Goodman R.L.,Robert rd Health Science Center |
Maltby M.J.,University of Western Ontario |
Millar R.P.,University of Pretoria |
Millar R.P.,University of Cape Town |
And 7 more authors.
Endocrinology | Year: 2012
Recent work has implicated stimulatory kisspeptin neurons in the arcuate nucleus (ARC) as important for seasonal changes in reproductive function in sheep, but earlier studies support a role for inhibitory A15 dopaminergic (DA) neurons in the suppression of GnRH (and LH) pulse frequency in the nonbreeding (anestrous) season. Because A15 neurons project to the ARC, we performed three experiments to test the hypothesis that A15 neurons act via ARC kisspeptin neurons to inhibit LH in anestrus: 1) we used dual immunocytochemistry to determine whether these ARC neurons contain D2 dopamine receptor (D2-R), the receptor responsible for inhibition of LH in anestrus; 2) we tested the ability of local administration of sulpiride, a D2-R antagonist, into the ARC to increase LH secretion in anestrus; and 3) we determined whether an antagonist to the kisspeptin receptor could block the increase in LH secretion induced by sulpiride in anestrus. In experiment 1, 40% of this ARC neuronal subpopulation contained D2-R in breeding season ewes, but this increased to approximately 80% in anestrus. In experiment 2, local microinjection of the two highest doses (10 and 50 nmol) of sulpiride into the ARC significantly increased LH pulse frequency to levels 3 times that seen with vehicle injections. Finally, intracerebroventricular infusion of a kisspeptin receptor antagonist completely blocked the increase in LH pulse frequency induced by systemic administration of sulpiride to anestrous ewes. These results support the hypothesis that DA acts to inhibit GnRH (and LH) secretion in anestrus by suppressing the activity of ARC kisspeptin neurons. Copyright © 2012 by The Endocrine Society.
Biondo L.,West Vir ginia University Hospitals |
Bodge M.,West Virginia University |
Paul S.R.,Robert rd Health Science Center
Annals of Pharmacotherapy | Year: 2013
OBJECTIVE: To report a case of erythematous rash induced by romiplostim administration in a patient with autoimmune lymphoproliferative syndrome (ALPS). CASE SUMMARY: A 19-year-old female with ALPS-related thrombocytopenia (platelet count 4 × 103/μL) successfully treated with romiplostim 500 μg weekly for 9 months presented with a grade 3 maculopapular rash. Symptoms on presen-tation included purpuric, erythematous pustules confined to the trunk following romiplostim administration the previous day. A punch biopsy of skin from the patient's right lower abdomen revealed perivascular chronic inflammation with numerous eosinophils consistent with drug reaction. The patient had received romiplostim 500 μg weekly with no other reports of rash until this time. Romiplos-tim was discontinued, the patient was monitored, and the rash resolved within 1 week. Romiplostim was then restarted at 200 μg weekly. The patient has achieved platelet normalization at a current romiplostim dose of 250 μg weekly with no further adverse reactions. DISCUSSION: ALPS is a rare autoimmune disorder with approximately 500 known cases worldwide. Pharmacotherapy for ALPS patients generally targets autoimmune cytopenias associated with the disorder. When standard therapies for ALPS-related cytopenias fail, clinicians are often forced to consider novel treatment options. Our patient had ALPS-related thrombocytopenia that was treated with romiplostim, which resulted in grade 3 maculopapular rash after almost 1 year of treatment. The likelihood that this patient's erythematous rash was due to romiplostim administration was determined to be possible based on the Naranjo probability scale. The reaction was reported to the drug manufacturer and to the Food and Drug Administration's MedWatch program. CONCLUSIONS: This is the first documented case, to our knowledge, of severe maculopapular rash occurring less than 24 hours after romiplostim administration for treatment of ALPS-related chronic thrombocytopenia. Rash has been reported as an adverse event of romiplostim therapy at higher doses (750 μg), but not at a dose of 500 μg. This report also describes successful rechallenge of romiplostim after resolution of the rash. © 1967-2013 Harvey Whitney Books Co. All rights reserved.
