Liberty Center, OH, United States
Liberty Center, OH, United States

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Gillombardo C.B.,University Hospital Case | Yamauchi M.,Nara Medical University | Adams M.D.,Case Western Reserve University | Dostal J.,University Hospital Case | And 5 more authors.
Journal of Applied Physiology | Year: 2012

Although central to the susceptibility of adult diseases characterized by abnormal rhythmogenesis, characterizing the genes involved is a challenge. We took advantage of the C57BL/6J (B6) trait of hypoxiainduced periodic breathing and its absence in the C57BL/6J-Chr 1A/J/NaJ chromosome substitution strain to test the feasibility of gene discovery for this abnormality. Beginning with a genetic and phenotypic analysis of an intercross study between these strains, we discovered three quantitative trait loci (QTLs) on mouse chromosome 1, with phenotypic effects. Fine-mapping reduced the genomic intervals and gene content, and the introgression of one QTL region back onto the C57BL/6J-Chr 1A/J/NaJ restored the trait. mRNA expression of non-synonymous genes in the introgressed region in the medulla and pons found evidence for differential expression of three genes, the highest of which was apolipoprotein A2, a lipase regulator; the apo a2 peptide fragment (THEQLTPLVR), highly expressed in the liver, was expressed in low amounts in the medulla but did not correlate with trait expression. This work directly demonstrates the impact of elements on mouse chromosome 1 in respiratory rhythmogenesis. Copyright © 2012 the American Physiological Society.


Morgan M.A.,Fox Chase Cancer Center | Morgan M.A.,The Surgical Center | Sill M.W.,Gynecologic Oncology Group | Fujiwara K.,Saitama University | And 8 more authors.
Gynecologic Oncology | Year: 2011

Objective: This study aimed to determine the first-cycle maximum tolerated dose (MTD) of intraperitoneal carboplatin in combination with intravenous paclitaxel and then assess the feasibility of this dose over multiple cycles. Methods: Beginning at an intraperitoneal (IP) carboplatin dose area under the curve (AUC) of 5 and a fixed intravenous dose of 175 mg/m2 paclitaxel, patients were entered on a dose-escalating phase evaluating first-cycle dose-limiting toxicity (DLT). After estimating the MTD, cohorts of 20 patients were then entered in an expanded phase to evaluate DLT over four cycles. Results: Twenty-one patients were entered on the dose-escalating phase. A first-cycle MTD of carboplatin at AUC 8 was tolerated although thrombocytopenia was dose-limiting over multiple cycles. An additional 69 patients were treated in expanded cohorts. Only 5/90 (5.6%) patients discontinued treatment because of a port problem. Four-cycle DLT required de-escalation to a carboplatin AUC of 6, and even at that dose, there were 14 dose-limiting toxic effects in 40 patients (35%). Seven dose-limiting toxicities were due to neutropenia, and 6 were due to grade 3/4 thrombocytopenia. Six cycles of therapy were completed in 75% of eligible patients, but dose adjustments were required. Conclusions: The first-cycle MTD did not predict the tolerability of this regimen over multiple cycles. Using an IP carboplatin dose of AUC 6 in combination with paclitaxel, the regimen can be administered with a high completion rate over multiple cycles. Because neutropenia is a frequent DLT, the addition of hematopoietic growth factors may permit a high completion rate while maintaining this dose. © 2011 Elsevier Inc. All rights reserved.


Ho V.P.,New York Medical College | Lee Y.,Sloan Kettering Cancer Center | Stein S.L.,University Hospital Case | Temple L.K.F.,Sloan Kettering Cancer Center
Diseases of the Colon and Rectum | Year: 2011

Sexual function is one element of QOL that may be significantly altered following treatment for rectal cancer, but the incidence and contributing risk factors are generally poorly understood. Nevertheless, the impact of rectal cancer therapy on sexual function should be conveyed to patients preoperatively. In addition to helping patients evolve realistic expectations, it will help clinicians identify those for whom interventions may be appropriate. In the past 10 years, there has been an increase in the number of studies reporting sexual dysfunction following rectal cancer treatment. However, these studies are difficult to interpret collectively for a variety of reasons. Most importantly, sexual dysfunction lacks a standardized definition, which leads to poor comparability between studies. The best inclusive definitions describe sexual dysfunction as a collection of distinct symptoms, which differ for men and women. The absence of sexual activity is sometimes used as a surrogate for sexual dysfunction, but this is confounded by an individual's desire and opportunity for sexual activity, and may not be an accurate reflection of physiologic functionality. Additional factors complicating assimilation of studies include the absence of baseline data, missing data, small sample sizes, and heterogeneity in use of validated and nonvalidated instruments. The purpose of this article is to systematically review the contemporary literature reporting sexual function after rectal surgery to determine the overall risk of sexual dysfunction, evaluate possible contributing factors, and identify questions that should be addressed in future studies. © The ASCRS 2010.

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