Left anterior descending artery disease in a 27-year-old with multiple endocrine neoplasia, type 2A: A case report.

Multiple endocrine neoplasia 2A is an autosomal dominant disease characterized by medullary thyroid cancer, pheochromocytoma, and primary hyperparathyroidism. Coronary artery disease is associated with the disorder, but the mechanism is unclear. A 27-year-old female presented with chest pain and palpitations. A left heart catheterization was performed and showed 80% stenosis of the left anterior descending artery. Imaging and workup also revealed primary hyperparathyroidism associated with a parathyroid adenoma and elevated serum and urine metanephrines and norepinephrines. A computed tomography of the abdomen revealed a large heterogeneous right adrenal mass measuring 7.9 cm × 6.8 cm × 8 cm consistent with a pheochromocytoma. The patient subsequently underwent adrenal mass resection and a complete thyroidectomy and parathyroidectomy. Early recognition and treatment of multiple endocrine neoplasia 2A can possibly reduce the risk of lethal heart disease in addition to the other associated endocrine disturbances.

Oral and Lower Extremity Ulcers as the Initial Presentation of Granulomatosis with Polyangiitis.

Background: Granulomatosis with polyangiitis (GPA) is a small vessel vasculitis characterized by lung and kidney involvement. It is typically a disease of white females and has a poor prognosis with the average life expectancy of 5 months for a patient without treatment. Oral and skin ulcers are considered to be rare presentations. Case: A 39-year-old black male presented to the hospital with oral and skin ulcers and was diagnosed with GPA based on the biopsies of both cutaneous lesions and kidney. He was started on rituximab with minimal improvement. Later he was admitted to the ICU and had plasmapheresis, and he gradually improved and was discharged home 8 days after admission. Conclusion: GPA is an aggressive vascular disorder resulting in possible organ system damage and failure. The role of the sickle cell trait in this patient is undefined, but this combination of gender, race, and presenting symptoms in GPA is extremely unusual.

Downregulation of the human peripheral myelin protein 22 gene by miR-29a in cellular models of Charcot-Marie-Tooth disease.

The majority of hereditary neuropathies are caused by duplication of the peripheral myelin protein 22 (PMP22) gene. Therefore, mechanisms to suppress the expression of the PMP22 gene have high therapeutic significance. Here we asked whether the human PMP22 gene is a target for regulation by microRNA 29a (miR-29a). Using bioinformatics, we determined that the human PMP22 gene contains the conserved seed sequence of the miR-29a binding site and this regulatory motif is included in the duplicated region in neuropathic patients. Using luciferase reporter assays in HEK293 cells, we demonstrated that transient transfection of a miR-29a mimic is associated with reduction in PMP22 3'UTR reporter activity. Transfecting normal and humanized transgenic neuropathic mouse Schwann cells with a miR-29a expression plasmid effectively lowered both the endogenous mouse and the transgenic human PMP22 transcripts compared with control vector. In dermal fibroblasts derived from neuropathic patients, ectopic expression of miR-29a led to ~50% reduction in PMP22 mRNA, which corresponded to ~20% decrease in PMP22 protein levels. Significantly, miR-29a-mediated reduction in PMP22 mitigated the reduced mitotic capacity of the neuropathic cells. Together, these results support further testing of miR-29a and/or PMP22-targeting siRNAs as therapeutic agents for correcting the aberrant expression of PMP22 in neuropathic patients.

Anti-high mobility group box 1 antibody suppresses local inflammatory reaction and facilitates olfactory nerve recovery following injury.

