptosis or programmed cell death regulates many aspects in immunological homeostasis and, thus, controls the initiation, magnitude, duration, and termination of immune responses. Recent studies on dendritic cells (DC), including Langerhans cells (LC), have reinforced this concept by documenting that these antigen presenting cells express surface receptors and ligands that are known to mediate apoptotic cell death and that they are highly susceptible to apoptotic signals. In this review article, four major topics concerning apoptosis in the biology of DC will be overviewed: (a) molecular mechanisms of apoptosis; (b) DC apoptosis induced by various stimuli; (c) regulation of DC apoptosis; and (d) cross-priming and cross-tolerance induced by DC ingesting apoptotic bodies.