An Interesting Case of Euthyroid Graves' Ophthalmopathy, With Negative Thyroid-Stimulating Hormone Receptor Antibodies.

Thyroid eye disease (TED), also known as Graves' orbitopathy or ophthalmopathy (GO) or Graves' eye disease, is an autoimmune condition of the retroocular tissues associated with Graves' disease. In isolated GO, the patient can present without thyroid hormone dysfunction or systemic symptoms of Graves' disease, in which case it is called euthyroid Graves' ophthalmopathy (EGO). It is very rare for this condition to have negative thyroid-stimulating hormone receptor (TSHR) autoantibodies, and we present such a rare case of a young female, who had progressive bilateral vision loss, intermittent left-sided retroocular headache, and severe bilateral proptosis. The patient was diagnosed with EGO based on multidisciplinary consults, diagnostic orbital magnetic resonance imaging (MRI) results, and a good response to treatment with intravenous steroids. Later, the patient was followed as an outpatient and treated with thyroid orbitopathy-specific immunotherapy with teprotumumab. The patient's response to teprotumumab was excellent and caused significant improvement in visual acuity, proptosis, and chemosis. This adds valuable literature to the medical field and gives insight to clinicians to consider the diagnosis of GO even with seronegative TSHR autoantibodies and euthyroid hormone status. It also adds to the understanding of the complex pathophysiology of this rare condition.

Sporadic, classic-type renal angiomyolipoma with renal vein and inferior vena cava extension: an incidental case.

Renal angiomyolipomas (AMLs) were first described in the early 1900s by Gravitz, but it was not until 1951 that they were named renal AML. These kidney tumours are rare, occurring in 0.13%-0.44% of the population. These mesenchymal tumours are composed of smooth muscle-like, adipocyte-like and epithelioid cells. Depending on the predominant cell population, it can be further subclassified into classic, epithelioid and AML with epithelial cyst. A 32-year-old woman presented with mild, intermittent, epigastric and right upper quadrant abdominal pain. Abdominal ultrasound revealed an incidental lesion within the inferior vena cava (IVC). A CT scan showed a lesion within the left renal vein extending into the IVC with 40% narrowing and a fat-containing mass in the lower pole of the left kidney of 15 mm suggesting an AML. Thrombectomy was performed. The specimen resulted positive for classic variant renal AML. Initial diagnosis is centred on imagining studies, based in fatty tissue concentration. The AML expresses melanocytic markers. This helps differentiate from renal cell carcinoma. Although AML is considered a benign condition, there is evidence of malignant transformation. Active surveillance is recommended for lesions <4 cm. Nephron sparing surgery is the procedure of choice. Nephrectomy is recommended if there is a high probability of malignancy. Mammalian target of rapamycin (mTOR) inhibitors have been proposed to be an alternative treatment.

Delayed Presentation of Drug-Induced Hepatic Injury.

Drug-induced hepatotoxicity is a major cause of acute liver failure (ALF) in the United States. There are many offending agents like prescription drugs and herbal remedies. However, the most common prescription medication involved worldwide is amoxicillin-clavulanate. We report an unusually delayed presentation of severe cholestatic hepatitis caused by amoxicillin-clavulanate in a 20-year-old female with worsening hyperbilirubinemia that was successfully treated with corticosteroids and ursodeoxycholic acid (UDCA).

More than Meets the Eye: Aspergillus-Related Orbital Apex Syndrome.

The patient is a 67-year-old Caucasian male with a past medical history of diabetes mellitus type 2, coronary artery disease (CAD) status post stent placement, renal cell carcinoma (RCC) status post left nephrectomy and bilateral adrenalectomy secondary to metastatic disease, and aspergillus pneumonia who was transferred from an outside hospital for evaluation of progressively worsening pulsating right temple and retrobulbar headache. Initial studies ruled out glaucoma, giant cell arteritis, and stroke, or aneurysmal pathology. The only positive finding was right sphenoid sinus disease on imaging that had caused bony destruction and infiltration of the right orbital apex. Broad-spectrum antibiotics were started for bacterial versus fungal sinusitis and the patient was admitted to the medical floor with consultations to Neurology, Otolaryngology (ENT), and Ophthalmology. ENT took the patient emergently to the OR. The final diagnosis was chronic aspergillus sinusitis and right-sided orbital apex syndrome (OAS). Antibiotics and antifungals were optimized by the infectious disease team. ENT also ordered steroid washouts post-operatively with budesonide and saline as well as sinus debridements every couple of weeks.