Goodman R.L.,Robert rd Health Science Center |
Holaskova I.,Robert rd Health Science Center |
Nestor C.C.,Robert rd Health Science Center |
Connors J.M.,Robert rd Health Science Center |
And 4 more authors.
Endocrinology | Year: 2011
There is now considerable evidence that dynorphin neurons mediate the negative feedback actions of progesterone to inhibit GnRH and LH pulse frequency, but the specific neurons have yet to be identified. In ewes, dynorphin neurons in the arcuate nucleus (ARC) and preoptic area (POA) are likely candidates based on colocalization with progesterone receptors. These studies tested the hypothesis that progesterone negative feedback occurs in either the ARC or POA by determining whether microimplants of progesterone into either site would inhibit LH pulse frequency (study 1) and whether microimplants of the progesterone receptor antagonist, RU486, would disrupt the inhibitory effects of peripheral progesterone (study 2). Both studies were done in ovariectomized (OVX) and estradiol-treated OVX ewes. In study 1, no inhibitory effects of progesterone were observed during treatment in either area. In study 2, microimplants of RU486 into the ARC disrupted the negative-feedback actions of peripheral progesterone treatments on LH pulse frequency in both OVX and OVX+estradiol ewes. In contrast, microimplants of RU486 into the POA had no effect on the ability of systemic progesterone to inhibit LH pulse frequency. We thus conclude that the ARC is one important site of progesterone-negative feedback in the ewe. These data, which are the first evidence on the neural sites in which progesterone inhibits GnRH pulse frequency in any species, are consistent with the hypothesis that ARC dynorphin neurons mediate this action of progesterone. Copyright © 2011 by The Endocrine Society.
Billings H.J.,West Virginia University |
Connors J.M.,Robert rd Health Science Center |
Altman S.N.,Robert rd Health Science Center |
Hileman S.M.,Robert rd Health Science Center |
And 6 more authors.
Endocrinology | Year: 2010
Recent data have demonstrated that mutations in the receptor for neurokinin B (NKB), the NK-3 receptor (NK3R), produce hypogonadotropic hypogonadism in humans. These data, together with reports that NKB expression increases after ovariectomy and in postmenopausal women, have led to the hypothesis that this tachykinin is an important stimulator of GnRH secretion. However, the NK3R agonist, senktide, inhibited LH secretion in rats and mice. In this study, we report that senktide stimulates LH secretion in ewes. A dramatic increase in LH concentrations to levels close to those observed during the preovulatory LH surge was observed after injection of 1 nmol senktide into the third ventricle during the follicular, but not in the luteal, phase. Similar increases in LH secretion occurred after insertion of microimplants containing this agonist into the retrochiasmatic area (RCh) in anestrous or follicular phase ewes. A low-dose microinjection (3 pmol) of senktide into the RCh produced a smaller but significant increase in LH concentrations in anestrous ewes. Moreover, NK3R immunoreactivity was clearly evident in the RCh, although it was not found in A15 dopaminergic cell bodies in this region. These data provide evidence that NKB stimulates LH (and presumably GnRH) secretion in ewes and point to the RCh as one important site of action. Based on these data, and the effects of NK3R mutations in humans, we hypothesize that NKB plays an important stimulatory role in the control of GnRH and LH secretion in nonrodent species. Copyright © 2010 by The Endocrine Society.
LeMasters T.J.,West Virginia University |
LeMasters T.J.,Robert rd Health Science Center |
Madhavan S.S.,West Virginia University |
Madhavan S.S.,Robert rd Health Science Center |
And 3 more authors.
