Immunohistochemical and ultrastructural study on effect of fibroblast growth factor on transformation of fibroblasts to regenerated mesothelial cells

To elucidate the effect of fibroblast growth factor on the phenotypical conversion of fibroblasts to mesothelial cells, both immunohistochemical and ultrastructural examinations were carried out on cultured spheroids that were composed of fibroblasts obtained from the parietal pleura of rats with and without addition of antifibroblast growth factor receptor antibody. In the present study, antifibroblast growth factor receptor antibody was employed to block the effect of the autocrine component of fibroblast growth factor in the culture medium. Phenotypical conversion from fibroblast to mesothelial cells was clearly blocked in the experimental group, to which culture medium had been added with antifibroblast growth factor receptor antibody, whereas the control group, cultured without addition of antifibroblast growth factor receptor antibody, showed phenotypical conversion of fibroblasts that was confirmed by the development of macula adherens, microvilli, and positive expression of cytokeratin. These results indicate the possibility that fibroblast growth factor plays a key role in the process of phenotypic conversion of fibroblasts to regenerated mesothelial cells.     

Self-Concept and Satisfaction With Physical Appearance in Youth With and Without Oral Clefts

This study investigated relationships between child/parent dissatisfaction with child facial appearance and the self-concept/social competence of 8- to 15-year-old children with (N = 34) and without (N = 34) oral clefts. Children in both groups had normative psychosocial adjustment, but also reported moderate dissatisfaction with facial appearance. Cleft group parents were more likely to agree with their child's dissatisfaction. When cleft group parents were more dissatisfied with child facial appearance, their children reported better quality of life. Results suggest that parents of children with clefts reporting greater dissatisfaction may respond in positive ways that enhance quality of life.     

Identification of a new familial case of 3q29 deletion syndrome associated with cleft lip and palate via whole-exome sequencing

Many unbalanced large copy number variants reviewed in the paper are associated with syndromic orofacial clefts, including a 1.6 Mb deletion on chromosome 3q29. The current report presents a new family with this recurrent deletion identified via whole-exome sequencing and confirmed by array comparative genomic hybridization. The proband exhibited a more severe clinical phenotype than his affected mother, comprising right-sided cleft lip/alveolus and cleft palate, advanced dental caries, heart defect, hypospadias, psychomotor, and speech delay, and an intellectual disability. Data analysis from the 3q29 registry revealed that the 3q29 deletion increases the risk of clefting by nearly 30-fold. No additional rare and pathogenic nucleotide variants were identified that could explain the clefting phenotype and observed intrafamilial phenotypic heterogeneity. These data suggest that the 3q29 deletion may be the primary risk factor for clefting, with additional genomic variants located outside the coding sequences, methylation changes, or environmental exposure serving as modifiers of this risk. Additional studies, including whole-genome sequencing or methylation analyses, should be performed to identify genetic factors underlying the phenotypic variation associated with the recurrent 3q29 deletion.     

Does job stress affect injury due to labor accident in Japanese male and female blue-collar workers?

To clarify whether job stressors affecting injury due to labor accidents differ between Japanese male and female blue-collar workers, the Job Content Questionnaire (JCQ), assessing dimensions of job stressors based on the demand-control-support model, was applied to 139 blue-collar workers in a manufacturing factory. Of them, 24 male and 15 female workers suffered from injuries at work. In the female workers with the experience of work injury, the job demand score and job strain index (i.e., the ratio of job demand to job control) of the JCQ were significantly higher and the score of coworker support was significantly lower, than those in the female workers without the experience. High job demand (or, high job strain and low coworker support) was significantly related to work injury in all the female workers. Between the male workers with and without work injury, however, there was no significant difference in any job stressors. This pilot study suggests that high job strain (specifically, high job demand), as well as low coworker support, are important factors affecting work injury in Japanese female blue-collar workers. Further research with a large number of male blue-collar workers will be required to seek other factors that may be associated with work injury.     

