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This study builds upon past research involving turnover among military women to develop a statistical model for active duty Female Naval Aviator (FNA) retention. A data set from Defense Manpower Data Center, which included FNAs from year groups 1989 to 1998 was analyzed to determine the impact of organizational, career, and personal factors on retention. A review of pertinent literature revealed that personal, organizational, and job factors unique to a FNA might have some impact on the retention decision. A logistical regression analysis determined that both number of dependents and age were statistically significant in predicting whether a FNA would stay in or leave active duty operational naval aviation (ADONA). The findings of this study could indicate that FNAs who desire to have children leave ADONA status earlier. Successful implementation of a continuous survey tool, such as the previous ARGUS survey, could better determine the true reasons behind a service member's choice to leave the Navy.

Three independent sets of normal breast tissues without evidence of cancer, either obtained from patients undergoing reduction mammoplasty or in women at time of autopsy, have been analyzed. The postdoctoral trainee has shown that moderate to dramatic telomere shortening occurs specifically in luminal epithelial cells, but not in myoepithelial cells, in the majority of histologically normal terminal ductal lobular units. However, the extent and degree of telomere shortening varies by the individual. These data imply that there is a reservoir of genetically altered, yet histologically normal, cells within normal breast tissues that may represent fertile ground for tumor development. Since telomere shortening has been associated with cellular senescence and dysfunctional telomeres have been linked to the DNA damage response pathway in cancerous tissues, ongoing experiments are assessing senescence-associated markers and DNA damage response pathway markers in histologically normal human breast tissues that display either normal or short telomeres (i.e. prior to tumor formation). In addition, the proposed investigation has provided grounding in both basic and translational breast cancer research for the trainee. The interactive, multidisciplinary research environment at Johns Hopkins has provided the investigator opportunities to interact with pathologists, oncologists and epidemiologists, thus fostering future success as an independent translational breast cancer researcher.

In the United States, cancer is one of the fi ve leading causes of death in all age groups among both men and women; overall, approximately one in four deaths is attributable to cancer. Compared to the general U.S. population military members have been estimated to have lower incidence rates of several cancers including colorectal, lung, and cervical cancers and higher rates of prostate, breast, and thyroid cancer. Between 2000 and 2011 in active component members of the U.S. military, crude incidence rates of most cancer diagnoses have remained stable. 9,368 active component service members were diagnosed with one of the cancers of interest and no specifi c increasing or decreasing trends were observed. Cancer is an uncommon cause of death among service members on active duty and accounted for a total of 1,185 deaths during the 12-year surveillance period., Published in Medical Surveillance Monthly Report, v19 n6 p18-23, June 2012. See also ADA563931. The original document contains color images.

Posttraumatic osteoarthritis affects approximately 5.6 million Americans annually. Those affected are typically younger and more active than persons with primary osteoarthritis. Arthrodesis is the typical management option for persons with end-stage ankle and subtalar posttraumatic arthritis. Arthroplasty is typically reserved for elderly persons. The functional limitations resulting from any of these strategies make treatment of this young population challenging. Combat wounds frequently lead to severe lower extremity injuries. We present a series of patients with severe posttraumatic osteoarthritis of the ankle and subtalar joint after combat trauma. They were treated at our institution with an integrated orthotic and rehabilitation initiative called the Return To Run clinical pathway. This clinical pathway may serve as an alternative or adjunct to arthrodesis and arthroplasty for young patients with severe posttraumatic osteoarthritis of the ankle and subtalar joint., Journal of the American Academy of Orthopaedic Surgeons, August 2012 vol. 20 no. suppl S48-S53. The original document contains color images.

Iron deficiency anemia (IDA) is the most common cause of anemia in the United States, and it particularly affects women of child-bearing age and black, non-Hispanic race/ethnicity. During the surveillance period there were 10,157 incident (new) cases of IDA among active component service members the overall incidence rate was 7.1 per 10,000 person-years. The annual incidence rates increased in both males and females during the period. Rates of IDA were higher among service members who were female, in the youngest (20 years) and oldest age groups (40+ years), and of black, non-Hispanic race/ethnicity. Most (85.3%) incident cases had no additional encounters for IDA one year or more after their incident encounter. The most common diagnoses associated with IDA during the one year before or after the incidence dates of IDA were gastrointestinal hemorrhage (12.4%) in males and disorders of menstruation and other abnormal bleeding from the female genital tract (15.2%) in females. Because IDA can adversely affect physical work capacity and cognitive functioning, health care providers should be alert to IDA among service members, particularly servicewomen, before intensive training activities and deployment., Published in Medical Surveillance Monthly Report, v19 n7 p17-21, July 2012. See also ADA564022. The original document contains color images.

