Cardiac expression of urocortin (Ucn) in diseased heart; preliminary results on possible involvement of Ucn in pathophysiology of cardiac diseases

Recently, several studies reported that urocortin (Ucn) had beneficial effects on cardiovascular system and was expressed both in the normal heart and in the heart of dilated cardiomyopathy (DCM), yet the relationship between high expression of Ucn and pathophysiology of Ucn in diseased heart has been discussed. Thus, the present study was designed to elucidate the expression of Ucn in the diseased heart by immunohistochemical approach using endomyocardial biopsy specimens. The involvement of immunoreactive Ucn in pathophysiology of cardiac disease was evaluated using endomyocardial biopsy specimens obtained from the patients with some heart diseases, including DCM and hypertrophic cardiomyopathy (HCM). Ucn was detected in all endomyocardial biopsy specimens of ventricular tissue obtained from the patients with such cardiac diseases, a specimens of atrial tissue, and normal heart specimens obtained from autopsy cases. In DCM patients, left ventricular end-diastolic pressure significantly elevated in severely stained group. On the contrary, in HCM patients, left ventricular ejection fraction was higher in the severely stained group. Ucn was expressed more abundantly in the diseased heart, especially in HCM and DCM, than in the normal heart. In conclusion, such close relationship between Ucn expression in the heart and cardiac function indicated that clinical features of Ucn resembled those of norepinephrine and Ucn could play a certain pathophysiological roles in the cardiac diseases.     

Serpens endocrania symmetrica (SES): a new term and a possible clue for identifying intrathoracic disease in skeletal populations

This paper describes a phenomenon in the endocranial plate, which we have termed "serpens endocrania symmetrica" (SES), and discusses its value as a diagnostic tool. The affected discolored bone area exhibits disruption of the endocranial surface, lending it a maze-like appearance. Histological sections demonstrate that the process is limited to the most superficial portion of the endocranium, with no diploic and ectocranial involvement (sinus areas excepted). Adult skulls (n = 1,884) from the Hamann-Todd collection (HTH), housed at the Cleveland Museum of Natural History, were utilized for the present study. SES was recognized in 32 of the 1,884 skulls studied (1.7%). The frequency of SES among individuals reported to have died from tuberculosis (TB) was 4.4%. The rate of SES in the non-TB sample was only 0.53%. The locations were as follows: limited to sinus area, 28.1%; calvarium (excluding the sinuses), 46.9%; sinus + calvarium, 25.0%. SES was bilateral in 90.9% of cases. Twenty-five of the 32 individuals (78.1%) with SES in the HTH collection had tuberculosis specifically listed as the cause of death. Six of the other 7 individuals had infections other than TB. In 29 of the 32 individuals with SES, infection involved structures within the thorax. As SES was also associated with another osteological phenomenon known to represent pulmonary disease, i.e., hypertrophic osteoarthropathy (HOA; 68.0% of SES individuals also had HOA), SES may be of diagnostic value in paleopathology for the recognition of intrathoracic disease, and perhaps tuberculosis.     

Primary production of phytoplankton and standing crops of zooplankton and zoobenthos in hypertrophic Lake Teganuma

Primary production of phytoplankton and standing crops of zooplankton and zoobenthos were intensively surveyed in Lake Teganuma during May 1983–April 1984. The annual mean chlorophyll a concentrations were as high as 304 µg · l^–1–383 µg · l^–1. The daily gross primary production of phytoplankton was high throughout the year. The peak production rate was recorded in August and September, when blue-green algae bloomed. The annual gross primary production was estimated as 1450 g C · m^–2 · y^–1, extremely high as compared with other temperate eutrophic lakes. Zooplankton was predominantly composed of rotifers. The annual mean standing crop of zooplankton was 0.182 g C · m^–2 around the middle between the inlets and the outlet and was lower than in most other temperate eutrophic lakes. Zoobenthos was mostly composed of Oligochaeta and chironomids. The annual mean standing crop of zoobenthos ranged from 0.052 g C · m^–2 to 0.265 g C · m^–2, the lowest values among temperate eutrophic lakes, which is in contrast to the high primary production.     

