Evaluation of skin perfusion pressure to assess refractory foot ulcers.

OBJECTIVE: The number of patients with foot gangrene caused by critical ischaemia and severe infection is increasing significantly in developed countries. The measurement of perilesional skin blood flow by skin perfusion pressure (SPP) is useful to select the appropriate treatment of gangrenous lesions, in that it is not affected by calcifications of blood vessels. However, the prognosis of a foot ulcer may also be affected by the level of blood sugar and infections. This study aimed to validate the use of SPP in cases of foot gangrene and ulcers in patients with and without diabetes mellitus (DM) and infection. METHOD: Clinical symptoms, ankle-brachial pressure index (ABPI) and SPP were assessed to evaluate the condition of each foot ulcer. Every foot ulcer was treated as independent, even if a participant had multiple ulcers. All ulcers for which we measured SPP were subject to the analysis. All ulcers were purely ischaemic in nature and were exclusively located on the foot or toes. RESULTS: Data were collected from 117 foot ulcers on 91 toes and feet from 65 patients. Almost all SPP values in healed cases were > 27 mmHg. There were three patients whose ulcers failed to heal by conservative treatments were complicated with severe infection. However, no effect of DM on the relationship between SPP values and prognosis was observed. Logistic regression analysis of all ulcers except for the 5 cases complicated with infection revealed that those with 30 mmHg or lower SPP values are likely to heal by conservative treatment with 23% or lower probability, whereas any ulcer with more than 50 mmHg SPP value and without severe infection may heal without the need for further operations with 80% or higher probability. CONCLUSION: The combination of SPP and careful evaluation of infection may be a good parameter to decide the appropriate treatment for ischaemic skin ulcers, regardless of the complication of DM.

Prognosis of chronic spontaneous urticaria in 117 patients not controlled by a standard dose of antihistamine.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a common skin disorder, but its clinical course reported so far is largely variable, probably due to the heterogeneity of the clinical background of patients and pathogenesis of this disease. METHODS: To reveal the prognosis of refractory CSU, we retrospectively studied the patients who suffered from spontaneous urticaria for six weeks or longer at their first visit to our outpatient clinic, who were insufficiently controlled by a standard dose of antihistamine, and revisited from 2003 to 2009. RESULTS: Among 223 patients with CSU, 117 patients fulfilled the criteria mentioned above. Mean disease duration at first visit and mean duration of follow-up at our hospital were 27.4 ± 4.2 months and 18.7 ± 1.9 months, respectively. By using Kaplan-Meier methods, the estimated improved rates at 12 months, 24 months, and 60 months were 36.6%, 51.2%, and 66.1%, respectively. The overall improvement rate of childhood cases (<19 years) was significantly higher than that of adult cases (P = 0.007, log-rank test). Moreover, the improvement rate of patients with short disease durations (<1 year at the first visit) was significantly (P = 0.003, log-rank test) higher than that of patients with long disease durations (one year or more). CONCLUSION: Our data indicate that the condition of patients with CSU can be gradually improved even in intractable cases. Information about the clinical course and prognostic factors of CSU in this study could help physicians predict the prognosis of patients and ensure medication adherence of patients with CSU.

New constraint on the existence of the µ+ → e+ γ decay.

The analysis of a combined data set, totaling 3.6 × 10(14) stopped muons on target, in the search for the lepton flavor violating decay µ(+) → e(+)γ is presented. The data collected by the MEG experiment at the Paul Scherrer Institut show no excess of events compared to background expectations and yield a new upper limit on the branching ratio of this decay of 5.7 × 10(-13) (90% confidence level). This represents a four times more stringent limit than the previous world best limit set by MEG.

A large heterozygous deletion including the entire C1 inhibitor gene in a sporadic case of hereditary angio-oedema.

