Loxosceles Spider Venom Induces the Production of α and β Chemokines: Implications for the Pathogenesis of Dermonecrotic Arachnidism

Bites from the brown recluse spider and other Loxosceles arachnids result in dermonecrotic skin lesions. Neutrophils (PMN) are essential to the development of Loxosceles-induced skin lesions, but paradoxically, in vitro PMN activation is inhibited by direct exposure to Loxosceles venom. Neutrophil activation occurs in response to a myriad of soluble mediators that include members of both the and chemokine families. Because arachnid envenomation results in the exposure of several different cell types to venom, we investigated venom-induced expression of and chemokines in both endothelial cells (human umbilical vein; HUVEC) and epithelial cells (A549 pneumocytes). Chemokine-specific capture enzyme immunoassays (EIA) were used to measure Loxosceles deserta venom-induced chemokines: interleukin-8 (IL-8), growth-related oncogene-alpha (GRO-), and chemokines: monocyte chemoattractant protein-1 (MCP-1), and regulated on activation, normal T cell expressed and secreted (RANTES) in cell-free conditioned media from HUVEC and A549 cell monolayers. Exposure of HUVECs (8 h) to Loxosceles venom resulted in the production of IL-8 (5.2 ± 1.30 ng/ml), MCP-1 (1.44 ± 0.11 ng/ml) and GRO- (1.97 ± 0.15 ng/ml) in a dose and time-dependent manner. Exposure of A549 cell monolayers to venom resulted in IL-8 (7.74 ± 0.30 ng/ml), and MCP-1 (2.61 ± 0.31 ng/ml), but neither GRO- nor RANTES accumulated during an 8-hour incubation period. Chemokines accumulated in a venom dose and time-dependent manner. Neither cell type secreted RANTES in response to Loxosceles venom. These data indicate that Loxosceles spider venom is a potent inducer of and chemokines in both endothelial and epithelial cell types. Based on the established roles of IL-8, MCP-1, and GRO-, in inflammation, these observations have relevance to the pathophysiology of Loxosceles-Induced dermonecrosis.     

Atlantoaxial dislocation associated with stenosis of canal at atlas

Three rare cases of stenosis of spinal canal at the level of atlas associated with atlantoaxial dislocation are presented. An atlantoaxial lateral mass fixation with plate and screws after posterior midline bony decompression was successfully performed in these cases.     

Proliferating cell nuclear antigen and epidermal growth factor receptor (EGFr) status in renal cell carcinoma patients with polysomy of chromosome 7

We investigated 40 cases of renal cell carcinoma (RCC) to study the polysomy 7 status in papillary and clear-cell types (nonpapillary RCC) and relationship with clinical, pathological, and biological features such as grade, stage, tumor proliferation rate (PCNA expression) and epidermal growth factor receptor (EGFr) expression and thereby to understand the prognostic significance of polysomy 7 and EGFr expression. In a prospective study, chromosome 7 copy number was analyzed in tumor cells by using fluorescence in situ hybridization (FISH) with an alpha-satellite DNA probe for chromosome 7. Both proliferating cell nuclear antigen (PCNA) and EGFr expression were examined in paraffin sections by immunostaining. The relationship between clinicopathological and clinicobiological parameters was evaluated by appropriate statistical methods. Polysomy 7 was present in 100% of papillary and 56.2% of clear-cell types RCC. In clear-cell RCC, in comparison with polysomy 7-dominant (D) category (20-50% polysomy-7 cells), polysomy 7-major (M) category (>50% polysomy 7 cells) was associated with higher tumor grade (P = 0.05). Polysomy 7 was also correlated with stage of the disease (P = 0.006). The PCNA index ranged between 12.8-89.6% and was comparatively high in high-grade tumors (P = 0.001). The PCNA index was also correlated with polysomy 7 (P = 0.002), and the association was stronger in tumors with polysomy M versus polysomy D category (P = 0.02). The EGFr expression did not correlate with either grade, stage, PCNA, or polysomy 7. The correlation of polysomy 7 with less favorable prognostic factors such as higher tumor grade, stage, and higher proliferative index in the present study indicates that polysomy 7 might be used as a prognostic predictor in clear-cell RCC. Evaluation of clinical end points will confirm the prognostic potential of the genetic marker polysomy 7 in our study.     

Evaluation of Opioid Overdose Reports in Patients Treated with Extended-Release Naltrexone: Postmarketing Data from 2006 to 2018

Introduction

After treatment with naltrexone extended-release injectable suspension (XR-NTX), a µ-opioid receptor antagonist, opioid tolerance is reduced from pretreatment baseline. Patients may be vulnerable to opioid overdose if they attempt to override the blockade during treatment, at the end of a dosing interval, after missing a dose, or after discontinuing treatment.

Objective

We analyzed postmarketing data to characterize reporting rates of opioid overdose during treatment with and after discontinuation of XR-NTX.

Methods

Postmarketing adverse event reports within the XR-NTX safety database, received 2006–2018, for patients treated with XR-NTX for any indication were reviewed for opioid overdose cases. Assessable cases were categorized by timing of the event from the last dose of XR-NTX (latency): ≤28 days (on treatment), 29–56 days, and >56 days from last dose of XR-NTX. Within each latency group, cases were further classified as serious and, of those, cases that had a fatal outcome.

Results

During the 12-year period, an estimated 495,602 patients received XR-NTX. Opioid overdose was reported in 161 cases; of these, 66 contained sufficient information to determine latency. Reporting rates of opioid overdose per 10,000 patients treated were similar among latency groups: 0.54 for ≤28 days (0.24 fatal), 0.34 for 29–56 days (0.16 fatal), and 0.44 for >56 days (0.40 fatal) from the last dose of XR-NTX.

Conclusions

Over the 12-year period, the reporting rates of opioid overdose were similar during treatment with or after discontinuation of XR-NTX and <10/10,000 patients exposed. Our findings are limited by the nature of spontaneously reported safety data.

     

Zygomatic dental implant induced orbital fracture and inferior oblique trauma

A 51-year-old female underwent four upper zygomatic dental implants (ZI) and one upper and four lower conventional implants. Immediately postoperatively, the patient had pain and diplopia upon manual elevation of the edematous eyelid. Panoramic x-ray showed a malpositioned right upper ZI, requiring removal of the right upper ZI the following day. The patient had delayed referral to ophthalmology one month later for persistent diplopia. Computed tomography scan and magnetic resonance imaging demonstrated a right inferolateral fracture with fibrosis surrounding the inferior oblique muscle. Clinical exam showed right lower eyelid retraction, right hypotropia, and inability to elevate in adduction, consistent with a right inferior oblique paresis. Surgical exploration revealed incarceration of lid and orbital tissue into the fracture. After repositioning of the prolapsed tissue, a high-density porous polyethylene implant was placed for fracture repair. The inferior fornix was reconstructed with amniotic membrane and 5-fluorouracil was injected into the scar tissue. Six months later, the patient underwent strabismus surgery with resolution of symptoms.