Mark Conaway

Publications (39)168.02 Total impact

• Article: Growth and health in children with moderate-to-severe cerebral palsy.

  Richard D Stevenson, Mark Conaway, W Cameron Chumlea, Peter Rosenbaum, Ellen B Fung, Richard C Henderson, Gordon Worley, Gregory Liptak, Maureen O'Donnell, Lisa Samson-Fang, Virginia A Stallings
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  ABSTRACT: Children with cerebral palsy frequently grow poorly. The purpose of this study was to describe observed growth patterns and their relationship to health and social participation in a representative sample of children with moderate-severe cerebral palsy. In a 6-site, multicentered, region-based cross-sectional study, multiple sources were used to identify children with moderate or severe cerebral palsy. There were 273 children enrolled, 58% male, 71% white, with Gross Motor Function Classification System levels III (22%), IV (25%), or V (53%). Anthropometric measures included: weight, knee height, upper arm length, midupper arm muscle area, triceps skinfold, and subscapular skinfold. Intraobserver and interobserver reliability was established. Health care use (days in bed, days in hospital, and visits to doctor or emergency department) and social participation (days missed of school or of usual activities for child and family) over the preceding 4 weeks were measured by questionnaire. Growth curves were developed and z scores calculated for each of the 6 measures. Cluster analysis methodology was then used to create 3 distinct groups of subjects based on average z scores across the 6 measures chosen to provide an overview of growth. Gender-specific growth curves with 10th, 25th, 50th, 75th, and 90th percentiles for each of the 6 measurements were created. Cluster analyses identified 3 clusters of subjects based on their average z scores for these measures. The subjects with the best growth had fewest days of health care use and fewest days of social participation missed, and the subjects with the worst growth had the most days of health care use and most days of participation missed. Growth patterns in children with cerebral palsy were associated with their overall health and social participation. The role of these cerebral palsy-specific growth curves in clinical decision-making will require further study.
  PEDIATRICS 10/2006; 118(3):1010-8. · 4.47 Impact Factor
• Article: Prospective evaluation of the prognostic relevance of molecular staging for urothelial carcinoma.

  Hillary L Copp, Joseph L Chin, Mark Conaway, Dan Theodorescu
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  ABSTRACT: Nearly 50% of urothelial carcinoma patients with lymph node-negative invasive cancers recur after radical surgery. In many cases, occult local or lymph node disease may be present but undetectable by current approaches. Reverse-transcriptase polymerase chain reaction (RT-PCR)-detectable mRNA of Uroplakin II (UPII), a urothelial-specific gene mRNA, was evaluated in perivesical and lymph node samples removed at radical surgery as a predictor of clinical recurrence. From November 1999 to August 2002, 46 patients with cTa-T4N0M0 urothelial bladder cancer enrolled in a prospective clinical trial and underwent radical cystectomy and pelvic lymphadenectomy. RT-PCR for UPII was performed on biopsies of the external surface of the bladder specimen and lymph nodes. Results were compared with conventional pathology. Patients were followed every 6 months for tumor recurrence. Pathologically node-negative patients had a UPII RT-PCR perivesical positivity of 27% and a lymph node positivity rate of 33%. All 22 UPII RT-PCR node-negative patients were pathologically node-negative and all 13 with pathologically positive nodes had positive UPII RT-PCR lymph node signals. In all, 46% of UPII RT-PCR lymph node-positive patients were pathologically node-negative and 5% of pathologically node-negative/UPII RT-PCR node-negative patients had disease recurrence, whereas 91% of pathologically node-negative/UPII RT-PCR node-positive patients (P < .001) recurred. UPII RT-PCR node positivity was a significant predictor of tumor recurrence in multivariate analysis Molecular determination of lymph node metastases by UPII RT-PCR node positivity apparently identifies patients with a poor prognosis and may be more predictive of disease recurrence than conventional pathologic analysis.
  Cancer 08/2006; 107(1):60-6. · 4.77 Impact Factor
• Article: Temperature dependence of cardiac performance in the lobster Homarus americanus.