How leukemia stem cells gained resistance to radiation and chemotheraphy is poorly defined, yet critically determines how leukemia cells tolerate conventional leukemia therapy. Normal hematopoietic stem cells and leukemia initiating cells are known to share many functional properties. Therefore, they are supposed to utilize many common mechanistic pathways for their survival and migration. Using genetically engineered mice we demonstrated the functional roles of P2Y14 in preserving regenerative capacity by constraining senescence induction and molecular events governing it. Since P2Y14 is highly expressed in differentiation-resistant leukemia cells, P2Y14 expression in leukemia cells may also function in modulating the resistance to conventional cancer treatment. We believe these data define for the first time in mammals the identity and impact of a receptor modulating stem/progenitor tolerance of stress. By providing a mechanistic insight for the roles of P2Y14 in the stress-induced injury, our preliminary results are expected to provide the foundation for an effective treatment to destroy therapy resistant leukemia cells. In addition, we identified a nucleotide sugar, UDP-Glc, as a novel mobilizer of long-term repopulating HSPCs. This finding may also have important clinical implications in designing new mobilization strategies to improve the efficiency and outcome of autologous and allogeneic peripheral blood stem cell (PBSC) transplantation., The original document contains color images.

China's demographic transition will create great difficulty in continuing the scale of economic development seen over the last 30 years. This difficulty will be experienced through the costs of the demographic detour, which began during the Great Leap Forward and was then magnified through the birth limiting campaigns up to and including the One-Child Policy. While the skewing of the dependency ratio over the last 30 years resulted in significant contributions to China's economic development, this has reached a limit such that the unborn laborers will present a strain on development. This strain will be present in the form of a shrinking and rapidly aging labor pool, resulting in a decrease in innovation and productivity as well as an overhaul to thousands of years of tradition of doing business through familial ties. This will culminate in the testing of an already failing pension system as China experiences the transition from the demographic stage of a slowly growing population to post-transition. My thesis will approach the topic of the relationship between China's demographic story and its economic development as a qualitative analysis spanning from 1949 until 2000, broken into three temporal case studies. The case studies will be China during the Great Leap Forward, China immediately after the One-Child Policy was instituted, and China in 2000. My hypothesis is that China's demographic transition -- consisting of its population's age structure, labor percentages, dependency ratios, and fertility rates -- has positively affected its economic development so far, but some of the factors that contributed to China's success will present long-term costs in the next 30 to 50 years. When evaluated individually, each factor bears only a fraction of responsibility, but when taken all together and compounded over a span of 60 years, I expect to find that China will experience a limitation on its labor pool, and hence its economic growth, within this century.

CXCL12 is a small molecular weight protein secreted by fibroblasts in the prostate stroma consequent to aging and activates CXCR4, a G-protein coupled receptor expressed in prostate epithelial cells. Activation of the CXCL12/CXCR4 axis has been shown to promote prostate cancer cell proliferation, motility, and invasiveness; furthermore, previous reports have shown phosphorylation of EGFR and HER2 in response to CXCL12 treatment. Here I examined the dimerization of EGFR and HER2 in response to varying concentrations of CXCL12. Although some instances of heterodimerization were observed using co-IP, there was no consistency in responses to specific concentrations and observed dimerization with CXCL12 treatment was not as robust as with EGF treatment; thus, these data are inconclusive and I am unable to report novel significant findings., The original document contains color images.

