Comparative analysis of mamushi (Gloydius blomhoffii) bite patients indicates that creatinine kinase levels/white blood cell count trends reflect severity.

Aim: There has been no indicator that allows an early quantitative evaluation of the severity of a mamushi snake (Gloydius blomhoffii) bite. Because the number of severe mamushi bite cases is much fewer than non-severe cases, a formal case-control study is difficult. Therefore, we tried to generate a preliminary quantitative, real-time index for its severity by referring to published reports of severe mamushi bite cases. Methods: We enrolled patients who presented with a mamushi bite and visited our outpatient clinic. Severe cases were collected from published works. Creatinine kinase levels and white blood cell counts of non-severe and severe cases were compared and analyzed. Results: There was a lag time of 10 h before the creatinine kinase level began to rise. The speed of the increase was higher in severe cases than in non-severe cases, and severe cases were recognized as those showing speeds of above 250 IU/L/h. White blood cell counts increased earlier than creatinine kinase levels without any lag time. Severe cases were recognized as those with the counts of over 1,000 × (h) + 6,000 [/µL] before 5 h and 300 × (h) + 10,000 [/µL] after 5 h. Conclusion: We herein present the creatinine kinase level and white blood cell count trends and demonstrate preliminary cut-off equations. The trends for both parameters serve as quantitative indicators of the severity of a mamushi bite until a large scale case-control study is achieved.

Results of second-stage screening for skin cancers in Oita Prefecture, Japan.

We performed skin cancer screenings for 2 or 3 days annually from 2006 through 2013 in Oita Prefecture, Japan. Screening of approximately 3000 people in total allowed us to identify and treat several skin cancers, including five cases of malignant melanoma, four of squamous cell carcinoma, 16 of basal cell carcinoma, 11 of Bowen's disease, 17 of actinic keratosis, one of extramammary Paget's disease and one of metastatic breast carcinoma. The sensitivity and specificity for the category defined by an identified lesion associated with risk of cancer and requiring further examination (category C) were 92.7% and 95%, respectively. We cannot estimate the outcome of our skin cancer screenings in terms of cancer mortality because of the small number of subjects examined and the brief follow-up period. However, we did estimate the effectiveness of these screenings in terms of stages or sizes of cancerous lesions. The relative numbers of subjects with malignant melanoma at various clinical stages, identified during skin cancer screenings and during a routine visit to our hospital, were significantly different. We also compared, statistically, the sizes of lesions in Bowen's disease that were found during cancer screenings and during a direct visit to our hospital. The former lesions were smaller than the latter. Our data suggest the benefits of our skin cancer screenings and the importance of campaigns and education to encourage people to visit dermatologists for the detection of skin cancers at an early stage.

Association between HLA-DRB1*0405, -DQB1*0401 and -DQA1*0303 alleles and lamotrigine-induced cutaneous adverse drug reactions. A pilot case-control study from Japan.

BACKGROUND: Human leukocyte antigen (HLA) genotypes in lamotrigine -induced (LTG-induced) cutaneous adverse drug reactions (cADRs) have been described in several reports but controversy remains even for a given ethnic group. We attempted to clarify a possible association between LTG-induced cADRs and HLA alleles in Japanese patients. METHOD: Sixteen subjects, including eight patients with LTG-induced cADRs and eight LTG-tolerant controls were included in this study. All eight patients with LTG-induced cADRs gave positive results in a drug-induced lymphocyte stimulation test (DLST) with LTG. We performed HLA-typing for HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1, using PCR with sequence-specific oligonucleotide probes and multiple analyte profiling (xMAP) technology (Luminex System; Luminex Corporation, Austin, TX). We examined differences between allele frequencies in our two groups of subjects and the allele frequencies in the general Japanese population. RESULTS: The frequencies of HLA-DRB1*0405, and HLA-DQB1*0401 alleles were higher in our LTG-cADRs patients than the reference frequencies in the general Japanese population. We also detected HLA-DQA1*0303 frequently in our LTG-cADRs patients, but data for this allele in the Japanese population was not available. Our observation was presumably due to the linkage disequilibrium among the three alleles. The haplotype frequency of HLA-DRB1*0405, DQB1*0401 and DQA1*0303 in our LTG-cADRs subjects was also different from the corresponding haplotype frequency in the database for the Japanese population and the difference was statistically significant. One patient with the HLA-DRB1*0405, -DQB1*0401 and DQA1*0303 haplotype was safely re-treated with LTG after results of a DLST with LTG ceased to be positive about 4 months after discontinuation of LTG. LIMITATIONS: Our analysis included only 16 patients. Associations between LTG-induced cADRs and specific HLA loci will have to be confirmed in larger studies. CONCLUSIONS: LTG-induced cADRs are associated with HLA-DRB1*0405, -DQB1*0401 and -DQA1*0303.

