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Purpose: We aimed to identify the underlying genetic cause for a novel form of distal arthrogryposis., Methods: Rare variant family-based genomics, exome sequencing, and disease-specific panel sequencing were used to detect ADAMTS15 variants in affected individuals. Adamts15 expression was analyzed at the single-cell level during murine embryogenesis. Expression patterns were characterized using in situ hybridization and RNAscope., Results: We identified homozygous rare variant alleles of ADAMTS15 in 5 affected individuals from 4 unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. Radiographic investigations showed physiological interphalangeal joint morphology. Additional features included knee, Achilles tendon, and toe contractures, spinal stiffness, scoliosis, and orthodontic abnormalities. Analysis of mouse whole-embryo single-cell sequencing data revealed a tightly regulated Adamts15 expression in the limb mesenchyme between embryonic stages E11.5 and E15.0. A perimuscular and peritendinous expression was evident in in situ hybridization in the developing mouse limb. In accordance, RNAscope analysis detected a significant coexpression with Osr1, but not with markers for skeletal muscle or joint formation., Conclusion: In aggregate, our findings provide evidence that rare biallelic recessive trait variants in ADAMTS15 cause a novel autosomal recessive connective tissue disorder, resulting in a distal arthrogryposis syndrome., Competing Interests: Conflict of Interest J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Genetics Center (RGC), and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic and genomic testing conducted at Baylor Genetics; J.R.L. serves on the Scientific Advisory Board of Baylor Genetics. U.K. has been a consultant for Alexion Pharmaceuticals, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Objective: Recently, there has been a paradigm shift toward uterine conservation during the surgical management of pelvic organ prolapse (POP), specifically uterine prolapse. There are few reports on transvaginal uterosacral ligament hysteropexy (TULH). This study aimed to describe our surgical technique and outcomes., Design: Retrospective review and description of surgical technique. Anatomic outcome has been reported using the POP quantification system. Complications were segregated. A comparison of parametric continuous variables was performed using paired t test. Categoric variables were evaluated using the Pearson χ 2 test and the Fisher exact test. A p-value <.05 was considered significant., Setting: Teaching hospital., Patients: Forty patients who underwent TULH from 2009 to 2017., Interventions: TULH., Measurements and Main Results: A total of 40 patients met the inclusion criteria. Of these, 56.1% had preoperative stage 3 prolapse. The median operative time was 116 minutes. The mean estimated blood loss was 158.5 mL. Transient ureteral obstruction occurred in 2 patients. The mean follow-up time was 17.2 months, and all patients had significant improvement of prolapse (p <.001). There was also an improvement in urinary incontinence and bladder storage symptoms (p <.001). None of the patients were reoperated on for recurrent POP., Conclusion: TULH is an effective uterus-preserving surgical alternative for the treatment of uterovaginal prolapse and provides good apical support. It is also associated with a low short-term recurrence and incidence of reoperation. TULH is a viable option for suitable patients with uterovaginal prolapse who desire uterine conservation., (Copyright © 2020 AAGL. Published by Elsevier Inc. All rights reserved.)