C1 inhibitor (C1-INH) deficiency [hereditary or acquired angio-oedema (HAE or AAE)] is characterized by recurring episodes of subcutaneous or submucosal oedema. Many different mutations in the C1-INH gene have been identified as a cause of HAE. We investigated the molecular basis of the disease in a Japanese woman with sporadic HAE. Direct sequencing of genomic DNA revealed no point mutation in the C1-INH gene. Quantitative real-time PCR showed that the copy number of the C1-INH gene in the patient was half that of a healthy control. Furthermore, we identified a 650-kbp deletion on the chromosome, which included the C1-INH gene. We evaluated the correlation between the patient's attacks and her coagulation activity. The levels of D-dimer were high during the angio-oedema attacks, and often exceeded the normal range even during remission, thus the level of D-dimer reflected the activity of HAE in this patient.

New limit on the lepton-flavor-violating decay µ+→e+γ.

We present a new result based on an analysis of the data collected by the MEG detector at the Paul Scherrer Institut in 2009 and 2010, in search of the lepton-flavor-violating decay µ(+)e(+)γ. The likelihood analysis of the combined data sample, which corresponds to a total of 1.8×10(14) muon decays, gives a 90% C.L. upper limit of 2.4×10(-12) on the branching ratio of the µ(+)→e(+)γ decay, constituting the most stringent limit on the existence of this decay to date.

Coagulation/fibrinolysis and inflammation markers are associated with disease activity in patients with chronic urticaria.

BACKGROUND: The evaluation of disease severity and activity of chronic urticaria (CU) is essential for the adequate treatment of patients. However, there is no reliable biomarker for such evaluations. Recently, markers of blood coagulation and fibrinolysis have been revealed to be elevated in severe cases of CU. In this article, we studied the coagulation/fibrinolysis and inflammation markers and their relationship to disease activity in patients with CU. METHODS: Plasma fibrin degradation products (FDP), d-dimer and serum C-reactive protein (CRP) were measured with the assessment of disease severity and skin reaction to autologous serum in 82 patients with CU and 37 patients with acute urticaria, idiopathic angioedema (AE) or inducible types of urticaria (IU). RESULTS: The levels of FDP in patients with CU were significantly higher than those in patients with IU, but no other differences in FDP, d-dimer and CRP were observed among patients with different types of urticaria. These markers of patients with CU were well correlated with each other and significantly associated with disease severity of CU, but not with skin reactions to autologous serum. In 37 patients with CU, levels of all these parameters reduced as their disease condition improved, while they increased when the disease became aggravated. Regarding FDP, this relationship was observed even if FDP concentrations were within normal range throughout the study. CONCLUSIONS: The measurement of plasma FDP, d-dimer and serum CRP may be useful for the assessment of disease activity of CU.

Nuclear-matter modification of decay widths in the phi-->e+e- and phi-->K+K- channels.

The invariant mass spectra of phi-->K+K- are measured in 12 GeV p+A reactions in order to search for the in-medium modification of phi mesons. The observed K+K- spectra are well reproduced by the relativistic Breit-Wigner function with a combinatorial background shape in three betagamma regions between 1.0 and 3.5. The nuclear mass number dependence of the yields of the K+K- decay channel is compared to the simultaneously measured e+e- decay channel for carbon and copper targets. We parameterize the production yields as sigma(A)=sigma0Aalpha and obtain alphaphi-->K+K- -alphaphi-->e+e- to be 0.14+/-0.12. Limits are obtained for the partial decay widths of the phi mesons in nuclear matter.

Evidence for in-medium modification of the phi meson at normal nuclear density.

Invariant mass spectra of e(+) e(-) pairs have been measured in 12 GeV p + A reactions to detect possible in-medium modification of vector mesons. Copper and carbon targets are used to study the nuclear-size dependence of e(+) e(-) invariant mass distributions. A significant excess on the low-mass side of the phi meson peak is observed in the low betagamma(= beta/square root(1-beta(2))) region of phi mesons (betagamma < 1.25) with copper targets. However, in the high betagamma region (betagamma > 1.25), spectral shapes of phi mesons are well described by the Breit-Wigner shape when experimental effects are considered. Thus, in addition to our earlier publications on rho/omega modification, this study has experimentally verified vector meson mass modification at normal nuclear density.

Experimental signature of medium modifications for rho and omega mesons in the 12 GeV p+A reactions.

