Forces on sutures when closing excisional wounds using the rule of halves.

BACKGROUND: To close elliptical excisions, surgeons commonly use the rule of halves which involves initially closing of the middle portion of the wound, followed by closure of the remaining halves. Understanding the forces required for suturing such wounds can aid excisional surgery planning to decrease complications and improve wound healing. METHODS: Following full thickness excision for removal of skin cancers, back wounds with 3:1 ratio of length-to-width were closed using the rule of halves. The force required to bring the wound edges into contact at the middle portion of the wound was measured, followed by the two bisected halves. FINDINGS: The average force to close the center of the wounds averaged 3.7 N and was six times larger than that of the bisected halves. The forces to close the bisected halves were consistently small, and essentially negligible (<0.5 N) for ~50% of the cases. INTERPRETATION: When planning excisional surgery to avoid complications such as tearing the dermis (cheese wiring), the use of special wound closure techniques (high tension and/or pully sutures, skin support or suture retention devices, etc.) should focus on the center suture only when using the rule of halves, as the remaining sutures require very low forces.

c-JUN Dimerization Protein 2 (JDP2) Is a Transcriptional Repressor of Follicle-stimulating Hormone ß (FSHß) and Is Required for Preventing Premature Reproductive Senescence in Female Mice.

Follicle-stimulating hormone (FSH) regulates follicular growth and stimulates estrogen synthesis in the ovaries. FSH is a heterodimer consisting of an α subunit, also present in luteinizing hormone, and a unique ß subunit, which is transcriptionally regulated by gonadotropin-releasing hormone 1 (GNRH). Because most FSH is constitutively secreted, tight transcriptional regulation is critical for maintaining FSH levels within a narrow physiological range. Previously, we reported that GNRH induces FSHß (Fshb) transcription via induction of the AP-1 transcription factor, a heterodimer of c-FOS and c-JUN. Herein, we identify c-JUN-dimerization protein 2 (JDP2) as a novel repressor of GNRH-mediated Fshb induction. JDP2 exhibited high basal expression and bound the Fshb promoter at an AP-1-binding site in a complex with c-JUN. GNRH treatment induced c-FOS to replace JDP2 as a c-JUN binding partner, forming transcriptionally active AP-1. Subsequently, rapid c-FOS degradation enabled reformation of the JDP2 complex. In vivo studies revealed that JDP2 null male mice have normal reproductive function, as expected from a negative regulator of the FSH hormone. Female JDP2 null mice, however, exhibited early puberty, observed as early vaginal opening, larger litters, and early reproductive senescence. JDP2 null females had increased levels of circulating FSH and higher expression of the Fshb subunit in the pituitary, resulting in elevated serum estrogen and higher numbers of large ovarian follicles. Disruption of JDP2 function therefore appears to cause early cessation of reproductive function, a condition that has been associated with elevated FSH in women.

Roles of binding elements, FOXL2 domains, and interactions with cJUN and SMADs in regulation of FSHß.

We previously identified FOXL2 as a critical component in FSHß gene transcription. Here, we show that mice deficient in FOXL2 have lower levels of gonadotropin gene expression and fewer LH- and FSH-containing cells, but the same level of other pituitary hormones compared to wild-type littermates, highlighting a role of FOXL2 in the pituitary gonadotrope. Further, we investigate the function of FOXL2 in the gonadotrope cell and determine which domains of the FOXL2 protein are necessary for induction of FSHß transcription. There is a stronger induction of FSHß reporter transcription by truncated FOXL2 proteins, but no induction with the mutant lacking the forkhead domain. Specifically, FOXL2 plays a role in activin induction of FSHß, functioning in concert with activin-induced SMAD proteins. Activin acts through multiple promoter elements to induce FSHß expression, some of which bind FOXL2. Each of these FOXL2-binding sites is either juxtaposed or overlapping with a SMAD-binding element. We determined that FOXL2 and SMAD4 proteins form a higher order complex on the most proximal FOXL2 site. Surprisingly, two other sites important for activin induction bind neither SMADs nor FOXL2, suggesting additional factors at work. Furthermore, we show that FOXL2 plays a role in synergistic induction of FSHß by GnRH and activin through interactions with the cJUN component of the AP1 complex that is necessary for GnRH responsiveness. Collectively, our results demonstrate the necessity of FOXL2 for proper FSH production in mice and implicate FOXL2 in integration of transcription factors at the level of the FSHß promoter.