Five Candidate Genes for Hamster Cardiomyopathy Did not Map to the Cardiomyopathy Locus by FISH Analysis

The Syrian cardiomyopathic hamster (BIO14.6), that developsboth muscular dystrophy and progressive cardiomyopathy, is widelyused as an animal model of autosomal recessive cardiomyopathymimicking human hypertrophic cardiomyopathy, and five geneshave been proposed as strong candidates for the cause of cardiomyopathy.We recently mapped the cardiomyopathy locus of the hamster tothe centromeric region of chromosome 9qa2.1-b1 by constructionof a genetic linkage map of the Syrian hamster. Thus, we analyzedthe loci of the five candidate genes, tropomyosin, cardiactroponin T, adhalin, calpain 3 and cardiac myosin binding protein-C,by the FISH method, and found that these genes were mapped onthe distal portion of chromosome 12qa5 and 4pa2 and the proximalportion of chromosomes 9qb7, 1qc1.1 and 1qb3, respectively.These results provide strong evidence that the five candidategenes previously proposed are not related to the hamster cardiomyopathy.     

Fibromodulin reduces scar size and increases scar tensile strength in normal and excessive‐mechanical‐loading porcine cutaneous wounds

Hypertrophic scarring is a major postoperative complication which leads to severe disfigurement and dysfunction in patients and usually requires multiple surgical revisions due to its high recurrence rates. Excessive‐mechanical‐loading across wounds is an important initiator of hypertrophic scarring formation. In this study, we demonstrate that intradermal administration of a single extracellular matrix (ECM) molecule—fibromodulin (FMOD) protein—can significantly reduce scar size, increase tensile strength, and improve dermal collagen architecture organization in the normal and even excessive‐mechanical‐loading red Duroc pig wound models. Since pig skin is recognized by the Food and Drug Administration as the closest animal equivalent to human skin, and because red Duroc pigs show scarring that closely resembles human proliferative scarring and hypertrophic scarring, FMOD‐based technologies hold high translational potential and applicability to human patients suffering from scarring—especially hypertrophic scarring.     

Epithelial–mesenchymal transition in the formation of hypertrophic scars and keloids

Abnormal wound healing is likely to induce the formation of hypertrophic scars and keloids, which leads to dysfunction, deformity, and mental problem in the patients. Despite the advances in prevention and management of hypertrophic scar and keloids, the mechanism underlying scar and keloid formation has not been fully elucidated. Recent insights into the role of the epithelial–mesenchymal transition (EMT) in development, wound healing, stem cell regulation, fibrosis, and tumorigenesis have increased our understanding of the pathophysiology of hypertrophic scarring and keloids and suggested new therapeutic targets. This review summarizes recent progress in the elucidation of the role of EMT in physiologic wound healing and pathologic scar formation. This knowledge will facilitate an understanding of EMT roles in scar formation and shed new light on the modulation and potential treatment of hypertrophic scars and keloids.     

The HCM-causing Y235S cMyBPC mutation accelerates contractile function by altering C1 domain structure

Mutations in cardiac myosin binding protein C (cMyBPC) are a major cause of hypertrophic cardiomyopathy (HCM). In particular, a single amino acid substitution of tyrosine to serine at residue 237 in humans (residue 235 in mice) has been linked to HCM with strong disease association. Although cMyBPC truncations, deletions and insertions, and frame shift mutations have been studied, relatively little is known about the functional consequences of missense mutations in cMyBPC. In this study, we characterized the functional and structural effects of the HCM-causing Y235S mutation by performing mechanical experiments and molecular dynamics simulations (MDS). cMyBPC null mouse myocardium was virally transfected with wild-type (WT) or Y235S cMyBPC (KO^Y235S). We found that Y235S cMyBPC was properly expressed and incorporated into the cardiac sarcomere, suggesting that the mechanism of disease of the Y235S mutation is not haploinsufficiency or poison peptides. Mechanical experiments in detergent-skinned myocardium isolated from KO^Y235S hearts revealed hypercontractile behavior compared to KO^WT hearts, evidenced by accelerated cross-bridge kinetics and increased Ca²⁺ sensitivity of force generation. In addition, MDS revealed that the Y235S mutation causes alterations in important intramolecular interactions, surface conformations, and electrostatic potential of the C1 domain of cMyBPC. Our combined in vitro and in silico data suggest that the Y235S mutation directly disrupts internal and surface properties of the C1 domain of cMyBPC, which potentially alters its ligand-binding interactions. These molecular changes may underlie the mechanism for hypercontractile cross-bridge behavior, which ultimately results in the development of cardiac hypertrophy and in vivo cardiac dysfunction.