The invariant mass spectra of e+e- pairs produced in 12 GeV proton-induced nuclear reactions are measured at the KEK Proton Synchrotron. On the low-mass side of the meson peak, a significant enhancement over the known hadronic sources has been observed. The mass spectra, including the excess, are well reproduced by a model that takes into account the density dependence of the vector meson mass modification, as theoretically predicted.

Fast omega-gliadin is a major allergen in wheat-dependent exercise-induced anaphylaxis.

BACKGROUND: Wheat-dependent exercise-induced anaphylaxis is an anaphylaxy induced by physical exercise after ingestion of wheat. An immediate-type hypersensitivity to water/salt-insoluble fraction of wheat proteins (gluten) has been considered to underlie in this disease. OBJECTIVE: The aim of the study is to determine the major allergen in Japanese patients with wheat-dependent exercise-induced anaphylaxis by using a panel of purified wheat gliadins and glutenins. METHODS: Water/salt-insoluble wheat proteins, alpha-gliadin, beta-gliadin, gamma-gliadin, fast omega-gliadin, slow omega-gliadin, high molecular weight glutenin and low molecular weight glutenin, were purified, and five patients with wheat-dependent exercise-induced anaphylaxis, whose diagnose had been determined by positive-challenge test, were evaluated for skin prick test, dot-blotting test and CAP-RAST inhibition test by using these purified wheat proteins. RESULTS: The fast omega-gliadin was the most potent allergen among these water/salt-insoluble proteins when evaluated by skin prick test and dot-blotting test. Fast and slow omega-gliadin, and gamma-gliadin caused dose-dependent inhibition of the serum IgE-binding to solid-phase gluten in the patients. The incubation with fast omega-gliadin of the patient's serum caused dose-dependent inhibition in the IgE-binding to gamma-gliadin as well as slow omega-gliadin, indicating a cross-reactivity of these proteins in IgE-binding. CONCLUSION: We concluded that fast omega-gliadin is a major allergen among these water/salt-insoluble proteins for wheat-dependent exercise-induced anaphylaxis in Japanese patients, and IgE against fast omega-gliadin cross-reacts to gamma-gliadin and slow omega-gliadin.

Combination of molecular mimicry and aberrant autoantigen expression is important for development of anti-Fas ligand autoantibodies in patients with systemic lupus erythematosus.

We have reported previously that circulating anti-Fas ligand (FasL) autoantibodies able to inhibit Fas/FasL-mediated apoptosis were present in patients with systemic lupus erythematosus (SLE). In the present study, we describe the epitopes recognized by these anti-FasL autoantibodies. Rabbit antihuman antibody, raised against a FasL fragment consisting of amino acids (aa) 103-179 (fragment 2.0), inhibited Fas/FasL-mediated apoptosis, whereas an antibody against a FasL aa 103-146 fragment (fragment 1.0) did not. This suggested that an epitope around aa 146-179 was important for Fas/FasL interaction. Epitope mapping of anti-FasL autoantibodies using deletion mutants indicated that the epitope was located around aa 163-179. Three-dimensional molecular modelling of the Fas/FasL complex revealed that the aa 162-169 region was located on the outermost side of FasL, which suggested that the anti-FasL autoantibody would easily have access to the epitope. FasL point mutants involving aa positions 162-169 resulted in complete loss of apoptosis-inducing capability, which suggested that the aa 162-169 region was important for Fas/FasL interaction. A synthetic FasL peptide consisting of aa 161-170 blocked the binding of anti-FasL autoantibodies to FasL fragment 2.0 (aa 103-179). The FasL aa 161-170 sequence was found to be highly homologous with aa sequences from several infectious agents. Synthetic peptides derived from some of these microorganisms cross-reacted with the epitope recognized by the autoantibodies, suggesting that several foreign infectious agent-derived proteins may share an epitope with human FasL. As lymphocytes from SLE patients aberrartly expressed FasL, it is possible that infection by one of several infectious agents may trigger cross-reactive antibody responses, after which aberrantly expressed endogenous FasL might induce the shift from a cross-reactive response to an authentic autoimmune response. Therefore, a combination of molecular mimicry and aberrant autoantigen expression may be important for the development of anti-FasL autoantibodies in SLE patients.

Observation of rho/omega meson modification in nuclear matter.