  Mary Kate Worden, Christine M Clark, Mark Conaway, Syed Aman Qadri
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  ABSTRACT: The lobster Homarus americanus inhabits ocean waters that vary in temperature over a 25 degrees C range, depending on the season and water depth. To investigate whether the lobster heart functions effectively over a wide range of temperatures we examine the temperature dependence of cardiac performance of isolated lobster hearts in vitro. In addition, we examined whether modulation of the heart by serotonin depends on temperature. The strength of the heartbeat strongly depends on temperature, as isolated hearts are warmed from 2 to 22 degrees C the contraction amplitude decreases by greater than 60%. The rates of contraction and relaxation of the heart are most strongly temperature dependent in the range from 2 to 4 degrees C but become temperature independent at warmer temperatures. Heart rates increase as a function of temperature both in isolated hearts and in intact animals, however hearts in intact animals beat faster in the temperature range of 12-20 degrees C. Interestingly, acute Q10 values for heart rate are similar in vivo and in vitro over most of the temperature range, suggesting that temperature dependence of heart rate arises mainly from the temperature effects on the cardiac ganglion. In contrast to earlier reports suggesting that the strength and the frequency of the lobster heartbeat are positively correlated, we observe no consistent relationship between these parameters as they change as a function of temperature. Stroke volume decreases as a function of temperature. However, the opposing temperature-dependent increase in heart rate partially compensates to produce a relationship between cardiac output and temperature in which cardiac output is maximal at 10 degrees C and significantly decreases above 20 degrees C. Serotonin potentiates contraction amplitude and heart rate in a temperature-independent manner. Overall, our results show that although the parameters underlying cardiac performance show different patterns of temperature dependence, cardiac output remains relatively constant over most of the wide range of environmental temperatures the lobster inhabits in the wild.
  Journal of Experimental Biology 04/2006; 209(Pt 6):1024-34. · 3.00 Impact Factor
• Article: Discovery and validation of new protein biomarkers for urothelial cancer: a prospective analysis.

  Dan Theodorescu, Stefan Wittke, Mark M Ross, Michael Walden, Mark Conaway, Ingo Just, Harald Mischak, Henry F Frierson
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  ABSTRACT: Non-invasive methods for diagnosis of urothelial carcinoma have reduced specificity in patients with non-malignant genitourinary disease or other disorders. We aimed to use mass spectrometry and bioinformatics to define and validate a cancer-specific proteomic pattern. We used capillary-electrophoresis-coupled mass spectrometry to obtain polypeptide patterns from urine samples of 46 patients with urothelial carcinoma and 33 healthy volunteers. From signatures of polypeptide mass, we established a model for predicting the presence of cancer. The model was refined further by use of 366 urine samples obtained from other healthy volunteers and patients with malignant and non-malignant genitourinary disease. We estimated the proportion of correct classifications from the refined model by applying it to a masked group containing 31 patients with urothelial carcinoma, 11 healthy individuals, and 138 patients with non-malignant genitourinary disease. We also sequenced several diagnostic polypeptides for urothelial carcinoma. We identified a diagnostic urothelial-carcinoma pattern of 22 polypeptide masses. On masked assessment, prediction models based on these polypeptides correctly classified all samples of urothelial carcinoma (sensitivity 100% [95% CI 87-100) and all healthy samples (specificity 100% [84-100]). Correct identification of patients with urothelial carcinoma from those with other malignant and non-malignant genitourinary disease ranged from 86% to 100%. A prominent polypeptide from the diagnostic pattern for urothelial carcinoma was identified as fibrinopeptide A-a known biomarker of ovarian cancer and gastric cancer. Validation of a highly specific biomarker pattern for urothelial carcinoma in a large group of patients with various urological disorders could be used in the diagnosis of other diseases that are identified in urine samples or in other body fluids.
  The Lancet Oncology 04/2006; 7(3):230-40. · 22.59 Impact Factor
• Article: The metastasis-associated gene CD24 is regulated by Ral GTPase and is a mediator of cell proliferation and survival in human cancer.

  Steven C Smith, Gary Oxford, Zhong Wu, Matthew D Nitz, Mark Conaway, Henry F Frierson, Garret Hampton, Dan Theodorescu
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  ABSTRACT: Ral GTPases are important mediators of transformation, tumorigenesis, and cancer progression. We recently identified the metastasis-associated protein CD24, a glycosyl phosphatidyl inositol-linked surface protein, as a downstream target of Ral signaling by profiling the expression of RalA/B-depleted bladder carcinoma cells. Because CD24 is highly expressed in bladder and many other tumor types, we sought to determine if this protein plays an essential role in maintaining the malignant phenotype. Here, we show that loss of CD24 function in cell lines derived from common tumor types is associated with decreased rates of cell proliferation, clonogenicity in soft agar, changes in the actin cytoskeleton, and induction of apoptosis. Given these phenotypes, we evaluated a human bladder cancer tissue microarray by immunohistochemistry for CD24 to determine if CD24 is a prognostic cancer biomarker. Multivariate analysis showed that increased CD24 expression correlated with shorter patient disease-free survival (P = 0.07). In conclusion, we show that CD24 is a novel and functionally relevant Ral-regulated target and a potentially important prognostic marker. We suggest that these insights may lead to future therapeutic approaches that seek to eliminate CD24 function in cancer cells.
  Cancer Research 03/2006; 66(4):1917-22. · 7.86 Impact Factor
• Article: Endothelin axis is a target of the lung metastasis suppressor gene RhoGDI2.