心肺功能是其中一項體能特質，而對於進行較長時間的中至高劇烈程度運動十分重要，也會影響日常活動和健康。但是，還沒有研究香港華裔長者心肺功能水平及其與體能活動參與程度和健康的關條。, 招募對象是從現有的兩個追蹤研究來的[男女骨折研究(n=998 和884 )和頸動脈粥樣硬化研究( 191 名婦女)， 70 - 79 歲年長男士最大攝氧量的參考範圖為22.3-23.0 毫升/分鐘/公斤(95%信賴區間) , 80 歲以上為19.2-20.2 毫升/分鐘/公斤。80 歲以上女性的參考範園為17.0-18.3 毫升/公斤/分鐘， 70-79 歲為19.3-20.0毫升/公斤/分鐘， 60-69 歲為2 1. 7-23.0 毫升/公斤/分鐘和年齡55-59 歲為22 .1 -23.8毫升/公斤/分鐘。男性的心肺功能與腰圍有相關性。<.0001) ，而女性的相關性還要加上體重(p<.02) ，與年齡有關的最大攝氧量衰退在男性為0.368 毫升/公斤/分鐘/年，而女性為0 .238 毫升/公斤/分鐘/年。, 70 - 79 歲年長男士6 分鐘步行距離的參考範圍為453.3-466 公尺， 80 歲以上為382.6-403.3 公尺。80 歲以上女性的參考範圍為333.9-357.2公尺和年齡70-79 歲為396.1-406.8 公尺。6 分鐘步行距離與腰圍、身高和學歷有相關性(p:S:.05) ，與年齡有關的6 分鐘步行距離衰退在男性為9.06 公尺/年，而女性為7.35 公尺/年。從長者活動評估量表得出的體能活動參與程度被認為是與最大攝氧量成正相關(男性:r=.241，'女性:r=.214 )和6 分鐘步行距離(男性: r=.257，女性:r=.1 84) 。長者日常步行時間越長最大攝氧量和6 分鐘步行距離較佳(p≤01) ，進行劇烈運動的女性有正常最大攝氧量的機會較高(p=.041) 。男性能符合美國運動醫學學院或香港衛生署指引的明顯比不能達到指引的有較好的心肺功能。能達到指引的男性有1. 68 倍的概率有正常的心肺功能。回溯性研究追查過去的PASE 分數與現在最大攝氧量的相關性，反應出過去的體能活動參與程度對現在的心肺功能影響隨時間減少(男性由目前回到7 年前: r=0.241、0.168、0.120; 女性: r= .214、0.106、0.069 )。, 患有高血壓男性的最大攝氧量和6 分鐘步行距離較差(p=.014) ，曾患有心肌硬塞或心絞痛男性和糖尿病女性的6 分鐘步行距離較差(p<.04) 。最大攝氧量分別與由社區認知篩選工具評估的男性認知水平（r=.107)和男女長者憂鬱量表分數男性:r=-.112 ，女性: r=-.123) 有相關性。另一方面， 6 分鐘步行距離被發現分別與簡易智能狀態測驗p<.02) 、男性的社區認知篩選工具(p=.046)的認知級別和男女長者憂鬱量表的抑鬱狀態p<.04)有差別。, 最大攝氧量和6分鐘步行距離的年齡調整相關性連中高程度(男性:R=.459、女性: R=.425) 。除了與最大攝氧量有滿意的相關性，6分鐘步行距離與精神健康有比較密切的相關性。6分鐘步行距離可作為香港華裔長者最大攝氧量的體能代表值。, Cardiorespiratory fitness (CRF) is one of the main attributes which is important toper form moderate-to-high intensity exercise for prolonged periods which affects daily activities as well as health. However, there are no studies among HK Chinese Elders' CRF and the relationship between this important parameter of physical fitness, PA participation and health outcomes., By recruiting subjects from two existing cohort studies, the Osteoporetic Fractures in Men & Women Study (n=998 & 884 respectively) and the Carotid Atherosclerosis Study (191 women), the reference ranges of VO₂ peak for men were 22.3-23.0ml/min/kg (95% C.I.) at age 70-79y, and 19.2-20.2 ml/min/kg at age ≥80y. Forwomen, the reference range at age ≥80y was 17.0-18.3 ml/kg/min, 70-79y was19.3-20.0 ml/kg/min, 60-69y was 21.7-23.0 ml/kg/min and for age 55-59y was22.1-23.8 ml/kg/min. Men's VO₂ peak was associated with waist circumference(WC, p<.000l) while women's VO₂ peak additionally associated with weight (p<.02).There was an age-related decline in VO₂ peak at 0.368 ml/kg/minly in men and 0.238ml/kg/minly in women., The reference ranges of 6MWD for men were 453.3-466.6m (95% C.I.) at age 70-79y, and 382.6-403.3m at age ≥80y. For women, the reference range at age 80≥y was 333.9-357.2m and for age 70-79y was 396.1-406.8 ml/kg/min. 6MWD was associated with WC, height and education (p≤.05). There was an age-related decline in 6MWD at 9.06m/y in men and 7.35m/y in women., Elders' participation in PA assessed by the Physical Activity Scale for Elderly (PASE), was positively correlated with VO₂ peak (r=.241 in men, r=.214 in women) and 6MWD (r=.257 in men, r=.184 in women). Elderly walked more everyday have better VO₂peak and longer 6MWD (p≤ .0l). Women did more strenuous sport had higher chance of having normal CRF (p=.041). Men who met the guidelines by American College of Sports Medicine (ACSM) & Department of Health (DH), HK had better VO₂ peak than those who failed to meet that guidelines (p<.005). By following the PA guidelines, men had a 1.68-fold probability having normal CRF. A novel approach to retrospectively explore the correlation between the past PASE score and the present VO₂ peak revealed that the effect of past PA participation diminished with time (correlations for men from present, 4y and 7y ago: r=.241, .168, .120; for women r=.214, .106, .069)., Men with hypertension had significantly lower V02 peak and shorter 6MWD (p<.03). Men with history of myocardial infarction and angina also walked shorter in 6MWT while women only with diabetes had shorter 6MWD (p<.04). CRF was found to be correlated with cognitive level in men estimated by CSI-D (p<.0001) and GDS-15 score in both genders (r=-.112 in men, r=-.123 in women). On the other hand, 6MWD was found to be different across cognitive status estimated by MMSE (p<.02) & CSI-D (p=.046 in men only), and depression status estimated by GDS-15 (p<.04) in both genders., Age-adjusted correlation between VO₂ peak & 6MWD was moderately high (R=.459 in men; R=.425 in women). In addition to the satisfactory correlation with VO₂ peak, stronger associations were found 6MWD, cognitive and mental health. It was suggested 6MWD might be a feasible surrogate for VO₂ peak as a physical fitness measure among HK Chinese elderly., Detailed summary in vernacular field only., Yau, Chung Fai Forrest., "December 2011.", Thesis (Ph.D.)--Chinese University of Hong Kong, 2012., Includes bibliographical references (leaves 215-237)., Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web., also in Chinese; appendix in Chinese., (IN ENGLISH) --- p.I, (IN CHINESE) --- p.IV, ACKNOWLEDGEMENT --- p.VI, LIST OF CONTENTS --- p.VII, LIST OF TABLES --- p.XII, SELECTED ABBREVIATIONS --- p.XV, Chapter 1 --- BACKGROUND & OBJECTIVES --- p.1, Chapter 1.1 --- INTRODUCTION --- p.1, Chapter 1.2 --- OBJECTIVES OF THE STUDY --- p.3, Chapter 1.3 --- OUTLINES OF THE THESIS --- p.4, Chapter 2 --- LITERATURE REVIEW --- p.6, Chapter 2.1 --- ELDERLY POPULATIONS --- p.6, Chapter 2.1.1 --- Health --- p.6, Chapter 2.1.1.1 --- Hypertension, Coronary Heart Disease & Stoke --- p.8, Chapter 2.1.1.2 --- Diabetes --- p.10, Chapter 2.1.1.3 --- Chronic Obstructive Pulmonary Disease --- p.11, Chapter 2.1.1.4 --- Cognitive Function --- p.12, Chapter 2.1.1.5 --- Depression --- p.13, Chapter 2.2 --- THE RELATIONSHIP BETWEEN PA & HEALTH --- p.15, Chapter 2.2.1 --- Participation in PA --- p.22, Chapter 2.2.1.1 --- PA Recommendation --- p.24, Chapter 2.2.2 --- Indirect Estimation ofPA Participation --- p.25, Chapter 2.2.2.1 --- Physical Activity Scale for Elderly. --- p.26, Chapter 2.3. --- PHYSICAL FITNESS & HEALTH. --- p.28, Chapter 2.3.1 --- Definition of Physical Fitness. --- p.28, Chapter 2.3.1.1 --- Cardiorespiratory Fitness --- p.30, Chapter 2.3.2 --- Direct Assessment of Physical Fitness --- p.33, Chapter 2.3.2.1 --- Cardiopulmonary Exercise Test --- p.33, Chapter 2.3.2.1.1 --- Affordable Device for CPET --- p.35, Chapter 2.3.2.2 --- Six Minutes Walk Test --- p.36, Chapter 3 --- MATERIALS & METHODS --- p.39, Chapter 3.1 --- SUBJECTS --- p.39, Chapter 3.1.1 --- Subjects Source --- p.39, Chapter 3.1.1.1 --- The Osteoporetic Fractures in Men & Women Study --- p.39, Chapter 3.1.1.2 --- Carotid Atherosclerosis Study --- p.40, Chapter 3.1.2 --- Follow up Situation --- p.40, Chapter 3.1.3 --- Ethical Consideration --- p.41, Chapter 3.2 --- INSTRUMENTATION --- p.41, Chapter 3.2.1 --- Questionnaire --- p.41, Chapter 3.2.1.1 --- Medical History --- p.41, Chapter 3.2.1.2 --- Smoking Habit --- p.41, Chapter 3.2.1.3 --- Cognitive & Mental Health --- p.42, Chapter 3.2.1.3.1 --- Cantonese Mini Mental State Examination & Community Screening Instrument for Dementia --- p.42, Chapter 3.2.1.3.2 --- Geriatric Depression Scale-15 --- p.42, Chapter 3.2.1.4 --- Physical Activity Scale for Elderly --- p.43, Chapter 3.2.1.5 --- Veteran Specific Activity Questionnaire --- p.44, Chapter 3.2.2 --- Physical Measurements --- p.45, Chapter 3.2.2.1 --- Height, Weight & Fat Percentage --- p.45, Chapter 3.2.2.2 --- Waist, Hip Circumferences & WHR --- p.45, Chapter 3.2.2.3 --- Blood Pressure --- p.45, Chapter 3.2.2.4 --- Electrocardiograph --- p.46, Chapter 3.2.3. --- Fitness Tests --- p.46, Chapter 3.2.3.1 --- Cardiopuhuonary Exercise Test --- p.46, Chapter 3.2.3.1.1 --- Exclusion Criteria --- p.46, Chapter 3.2.3.1.2 --- PreTest Consideration --- p.47, Chapter 3.2.3.1.3 --- Test Sequence & Measures --- p.48, Chapter 3.2.3.1.4 --- Test Tennination Criteria --- p.49, Chapter 3.2.3.2 --- Six Minutes Walk Test --- p.50, Chapter 3.2.3.2.1 --- Six Minute Walk Test Sequence --- p.50, Chapter 3.3 --- STATISTICS --- p.52, Chapter 3.3.1 --- Description of Variables --- p.52, Chapter 3.3.2 --- General Statistical Method --- p.53, Chapter 3.3.3 --- Comparison between VO₂ peak & 6MWD Relationship with other Variables --- p.54, Chapter 4 --- RESULTS --- p.56, Chapter 4.1 --- RESPONSE & PARTICIPATION OF SUBJECTS --- p.56, Chapter 4.2 --- DEMOGRAPHIC PROPERTIES --- p.63, Chapter 4.2.1 --- Men --- p.63, Chapter 4.2.2 --- Women --- p.68, Chapter 4.2.3 --- Sample Representativeness --- p.71, Chapter 4.2.4 --- Physical Measurements --- p.75, Chapter 4.2.4.1 --- Peak Oxygen Uptake --- p.75, Chapter 4.2.4.2 --- Correlations with Demographic Properties --- p.82, Chapter 4.2.4.2.1 --- Mean VO₂ peak in Different WC Status --- p.83, Chapter 4.2.4.2.2 --- Reference Range across Age Groups 98 --- p.84, Chapter 4.2.4.2.3 --- Mllltivariat Analysis of VO₂ peak --- p.86, Chapter 4.2.4.3 --- Six Minutes Walk Test --- p.88, Chapter 4.2.4.3.1 --- UnivariateAnalysis