Structure-function analysis of vaccinia virus H7 protein reveals a novel phosphoinositide binding fold essential for poxvirus replication.

UNLABELLED: Phosphoinositides and phosphoinositide binding proteins play a critical role in membrane and protein trafficking in eukaryotes. Their critical role in replication of cytoplasmic viruses has just begun to be understood. Poxviruses, a family of large cytoplasmic DNA viruses, rely on the intracellular membranes to develop their envelope, and poxvirus morphogenesis requires enzymes from the cellular phosphoinositide metabolic pathway. However, the role of phosphoinositides in poxvirus replication remains unclear, and no poxvirus proteins show any homology to eukaryotic phosphoinositide binding domains. Recently, a group of poxvirus proteins, termed viral membrane assembly proteins (VMAPs), were identified as essential for poxvirus membrane biogenesis. A key component of VMAPs is the H7 protein. Here we report the crystal structure of the H7 protein from vaccinia virus. The H7 structure displays a novel fold comprised of seven α-helices and a highly curved three-stranded antiparallel ß-sheet. We identified a phosphoinositide binding site in H7, comprised of basic residues on a surface patch and the flexible C-terminal tail. These residues were found to be essential for viral replication and for binding of H7 to phosphatidylinositol-3-phosphate (PI3P) and phosphatidylinositol-4-phosphate (PI4P). Our studies suggest that phosphoinositide binding by H7 plays an essential role in poxvirus membrane biogenesis. IMPORTANCE: Poxvirus viral membrane assembly proteins (VMAPs) were recently shown to be essential for poxvirus membrane biogenesis. One of the key components of VMAPs is the H7 protein. However, no known structural motifs could be identified from its sequence, and there are no homologs of H7 outside the poxvirus family to suggest a biochemical function. We have determined the crystal structure of the vaccinia virus (VACV) H7 protein. The structure displays a novel fold with a distinct and positively charged surface. Our data demonstrate that H7 binds phosphatidylinositol-3-phosphate and phosphatidylinositol-4-phosphate and that the basic surface patch is indeed required for phosphoinositide binding. In addition, mutation of positively charged residues required for lipid binding disrupted VACV replication. Phosphoinositides and phosphoinositide binding proteins play critical roles in membrane and protein trafficking in eukaryotes. Our study demonstrates that VACV H7 displays a novel fold for phosphoinositide binding, which is essential for poxvirus replication.

Physical and functional interaction between the ID1 and p65 for activation of NF-κB.

Inhibitor of differentiation or DNA binding-1 (ID1) is an important helix-loop-helix (HLH) transcription factor involved in diverse biological functions including cell differentiation, proliferation, apoptosis, and senescence. Recently, it was reported that ID1 can activate the NF-κB signaling pathway in a variety of cancer cells and a T cell line, but the mechanisms involved in ID1-mediated transactivation of NF-κB are not clear. In this study, we demonstrate by both in vitro pull-down assays and a cell-based in vivo two-hybrid system that ID1-mediated NF-κB activation is due to its physical interaction with p65. We have identified that the transcriptional activation domain (TAD) in p65 and the HLH domain in ID1 are vital for their interaction. Interestingly, a single site mutation (Leu76) in the HLH domain of ID1 protein drastically decreased its ability to bind with p65. Using a dual-luciferase assay, we demonstrated that the interaction between ID1 and p65 modulates activation of the NF-κB signaling pathway in vivo. In addition, we demonstrated that, by affecting the nuclear translocation of p65, ID1 is essential in regulating TNF-α-induced p65 recruitment to its downstream target, the cellular inhibitor of apoptosis protein 2 (cIAP2) promoter.