  Brian Titus, Henry F Frierson, Mark Conaway, Keith Ching, Theresa Guise, John Chirgwin, Garret Hampton, Dan Theodorescu
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  ABSTRACT: Half of patients treated for locally advanced bladder cancer relapse with often fatal metastatic disease to the lung. We have recently shown that reduced expression of the GDP dissociation inhibitor, RhoGDI2, is associated with decreased survival of patients with advanced bladder cancer. However, the effectors by which RhoGDI2 affects metastasis are unknown. Here we use DNA microarrays to identify genes suppressed by RhoGDI2 reconstitution in lung metastatic bladder cancer cell lines. We identify such RNAs and focus only on those that also increase with tumor stage in human bladder cancer samples to discover only clinically relevant targets of RhoGDI2. Levels of endothelin-1 (ET-1), a potent vasoconstrictor, were affected by both RhoGDI2 reconstitution and tumor stage. To test the hypothesis that the endothelin axis is important in lung metastasis, lung metastatic bladder carcinoma cells were injected in mice treated with the endothelin receptor-specific antagonist, atrasentan, thereby blocking engagement of the up-regulated ET-1 ligand with its cognate receptor. Endothelin antagonism resulted in a dramatic reduction of lung metastases, similar to the effect of reexpressing RhoGDI2 in these metastatic cells. Taken together, these experiments show a novel approach of identifying therapeutic targets downstream of metastasis suppressor genes. The data also suggest that blockade of the ET-1 axis may prevent lung metastasis, a new therapeutic concept that warrants clinical evaluation.
  Cancer Research 09/2005; 65(16):7320-7. · 7.86 Impact Factor
• Article: Combination antiangiogenic and androgen deprivation therapy for prostate cancer: a promising therapeutic approach.

  Brian Nicholson, Kathryn Gulding, Mark Conaway, Stephen R Wedge, Dan Theodorescu
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  ABSTRACT: Androgen ablation therapy leads to mild regression or stabilization of prostate cancer, followed by progression to the fatal androgen-independent state. Whereas androgen ablation diminishes tumor angiogenesis by suppressing vascular endothelial growth factor (VEGF) production, androgen-independent disease is marked by androgen-independent VEGF expression. We examined combined androgen ablation and inhibition of VEGF signaling in an androgen-sensitive human prostate cancer xenograft model (LNCaP) that is known to develop androgen-independent growth after androgen ablation. N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine (ZD6474) is an orally active inhibitor of VEGF receptor tyrosine kinase activity, with additional activity against epidermal growth factor receptor tyrosine kinase. ZD6474 (50 mg/kg/d, per os) was administered to groups of castrated and noncastrated athymic mice bearing established (4-616 mm3) LNCaP xenografts. To evaluate the extent of tumor regrowth after ZD6474, treatment was stopped after 40 days of continuous dosing, and subsequent tumor growth was monitored. Prostate-specific antigen expression was assessed to determine the effect of ZD6474 on androgen-regulated genes. In comparison with orchiectomy, ZD6474 treatment produced greater tumor growth inhibition (P < 0.001), inducing complete cytostasis for the duration of dosing. An analysis of serum prostate-specific antigen concentration and tumor weight indicated that ZD6474 did not have a direct effect on androgen-related gene expression. Combination therapy (castration plus ZD6474) produced a comparable therapeutic effect to treatment with ZD6474 alone (in noncastrated mice), for the duration of ZD6474 administration. However, when ZD6474 treatment was discontinued, the rate of tumor regrowth was significantly less in the combination group. Tumors from mice receiving combined treatment were also found to be more necrotic than tumors from mice receiving either androgen ablation or ZD6474 alone. These data indicate that inhibition of VEGF signaling produces a highly significant inhibition of tumor growth in a human androgen-dependent prostate tumor model, which far exceeds that produced by androgen ablation alone. However, when ZD6474 treatment is removed, concurrent androgen ablation produces a greater inhibition of tumor regrowth than is observed in mice without androgen ablation. Increased necrosis observed in tumors from orchiectomized mice receiving ZD6474 also suggests benefit from combining anti-androgen and anti-VEGF signaling approaches.
  Clinical Cancer Research 01/2005; 10(24):8728-34. · 7.74 Impact Factor
• Article: Bodily pain and health-related quality of life in children with cerebral palsy.

  Christine M Houlihan, Maureen O'Donnell, Mark Conaway, Richard D Stevenson
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  ABSTRACT: Pain frequency and its association with participation, function, and health-related quality of life were evaluated in a sample of 198 children (58% male; mean age 10 years 7 months, SD 3 years 11 months; range 5 to 18 years) with moderate to severe cerebral palsy (CP). Gross Motor Functional Classification System (GMFCS) levels were III to V (23% level III, 23% level IV, 31% level V without a gastrostomy tube, and 23% were level V with a gastrostomy tube). Assessment was carried out using the parent-report Child Health Questionnaire (CHQ) and questions assessing health, medical utilization, and medication use. Pain frequency ranged from 'none' to 'every day'. Eleven percent of parents reported pain almost every day (z score=-0.38, p<0.001). Pain was related to severity of motor impairment and the presence of a gastrostomy; parents of the most severely affected children reported the highest pain frequency (p=0.05). Pain was correlated with school days missed (p=0.03) and days in bed (p=0.01). Children taking gastrointestinal medications were reported to have greater pain frequency (p<0.001). The Parental Impact--Emotional subscale of the CHQ was correlated with reported pain (r=0.38, p<0.001). Pain was frequent in children with moderate or severe CP. Pain was more prevalent with more severe impairment and was associated with educational and social consequences.
  Developmental Medicine & Child Neurology 06/2004; 46(5):305-10. · 2.92 Impact Factor
• Article: Long-term exposure to tamoxifen induces hypersensitivity to estradiol.

  Lev M Berstein, Ji-Ping Wang, Hong Zheng, Wei Yue, Mark Conaway, Richard J Santen
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  ABSTRACT: In women with hormone-dependent breast cancer, tamoxifen (TAM) frequently induces tumor regression, but regrowth occurs with continuation of antiestrogen therapy. Studies of breast xenografts in nude mice suggest that this secondary resistance to TAM may reflect the development of enhanced sensitivity to the estrogenic properties of TAM. In the current study, we examined the hypothesis that TAM could also induce a state of hypersensitivity to estradiol (E(2)) itself. Oophorectomized nude mice with MCF-7 cell xenografts received 25-mg implants of TAM [long-term TAM treated (LTTT) mice] or cholesterol (C-MCF-7) over a 5-month period (phase 1). The LTTT group regressed to a lesser extent than did C-MCF-7 tumors. After 4 months of TAM exposure, the LTTT tumors begin to regrow, as did the C-MCF-7, as assessed by slope analysis. At 5 months, TAM or vehicle implants were removed, and the LTTT and C-MCF-7 subgroups were given vehicle or two doses of E(2) to test estrogen sensitivity (phase 2). We used our "E(2) clamp" technique to maintain levels of plasma E(2) at either 1.25 or 20 pg/ml. Neither group responded to the very low concentrations of E(2) (1.25 pg/ml) or vehicle. The LTTT tumors but not C-MCF-7 tumors exhibited a growth response on exposure to 20 pg/ml E(2) during 7 weeks, as demonstrated with mixed models analysis. These studies provide evidence that long-term TAM exposure enhances sensitivity to the estrogenic effects of TAM and also to E(2) itself.
  Clinical Cancer Research 03/2004; 10(4):1530-4. · 7.74 Impact Factor
• Article: Effect of shortened length of stay on functional and educational outcome after pediatric rehabilitation.

  Sydney A Rice, Janet Allaire, Kevin Elgin, Walter Farrell, Mark Conaway, James A Blackman
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  ABSTRACT: The purpose of this study was to assess changes in the length of stay and its effect on effectiveness and return to school in an inpatient pediatric rehabilitation unit during a 5-yr period from fiscal year 1997 through 2001. We reviewed prospectively collected data for a cohort of 321 children during fiscal years 1997-2001. Length of stay was significantly shortened, with mean lengths of stay of 58.9, 43.5, 30.7, 40.9, and 24.0 days in years 1997 through 2001, respectively. Change in length of stay remained significantly decreased after adjusting for age, sex, admission diagnosis, admission severity, and type of health insurance. There was no difference in mean change in effectiveness measured by change in admission and discharge WeeFIM ratings. There were significant differences across years in the educational placement of children at discharge, with a declining trend in the proportion of children discharged to classroom-based educational services. There was a reduction in inpatient length of stay during a 5-yr period for children in this pediatric rehabilitation setting. During this time, there was no change in the effectiveness of rehabilitation as measured by functional outcome. However, using return to a classroom setting as a marker of reintegration into routine activities, fewer children returned to a similar level of community participation.
  American Journal of Physical Medicine & Rehabilitation 02/2004; 83(1):27-32. · 1.58 Impact Factor
• Article: Relationships among musculoskeletal impairments and functional health status in ambulatory cerebral palsy.

