Elevated expression of interleukin-6 (IL-6) and serum amyloid A (SAA) in the skin and the serum of recessive dystrophic epidermolysis bullosa: Skin as a possible source of IL-6 through Toll-like receptor ligands and SAA

The effect of persistent skin inflammation on extracutaneous organs and blood is not well studied. Patients with recessive dystrophic epidermolysis bullosa (RDEB), a severe form of the inherited blistering skin disorder, have widespread and persistent skin ulcers, and they develop various complications including anaemia, hyperglobulinaemia, hypoalbuminaemia and secondary amyloidosis. These complications are associated with the bioactivities of IL-6, and the development of secondary amyloidosis requires the persistent elevation of serum amyloid A (SAA) level. We found that patients with RDEB had significantly higher serum levels of IL-6 and SAA compared to healthy volunteers and patients with psoriasis or atopic dermatitis. Both IL-6 and SAA were highly expressed in epidermal keratinocytes and dermal fibroblasts of the skin ulcer lesions. Keratinocytes and fibroblasts surrounding the ulcer lesions are continuously exposed to Toll-like receptor (TLR) ligands, pathogen-associated and damage-associated molecular pattern molecules. In vitro, TLR ligands induced IL-6 expression via NF-κB in normal human epidermal keratinocytes (NHEKs) and dermal fibroblasts (NHDFs). SAA further induced the expression of IL-6 via TLR1/2 and NF-κB in NHEKs and NHDFs. The limitation of this study is that NHEKs and NHDFs were not derived from RDEB patients. These observations suggest that TLR-mediated persistent skin inflammation might increase the risk of IL-6-related systemic complications, including RDEB

The protective effect of CD40 ligand–CD40 signalling is limited during the early phase of Plasmodium infection

Abstractγδ T cells are essential for eliminating Plasmodium berghei XAT. Because administration of the agonistic anti-CD40 antibody can induce elimination of P. berghei XAT parasites in γδ T cell-deficient mice, we considered that γδ T cells might activate dendritic cells via CD40 signalling during infection. Here we report that administration of the anti-CD40 antibody to γδ T cell-deficient mice 3–10days post-P. berghei XAT infection could eliminate the parasites. Our data suggest that dendritic cell activation via γδ T cells expressing CD40 ligand is critical during the early phase of infection

Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ): Part 2. Endorsement of the alternative item

AbstractBackgroundA new self-administered questionnaire as an outcome measure for patients with cervical myelopathy was drawn up in Part 1 (Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire, JOACMEQ). Because a question with regard to driving a car (C-41) was not suitable for this patient group, the authors composed an alternative question related to neck motion (C-41-2). The purposes of the present study were to perform a secondary survey on patients with cervical myelopathy and to statistically analyze the responses to validate the JOACMEQ, and also to determine if it was possible to convert item C-41 to the alternative question.MethodsA member of the Subcommittee on Low Back Pain and Cervical Myelopathy Evaluation from each hospital administered the questionnaire to more than 50 patients with cervical myelopathy in each hospital. The questionnaire consisted of 25 questions, 24 of which were extracted in the primary survey. The authors statistically examined whether it was possible to convert question C-41 to C-41-2.ResultsThree hundred and sixty-eight patients with cervical myelopathy were enrolled in the present study. No questions elicited no answer or “I am not sure” in more than 5% of patients except question C-41. There were no questions that the patients answered with difficulty. There was no tendency that was concentrated on one option as an answer to questions. There was a high correlation between questions C-41 and C-41-2. Spearman’s correlation coefficient and κ value showed that there was high coincidence between the two questions C-41 and C-41-2. It is possible to convert the question C-41 to the alternative question C41-2.ConclusionThe questionnaire has sufficient reliability for clinical use. It is possible that the JOACMEQ will prevail and become a global standard to evaluate outcomes in patients with cervical myelopathy

Japanese Orthopaedic Association Back Pain Evaluation Questionnaire. Part 3. Validity study and establishment of the measurement scale: Subcommittee on Low Back Pain and Cervical Myelopathy Evaluation of the Clinical Outcome Committee of the Japanese Orthopaedic Association, Japan