Epiplakin modifies the motility of the HeLa cells and accumulates at the outer surfaces of 3-D cell clusters.

Elimination of epiplakin (EPPK) by gene targeting in mice results in acceleration of keratinocyte migration during wound healing, suggesting that epithelial cellular EPPK may be important for the regulation of cellular motility. To study the function of EPPK, we developed EPPK knock-down (KD) and EPPK-overexpressing HeLa cells and analyzed cellular phenotypes and motility by fluorescence/differential interference contrast time-lapse microscopy and immunolocalization of actin and vimentin. Cellular motility of EPPK-KD cells was significantly elevated, but that of EPPK-overexpressing cells was obviously depressed. Many spike-like projections were observed on EPPK-KD cells, with fewer such structures on overexpressing cells. By contrast, in EPPK-KD cells, expression of E-cadherin was unchanged but vimentin fibers were thinner and sparser than in controls, and they were more concentrated at the peri-nucleus, as observed in migrating keratinocytes at wound edges in EPPK(-/-) mice. In Matrigel 3-D cultures, EPPK co-localized on the outer surface of cell clusters with zonula occludens-1 (ZO-1), a marker of tight junctions. Our results suggest that EPPK is associated with the machinery for cellular motility and contributes to tissue architecture via the rearrangement of intermediate filaments.

Cutaneous horn malignant melanoma.

A 73-year-old Japanese woman presented with cutaneous horn on the right cheek. The resected tumor was 9 mm in diameter, with 14 mm protrusion, and showed exophytic growth with marked papillomatosis. Histopathology showed proliferation of atypical melanocytes with melanin pigments in the epidermis and dermis under the cutaneous horn. These cells were confined to the base of the cutaneous horn, and did not spread to the surrounding epidermis. The final diagnosis was cutaneous horn malignant melanoma. This pathological entity is considered a specific form of verrucous melanoma, and might be added to the list of cutaneous horn-forming lesions.

Autoimmune thyroid disease in children and adolescents with idiopathic pulmonary arterial hypertension.

BACKGROUND: Previous studies have reported a high prevalence of autoimmune thyroid disease (AITD) in adult patients with pulmonary arterial hypertension (PAH). The aim of this retrospective study was to determine the prevalence of AITD in children and adolescents with idiopathic PAH (IPAH). METHODS AND RESULTS: The study group included 16 patients who had been diagnosed as having idiopathic PAH when they were younger than 15 years old; all were younger than 20 years of age. Thyroid function and antithyroid antibody levels were examined regularly at 6-12-month intervals and when there were clinical signs of thyroid dysfunction. In total, 7 patients (44%) had AITD; 2 patients developed Graves' disease, 2 developed silent thyroiditis, and 3 had antithyroid antibodies with euthyroidism. The duration after PAH onset and the prostacyclin (PGI(2)) treatment period were significantly longer in patients with AITD (7.6+/-2.1 and 7.4+/-2.3 years, respectively) than in patients without AITD (5.0+/-1.1 and 4.8+/-1.2 years, respectively; P<0.01 and P<0.05). CONCLUSIONS: The prevalence of AITD is high in children and adolescents with IPAH, so evaluation of thyroid function is important to prevent deterioration of right heart failure.

Efficacy and limitations of continuous intravenous epoprostenol therapy for idiopathic pulmonary arterial hypertension in Japanese children.

BACKGROUND: There is little data on the long-term effects of continuous intravenous epoprostenol for children with idiopathic pulmonary arterial hypertension (IPAH) in Japan. METHODS AND RESULTS: Thirty-one IPAH patients younger than 18 years old who had begun epoprostenol therapy at Toho University Omori Medical Center between January 1999 and June 2004 were reviewed. During a mean follow up of 3.4 years, the rate of those who survived or did not undergo a lung transplantation among the 27 patients who received home infusion therapy of epoprostenol was 100% at 1 year, 96.3% at 2 years, and 79.4% at 3 years. In 82% of survivors, the World Health Organization functional class was changed from III or IV to II according to improvements in the plasma brain natriuretic peptide level and the distance walked in 6 min during the follow-up period. In most cases, mean pulmonary artery pressure and the ratio of pulmonary to systemic vascular resistance remained high, although the cardiac index had improved to within a normal range 1 year after the initiation of epoprostenol. Therefore, sildenafil was administered as an additional therapy to 16 patients who presented with sustained severe PAH. CONCLUSIONS: Continuous IV epoprostenol certainly improves survival and exercise tolerance in childhood IPAH, although the improvement of pulmonary vascular resistance regardless of long-term epoprostenol therapy is insufficient. Therefore, the addition of a new drug, such as sildenafil, is recommended to be administered in adjunction with epoprostenol.