Laparoscopic Heller's myotomy for achalasia after gastric bypass: A case report

INTRODUCTIONDisorders of the oesophagus have been linked to surgical bariatric procedures and obesity. However the relationship between achalasia and gastric bypass is not clearly understood and has only recently been reported following gastric bypass.PRESENTATION OF CASEWe present the case of a 53-year-old woman who re-presented following a gastric bypass with a new diagnosis of achalasia. This was treated successfully with laparoscopic Heller's Myotomy with discharge from hospital 10 days post operatively.DISCUSSIONIt is not clear whether achalasia is a complication of gastric bypass procedures. This is only the second reported case of the condition developing after this operation. The mechanism by which it may develop is yet to be clearly established.CONCLUSIONThis case highlights the need to investigate further a possible link between achalasia and gastric bypass and to manage susceptible patients accordingly in the pre-operative stage.     

Humanized C3 Mouse: A Novel Accelerated Model of C3 Glomerulopathy

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A prospective study of the clinical benefits of prostacyclin in 554 cardiopulmonary bypass procedures

Abnormal bleeding after cardiopulmonary bypass (CPB) may result from incomplete neutralization of heparin, increased fibrinolytic activity, consumption of coagulation factors, or from a reduction in the number of circulating platelets together with impairment of platelet function. Although researchers have reason to believe that hemostasis after CPB could be improved with prostacyclin (PGI(2)), a potent inhibitor of platelet aggregation, the drug's clear-cut benefits in this respect have not yet been confirmed. After conducting an initial study concerning the fate of platelets during CPB, in which we determined that PGI(2) had a protective effect, we investigated the effects of PGI(2) infusion during CPB on postoperative blood loss in 554 open-heart surgery patients, 200 of whom underwent valve replacement, 200 of whom had coronary artery bypass grafting (CABG), and 154 of whom underwent repeat valve replacement or CABG. The patients were divided into 2 groups: 277 patients (the study group) received both heparin and PGI(2) during CPB, whereas the remaining 277 patients (the control group) were given heparin alone. Of the patients who underwent surgery for the first time, those treated with PGI(2) had a reduced mean blood loss (p < 0.05 only in CABG patients) in comparison with those who received heparin alone. Of the patients who underwent redo operations, those who received PGI(2) had a nonsignificant tendency toward reduced blood loss. The mean difference in blood loss between the study group and the control group had no clinical relevance, however, because it was less than the smallest practical unit of measurement (i.e., 1 unit of blood).     

Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist

Aims

Calcitonin gene related peptide (CGRP) receptor antagonists are effective acute migraine treatments. A capsaicin-induced dermal vasodilatation (CIDV) model has been developed to provide target-engagement information in healthy volunteers. In the model, CGRP release is provoked after dermal capsaicin application, by activating transient receptor potential vanilloid-type-1 (TRPV1) receptors at peripheral sensory nerves. Laser Doppler imaging is used to quantify CIDV and subsequent inhibition by CGRP receptor antagonists. We sought to evaluate a CGRP receptor antagonist, MK-3207, in the biomarker model and to assess the predictability of the CIDV response to migraine clinical efficacy.

Methods

An integrated population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the exposure−response relationship for CIDV inhibition by CGRP and TRPV1 receptor antagonists. MK-3207 dose−response predictions were made based on estimated potency from the PK/PD model and mean plasma concentrations observed at the doses investigated.

Results

The results suggested that a 20 mg dose of MK-3207 (EC₅₀ of 1.59 nm) would be required to attain the peripheral CIDV response at a target level that was shown previously to correlate with 2 h clinical efficacy based on phase 3 telcagepant clinical data, and that a plateau of the dose−response would be reached around 40–100 mg. These predictions provided a quantitative rationale for dose selection in a phase 2 clinical trial of MK-3207 and helped with interpretation of the efficacy results from the trial.

Conclusions

The integrated CIDV PK/PD model provides a useful platform for characterization of PK/PD relationships and predictions of dose−response relationships to aid in future development of CGRP and TRPV1 receptor antagonists.