Faculty Bibliography

European and North American strains of the parasite Toxoplasma gondii belong to three distinct clonal lineages, type I, type II, and type III, which differ in virulence. Understanding the basis of Toxoplasma strain differences and how secreted effectors work to achieve chronic infection is a major goal of current research. Here we show that type I and III infected macrophages, a cell type required for host immunity to Toxoplasma, are alternatively activated, while type II infected macrophages are classically activated. The Toxoplasma rhoptry kinase ROP16, which activates STAT6, is responsible for alternative activation. The Toxoplasma dense granule protein GRA15, which activates NF-kappaB, promotes classical activation by type II parasites. These effectors antagonistically regulate many of the same genes, and mice infected with type II parasites expressing type I ROP16 are protected against Toxoplasma-induced ileitis. Thus, polymorphisms in determinants that modulate macrophage activation influence the ability of Toxoplasma to establish a chronic infection.

OBJECTIVES/HYPOTHESIS.: Prostaglandin (PG)E(2) has been implicated in a variety of disease processes. It has been described as antifibrotic in the lower airway, yet scar-inducing in the skin. We seek to describe the effects of PGE(2) on vocal fold fibroblasts and its interactions with transforming growth factor (TGF)-beta1. In addition, we describe a novel organotypic model, a critical step in the development of therapeutic trials. STUDY DESIGN.: In vitro, ex vivo. METHODS: Collagen secretion by human vocal fold fibroblasts (HVFF) was assayed in response to TGF-beta1, PGE(2) , and specific EP receptor agonists. Basal HVFF migratory rate was also quantified in response to PGE(2) . TGF-beta1 induced COX-2 mRNA expression/PGE(2) secretion was assayed. Excised vocal folds were subjected to exogenous IL-1beta; PGE(2) secretion into the supernatant was then assayed. RESULTS: TGF-beta1-induced collagen secretion was blunted in a dose-dependent manner in response to PGE(2) . This effect appears to be mediated primarily through the EP1 and EP2 receptors. TGF-beta1 induced COX-2 mRNA expression and PGE(2) secretion. In our organ culture model, IL-1beta stimulated PGE(2) secretion in a dose-dependent manner. CONCLUSIONS: PGE(2) is antifibrotic; this finding suggests that the upper airway response to this inflammatory mediator differs significantly from the lower airway. These data have important clinical implications for a variety of pathological processes. Furthermore, exogenous TGF-beta1 elicits induction of COX-2, suggesting inherent complexity regarding these processes and PGE(2) signaling, specifically. In addition, our organ culture model may prove useful as a means to quantify biological phenomena in the vocal folds

OBJECTIVES: In this article, we report our decade-long experience in using modified 4D-computed tomography in combination with ultrasonography (Mod 4D-CT/US) to localize abnormal parathyroid glands in patients with primary hyperparathyroidism. STUDY DESIGN: Retrospective medical record review at a university-based academic medical center. METHODS: Patients with primary hyperparathyroidism who underwent a Mod 4D-CT/US and parathyroidectomy between January 1998 and May 2009 were included in the study. Results from preoperative localization studies were compared with operative findings, pathologic data, and biochemical measurements to assess the sensitivity and specificity as well as the positive and negative predictive values of Mod 4D-CT/US. RESULTS: Mod 4D-CT/US demonstrated 94% sensitivity and 96% specificity when these imaging studies were used to lateralize the hyperfunctioning parathyroid glands to one side of the neck. In regard to localizing abnormal parathyroid glands to a specific quadrant of the neck (i.e., right-left; superior-inferior), the sensitivity and specificity of Mod 4D-CT/US was 82% and 93%, respectively. Mod 4D-CT/US had a 92% positive predictive value for single-gland disease and 75% for multigland disease. The negative predictive value for single and multigland disease (MGD) were 73% and 92%, respectively. CONCLUSIONS: Mod 4D-CT/US provides excellent sensitivity and specificity in terms of localizing abnormal parathyroid glands to the correct side and quadrant in patients with primary hyperparathyroidism, and it correctly identifies many patients with MGD.