Purpose: To report the cytologic characteristics of uveal melanoma., Design: This is a prospective, single-center study of consecutive patients., Subjects: All patients with a clinical diagnosis of uveal melanoma from May 2009 to July 2013 who underwent prognostication fine-needle aspiration biopsy (FNAB) were included., Methods: The cytologic characteristics of uveal melanoma were analyzed for 150 consecutive patients with a clinical diagnosis of uveal melanoma who were treated at the Cleveland Clinic Cole Eye Institute between May 2009 and August 2012., Main Outcome Measures: Cellular features of all cases were analyzed for cell type, presence of melanin, nuclear grade, tumor-infiltrating lymphocytes, and necrosis. Cytology was then correlated with histopathology in enucleated eyes., Results: A total of 150 patients were included. Seven samples of tumor resections were excluded from the study because they were studied by impression smears. A total of 143 FNAB samples of 143 patients formed the basis for analysis. Fifty-three percent of the patients were male, and the average age for all patients was 60 years. Transcorneal (n = 8), transscleral (n = 71), and transvitreal (n = 64) approaches were used. Of 143 samples, 131 were adequate. Among these, spindle cells were observed in 98% (63% mixed and 35% spindle only), whereas only epithelioid cells were observed in 2 samples. Melanin granules were observed in 80% of samples. Tumor nuclear grade (atypia) increased with tumor height and by tumor location (least atypia with iris tumors)., Conclusions: Cytologic features such as spindle cells and melanin granules, present in 98% and 80% of samples, respectively, are important cytologic diagnostic features. Tumor nuclear grade (atypia) increased with tumor height. Iris melanoma has bland features compared with ciliary and choroidal melanoma., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To compare smooth muscle regulatory protein expression in the uterosacral ligament (USL) of women with and without uterine prolapse., Study Design: USLs ligament were sampled in women with (n = 9) or without (n = 9) uterine prolapse. Caldesmon, smooth muscle actin (SMA), myosin heavy chain, and zinc finger protein messenger RNA expression was assessed by quantitative real-time polymerase chain reaction. Immunohistochemistry and digital image analysis were used to determine protein expression., Results: Caldesmon messenger RNA expression and the ratio of caldesmon-SMA messenger RNA expression was significantly increased in the USL from women with uterine prolapse compared with women without prolapse (caldesmon mean +/- standard deviation messenger RNA, 0.81 +/- 0.46 vs 0.39 +/- 0.16; P = .01 and caldesmon-SMA messenger RNA ratio, mean +/- standard deviation, 0.11 +/- 0.04 vs 0.07 +/- 0.02; P = .01). In addition, the ratio of caldesmon-SMA staining was significantly increased in women with uterine prolapse compared with women without prolapse (mean +/- standard deviation, 0.44 +/- 0.28 vs 0.28 +/- 0.16; P = .03)., Conclusion: Uterine prolapse is associated with an increased ratio of caldesmon-SMA actin expression., (Copyright 2010 Mosby, Inc. All rights reserved.)

Purpose: Male breast cancer has been linked extensively to mutations of BRCA2 and, to a lesser extent, BRCA1. The aim of this study was to perform a comprehensive analysis of point mutations and genomic rearrangements in the BRCA1 and BRCA2 genes in 41 men with breast cancer., Patients and Methods: Deleterious point mutations were identified in 15 men (37%): 4 (10%) and 11 (27%) in BRCA1 and BRCA2, respectively. In the remaining 26 men, we screened for large genomic rearrangements in BRCA1 and BRCA2 using multiplex ligation-dependent probe amplification., Results: We did not detect any large genomic rearrangements. Men with BRCA1 or BRCA2 mutations were more likely to have a family history of prostate cancer (P = 0.025). Three of 4 male breast tumors with BRCA1 mutations (75%) were estrogen receptor positive. Whereas some studies have reported an 8%-0 rate of large BRCA2 genomic rearrangement in familial male breast cancer cases, we did not detect any such genomic rearrangements in BRCA1 or BRCA2 for our cohort., Conclusion: Despite this negative finding, our study, to the best of our knowledge, is one of the first to comprehensively screen for mutations, including large genomic rearrangement mutations, in BRCA1 and BRCA2 in men with breast cancer in the United States.

The addition of 0.5% globulin-free (GF-BSA) or 0.5% delipidated BSA (D-BSA) to short-term murine bone marrow (BM) (cultures) increased the number of plaque-forming cells (PFC) responding to trinitrophenylated lipopolysaccharide (TNP-LPS) 2-5-fold (1.1 X 10(4)-2.7 X 10(4) PFC per 10 X 10(6) nucleated BM cells). Although it was necessary to continue to supplement these cultures with 5% fetal calf serum (FCS), the inclusion of the aforementioned BSA preparations provided enhanced PFC production for all lots of FCS tested. Similarly, these preparations of BSA made it feasible to also culture BM in autologous mouse sera (MS) or in medium without 2-mercaptoethanol (2-ME) if in the latter case the D-BSA was pretreated with 2-ME. Thus, the inclusion of GF-BSA or D-BSA in short term cultures of BM not only substantially increased the number of Ig-secreting B cells produced in response to TNP-LPS but seemed to eliminate the need to screen for supportive batches of FCS or MS. These preparations of BSA also facilitated hapten specific PFC responses of fetal liver cultures.