Seidman J.D.,Washington Hospital Center |
Yemelyanova A.,Johns Hopkins University |
Zaino R.J.,Milton rshey Medical Center |
Kurman R.J.,Johns Hopkins University
International Journal of Gynecological Pathology | Year: 2011
Junctions between different types of epithelia are hot spots for carcinogenesis, but the junction of the peritoneal mesothelium with the fallopian tubal epithelium, the tubal-peritoneal junction, has not been characterized earlier. A total of 613 junctional foci in 228 fallopian tube specimens from 182 patients who underwent surgery for a variety of indications, including 27 risk-reducing salpingo-oophorectomy specimens, were studied. Edema, congestion, and dilated lymphatic channels were commonly present. Transitional metaplasia was found at the junction in 20% of patients and mesothelial hyperplasia in 17%. Inflammation at the junction was seen predominantly in patients with salpingitis, torsion, or tubal pregnancy. Ovarian-type stroma was found at the junction in 5% of patients, and was found elsewhere in the tubal lamina propria in an additional 27% of patients. Findings in risk-reducing salpingo-oophorectomy specimens in women with BRCA mutations, a personal history of breast cancer, and/or a family history of breast/ovarian cancer were similar to those in controls. Transitional metaplasia specifically localizes to this junction, and is the probable source of Walthard cell nests. The recently highlighted significance of fimbrial tubal epithelium in the origin of serous ovarian carcinomas and a study suggesting that mucinous and Brenner tumors may arise from transitional-type epithelium in this location suggest that the tubal-peritoneal junction may play a role in the development of these tumors. This is the first comprehensive description of a hitherto unrecognized transitional zone in the adnexa. © 2010 International Society of Gynecological Pathologists.
Cui J.,Penn State College of Medicine |
Boehmer J.P.,Penn State College of Medicine |
Blaha C.,Penn State College of Medicine |
Lucking R.,Penn State College of Medicine |
And 2 more authors.
Circulation: Heart Failure | Year: 2013
Background.Previous studies show that the rise in skin blood flow and cutaneous vascular conductance during heat stress is substantially attenuated in chronic heart failure (CHF) patients. The mechanisms responsible for this finding are not clear. In particular, little is known regarding the responses of skin sympathetic nerve activity (SSNA) that control the skin blood flow during heat stress in CHF patients. We examined the effects of a modest heat stress to test the hypothesis that SSNA responses could be attenuated in CHF. Methods and Results.We assessed SSNA (microneurography) from the peroneal nerve and skin blood flow (forearm laser Doppler) in 9 patients with stable class II.III CHF and in matched healthy subjects during passive whole-body heating with a water-perfused suit. Whole-body heating induced similar increases in internal temperature (.0.6-C) in both groups. Whole-body heat stress evoked similar SSNA activation in CHF patients (δ891±110 U/min) and the control subjects (δ787±84 U/min; P=0.66), whereas the elevation in forearm cutaneous vascular conductance in patients with CHF was significantly lower than that in healthy control subjects (δ131±29% vs δ623± 131%; P=0.001). Conclusions.The present data show that SSNA activation during a modest whole-body heat stress is not attenuated in CHF. Thus, the attenuated skin vasodilator response in CHF patients is not attributable to a reduction in total activity of sympathetic outflow to skin. © 2013 American Heart Association, Inc.
Connelly T.M.,Penn State College of Medicine |
Berg A.S.,Milton rshey Medical Center |
Hegarty J.P.,Penn State College of Medicine |
Deiling S.,Penn State College of Medicine |
And 3 more authors.
