Surgical menopause initiates molecular changes that do not result in mechanical changes in normal and healing ligaments.

OBJECTIVES: Ligaments which heal spontaneously have a healing process that is similar to skin wound healing. Menopause impairs skin wound healing and may likewise impair ligament healing. Our purpose in this study was to investigate the effect of surgical menopause on ligament healing in a rabbit medial collateral ligament model. METHODS: Surgical menopause was induced with ovariohysterectomy surgery in adult female rabbits. Ligament injury was created by making a surgical gap in the midsubstance of the medial collateral ligament. Ligaments were allowed to heal for six or 14 weeks in the presence or absence of oestrogen before being compared with uninjured ligaments. Molecular assessment examined the messenger ribonucleic acid levels for collagens, proteoglycans, proteinases, hormone receptors, growth factors and inflammatory mediators. Mechanical assessments examined ligament laxity, total creep strain and failure stress. RESULTS: Surgical menopause in normal medial collateral ligaments initiated molecular changes in all the categories evaluated. In early healing medial collateral ligaments, surgical menopause resulted in downregulation of specific collagens, proteinases and inflammatory mediators at 6 weeks of healing, and proteoglycans, growth factors and hormone receptors at 14 weeks of healing. Surgical menopause did not produce mechanical changes in normal or early healing medial collateral ligaments. With or without surgical menopause, healing ligaments exhibited increased total creep strain and decreased failure stress compared with uninjured ligaments. CONCLUSIONS: Surgical menopause did not affect the mechanical properties of normal or early healing medial collateral ligaments in a rabbit model. The results in this preclinical model suggest that menopause may result in no further impairment to the ligament healing process. Cite this article: Bone Joint Res 2015;4:38-44.

The pig as a model for excisional skin wound healing: characterization of the molecular and cellular biology, and bacteriology of the healing process.

A pig model of wound healing was developed by excision of 2-cm-diameter full thickness skin in young Yorkshire pigs. The results indicated that wound re-epithelialization in this animal model took an average of 20 days. Analysis of cellular change was assessed by use of DNA quantification and determination of apoptotic cells in tissue sections. The results indicate that RNA and DNA contents paralleled each other throughout the healing process, and observed changes in the pattern of RNA and DNA content of the scar tissues were consistent with cell loss due to apoptosis in this model. Expression of mRNA for relevant genes was assessed by use of semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis, using porcine specific primer sets and RNA isolated from normal skin and specimens obtained at various times after wounding. The mRNA values for tumor necrosis factor-alpha (TNF-alpha), connective tissue growth factor (CTGF), insulin-like growth factor II (IGF-II), and decorin were significantly high at specific times after wounding, but mRNA values for the transcription factors (c-fos and c-jun) were significantly decreased. Quantitative bacteriologic results indicated that the total bacterial count in this animal model reached 10(9) colony-forming units (CFU)/g, with the highest value at post-wounding day 7, and Pseudomonas aeruginosa and Staphylocococci aureus were the most common bacteria detected in this model. Further definition of this model should identify unique points in the healing process, and such information could lead to development of therapeutic interventions to improve skin wound healing.

Molecular and cell biology of skin wound healing in a pig model.

To define the pattern of change at the molecular and cellular levels during the healing of excisional skin wounds in the skeletally immature pig, mRNA levels for relevant molecules were assessed by semiquantitative RT-PCR using porcine specific primer sets and RNA isolated from normal skin and samples at various time post-wounding. Analysis of cellular change was assessed by DNA quantification and histology of tissue sections. The results demonstrated that the changes in the pattern of RNA and DNA content of the scar tissue were consistent with the observed increasing cellularity. The mRNA levels for collagen I, III, HSP47, IL-1, TGF-beta, MMP-1, -2 and -9, TIMP-1, -2, and-4, PAI-1, versican were significantly elevated during healing; levels for biglycan and fibromodulin were not significantly altered; and the mRNA levels for TIMP-3 were depressed. These findings suggest that skin wound healing is a series of complex matrix-cell interactions that involve cellular migration and inflammation, followed by proliferation of fibroblasts with new collagen synthesis, and lastly tissue remodeling of the scar.

Dose-dependent effects of DDAVP on memory in healthy young adult males: a preliminary study.

Although several studies have demonstrated the efficacy of the vasopressin analog DDAVP in enhancing human memory, no previous study has reported the dose-response relationship of DDAVP to memory in healthy young adults. The present study was undertaken to explore the dose-response curve for DDAVP on recall of implicational sentences. Five doses of DDAVP (0, 5, 15, 30, and 60 micrograms) were administered intranasally to healthy young adult male volunteers. Results demonstrated a facilitation in cued recall after treatment with the 60-micrograms dose and a general impairment in recall after treatment with the 15-micrograms dose. These effects were independent of subject's weight, vocabulary ability, and concentration of salivary cortisol.