BACKGROUND: Refractory olfactory dysfunction is a common finding in head trauma due to olfactory nerve injury. Anti-inflammatory treatment using steroids is known to contribute to functional recovery of the central and peripheral nervous systems in injury models, while there is a concern that steroids can induce side effects. The present study examines if the inhibition of proinflammatory cytokine, high mobility group box 1 (HMGB1), can facilitate olfactory functional recovery following injury. METHODS: Olfactory nerve transection (NTx) was performed in OMP-tau-lacZ mice to establish injury models. We measured HMGB1 gene expression in the olfactory bulb using semi-quantitative polymerase chain reaction (PCR) assays and examined HMGB1 protein localization in the olfactory bulb using immunohistochemical staining. Anti-HMGB1 antibody was intraperitoneally injected immediately after the NTx and histological assessment of recovery within the olfactory bulb was performed at 5, 14, 42, and 100 days after the drug injection. X-gal staining labeled OMP in the degenerating and regenerating olfactory nerve fibers, and immunohistochemical staining detected the presence of reactive astrocytes and macrophages/microglia. Olfactory function was assessed using both an olfactory avoidance behavioral test and evoked potential recording. RESULTS: HMGB1 gene and protein were significantly expressed in the olfactory bulb 12 h after NTx. Anti-HMGB1 antibody-injected mice showed significantly smaller areas of injury-associated tissue, fewer astrocytes and macrophages/microglia and an increase in regenerating nerve fibers. Both an olfactory avoidance behavioral test and evoked potential recordings showed improved functional recovery in the anti-HMGB1 antibody-injected mice. CONCLUSIONS: These findings suggest that inhibition of HMGB1 could provide a new therapeutic strategy for the treatment of olfactory dysfunction following head injuries.

Elevated Peripheral Myelin Protein 22, Reduced Mitotic Potential, and Proteasome Impairment in Dermal Fibroblasts from Charcot-Marie-Tooth Disease Type 1A Patients.

A common form of hereditary autosomal dominant demyelinating neuropathy known as Charcot-Marie-Tooth disease type 1A (CMT1A) is linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Although studies from animal models have led to better understanding of the pathobiology of these neuropathies, there continues to be a gap in the translation of findings from rodents to humans. Because PMP22 was originally identified in fibroblasts as growth arrest specific gene 3 (gas3) and is expressed broadly in the body, it was tested whether skin cells from neuropathic patients would display the cellular pathology observed in Schwann cells from rodent models. Dermal fibroblasts from two CMT1A pedigrees with confirmed PMP22 gene duplication were studied. Samples from age-matched non-neuropathic individuals were used as controls. CMT1A patient-derived cultures contain approximately 1.5-fold elevated levels of PMP22 mRNA, exhibit reduced mitotic potential, and display intracellular protein aggregates as compared to cells from unaffected individuals. The presence of cytosolic PMP22 coincides with a decrease in proteasome activity and an increase in autophagy-lysosomal proteins, including LC3-II and LAMP1. These results indicate that the abnormalities in the subcellular processing of excess PMP22 elicit a detectable response in human CMT1A fibroblasts, a phenotype that resembles Schwann cells from neuropathic mice. These findings support the use of human CMT1A fibroblasts as a platform for therapy testing.

Tumor necrosis factor-α antagonist suppresses local inflammatory reaction and facilitates olfactory nerve recovery following injury.

OBJECTIVE: Olfactory dysfunction is a common finding in head trauma due to injury to the olfactory nerve. We previously reported that anti-inflammatory treatment with steroids improves recovery outcome in olfactory nerve injury models. Clinically, however, steroid administration is not recommended in the acute phase of head injury cases because of concerns regarding its side effects. Tumor necrosis factor (TNF-α) is known to play a key role in inflammatory response to injury. The present study examines if the inhibition of TNF-α can facilitate functional recovery in the olfactory system following injury. MATERIALS AND METHODS: Olfactory nerve transection (NTx) was performed in olfactory marker protein (OMP-tau-lacZ) mice to establish injury models. We measured TNF-α gene expression in the olfactory bulb using semi-quantitative and real time polymerase chain reaction (PCR) assays and found that they increase within hours after NTx injury. A TNF-α antagonist (etanercept) was intraperitoneally injected immediately after the NTx and histological assessment of recovery within the olfactory bulb was performed at 5-70 days. X-gal staining labeled OMP in the degenerating and regenerating olfactory nerve fibers, and immunohistochemical staining detected the presence of reactive astrocytes and macrophages/microglia. RESULTS: Etanercept-injected mice showed significantly smaller areas of injury-associated tissue, fewer astrocytes and macrophages/microglia, and an increase in regenerating nerve fibers. Olfactory function assessments using both an olfactory avoidance behavioral test and evoked potential recordings showed improved functional recovery in etanercept-injected animals. CONCLUSION: These findings suggest that inhibition of TNF-α could provide a new therapeutic strategy for the treatment of olfactory dysfunction following head injuries.