Annals of Surgery | Year: 2014
OBJECTIVE:: To determine if single nuclear polymorphisms (SNPs) in the TFNSF15 gene play a role in patients requiring surgery for diverticulitis. BACKGROUND:: A role for a genetic predisposition in diverticulitis is suggested by its association with hereditary connective tissue disorders, youthful onset in some patients, and the observation of families with multiple affected individuals. The TNFSF15 gene has been associated with other inflammatory diseases affecting the colon such as medically refractory ulcerative colitis (UC), aggressive Crohn's disease (CD), and pouchitis after restorative proctocolectomy. METHODS:: In the discovery phase of this study, 21 sporadic surgical diverticulitis (SD) patients (9 female, mean age = 52 ± 5) and 5 individuals from a single family with surgically managed diverticulitis [familial diverticulitis (FD), 4 female, mean age = 51.1 ± 7] were studied. SD patients were age and sex matched with 3 separate groups of healthy, CD and UC control patients. All patients were genotyped for 5 known TNFSF15-associated SNPs. The SNP discovered to be associated with diverticulitis (rs7848647) was then confirmed in a separate test group composed of 34 additional patients (20 female, mean age 57.7 ± 2) who also underwent surgical treatment for diverticulitis. These patients were age matched to a new control cohort of patients having no history of diverticulitis (26 female). Patients were genotyped using a TaqMan assay. In the discovery phase, logistical regression on matched subjects was performed to determine an association of TNFSF SNP with diverticulitis versus the control groups. In the test phase, significance for the rs7848647 SNP was assessed by the Fischer's exact test. RESULTS:: In the discovery phase, the TNFSF15 SNP rs7848647 was significantly associated with SD (p = 0.0003) versus all control groups studied. The risk allele for this SNP (G substituted for A) was found in all SD patients. The homozygous GG allele was found in 62% (13/21) of SD patients versus only 5% (1/21) of healthy controls (p = 0.001) and 24% (10/42) of all UC + CD controls (p = 0.002). All 5 members of the FD cohort were homozygous for the at-risk "G" allele. In the test group, the homozygous GG genotype was found in 56% of SD patients compared with 17% of healthy controls (p = 0.006). Risk of SD seemed to increase with number of the G alleles with 8% of SD patients having AA homozygosity, 35% of SD patients having AG heterozygosity, and 56% of SD patients having GG homozygosity. CONCLUSIONS:: The SNP rs7848647 associated with the TNFSF15 gene is associated with surgical diverticulitis. This finding suggests a fundamental role for TNFSF15, a T-cell receptor gene involved in T-cell maturation, in the pathophysiology of diverticulitis requiring surgery. This SNP may be a marker of diverticular disease severity that might assist in surgical decision making. © 2013 Lippincott Williams & Wilkins.
O'Hara C.,Milton rshey Medical Center
Infant, Child, and Adolescent Nutrition | Year: 2015
A family was administering a homemade formula to empirically treat presumed food allergies in their tube feeding–dependent child. He presented with widespread bruising and tenderness, loose teeth, swollen gums, and anemia. Scurvy was diagnosed, and he showed rapid improvement with vitamin C therapy. Providers who care for individuals who are fed homemade formulas, or who have unusual dietary practices, need to be aware of possible macro- and micronutrient deficiencies. © 2015, © 2015 The Author(s).
Green J.,Novartis |
Lipton A.,Milton rshey Medical Center
Cancer Investigation | Year: 2010
Zoledronic acid effectively reduces/delays skeletal-related events in patients with metastatic disease or skeletal-related cancers. Emerging data suggest that zoledronic acid may also exhibit anticancer properties. Zoledronic acid ± anticancer therapies in animal models inhibits soft-tissue tumor growth, decreases tumor cell proliferation, increases apoptosis, inhibits angiogenesis, alters tumor-associated macrophage function, and enhances immune surveillance. Data from in vitro and pilot studies suggest that zoledronic acid inhibits tumor cell dissemination in bone marrow, and early clinical data show that it may improve disease-related outcomes. Ongoing studies will further elucidate the role of zoledronic acid in cancer patients. © 2010 Informa Healthcare USA, Inc.
