Del1 Is a Growth Factor for Skeletal Progenitor Cells in the Fracture Callus.

Failure to properly form bone or integrate surgical implants can lead to morbidity and additional surgical interventions in a significant proportion of orthopedic surgeries. While the role of skeletal stem cells (SSCs) in bone formation and repair is well-established, very little is known about the factors that regulate the downstream Bone, Cartilage, Stromal, Progenitors (BCSPs). BCSPs, as transit amplifying progenitor cells, undergo multiple mitotic divisions to expand the pool of lineage committed progenitors allowing stem cells to preserve their self-renewal and stemness. Del1 is a protein widely expressed in the skeletal system, but its deletion led to minimal phenotype changes in the uninjured mouse. In this paper, we demonstrate that Del1 is a key regulator of BCSP expansion following injury. In Del1 knockout mice, there is a significant reduction in the number of BCSPs which leads to a smaller callus and decreased bone formation compared with wildtype (WT) littermates. Del1 serves to promote BCSP proliferation and prevent apoptosis in vivo and in vitro. Moreover, exogenous Del1 promotes proliferation of aged human BCSPs. Our results highlight the potential of Del1 as a therapeutic target for improving bone formation and implant success. Del1 injections may improve the success of orthopedic surgeries and fracture healing by enhancing the proliferation and survival of BCSPs, which are crucial for generating new bone tissue during the process of bone formation and repair.

Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration.

Sexually dimorphic tissues are formed by cells that are regulated by sex hormones. While a number of systemic hormones and transcription factors are known to regulate proliferation and differentiation of osteoblasts and osteoclasts, the mechanisms that determine sexually dimorphic differences in bone regeneration are unclear. To explore how sex hormones regulate bone regeneration, we compared bone fracture repair between adult male and female mice. We found that skeletal stem cell (SSC) mediated regeneration in female mice is dependent on estrogen signaling but SSCs from male mice do not exhibit similar estrogen responsiveness. Mechanistically, we found that estrogen acts directly on the SSC lineage in mice and humans by up-regulating multiple skeletogenic pathways and is necessary for the stem cell's ability to self- renew and differentiate. Our results also suggest a clinically applicable strategy to accelerate bone healing using localized estrogen hormone therapy.

Comprehensive laparoscopic lymphadenectomy from the deep circumflex iliac vein to the renal veins: Impact on quality of life.

OBJECTIVE: Compare quality of life metrics for consecutive patients having total laparoscopic hysterectomy, bilateral salpingo-oophorectomy (TLHBSO) with and without comprehensive pelvic/aortic lymphadenectomy (CPALND) from proximal to the distal circumflex iliac nodes and vessels to the renal vessels. METHODS: Analysis of mailed survey responses with 25 validated questions regarding musculoskeletal/lower extremity, gastro-intestinal, abdominal, urological, and energetic/activities of daily living. Data analyzed with Chi-Square tests of Association, Mann-Whitney U tests and follow up regression analysis. RESULTS: Of 533 surveys mailed, 197 (37%) responded; 57 (28.9%) received CPALND. Age and parity were not different between groups, but the TLHBSO group had a higher BMI (31.4 v. 25.8, p<0.001), and were less likely to receive chemotherapy (CT), radiotherapy (RT), or both (CT+RT). In the CPALND cohort, a mean of 47 nodes were removed, of which 26% were positive: 21% pelvic, 11% inframesenteric, 11% infrarenal. Both groups had similar total quality of life total scores of 86/92. Those having CPALND did not report more swelling but they did report more tingling/numbness (2.8 v. 3.5, p<0.001). A series of hierarchical regressions confirmed that CPALND, per se, did not significantly reduce lower extremity scores apart from CT (p=0.402) and CT+RT (p=0.108). However, CPALND did predict for lower extremity swelling after receipt of CT, RT, or CT+RT. Node count, in total, or from each basin, did not correlate with any QOL decrement. CONCLUSIONS: CPALND did not cause lymphedema or a reduction in overall quality of life. Only after controlling for BMI, and receipt of radiation and/or chemotherapy were QOL scores mildly reduced. Routine omission of the distal circumflex nodes from the dissection may account for the low risk of lymphedema from the dissection. Larger prospective studies are needed to determine the optimal staging protocols that address all the likely sites of metastasis and recurrence, and optimize survival, while maintaining our patients' quality of life.

