XRCC4 protein interactions with XRCC4-like factor (XLF) create an extended grooved scaffold for DNA ligation and double strand break repair.

The XRCC4-like factor (XLF)-XRCC4 complex is essential for nonhomologous end joining, the major repair pathway for DNA double strand breaks in human cells. Yet, how XLF binds XRCC4 and impacts nonhomologous end joining functions has been enigmatic. Here, we report the XLF-XRCC4 complex crystal structure in combination with biophysical and mutational analyses to define the XLF-XRCC4 interactions. Crystal and solution structures plus mutations characterize alternating XRCC4 and XLF head domain interfaces forming parallel super-helical filaments. XLF Leu-115 ("Leu-lock") inserts into a hydrophobic pocket formed by XRCC4 Met-59, Met-61, Lys-65, Lys-99, Phe-106, and Leu-108 in synergy with pseudo-symmetric ß-zipper hydrogen bonds to drive specificity. XLF C terminus and DNA enhance parallel filament formation. Super-helical XLF-XRCC4 filaments form a positively charged channel to bind DNA and align ends for efficient ligation. Collective results reveal how human XLF and XRCC4 interact to bind DNA, suggest consequences of patient mutations, and support a unified molecular mechanism for XLF-XRCC4 stimulation of DNA ligation.

Patient characteristics of suspected mast-cell activation syndrome with sinonasal obstruction: a single institution experience.

BACKGROUND: Mast-cell activation syndrome (MCAS) is increasingly recognized. Sinonasal obstruction is common among these patients. There is a paucity of literature describing the characteristics of MCAS and treatment outcomes. METHODS: Retrospective review of 192 patients with nasal congestion July 2017 to May 2019 among 3 providers (1 allergist, 2 rhinologists) was conducted. Suspected MCAS criteria were as follows: (1) at least 2 recurrent severe symptoms in addition to nasal congestion: flushing, pruritus, urticaria, angioedema, wheezing, throat swelling, headache, hypotension, diarrhea; (2) clinical response to medications that target mast cell mediators. Quality of life (QOL) outcomes were quantified using the 22-item Sino-Nasal Outcome Test (SNOT-22). RESULTS: Thirty-two patients with nasal congestion were suspected of MCAS. The median age was 47 years; 24 of 32 were female; 13 of 32 had prior history of sinonasal surgery and 11 of 32 allergen immunotherapy. Out of 32, 19 had history of asthma, 10 drug allergy, 11 food allergy, and 10 anaphylaxis. The median number of medications targeting mast cell activation was 4 (range, 2-7). Eleven patients were offered surgery by a rhinologist after adequate medical management. Three of 32 patients showed elevation of serum tryptase. Fourteen completed pretreatment and posttreatment SNOT-22 (4/14 surgery, 10/14 medical management). Pretreatment score was 59.8 ± 6.2 (mean ± standard error [SEM]) and posttreatment score was 42.8 ± 6.7; the difference was statistically and clinically significant (p = 0.0015). Both groups showed a mean 17-point reduction. CONCLUSION: A multidisciplinary approach to the treatment of sinonasal symptoms using both escalation of medical therapy and surgical approaches may improve QOL of patients with suspected MCAS. Consensus criteria for MCAS, which includes elevation in tryptase over baseline during an episode, may exclude the full spectrum of individuals with MCAS from potentially beneficial treatment.

Rectal perforation following paclitaxel and carboplatin chemotherapy for advanced ovarian cancer: a case report and review of the literature.