  Mark F Abel, Diane L Damiano, John S Blanco, Mark Conaway, Freeman Miller, Kirk Dabney, David Sutherland, Henry Chambers, Luciano Dias, John Sarwark, John Killian, Scott Doyle, Leon Root, Javier LaPlaza, Roger Widmann, Brian Snyder
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  ABSTRACT: Orthopedic surgery for patients with cerebral palsy addresses motion impairments, assuming that this will improve motor function. This study evaluates the relationships among clinical impairment measures with standardized assessments of function and disability as an initial step in testing this assumption. A total of 129 ambulatory children and adolescents across six institutions participated in a prospective evaluation that consisted of passive motion and spasticity examination of the lower extremities, three-dimensional gait temporal-spatial and kinematic analysis, and administration of the Gross Motor Function Measure (GMFM) and the Pediatric Outcomes Data Collection Instrument (PODCI). The analysis found that isolated impairment measures of motion and spasticity were only weakly related to motor function in cerebral palsy and even when averaged across multiple joints yielded no more than a fair correlation with functional scores, nor did a combination of impairments emerge that could predict substantial variance in motor function. These findings suggest that caution should be exercised when anticipating functional change through the treatment of isolated impairment and that addressing multiple impairments may be needed to produce appreciable effects.
  Journal of Pediatric Orthopaedics 06/2003; 23(4):535-41. · 1.16 Impact Factor
• Article: Secondary sexual characteristics in children with cerebral palsy and moderate to severe motor impairment: a cross-sectional survey.

  Gordon Worley, Christine M Houlihan, Marcia E Herman-Giddens, Maureen E O'Donnell, Mark Conaway, Virginia A Stallings, W Cameron Chumlea, Richard C Henderson, Ellen B Fung, Peter L Rosenbaum, Lisa Samson-Fang, Gregory S Liptak, Randy E Calvert, Richard D Stevenson
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  ABSTRACT: To compare the development of secondary sexual characteristics in children with cerebral palsy (CP) of moderate to severe motor impairment to children in the general population and to relate their sexual maturation to a measure of their body fat. A multicenter, cross-sectional survey of 207 children who were 3 to 18 years of age and had CP of moderate to severe motor impairment (Gross Motor Functional Classification System [GMFCS] levels 3, 4, and 5) was conducted at 6 geographic sites; attempts were made to identify all eligible children through multiple methods and enroll them in the study. Trained research assistants performed anthropometric measurements, including subscapular skinfold thickness, determined GMFCS level, and assessed sexual maturation by Tanner stage. Secondary sexual characteristics were compared with the general population of children using cross-sectional surveys of the American Academy of Pediatrics Pediatric Research in Office Settings network and of the National Center for Health Statistics National Health and Nutrition Examination Survey (NHANES) III. Girls were classified as having begun puberty when they were at Tanner stage 2 or greater for pubic hair and breast development and to have completed puberty when they were at Tanner stage 4 or greater for pubic hair and breast development. Boys were classified as having begun puberty when they were at Tanner stage 2 or greater for pubic hair and genital development and to have completed puberty when they were at Tanner stage 4 or greater for pubic hair and genital development. The mean age (standard deviation) of subjects was 9.6 (4.6) years. Of the 207 subjects, 71% were white, 21% were black, and 8% were of other races; 59% were boys, and 41% were girls. Girls with CP (n = 84) entered puberty earlier than did boys with CP (n = 123). In contrast, girls with CP tended to complete puberty later than did boys with CP. Black boys and girls with CP (n = 43) entered puberty earlier than did white boys and girls with CP (n = 147). No difference between races was found in completion of puberty. Only for white children with CP were there a sufficient number of subjects for comparisons of sexual maturation to race-matched children in the general population, using data from the American Academy of Pediatrics Pediatric Research in Office Settings network and the NHANES III study. White girls with CP initiated pubic hair development (Tanner stage 2 or greater) earlier than in the general population, but the age of onset of breast development was similar to the general population, although the age distribution was different. A greater proportion of white girls with CP had early onset of breast development (Tanner stage 2 or greater), and a greater proportion had delayed onset of breast development than in the general population. White girls with CP completed breast development later than in the general population but not pubic hair development. For white boys ages 8 to 18 years with CP (n = 75), pubic hair and genital development both began earlier than in the general population, but genital development was completed later. The estimated median age of menarche for white girls with CP was 14.0 years, which was 1.3 years later (95% confidence interval: 0.7-2.3) than for the general population (estimated median age: 12.8 years; NHANES III). Relationships between sexual maturation and nutritional state, as assessed by subscapular skinfold thickness z score, were determined separately in white boys and in white girls with CP, between the ages of 8 and 18 years. For white girls with CP, more advanced sexual maturation was associated with more body fat, adjusting for age and GMFCS level (Spearman partial correlation: 0.41). In contrast, for white boys with CP, the opposite relationship pertained: more advanced sexual maturation was associated with less body fat (-0.29). The pattern of sexual maturation in children with CP of moderate to severe motor impairment differs from that of children in the general population. Puberty begins earlier but ends later in white children with CP, compared with white children in the general population. In addition, menarche occurs later in white girls with CP. More advanced sexual maturation was associated with more body fat in girls but less body fat in boys.
  PEDIATRICS 12/2002; 110(5):897-902. · 4.47 Impact Factor
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  Available from: Peter L Rosenbaum