Ganapathi S.B.,Milton rshey Medical Center |
Fox T.E.,Milton rshey Medical Center |
Kester M.,Milton rshey Medical Center |
Elmslie K.S.,Milton rshey Medical Center
American Journal of Physiology - Cell Physiology | Year: 2010
Human ether-à-go-go-related gene (HERG) potassium channels play an important role in cardiac action potential repolarization, and HERG dysfunction can cause cardiac arrhythmias. However, recent evidence suggests a role for HERG in the proliferation and progression of multiple types of cancers, making it an attractive target for cancer therapy. Ceramide is an important second messenger of the sphingolipid family, which due to its proapoptotic properties has shown promising results in animal models as an anticancer agent. Yet the acute effects of ceramide on HERG potassium channels are not known. In the present study we examined the effects of cell-permeable C6-ceramide on HERG potassium channels stably expressed in HEK-293 cells. C6-ceramide (10 μM) reversibly inhibited HERG channel current (IHERG) by 36 ± 5%. Kinetically, ceramide induced a significant hyperpolarizing shift in the current-voltage relationship (ΔV1/2=-8 ± 0.5 mV) and increased the deactivation rate (43 ± 3% for τfast and 51 ± 3% for τslow). Mechanistically, ceramide recruited HERG channels within caveolin-enriched lipid rafts. Cholesterol depletion and repletion experiments and mathematical modeling studies confirmed that inhibition and gating effects are mediated by separate mechanisms. The ceramide-induced hyperpolarizing gating shift (raft mediated) could offset the impact of inhibition (raft independent) during cardiac action potential repolarization, so together they may nullify any negative impact on cardiac rhythm. Our results provide new insights into the effects of C 6-ceramide on HERG channels and suggest that C6-ceramide can be a promising therapeutic for cancers that overexpress HERG. Copyright © 2010 the American Physiological Society.
Dallon J.C.,Brigham Young University |
Ehrlich H.P.,Milton rshey Medical Center
Journal of Cellular Biochemistry | Year: 2010
Both rat derived vascular smooth muscle cells (SMC) and human myofibroblasts contain a smooth muscle actin (SMA), but they utilize different mechanisms to contract populated collagen lattices (PCLs). The difference is in how the cells generate the force that contracts the lattices. Human dermal fibroblasts transform into myofibroblasts, expressing α-SMA within stress fibers, when cultured in lattices that remain attached to the surface of a tissue culture dish. When attached lattices are populated with rat derived vascular SMC, the cells retain their vascular SMC phenotype. Comparing the contraction of attached PCLs when they are released from the culture dish on day 4 shows that lattices populated with rat vascular SMC contract less than those populated with human myofibroblast. PCL contraction was evaluated in the presence of vanadate and genistein, which modify protein tyrosine phosphorylation, and ML-7 and Y-27632, which modify myosin ATPase activity. Genistein and ML-7 had no affect upon either myofibroblast or vascular SMC-PCL contraction, demonstrating that neither protein tyrosine kinase nor myosin light chain kinase was involved. Vanadate inhibited myofibroblast-PCL contraction, consistent with a role for protein tyrosine phosphatase activity with myofibroblast-generated forces. Y-27632 inhibited both SMC and myofibroblast PCL contraction, consistent with a central role of myosin light chain phosphatase. © 2010 Wiley-Liss, Inc.
Adams D.R.,Milton rshey Medical Center |
Yankura J.A.,Milton rshey Medical Center |
Fogelberg A.C.,Milton rshey Medical Center |
Anderson B.E.,Milton rshey Medical Center
Archives of Dermatology | Year: 2010
Objectives: To observe the effects of etanercept treatment on the cutaneous manifestations of hidradenitis suppurative (HS) and to evaluate physician and patient global assessment scores of cutaneous manifestations. Design: Single-center, randomized, prospective, double-blind, placebo-controlled study. Setting: Academic dermatology practice. Patients: Twenty patients with active moderate to severe HS who fulfilled all inclusion criteria. Intervention: Etanercept, 50 mg, or placebo was administered subcutaneously (SC) twice weekly for 12 weeks. After 12 weeks, all patients received open-label etanercept, 50 mg, SC twice weekly for 12 more weeks. Main Outcome Measures: Primary end point: physician global assessment of HS as clear or mild at week 12. Secondary end points: patient global assessment and Dermatology Life Quality Index (DLQI). Results: There was no statistically significant difference among physician global assessment, patient global assessment, and DLQI at 12 or 24 weeks between treatment and placebo groups (P>.05 for all comparisons). Conclusions: Etanercept, 50 mg, SC administered twice weekly did not have significant efficacy in the improvement of HS. In light of our negative results, as well as those of previous studies, we suggest that future studies focus on other agents for the treatment of HS. Trial Registration: clinicaltrials.gov Identifier: NCT00949546 ©2010 American Medical Association. All rights reserved.