Journal of Cancer Survivorship | Year: 2014
Purpose: The aim of this study is to compare health behaviors between breast, prostate, female, and male colorectal cancer survivors to noncancer controls, stratified by short- and long-term survivors, and between cancer types and genders. Methods: A 3:1 population-based sample of breast (6,259), prostate (3,609), female colorectal (1,082), and male colorectal (816) cancer survivors from the 2009 Behavioral Risk Factor Surveillance System survey were matched to noncancer controls on age, gender, race/ethnicity, income, insurance, and region of the US. The likelihood of flu immunization, physical check-up, cholesterol check, body mass index (BMI), physical activity, diet (5-A-Day), smoking, and alcohol use were compared between groups using binomial logistic regression models. Results: Short-term breast cancer survivors were significantly more likely to meet multiple behavioral recommendations, than controls, but the likelihood decreased in the long term. Breast and female colorectal cancer survivors were up to 2.27 (95 % CI 1.90, 2.71) and 1.89 times more likely (95 % CI 1.60, 2.24) to meet the 5-A-Day and BMI recommendations, up to 0.54 times less likely (95 % CI 0.46, 0.64) to drink any alcohol, but were 0.68 times less likely (95 % CI 0.49, 0.95) to meet the physical activity recommendation, compared to prostate and male colorectal cancer survivors. Conclusions: Some cancer survivors may engage in better health behaviors shortly after diagnosis, but the majority of cancer survivors do not have better health behaviors than individuals without a history of cancer. However, a consistent pattern of behavioral differences exist between male and female cancer survivors. Implications for Cancer Survivors: Gender differences in health behaviors among cancer survivors may be influenced by perceptions of masculinity/femininity and disease risk. Ongoing health behavioral promotion and disease prevention efforts could be improved by addressing these perceptions. © 2014 Springer Science+Business Media New York.
Higa G.M.,West Virginia University |
Higa G.M.,Robert rd Health Science Center
Breast Cancer | Year: 2011
Manifestations of non-equilibrium polarity, random transgressions, and catastrophes are not conditions usually associated with a sense of normalcy. Yet these disquieting features distinguish a utilitarian behavior known as dynamic instability, the signature characteristic of the microtubule. Long known to be a tumor target, disruption of this fragile attribute is associated with some of the most effective agents used to treat breast cancer today. Although the biology of the microtubule is under intense investigation much still remains unknown. As such, our understanding of regulatory molecules and resistance mechanisms are still rudimentary, further compromising our ability to develop novel therapeutic strategies to improve microtubule inhibitors. This review focuses on several classes of anti-microtubule agents and their effects on the functional dynamics of the targeted polymer. The primary objective is to critically examine the molecular mechanisms that contribute to tumor cell death, tumor-resistance, and incident neurotoxicity. © 2010 The Japanese Breast Cancer Society.
Goins R.T.,Oregon State University |
Innes K.,Robert rd Health Science Center |
Dong L.,West Virginia University
Journal of the American Geriatrics Society | Year: 2012
The objective of this study was to use performance-based measurements to identify, in a population of community-dwelling American Indians aged 55 and older, the prevalence and correlates of lower body functioning. Data were collected as part of a cross-sectional study of disability from members of a tribe in the southeast. Lower body functioning was measured using the Short Physical Performance Battery (SPPB), where higher scores reflect better functioning. Independent variables included age, sex, marital status, educational attainment, current cigarette smoking, physical activity, body mass index (BMI), hearing loss, vision loss, bone or joint trauma, chronic pain syndrome, osteoporosis, medical comorbidity, and depressive symptomatology. The total composite SPPB score (8.8 ± 3.4) declined significantly with increasing age and was negatively associated with unmarried status, physical inactivity, vision loss, bone or joint trauma, and medical comorbidity after adjustment for all other factors in the model. Likewise, all individual SPPB component scores declined significantly with increasing age and were negatively associated with physical inactivity and comorbidity. The balance test score was significantly and negatively associated with unmarried status and vision loss; gait speed was negatively related to unmarried status; and chair stand test score was negatively related to BMI, vision loss, bone or joint trauma, and chronic pain syndrome. In the clinical setting, the SPPB can be an important screening tool for adverse health-related events. Further studies are needed to investigate the determinants and sequelae of physical dysfunction in this population. © 2012, The American Geriatrics Society.