  Article: Relationship of nutritional status to health and societal participation in children with cerebral palsy.

  Lisa Samson-Fang, Ellen Fung, Virginia A Stallings, Mark Conaway, Gordon Worley, Peter Rosenbaum, Randy Calvert, Maureen O'donnell, Richard C Henderson, W Cameron Chumlea, Gregory S Liptak, Richard D Stevenson
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  ABSTRACT: To describe nutritional status in a population-based sample of children with moderate or severe cerebral palsy (CP) and to explore the relationships between nutritional status and health and functional outcomes. A population-based strategy was used to enroll children with CP at 6 geographic sites. Research assistants performed anthropometric assessment, determined severity of motor impairment, and interviewed caregivers with the Child Health Questionnaire and a questionnaire designed specifically for this study. Anthropometric measures were converted to Z scores and the relationship between health and nutritional status was assessed using regression models. Among the 235 participants, indicators of malnutrition were common. Poor nutritional status correlated with increased health care utilization (hospitalizations, doctor visits) and decreased participation in usual activities by the child and parent. Malnutrition is common in children with moderate or severe CP and associated with poorer health status and limitations in societal participation. Further studies are needed to determine the nature of these associations and how to manage nutrition in children with CP to optimize growth and health outcomes.
  Journal of Pediatrics 12/2002; 141(5):637-43. · 4.11 Impact Factor
• Article: Activation of the MAPK pathway enhances sensitivity of MCF-7 breast cancer cells to the mitogenic effect of estradiol.

  Wei Yue, Ji-Ping Wang, Mark Conaway, Shigeru Masamura, Yuebai Li, Richard J Santen
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  ABSTRACT: Long-term estrogen deprivation causes human breast cancer cells to develop hypersensitivity to the mitogenic effect of estradiol (E(2)). Our prior studies demonstrated an association between enhanced MAPK activation and hypersensitivity in long-term estrogen-deprived (LTED) MCF-7 cells. Herein, we report that MAPK is constitutively activated in LTED cells and not dependent on serum factors. Additionally, activated MAPK levels fall upon reversion of the hypersensitivity. Importantly, we now provide direct evidence that enhanced MAPK causes hypersensitivity to E(2). We activated MAPK in wild-type MCF-7 cells using TGFalpha, and demonstrated a 2-3 log enhancement of sensitivity to E(2). PD98059 abrogated the TGFalpha-induced effect, indicating that MAPK activation is responsible for E(2) hypersensitivity. To determine the level at which MAPK activation enhanced E(2) sensitivity, we examined the dose-response effects of E(2) on several transcriptional readouts, including ERE-reporter activity and the levels of progesterone receptor and pS2. Wild-type and LTED cells exhibited nearly identical responses to E(2), suggesting that mechanisms downstream of estrogen receptor-mediated transcription are involved in inducing hypersensitivity. In support of this possibility, LTED and TGFalpha-treated wild-type cells were hypersensitive to the effects of E(2) on the key cell cycle regulator, E2F1.
  Endocrinology 10/2002; 143(9):3221-9. · 4.46 Impact Factor
• Article: Bone density and metabolism in children and adolescents with moderate to severe cerebral palsy.

  Richard C Henderson, Robert K Lark, Matthew J Gurka, Gordon Worley, Ellen B Fung, Mark Conaway, Virginia A Stallings, Richard D Stevenson
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  ABSTRACT: Diminished bone density and a propensity to fracture with minimal trauma are common in children and adolescents with moderate to severe cerebral palsy (CP). The purpose of this study was to provide a detailed evaluation of bone mineral density (BMD) and metabolism in this population and to assess the relationship of these measures to multiple other clinical, growth, and nutrition variables. The study group consisted of 117 subjects ages 2 to 19 years (mean: 9.7 years) with moderate to severe CP as defined by the Gross Motor Functional Classification scale. Population-based sampling was used to recruit 62 of the participants, which allows for estimations of prevalence. The remaining 55 subjects were a convenience sampling from both hospital- and school-based sources. The evaluation included measures of BMD, a detailed anthropometric assessment of growth and nutritional status, medical and surgical history, the Child Health Status Questionnaire, and multiple serum analyses. BMD was measured in the distal femur, a site specifically developed for use in this contracted population, and the lumbar spine. BMD measures were converted to age and gender normalized z scores based on our own previously published control series (n > 250). Osteopenia (BMD z score <-2.0) was found in the femur of 77% of the population-based cohort and in 97% of all study participants who were unable to stand and were older than 9 years. BMD was not as low in the lumbar spine (population-based cohort mean +/- standard error z score: -1.8 +/- 0.1) as in the distal femur (mean z score: -3.1 +/- 0.2). Fractures had occurred in 26% of the children who were older than 10 years. Multiple clinical and nutritional variables correlated with BMD z scores, but interpretation of these findings is complicated by covariance among variables. In stepwise regression analyses, it was found that severity of neurologic impairment as graded by Gross Motor Functional Classification level, increasing difficulty feeding the child, use of anticonvulsants, and lower triceps skinfold z scores (in decreasing order of importance) all independently contribute to lower BMD z scores in the femur. Low BMD is prevalent in children with moderate to severe CP and is associated with significant fracture risk. The underlying pathophysiology is complex, with multiple factors contributing to the problem and significant variation between different regions of the skeleton.
  PEDIATRICS 07/2002; 110(1 Pt 1):e5. · 4.47 Impact Factor
• Article: Feeding dysfunction is associated with poor growth and health status in children with cerebral palsy.

  Ellen B Fung, Lisa Samson-Fang, Virginia A Stallings, Mark Conaway, Gregory Liptak, Richard C Henderson, Gordon Worley, Maureen O'Donnell, Randy Calvert, Peter Rosenbaum, William Chumlea, Richard D Stevenson
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  ABSTRACT: To describe parent-reported feeding dysfunction and its association with health and nutritional status in children with cerebral palsy. Anthropometry was measured and z scores calculated. The Child Health Questionnaire was used to assess health status, and a categorical scale (none to severe) was used to classify subjects according to severity of feeding dysfunction. 230 children (9.7+/-4.6 years; 59% boys) with moderate to severe cerebral palsy were recruited from 6 centers in the United States and Canada. Descriptive statistics, the Kruskal-Wallis and Pearson chi2 tests. Severity of feeding dysfunction was strongly associated with indicators of poor health and nutritional status. The mean weight z scores were -1.7, -2.5, -3.3, and -1.8 among children with none, mild, moderate, or severe (largely tube-fed) feeding dysfunction, respectively (P= .003). Similar results were observed for height z score (P=.008), triceps z score (P=.03), and poor Global Health score (part of the Child Health Questionnaire) (P<.001). Subjects who were tube fed were taller (P=.014) and had greater body fat stores (triceps z score, P=.001) than orally fed subjects with similar motor impairment. For subjects exclusively fed by mouth, a dose-response relationship was observed between feeding dysfunction severity and poor nutritional status. Subjects with only mild feeding dysfunction had reduced triceps z score (-0.9) compared with those with no feeding problems (-0.3). For children with moderate to severe cerebral palsy, feeding dysfunction is a common problem associated with poor health and nutritional status. Even children with only mild feeding dysfunction, requiring chopped or mashed foods, may be at risk for poor nutritional status. Parental report of feeding dysfunction with a structured questionnaire may be useful in screening children for nutritional risk.
  Journal of the American Dietetic Association 04/2002; 102(3):361-73. · 3.59 Impact Factor
• Article: Fracture rate in children with cerebral palsy.