AbstractBackgroundThe Japanese Orthopaedic Association decided to revise the JOA score for low back pain and to develop a new outcome measure. In February 2002, the first survey was performed with a preliminary questionnaire consisting of 60 evaluation items. Based on findings of that survey, 25 items were selected for a draft of the JOA Back Pain Evaluation Questionnaire (JOABPEQ). The second survey was performed to confirm the reliability of the draft questionnaire. This article further evaluates the validity of this questionnaire and establishes a measurement scale.MethodsThe subjects of this study consisted of 355 patients with low back disorders of any type (201 men, 154 women; mean age 50.7 years). Each patient was asked to fill in a self-administered questionnaire. Superficial validity was checked in terms of the completion rate for filling out the entire questionnaire. Factor analysis was then performed to evaluate the validity of the questionnaire and establish a measurement scale.ResultsAs a result of the factor analysis, 25 items were categorized into five factors. The factors were named based on the commonality of the items: social function, mental health, lumbar function, walking ability, and low back pain. To establish a measurement scale for each factor, we determined the coefficient for each item so the difference between the maximum factor scores and minimum factor scores was approximately 100. We adjusted the formula so the maximum for each factor score was 100 and the minimum was 0.ConclusionsWe confirmed the validity of the JOA Back Pain Evaluation Questionnaire and est ablished a measurement scale

New Classification of the Dictyostelids

Traditional morphology-based taxonomy of dictyostelids is rejected by molecular phylogeny. A new classification is presented based on monophyletic entities with consistent and strong molecular phylogenetic support and that are, as far as possible, morphologically recognizable. All newly named clades are diagnosed with small subunit ribosomal RNA (18S rRNA) sequence signatures plus morphological synapomorphies where possible. The two major molecular clades are given the rank of order, as Acytosteliales ord. nov. and Dictyosteliales. The two major clades within each of these orders are recognized and given the rank of family as, respectively, Acytosteliaceae and Cavenderiaceae fam. nov. in Acytosteliales, and Dictyosteliaceae and Raperosteliaceae fam. nov. in Dictyosteliales. Twelve genera are recognized: Cavenderia gen. nov. in Cavenderiaceae, Acytostelium, Rostrostelium gen. nov. and Heterostelium gen. nov. in Acytosteliaceae, Tieghemostelium gen. nov., Hagiwaraea gen. nov., Raperostelium gen. nov. and Speleostelium gen. nov. in Raperosteliaceae, and Dictyostelium and Polysphondylium in Dictyosteliaceae. The polycephalum complex is treated as Coremiostelium gen. nov. (not assigned to family) and the polycarpum complex as Synstelium gen. nov. (not assigned to order and family). Coenonia, which may not be a dictyostelid, is treated as a genus incertae sedis. Eighty-eight new combinations are made at species and variety level, and Dictyostelium ammophilum is validated

Deletion of CDKAL1 Affects Mitochondrial ATP Generation and First-Phase Insulin Exocytosis

A variant of the CDKAL1 gene was reported to be associated with type 2 diabetes and reduced insulin release in humans; however, the role of CDKAL1 in β cells is largely unknown. Therefore, to determine the role of CDKAL1 in insulin release from β cells, we studied insulin release profiles in CDKAL1 gene knockout (CDKAL1 KO) mice.Total internal reflection fluorescence imaging of CDKAL1 KO β cells showed that the number of fusion events during first-phase insulin release was reduced. However, there was no significant difference in the number of fusion events during second-phase release or high K(+)-induced release between WT and KO cells. CDKAL1 deletion resulted in a delayed and slow increase in cytosolic free Ca(2+) concentration during high glucose stimulation. Patch-clamp experiments revealed that the responsiveness of ATP-sensitive K(+) (K(ATP)) channels to glucose was blunted in KO cells. In addition, glucose-induced ATP generation was impaired. Although CDKAL1 is homologous to cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1, there was no difference in the kinase activity of CDK5 between WT and CDKAL1 KO islets.We provide the first report describing the function of CDKAL1 in β cells. Our results indicate that CDKAL1 controls first-phase insulin exocytosis in β cells by facilitating ATP generation, K(ATP) channel responsiveness and the subsequent activity of Ca(2+) channels through pathways other than CDK5-mediated regulation

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation