Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding.

The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca2+ is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca2+ increases the affinity and potency of the endogenous agonist α-melanocyte-stimulating hormone at the MC4R by 37- and 600-fold, respectively. The ability of the MC4R crystallized construct to couple to ion channel Kir7.1, while lacking cyclic adenosine monophosphate stimulation, highlights a heterotrimeric GTP-binding protein (G protein)-independent mechanism for this signaling modality. MC4R is revealed as a structurally divergent G protein-coupled receptor (GPCR), with more similarity to lipidic GPCRs than to the homologous peptidic GPCRs.

Are systemic antibiotics required during and after dacryocystitis-related dacryocystorhinostomy?

PURPOSE: To compare the outcomes of patients with and without a history of dacryocystitis that undergo dacryocystorhinostomy without systemic intra- and post-operative antibiotics. METHODS: A retrospective review was performed to identify all cases of patients that received surgery under this paradigm and had at least three months of follow up care. Key demographic and outcome data were captured, and a statistical analysis was performed via a dedicated software package (Microsoft Excel, Redmond, WA). RESULTS: For the study period, 83 patients without and 69 patients with a history of dacryocystitis were identified, and the two groups were not statistically significantly different in age, gender, or postoperative follow up duration (mean = 6.4 months for patients without and 6.3 months for those with dacryocystitis, respectively). No patient developed a postoperative infection or a recurrence of dacryocystitis during the follow up period. DISCUSSION: While many surgeons routinely use systemic antibiotics in patients with a history of dacryocystitis who undergo dacryocystorhinostomy, these agents may not be necessary. As a result, patients may be able to avoid the complications and side effects inherent to systemic antibiotics. Large-scale, prospective studies will likely help to further clarify this issue.

Preoperative Intravenous Ketorolac Safely Reduces Postoperative Pain in Levator Advancement Surgery.

PURPOSE: To assess the impact of intravenous ketorolac (IVK) on self-reported pain scores, requirements for opioid analgesic and anti-emetic medications, and bleeding complications in the setting of levator advancement surgery METHODS:: A prospective randomized controlled trial was performed among adult patients undergoing levator advancement surgery. Pain scores were measured immediately after surgery, prior to discharge from the surgical facility, and on the first postoperative day. The requirements for postoperative analgesic and anti-emetic medications were recorded. Statistical comparisons were performed via a dedicated computerized software package. RESULTS: Fifty patients (20 males, 30 females, mean age = 65.7 years, standard deviation = 11.9 years) underwent levator advancement without IVK and acted as controls. An additional 50 patients received IVK (19 males, 31 females, mean age = 64.6 years, standard deviation = 12.0 years). As compared with control patients, IVK resulted in statistically significant reductions in pain score immediately after surgery (4.62 vs. 1.44, p = 0.0001) and on postoperative day 1 (3.22 vs. 1.24, p = 0.0001). Fourteen patients (28%) in the control and 4 patients (8%) in the group that received IVK required opioid analgesics (p = 0.017). Seven patients (14%) in the control group and 1 patient in the group that received IVK required anti-emetic medications (p = 0.059). No patient experienced a hemorrhagic complication. CONCLUSIONS: In the setting of levator advancement surgery, IVK results in a dramatic reduction in self-reported pain score immediately after surgery and on postoperative day 1 and the requirement for opioid analgesics. This medication may be safely utilized for ptosis repair.

Review of periorbital nerve enlargement and biopsy techniques.

Periorbital nerve enlargement commonly indicates perineural invasion of malignancy or inflammatory conditions. This study reviews the role of supraorbital and infraorbital nerve biopsies in patients presenting with radiographic enlargement and to elucidate the surgical technique involved. A retrospective chart review (1997-2014) was performed at a single tertiary center. Patients with radiographic confirmation of enlarged supraorbital/infraorbital nerves that underwent biopsy were included. Charts were reviewed for: patient demographics and history, clinical symptoms and findings, radiographic findings, surgical method, and treatment. Five patients (4 female, 1 male) met inclusion criteria. Average age was 72.4 years (range 36-90). Four patients had history of cutaneous malignancy. All presented with diplopia and/or dysesthesias. Clinical examination confirmed decreased V1 and/or V2 sensation for 4 patients. Imaging revealed enlargement of V1, V2, and/or V3 in all patients. Infraorbital nerve biopsies were performed in 3 patients via transconjunctival fornix-based orbitotomy with subperiosteal dissection along orbital floor followed by unroofing of infraorbital canal. The remaining 2 underwent supraorbital nerve biopsy via sub-brow incision onto superior orbital rim with reflection of periosteum. Biopsies confirmed squamous cell carcinoma(3), mucoepidermoid carcinoma(1), and idiopathic orbital inflammation(1). Three patients initiated treatment in <1 month. One decided to follow-up closer to home, one was lost to follow-up. For patients presenting with enlarged supraorbital/infraorbital nerves, biopsy can rapidly confirm the underlying condition and facilitate early treatment. A sub-brow approach offers direct access to supraorbital nerve while transconjunctival fornix-based anterior orbitotomy with canal unroofing allows access to infraorbital nerve.

A Concomitant Case of Orbital Granuloma Faciale and Eosinophilic Angiocentric Fibrosis.

Granuloma faciale is an eosinophilic dermatosis that typically presents as red-brown facial plaques of middle-aged white men, while eosinophilic angiocentric fibrosis is a histologically similar fibrotic condition affecting the respiratory mucosa. Both are very uncommon conditions and pose a therapeutic challenge. While a handful of reports have reported concurrent presentation, the authors present the first case of eyelid granuloma faciale with eosinophlilic angiocentric fibrosis.

Human ß-Defensin 3 [corrected] Exacerbates MDA5 but Suppresses TLR3 Responses to the Viral Molecular Pattern Mimic Polyinosinic:Polycytidylic Acid.

Human ß-defensin 3 (hBD3) is a cationic host defence peptide and is part of the innate immune response. HBD3 is present on a highly copy number variable block of six ß-defensin genes, and increased copy number is associated with the autoimmune disease psoriasis. It is not known how this increase influences disease development, but psoriasis is a T cell-mediated disease and activation of the innate immune system is required for the initial trigger that leads to the amplification stage. We investigated the effect of hBD3 on the response of primary macrophages to various TLR agonists. HBD3 exacerbated the production of type I Interferon-ß in response to the viral ligand mimic polyinosinic:polycytidylic acid (polyI:C) in both human and mouse primary cells, although production of the chemokine CXCL10 was suppressed. Compared to polyI:C alone, mice injected with both hBD3 peptide and polyI:C also showed an enhanced increase in Interferon-ß. Mice expressing a transgene encoding hBD3 had elevated basal levels of Interferon-ß, and challenge with polyI:C further increased this response. HBD3 peptide increased uptake of polyI:C by macrophages, however the cellular response and localisation of polyI:C in cells treated contemporaneously with hBD3 or cationic liposome differed. Immunohistochemistry showed that hBD3 and polyI:C do not co-localise, but in the presence of hBD3 less polyI:C localises to the early endosome. Using bone marrow derived macrophages from knockout mice we demonstrate that hBD3 suppresses the polyI:C-induced TLR3 response mediated by TICAM1 (TRIF), while exacerbating the cytoplasmic response through MDA5 (IFIH1) and MAVS (IPS1/CARDIF). Thus, hBD3, a highly copy number variable gene in human, influences cellular responses to the viral mimic polyI:C implying that copy number may have a significant phenotypic effect on the response to viral infection and development of autoimmunity in humans.

The effect of noise-cancelling headphones or music on pain perception and anxiety in men undergoing transrectal prostate biopsy.

OBJECTIVE: To assess the effect of noise-cancelling headphones with or without music on patient pain and anxiety associated with routine, office-based transrectal ultrasound (TRUS)-guided prostate biopsy in a prospective randomized study. METHODS: Patients scheduled for prostate biopsy as a result of elevated prostate-specific antigen and/or abnormal digital rectal examination were prospectively enrolled and randomized into a control, noise-cancelling headphones, or music-headphones group. Patients completed pain and anxiety questionnaires and had their physiological parameters assessed before and after the procedure and compared across groups. RESULTS: Eighty-eight patients were enrolled. Pain scores increased from baseline across all study groups, with the lowest mean score in the music group. No appreciable change was noted in anxiety scores after the procedure between groups (P>.05). Although postbiopsy systolic blood pressure values remained comparable with baseline levels in all groups, postbiopsy diastolic blood pressure increased in the control and headphones groups (P=.062 and .088, respectively) but remained stable in the music group (P=.552) after biopsy, indicating lesser physiological response to anxiety and pain in this group. CONCLUSION: Music-induced attention shift during prostate biopsy may have a beneficial impact on procedural anxiety and pain perception, but no apparent effect was noted for use of headphones alone. Further studies are necessary to explore strategies to reduce perceived anxiety and pain in men undergoing prostate biopsy.

Complications of laparoscopic and percutaneous renal cryoablation in a single tertiary referral center.

BACKGROUND: Laparoscopic cryoablation (LCA) and percutaneous cryoablation (PCA) of small renal masses have gained popularity, but only limited data exist on the complication rates. OBJECTIVES: In this study, we report on postoperative complications associated with LCA and PCA in a single tertiary center experience. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective review of electronic medical records for patients undergoing LCA or PCA between 2001 and 2008 at our institution. INTERVENTIONS: All patients underwent LCA or PCA. MEASUREMENTS: Demographics, radiographic variables, and complication rates were compared between the two groups. Complications were classified according to the modified Clavien system. RESULTS AND LIMITATIONS: Of a total of 195 patients included in this study, 72 underwent LCA and 123 underwent PCA. There were no differences in demographics between the groups. We observed complications in 10 LCA procedures (13.9%) and 26 PCA procedures (21.1%) (p=0.253). The distribution of the complications differed significantly between the groups with mild complications (grades 1 and 2) more common in the PCA group (20.3% vs 5.6%, respectively; p=0.001), whereas severe events (grades 3 and 4) were more frequent in the LCA group (8.3% vs 0.8%, respectively; p=0.011). On multivariate analysis, age and body mass index were inversely associated with complications, whereas female gender, multiple tumors, and preexisting comorbidities showed a trend toward increased risk. CONCLUSIONS: LCA and PCA, although minimally invasive, are not void of complications. Most of the complications encountered are mild; however, severe (grade 3 or 4) events may occur in up to 3.6% of patients. PCA may be associated with a higher rate of complications, although most of these are mild and transient. However, on multivariate analysis, the chosen ablative approach (laparoscopic or percutaneous) is not associated with the risk of complications.

Utility of a 3-dimensional transrectal ultrasound-guided prostate biopsy system for prostate cancer detection.

The 3-D transrectal ultrasound (TRUS)-guided prostate biopsy system is a novel device that allows precise needle placement in a template fashion. We evaluate its utility for prostate cancer (PCa) detection. A retrospective analysis was performed evaluating 68 prospective patients at the Duke Prostate Center who underwent a prostate biopsy using a 3-D TRUS-guided system. After creation of a three-dimensional map of the prostate, a computer algorithm identified an ideal biopsy scheme based on the measured dimensions of the prostate. The system then used a fixed template that allowed prostate biopsy at specific locations with the ability to target the same region of the prostate in the future if needed. For all patients, a 12-core biopsy pattern was used to cover medial and lateral areas of the base, mid-gland, and apex. In total, 68 patients underwent 3-D TRUS-guided prostate biopsies between April 2006 and November 2007 for prostate cancer detection. The indication for prostate biopsy was PSA > or = 4.0 ng/ml in 47 (69%) patients, abnormal digital rectal examination (DRE) in 17 (25%), and atypia on previous biopsy in 4 (6%) patients. Prostate cancer was detected in 18 patients (26.5%) and 7 (10.3%) had atypical small acinar proliferation (ASAP). The highest frequency (55.5%) from all cases of cancer detected was identified when 3-D TRUS biopsy was used as the initial biopsy. This study demonstrates that a 3-D TRUS-guided biopsy system translates to a more frequent detection of prostate cancer among patients undergoing an initial prostate biopsy than a subsequent one. More comprehensive studies are warranted to corroborate and extend the results of this study.

Persistent contrast enhancement several months after laparoscopic cryoablation of the small renal mass may not indicate recurrent tumor.

PURPOSE: We evaluated the clinical implication of persistent contrast enhancement demonstrated several months after laparoscopic renal cryoablation of a small renal mass. PATIENTS AND METHODS: Between September 2000 and May 2007, 30 patients underwent laparoscopic cryosurgery for an organ-confined renal tumor measuring

The effect of cryoablation on the histologic interpretation of intraoperative biopsy of small clear cell renal carcinoma and renal oncocytoma.

BACKGROUND AND PURPOSE: We evaluated the effects of the first freeze-thaw cycle of cryoablation on Fuhrman grade, histology, and tumor architecture of small clear cell renal carcinomas and renal oncocytomas using an 18-gauge needle biopsy. PATIENTS AND METHODS: Between August 2006 and June 2007, 11 patients underwent cryoablation for 14 renal neoplasms. A laparoscopic approach was employed using third-generation argon/helium cryotechnology. Biopsies were taken prior to and following the first freeze-thaw cycle. Each biopsy sample was semiquantitively evaluated for cytoplasmic fraying, nuclear hyperchromasia, nuclear breakdown, and tissue discohesion as well as Fuhrman grade and interpretability by a single pathologist. RESULTS: Eighteen precryoablation and 15 post-first freeze biopsies were taken. A tissue diagnosis was rendered in 100% of 11 patients. Pathologic diagnosis following the first freeze-thaw cycle of cryotherapy, as compared with the pretreatment biopsy, was accurate in 10 (91%) cases. Neither of the two post-first freeze biopsies in the remaining patient rendered a diagnosis: one had an insufficient quantity of tissue and the second missed the tumor, abstracting benign renal tissue. There was no significant difference in cytoplasmic fraying (P = 0.30), nuclear hyperchromasia (P = 0.43), nuclear breakdown (P = 0.58), or tissue discohesion (P = 0.84) observed between biopsies taken before and after the first freeze-thaw cycle of cryoablation. In no case did we note a change in Fuhrman grade greater than 1. CONCLUSIONS: One cycle of cryoablation does not significantly alter the architecture or Fuhrman grade of biopsy tissue, thus allowing for another method to obtain sufficient histologic tissue when bleeding is minimal.

Urothelial sloughing with obstruction after laparoscopic cryoablation of small renal carcinoma in solitary kidney.

Laparoscopic cryoablation is a minimally invasive treatment that is currently used to treat small renal tumors. Despite its growing use and promising outcomes, complications can occur. We report the first clinical case of urothelial sloughing with obstruction after cryoablation of a small renal tumor in a solitary kidney.