  Richard D Stevenson, Mark Conaway, John W Barrington, Sara L Cuthill, Gordon Worley, Richard C Henderson
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  ABSTRACT: To determine the prevalence of previous fracture, the rate of fracture over time and associated risk factors for fracture in children with moderate or severe cerebral palsy (CP). Three hundred and sixty-four children with moderate-to-severe motor impairment (Gross Motor Function Classification System III, IV and V) enrolled in a multi-centre, region-based longitudinal study of growth, nutrition and health. Of these, 297 had baseline fracture information and 261 children had at least one follow-up assessment. Median duration of follow-up was 1.6 years, for over 600 person-years of follow-up. Forty-six (15.5%) children reported 62 previous fractures at baseline assessment. Children with a history of fractures at baseline were older (mean age 11.9 vs. 8.9 years, p<0.0001) and had greater body fat (triceps z-score -0.01 vs. -0.68, p=0.0003) than children with no previous fracture. Twenty children (6.7%) reported 24 fractures during the follow-up period. Factors associated with risk of fracture during the follow-up period were higher body fat (p=0.03), gastrostomy use (p=0.05) and previous fracture (p=0.10). Based on 24 fractures in 604.5 person-years of follow-up, the rate of fracture was 4.0 per hundred children (4.0%) per year. For children with a history of fracture at baseline, the fracture rate was 7.0% per year; for children with gastrostomy, 6.8% per year; and for children with high triceps skinfold, 9.7% per year. Children with moderate or severe CP are at high risk for fracture. Children with greater body fat, feeding gastrostomy and prior history of fracture are at highest risk and may benefit most from intervention. Further longitudinal study and clinical trials in children with CP are needed to better understand the factors contributing to fracture risk in this population and the best methods of prevention and treatment.
  Pediatric Rehabilitation 9(4):396-403.
• Article: Treatment of urogenital atrophy with low-dose estradiol: preliminary results.

  Richard J Santen, JoAnn V Pinkerton, Mark Conaway, Mary Ropka, Lisa Wisniewski, Larry Demers, Karen O Klein
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  ABSTRACT: To determine the lowest dosage of vaginally administered estradiol (E2) that reverses signs and symptoms of urogenital atrophy but does not substantially increase plasma E2 levels. Single-blind, single-arm study to determine the effects of de-escalating doses of vaginal estrogen on symptoms of urogenital atrophy, vaginal pH, and vaginal and urethral cytology. A questionnaire was used to assess subjective vaginal and urethral symptoms. Objective measurements included vaginal and urethral cytology, pH, endometrial biopsy, and 24-h circulating plasma luteinizing hormone, follicle-stimulating hormone (FSH), E2, and estrone levels obtained in a Clinical Research Unit. Circulating E2 levels were assayed with an ultrasensitive yeast bioassay with a detection limit of 0.02 pg/mL. Measurements were obtained over a 24-h period after administration of vehicle alone, on day 1 after the initial vaginal E2 dosage, after 3 weeks of daily E2 administration, and after an additional 9 weeks of twice weekly administration. From the first seven subjects studied at a 10-microg dose of E2, 100% responded according to predefined criteria. Vaginal cytology showed statistical improvement at 3 and 12 weeks. Urethral cytology was statistically improved after 12 weeks. Vaginal pH decreased from postmenopausal to premenopausal levels at both 3 and 12 weeks. Eighty-two percent of symptoms were cured or improved. Endometrium remained atrophic. Circulating E2 levels remained within the postmenopausal range of 3-10 pg/mL. A 10-microg dose of vaginal E2 effectively treated urogenital atrophy in seven women and did not cause endometrial hyperplasia or increase E2 levels.
  Menopause 9(3):179-87. · 3.76 Impact Factor
• Article: Weight management practices among heart and vascular health care providers in an ambulatory setting.

  Melly Turner, Suzanne M Burns, Laura Knight, Kathryn Ward, Adrienne Garo, Theresa Morris, Elizabeth Hooper, Mark Conaway
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  ABSTRACT: In this study, health care providers' assessment, intervention practices, and perceived barriers to weight management approaches in an ambulatory adult heart and vascular setting are reported. Their knowledge of the National Institutes of Health National Heart, Lung and Blood Institute's The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults are also described.
  Medsurg nursing: official journal of the Academy of Medical-Surgical Nurses 21(4):222-32.