Analysis of a Standardized Technique for Laparoscopic Cuff Closure following 1924 Total Laparoscopic Hysterectomies.

Objective. To review the vaginal cuff complications from a large series of total laparoscopic hysterectomies in which the laparoscopic culdotomy closure was highly standardized. Methods. Retrospective cohort study (Canadian Task Force Classification II-3) of consecutive total and radical laparoscopic hysterectomy patients with all culdotomy closures performed laparoscopically was conducted using three guidelines: placement of all sutures 5 mm deep from the vaginal edge with a 5 mm interval, incorporation of the uterosacral ligaments with the pubocervical fascia at each angle, and, whenever possible, suturing the bladder peritoneum over the vaginal cuff edge utilizing two suture types of comparable tensile strength. Four outcomes are reviewed: dehiscence, bleeding, infection, and adhesions. Results. Of 1924 patients undergoing total laparoscopic hysterectomy, 44 patients (2.29%) experienced a vaginal cuff complication, with 19 (0.99%) requiring reoperation. Five patients (0.26%) had dehiscence after sexual penetration on days 30-83, with 3 requiring reoperation. Thirteen patients (0.68%) developed bleeding, with 9 (0.47%) requiring reoperation. Twenty-three (1.20%) patients developed infections, with 4 (0.21%) requiring reoperation. Three patients (0.16%) developed obstructive small bowel adhesions to the cuff requiring laparoscopic lysis. Conclusion. A running 5 mm deep × 5 mm apart culdotomy closure that incorporates the uterosacral ligaments with the pubocervical fascia, with reperitonealization when possible, appears to be associated with few postoperative vaginal cuff complications.

Infrarenal lymphadenectomy for gynecological malignancies: two laparoscopic approaches.

OBJECTIVE: Compare two approaches for laparoscopic infrarenal lymphadenectomy. METHODS: Retrospective chart review. Statistical analyses with SPSS. PATIENTS: 4 stage II/III cervical carcinoma, 75 clinical stage I/II endometrial carcinoma, 36 clinically stage I/II tubal/ovarian cancer. 36 transperitoneal approaches; 79 extraperitoneal approaches. Both groups had similar age, 58years (range 29-80), BMI of 25 (range 18-41), blood loss, 150cm(3) (range 25-1500), and hospital stay, 1day (range 1-6). The extraperitoneal surgery took longer (240 v 202min; p=.001); yielded more nodes (50 v 41; p=.004). Extraperitoneal approach yielded more inframesenteric (14 v 10; p=.036), and infrarenal nodes (14 v 9; p=.001). 25% of cervical, 19% of endometrial and 14% of ovarian cancer patients had metastases in radiographically negative infrarenal nodes. 50% of cervical, 33% of endometrial and 17% of ovarian cancer patients had therapy altered by aortic lymphadenectomy. When the inframesenteric nodes were positive, 63% of endometrial and 80% of ovarian cancer patients had infrarenal metastases. More metastases were identified with increasing aortic node count. Extraperitoneal lymphadenectomy had no learning curve (p=0.320), while transperitoneal lymphadenectomy did (p=0.016). Higher BMI patients had lower aortic node yields by transperitoneal (p=.057) but not extraperitoneal approach (p=.578). Among the 14 patients whose BMI was 35-41, mean extraperitoneal total aortic nodal yield was 30; transperitoneal yield was 6. CONCLUSIONS: Infrarenal aortic lymphadenectomy may offer higher aortic nodal yields, even in patients with BMI's of 45. Larger prospective studies are needed to confirm whether this dissection in high-risk patients ensures more accurate therapy, and possibly improves cure rates.