Pistorio A.L.,Milton rshey Medical Center |
Ehrlich H.P.,Milton rshey Medical Center |
Ehrlich H.P.,500 University Drive
Journal of Cellular Biochemistry | Year: 2011
The influence of mast cells upon aberrant wound repair and excessive fibrosis has supportive evidence, but the mechanism for these mast cell activities is unclear. It is proposed that heterocellular gap junction intercellular communication (GJIC) between fibroblasts and mast cells directs some fibroblast activities. An in vitro model was used employing a rodent derived peritoneal mast cell line (RMC-1) and human dermal derived fibroblasts. The influence of the expression of the gap junction channel structural protein, connexin 43 (Cx-43) on heterocellular GJIC, the expression of microtubule β-tubulin and microfilament α smooth muscle actin (SMA) were investigated. The knockdown of Cx-43 by siRNA in RMC-1 cells completely blocked GJIC between RMC-1 cells. SiRNA knockdown of Cx-43 within fibroblasts only dampened GJIC between fibroblasts. It appears Cx-43 is the only expressed connexin (Cx) in RMC-1 cells. Fibroblasts express other Cxs that participate in GJIC between fibroblasts in the absence of Cx-43 expression. Heterocellular GJIC between RMC-1 cells and fibroblasts transformed fibroblasts into myofibroblasts, expressing α SMA within cytoplasmic stress fibers. The knockdown of Cx-43 in RMC-1 cells increased β-tubulin expression, but its knockdown in fibroblasts reduced β-tubulin expression. Knocking down the expression of Cx-43 in fibroblasts limited αSMA expression. Cx-43 participation is critical for heterocellular GJIC between mast cells and fibroblasts, which may herald a novel direction for controlling fibrosis. © 2011 Wiley-Liss, Inc.
Henry C.,Milton rshey Medical Center |
Samson T.,Milton rshey Medical Center |
MacKay D.,Milton rshey Medical Center |
MacKay D.,500 University Drive
Plastic and Reconstructive Surgery | Year: 2014
LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Describe the components of unilateral and bilateral secondary cleft lip nasal deformity. 2. Discuss current methods of assessing the deformity and outcomes. 3. Discuss primary treatment options including the use of preoperative orthopedics, nasal molding techniques, and the primary cleft rhinoplasty. 4. Design a treatment plan for cleft patients that will optimize the outcome of nasal appearance and function. 5. Discuss the evidence regarding outcomes of current practices, and describe areas where more research is needed. SUMMARY: This is the third Maintenance of Certification article on the secondary cleft lip nose deformity. In the first article, Guyuron defined the deformities and described techniques for the definitive (adult) rhinoplasty. The second article, by Zbar and Canady, presented evidence regarding the assessment, surgical treatment, and outcomes from the literature published between 1999 and 2009. In this article, the authors summarize important points from the first two articles and then concentrate on the evidence for the following topics: (1) methods currently used in evaluating the severity of the deformities; (2) methods used in evaluating outcomes of different treatments; (3) benefits of rhinoplasty performed at the time of the lip repair and evidence for the effect of rhinoplasties performed after infancy but before maturity; (4) presurgical orthopedics and nasoalveolar molding; (5) common surgical techniques used in primary cleft rhinoplasties; and (6) impact of the nasal deformity on quality of life. Overall, there is little high-level evidence regarding the outcomes of cleft nasal deformity treatment, leaving much room for future study. Copyright © 2014 by the American Society of Plastic Surgeons.