Synthesis, Magnetic Properties, and Incomplete Double-Cubane Structure of Manganese(III)-Metal(II) Complexes [Mn(MeOH)L(OH)M(bpy)](2) (M = Zn, Cu, Ni, and Mn; H(4)L = 1,2-Bis(2-hydroxybenzamido)benzene; bpy = 2,2'-Bipyridine).

The manganese(III) complex K[MnL(py)(2)].py (H(4)L = 1,2-bis(2-hydroxybenzamido)benzene, py = pyridine) reacted as a ligand complex at the two phenoxo oxygen atoms with metal(II) ion and 2,2'-bipyridine to give a series of heterometal complexes [Mn(MeOH)L(OH)M(bpy)](2) (M(II) = Zn (1); Cu (2); Ni (3); Mn (4)). X-ray structures were determined 1, C(68)H(74)N(8)O(18)Mn(2)Zn(2): a = 12.367(3) Å, b = 12.844(2) Å, c = 12.262(2) Å, alpha = 106.58(1) degrees, beta = 117.89(1) degrees, gamma = 78.57(2) degrees, triclinic, P&onemacr;, and Z = 1. 2, C(68)H(74)N(8)O(18)Mn(2)Cu(2): a = 13.447(1) Å, b = 12.670(2) Å, c = 21.732(1) Å, beta = 107.076(5) degrees, monoclinic, P2(1)/n, and Z =2. 3, C(68)H(74)N(8)O(18)Mn(2)Ni(2): a = 12.358(3) Å, b = 12.847(3) Å, c = 12.315(3) Å, alpha = 106.63(2) degrees, beta = 118.71(1) degrees, gamma = 78.32(2) degrees, triclinic, P&onemacr;, and Z = 1. 4, C(66)H(66)N(8)O(16)Mn(4): a = 12.511(2) Å, b = 21.129(3) Å, c = 12.811(1) Å, beta = 110.12(1) degrees, monoclinic, P2(1)/n, and Z = 2. The X-ray analyses confirmed that each of the crystals consists of an incomplete double-cubane molecule with a [Mn(2)M(2)O(6)] core, in which two M(II) ions are bridged by two hydroxo groups to form a planar dinuclear moiety bridged by di-&mgr;-hydroxo groups [(bpy)M(OH)(2)M(bpy)](2+) and the dinuclear moiety is sandwiched between two Mn(III) complexes [Mn(MeOH)L](-). The Mn(III) ion and the dinuclear M(II) moiety are triply bridged by the one hydroxo oxygen of the dinuclear moiety and two phenoxo oxygen atoms of the Mn(III) ligand complex. The two phenoxo oxygen atoms of the Mn(III) ligand complex coordinate as an axial ligand to two independent metal(II) ions of the dinuclear moiety. The magnetic susceptibilities of 1-4 were measured in the temperature range of 2-300 K. All the Mn(III) ions in these complexes are in a high-spin state of S(Mn) = 2 with a d(4) electronic configuration, and the metal(II) ions are in the spin states of S(Zn) = 0, S(Cu) = 1/2, S(Ni) = 1, and S(Mn(II)) = 1/2 (low-spin). The magnetic susceptibility data are well reproduced by the following spin Hamiltonian based on the rhombus spin coupling model with spin (S(1), S(2), S(3), S(4)) = (2, S(M), 2, S(M)), including a zero-field splitting term for the Mn(III) centers: H = g(Mn)beta(S(1) + S(3)).H + g(M)beta(S(2) + S(4)).H - 2J(S(1).S(2) + S(2).S(3) + S(3).S(4) + S(4).S(1)) - 2J'(S(2).S(4)) + D(Mn)[S(1z)(2) + S(3z)(2)], in which g(Mn) and g(M) are the g factors of the Mn(III) and M(II) ions, J and J' are the Mn(III)-M(II) and M(II)-M(II) Heisenberg coupling constants, and D is the zero-field splitting parameter of Mn(III). The calculated best-fit parameters are as follows: g(Mn) = 1.91, g(Cu) = 2.39, J = -4.5 cm(-)(1), J' = -8.1 cm(-)(1), and D(Mn) = -4.9 cm(-)(1) for 2; g(Mn) = 1.97, g(Ni) = 2.23, J = -1.5 cm(-)(1), J' = -2.6 cm(-)(1), and D(Mn) = -5.5 cm(-)(1) for 3; and g(Mn) =1.95, g(Mn(II)) = 2.29, J = -3.5 cm(-)(1), J' = -14.1 cm(-)(1), and D(Mn) = -12.0 cm(-)(1) for 4. The spin frustration due to the incomplete double-cubane structure is discussed.