We measured the invariant mass spectra of electron-positron pairs in the target rapidity region of 12-GeV p+A reactions. We have observed a significant difference in the mass spectra below the omega meson between p+C and p+Cu interactions. This difference indicates that the spectral shape of mesons is modified at normal nuclear-matter density.

Synthesis and structure-activity relationships of potent and orally active sulfonamide ETB selective antagonists.

The synthesis and structure activity relationships of a series of N-pyrimidinyl benzenesulfonamides as ETB selective antagonists are described. N-Isoxazolyl benzenesulfonamide 1a, previously reported, (1) was selected as a lead compound, and isosteric replacement of the isoxazole ring of 1a with a pyrimidine ring led to the discovery of the highly potent ETB selective antagonist 6e with oral bioavailability. Modification of the terminal aldehyde group at the 6-position of the pyrimidine ring was investigated, and malonate 15b and acylhydrazone 16f were found to be equipotent to aldehyde 6e. Compound 6e showed ETB antagonistic activity on in vivo evaluation.

Identification of leukemia inhibitory factor as a potent mast cell growth-enhancing factor produced by mouse keratinocyte cell line, KCMH-1.

Inoculation of KCMH-1 cells, a keratinocyte-derived cell line established from a chemically induced skin tumor, into the skin of mice results in accumulation of mast cells around the resulting tumors. The conditioned medium of KCMH-1 cells enhances the growth of mast cells in vitro when they are cultured in the presence of NIH/3T3 fibroblasts, suggesting an important role for keratinocytes in mast cell hyperplasia in the skin. The aim of this study was to identify this mast cell growth-enhancing factor (MCGEF) by screening a KCMH-1 cDNA library. We first established a polyclonal antibody raised against the partially purified factor obtained from KCMH-1-conditioned medium which neutralized the MCGEF activity in KCMH-1-conditioned medium. Expression cloning of 1 x 10(6) cDNAs from the KCMH-1 cDNA library led to 16 cDNAs. One of these cloned cDNAs was found to be leukemia inhibitory factor (LIF). Both LIF produced by COS cells and the recombinant protein obtained commercially showed MCGEF activity when added to mast cell/fibroblast cocultures. MCGEF activity in KCMH-1-conditioned medium was completely neutralized by an anti-LIF monoclonal antibody. These results suggest that MCGEF produced by KCMH-1 cells is identical to LIF.

Pharmacologic characterization of S-1255, a highly potent and orally active endothelin A receptor antagonist.

The pharmacologic properties of a novel nonpeptide endothelin (ET) receptor antagonist, S-1255 ([R]-[+]-2-[benzo(1,3)dioxol-5-yl]-6-isopropyl-4-[4-methoxyphenyl]-2H-chromene-3-carboxylic acid), was studied. [3H]S-1255 specifically bound to porcine aortic smooth muscle membranes expressing only ET(A) receptors with a Kd value of 0.39 nM. [3H]S-1255 binding was potently inhibited by ET-1 and selective ET(A) or ET(A)/ET(B) receptor antagonists, such as L-749329, SB209670, bosentan, and BQ-123, but the inhibitory effect of ET-3 and the selective ET(B) receptor antagonist, BQ-788, on the binding was weak. These inhibitory effects on [3H]S-1255 binding correlated well with those on [125I]ET-1 binding. S-1255 inhibited ET(A) receptor- and ET(B) receptor-mediated contractions in isolated rabbit femoral and pulmonary arteries with pA2 values of 8.8 and 6.3, respectively. The pA2 value of S-1255 for ET(B) receptor-mediated relaxation in isolated rabbit mesenteric artery was 7.4. Oral administration of S-1255 (0.3-10 mg/kg) caused dose-dependent inhibition of the pressor response to exogenous ET-1 (0.1 nmol/kg) in conscious normotensive rats, which was similar to that produced by intravenous administration (1 and 3 mg/kg). S-1255 (10 and 30 mg/kg, p.o.) significantly reduced blood pressure in deoxycorticosterone acetate-salt hypertensive rats from 6 h after administration, and the hypotensive effects were sustained up to 24-48 h. These results suggest that S-1255 is a highly potent and orally active ET(A) receptor antagonist.