Jang D.H.,Clinical Translational Science Institute |
Weaver M.D.,University of Pittsburgh |
Pizon A.F.,University of Pittsburgh |
Pizon A.F.,Robert rd Health Science Center
Journal of Medical Toxicology | Year: 2013
Introduction: In the treatment of acetaminophen toxicity, clinicians believe that N-acetylcysteine (NAC) artificially elevates prothrombin time (PT). However, the effect of NAC on human blood coagulation remains unverified. In a previous study, we show that NAC had a dose-dependent effect on PT. To our knowledge, there are no studies that specifically examine the mechanism by which NAC affects PT. This study evaluates the effect from a therapeutic NAC dose on the activity of coagulation factors II, VII, IX, and X in human plasma. Method: We obtained blood samples from ten volunteer subjects. After centrifugation of each volunteer's blood sample, the plasma was pipetted and divided into two 1-mL aliquots. We used the first-1 mL sample as a control. The second 1-mL plasma sample had 5 μL of 20 % NAC, added to make a final concentration of 1,000 mg of NAC per L of plasma. This concentration of NAC approximates the plasma levels achieved after a 150-mg/kg dose. We incubated the two samples for each subject (control and 1,000 mg/L) at 37°C for 1 h and measured the activity of coagulation factors II, VII, IX, and X. We compared factor activity using the paired student t test. Results: Participants included ten healthy subjects; six males, four females, median age 31 years. Mean values of the control samples for factors II, VII, IX, and X were 134 (CI 119-149), 126 (CI 90-163), 137 (CI 117-157), and 170 (CI 144-196) %, respectively. Mean values of the NAC-containing samples for factors II, VII, IX, and X were 90 (CI 79-100), 66 (CI 51-80), 74 (CI 63-85), and 81 (CI 71-90) %, respectively. All samples containing NAC had significantly lower coagulation factor activity level than their controls with a p < 0. 001. Discussion: In a previous study, we were able to demonstrate that NAC had a dose-dependent effect on PT. In this study, we compared activity of factors II, VII, IX, and X at baseline and for samples that received NAC. All factor activity had a significant decrease with the addition of NAC. This fall in factor activity is not explained by the dilution of adding NAC to the test samples. Conclusion: We are able to demonstrate a significant decrease in the activity of coagulation factors II, VII, IX, and X with the addition of NAC. This may be the mechanism by which PT increased in our previous study. © 2012 American College of Medical Toxicology.
Jansen R.,Robert rd Health Science Center |
Kandzari S.J.,Robert rd Health Science Center |
Zaslau S.,Robert rd Health Science Center
Canadian Journal of Urology | Year: 2012
Testicular ischemia is typically seen with cases of testicular torsion. Twisting of the spermatic cord and compromise of testicular blood supply can induce testicular loss if not promptly discovered and treated. Non-torsion causes of testicular ischemia are uncommon with rare citations in the literature. Herein, we present a case of testicular ischemia induced by traumatic thrombosis of the spermatic vessels. © The Canadian Journal of Urology™.
Murray G.F.,Robert rd Health Science Center
The Annals of thoracic surgery | Year: 2010
The 29th President of the Society of Thoracic Surgeons, Benson R. Wilcox, MD, died at his home in Fearington Village Center, NC, on May 11, 2010. In 2 weeks, he would have been 78 years old, and the focus of a birthday celebration for his wife, Patsy Davis, his 4 children, Adelaide, Sandra, Melissa, and Reid, 11 grandchildren, and many loved ones. With his death, caused by brain cancer, the University of North Carolina lost one of its most prolific and loyal sons, and the profession of thoracic surgery, one of its wisest leaders. Two facts are certain: Ben will be remembered forever by his students, residents, and colleagues, and our sky is, indeed, Carolina blue. 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.