BACKGROUND.: Parathyroid lipoadenoma is an uncommon tumor that may be difficult to diagnose on intraoperative frozen section. Intraoperative parathyroid hormone (PTH) measurement is useful in assessing the adequacy of parathyroidectomy. This case demonstrates the value of intraoperative PTH measurement in recognizing a parathyroid lipoadenoma. METHODS AND RESULTS.: A case of a 62-year-old woman with primary hyperparathyroidism in which intraoperative PTH measurement helped confirm the diagnosis of parathyroid lipoadenoma is presented. CONCLUSIONS.: In patients with primary hyperparathyroidism, a significant decrease in intraoperative PTH confirms that an enlarged parathyroid with normal to low cellularity containing abundant fat is a lipoadenoma and that further exploration is not necessary. (c) 2010 Wiley Periodicals, Inc. Head Neck, 2011

OBJECTIVE: To review the authors' experience with Gamma Knife radiosurgery (GKR) for small recurrent high-grade gliomas (HGGs) following prior radical resection, external-beam radiation therapy (EBRT), and chemotherapy with temozolomide (TMZ). METHODS: The authors retrospectively analyzed 26 consecutive adults (9 women and 17 men; median age 60.4 years; Karnofsky Performance Status [KPS] >/=70) who underwent GKR for recurrent HGGs from 2004-2009. Median lesion volume was 1.22 cc, and median treatment dose was 15 Gy. Pathology included glioblastoma multiforme (GBM; n = 16), anaplastic astrocytoma (AA; n = 5), and anaplastic mixed oligoastrocytoma (AMOA; n = 5). Two patients lost to follow-up were excluded from radiographic outcome analyses. RESULTS: Median overall survival (OS) for the entire cohort from the time of GKR was 13.5 months. Values for 12-month actuarial survival from time of GKR for GBM, AMOA, and AA were 37%, 20% and 80%. Local failure occurred in 9 patients (37.5%) at a median time of 5.8 months, and 18 patients (75%) experienced distant progression at a median of 4.8 months. Complications included radiation necrosis in two patients and transient worsening of hemiparesis in one patient. Multivariate hazard ratio (HR) analysis showed KPS 90 or greater, smaller tumor volumes, and increased time to recurrence after resection to be associated with longer OS following GKR. CONCLUSIONS: GKR provided good local tumor control in this group of clinically stable and predominantly high-functioning patients with small recurrent HGGs after radical resection. Meaningful survival times after GKR were seen. GKR can be considered for selected patients with recurrent HGGs

Purpose: The role of invasion as a prognostic factor in high-grade gliomas (HGG) remains controversial. An apparent increase in invasiveness following anti-angiogenic therapy makes this question clinically relevant. The goal of this study is to assess survival differences in patients with newly diagnosed HGG who present with diffuse invasive disease compared to those who did not, but went on to develop diffuse invasive disease following bevacizumab therapy. Materials and Methods: Twenty-three patients presented as newly diagnosed diffuse invasive HGG. All patients underwent surgical resection with radiation therapy and temozolomide for one year. Progression-free survival (PFS) and overall survival (OS) were compared to a control of 58 patients with focal high-grade glioma who received similar therapy, but that included bevacizumab at 10 mg/kg given every two weeks. Results: The patient characteristics were similar in each group. The median PFS and OS for invasive HGG patients were 6 and 13 months and for the focal HGG patients, 11 and 24 months, respectively (P=0.092 and P=0.071). In the subgroup of invasive HGG that showed significant angiogenesis, the median PFS and OS were 3 and 9 months, respectively. 56% of the focal HGG patients recurred as diffuse invasive relapse. For patients with focal HGG who recurred as invasive disease, the median PFS and OS were 9 and 21 months respectively. Conclusions: Presence of diffuse invasive disease not accompanied by angiogenesis either prior to therapy or subsequent to anti-angiogenic therapy does not seem to have prognostic significance. However, invasion accompanied by angiogenesis in newly diagnosed HGG may confer a poor prognosis

Classical and subtypes of kernicterus associated with bilirubin toxicity can be differentiated in part with physiological auditory measures that include auditory-evoked potentials and measures of cochlear integrity. The combination of these auditory measures suggests that bilirubin exposure results in auditory system damage initially at the level of the brainstem, progressing to the level of the VIII cranial nerve and then to greater neural centers. There is no evidence of neural damage at the level of the cochlea. Auditory neural damage from bilirubin toxicity ranges from neural timing deficits, including neural firing delays and dyssynchrony, to neural response reduction and even elimination of auditory neural responses. This condition is comprehensively described as auditory neuropathy spectrum disorder. Independent measures of cochlear function and auditory neural function up to the level of the brainstem can effectively diagnose auditory neural damage resulting from bilirubin neurotoxicity. Intervention, including cochlear implants can be effective.