BACKGROUND: Paclitaxel is a chemotherapy drug commonly used in the management of ovarian cancer. Colonic perforation is an extremely rare complication of paclitaxel administration with few case reports in the medical literature. We report a case of a patient with advanced ovarian cancer who had a rectal perforation following administration of paclitaxel. There has only been one other case report of rectal perforation in the medical literature following paclitaxel therapy. CASE PRESENTATION: A 55-year-old Caucasian woman with advanced ovarian cancer awaiting elective debulking surgery for her tumor presented to our emergency department with abdominal pain, vomiting, and diarrhea. She was admitted to hospital for neoadjuvant chemotherapy and management of her systemic symptoms. She became acutely unwell following one cycle of chemotherapy with paclitaxel. A computed tomography scan of her abdomen showed typhlitis of her descending colon and a corresponding rectal perforation. Surgical intervention was deemed inappropriate as she had a heavy burden of disease and neutropenia. She died following a period of conservative management with strong intravenously administered antibiotics. CONCLUSIONS: This case highlights the importance of recognizing gastrointestinal complications following chemotherapy and the need to be aware of the possibility of bowel perforation. Prompt surgical review and intervention must be requested in patients with acute abdominal pain and persistent gastrointestinal symptoms such as diarrhea and vomiting.

Tree nut allergy: risk factors for development, mitigation of reaction risk and current efforts in desensitization.

Allergy to tree nuts has grown widespread among patients, specifically in the pediatric population, in recent years. In this review, we evaluate and summarize the literature specific to development and treatment of tree nut allergy. The cause of tree nut allergy, such as most food allergies, is unknown; there are theories regarding maternal dietary factors as well as sensitization related to cross-reactivity to peanut allergens. The gold standard for the diagnosis of tree nut allergy is the double-blind, placebo-controlled, oral food challenge; however, simpler and more cost-effective diagnostic methods, such as the skin prick test and serum-specific IgE are often used as a supplement for diagnosis. Management of tree nut allergy consists of dietary avoidance and using epinephrine to manage serious allergic reactions. Alternative therapeutic methods, such as oral and sublingual immunotherapy and modification of allergenic proteins are being explored to develop safer, more effective and long-lasting management of tree nut allergy. We comment on the current studies involving risk factors for sensitization, diagnosis and management of tree nut allergy.

Assessment of postoperative outcomes of hypospadias repair with validated questionnaires.

PURPOSE: A standardized assessment for the optimal repair of hypospadias remains elusive. This study utilized validated questionnaires to assess the postoperative functional, cosmetic, and psychosocial outcomes of hypospadias repair. MATERIALS AND METHODS: 172 patients who underwent hypospadias repair under the care of a single surgeon were identified. 25 agreed for follow-up using the validated questionnaires of Hypospadias Objective Scoring Evaluation (HOSE), Pediatric Penile Perception Scale (PPPS), and Pediatric Quality of Life Inventory (PedsQL™4.0). RESULTS: Mean follow-up was 59months postoperatively (range 7-113months). Techniques used included tubularized incised plate urethroplasty, meatal advancement and glanuloplasty, and a 2-stage repair. 23 of 25 patients achieved a HOSE score of 14 or more (maximum of 16). The PPPS scores correlated with severity of the hypospadias. Those with glanular hypospadias (mean score=10) scored higher than those with coronal (mean score=9) and penile/penoscrotal hypospadias (mean score=7). There was no correlation between PedsQL™4.0 scores and the severity of hypospadias or procedure used. CONCLUSION: Validated questionnaires revealed generally good functional, cosmetic, and early psychosocial outcomes after hypospadias repair. The use of validated questionnaires in routine follow-up sessions may facilitate objective assessment of both functional outcomes and patient satisfaction.

Teaching Furlow palatoplasty: the sticky note method.

OBJECTIVE: The double-opposing Z-plasty (Furlow palatoplasty) procedure is a well-established method for palate repair in children. We propose a simple and easily accessible sticky note model to demonstrate the lengthening in palatal anatomy afforded by this technically challenging procedure. METHODS: Our model involves creating a lengthened three-dimensional representation of the Z-plasty through making specified incisions and rearrangements of the palatal layers. The sticky note model was made a total of 20 times and length of the palate model pre and post Z-plasty was measured. RESULTS: The average length of the palate pre-procedure was 72 mm. The average length of the palate post procedure was 78.9 mm, showing an increase of 6.9 mm (9.6%). CONCLUSION: Our model provides an accurate and valuable educational tool that will aid in the visualization and understanding of the Furlow palatoplasty procedure.