with Demographic Properties --- p.90, Chapter 4.2.4.3.2 --- Mean 6MWD by WC Status --- p.92, Chapter 4.2.4.3.3 --- Reference Range by Age Groups --- p.92, Chapter 4.2.4.3.4 --- Multivariate analysis of 6MWD --- p.94, Chapter 4.2.5 --- Physical Activity Scale for Elderly --- p.96, Chapter 4.2.5.1 --- Univariate Analysis with Demographic Properties --- p.97, Chapter 4.2.5.2 --- Reference Range across Age Groups --- p.98, Chapter 4.2.5.3 --- Reference Range of PASE --- p.99, Chapter 4.2.5.4 --- Multivariate Analysis of PASE --- p.100, Chapter 4.2.6 --- Cognitive & Mental Scores --- p.101, Chapter 4.2.6.1 --- Community Screening Instrument for Dementia --- p.101, Chapter 4.2.6.2 --- Mini-Mental State Examination --- p.102, Chapter 4.2.6.3 --- Geriatric Depression Scale-15 --- p.103, Chapter 4.3 --- CORRELATIONS OF CRF TESTS --- p.104, Chapter 4.3.1.1 --- Relationship between 6MWD & VO₂ peak --- p.104, Chapter 4.3.1.1.1 --- Pearson Correlation between 6MWD & VO₂ peak --- p.104, Chapter 4.4 --- CRF & LIFESTYLES --- p.106, Chapter 4.4.1 --- How PA correlates with CRF --- p.107, Chapter 4.4.1.1 --- Relationship between PASE& VO₂ Peak --- p.107, Chapter 4.4.1.1.1 --- Pearson Correlation between PASE & V02 peak. --- p.107, Chapter 4.4.1.1.2 --- Mean VO₂ peak by Quartiles of PASE --- p.109, Chapter 4.4.1.1.3 --- Mean PASE scores by VO₂ peak status --- p.110, Chapter 4.4.1.1.4 --- Relationship between PASE leisure activities & VO₂ peak --- p.111, Chapter 4.4.1.1.5 --- Time spent daily on PASE leisure activities by VO₂ peak status --- p.113, Chapter 4.4.1.2 --- Relationship between PASE & 6MWD --- p.116, Chapter 4.4.1.2.1 --- Mean 6MWD by Quartiles of PASE --- p.118, Chapter 4.4.2 --- Relationship between CRF & Recommended PA Guidelines --- p.119, Chapter 4.4.2.1 --- ACSM Guidelines --- p.119, Chapter 4.4.2.2 --- HKDH Guidelines --- p.121, Chapter 4.4.3 --- Does PASE in the Past Predict Present Maximal Oxygen Uptake --- p.122, Chapter 4.4.3.1 --- Pearson Correlation between PASE at 3y before & Present VO₂ peak --- p.122, Chapter 4.4.3.2 --- Pearson Correlation between PASE at 7y before & Present VO₂ peak --- p.124, Chapter 4.5 --- CRF & HEALTH --- p.126, Chapter 4.5.1 --- CRF & Physical Health --- p.126, Chapter 4.5.1.1 --- Relationship between VO₂ peak & Medical History --- p.126, Chapter 4.5.1.2 --- Relationship between 6MWD and medical history --- p.129, Chapter 4.5.1.2.1 --- Mean 6MWD of men by chronic diseases --- p.130, Chapter 4.5.1.2.2 --- Mean 6MWD of women by diabetes --- p.134, Chapter 4.5.1.3 --- Comparison between VO₂ peak & 6MWD relationship with medical history --- p.135, Chapter 4.5.2 --- CRF & Cognitive Function --- p.137, Chapter 4.5.2.1 --- Relationship between MMSE& VO₂ Peak --- p.137, Chapter 4.5.2.1.1 --- Pearson Correlation betweenMMSE & VO₂ peak --- p.137, Chapter 4.5.2.1.2 --- Mean VO₂ peak by MMSE Status --- p.139, Chapter 4.5.2.2 --- Relationship between MMSE & 6MWD --- p.141, Chapter 4.5.2.2.1. --- Pearson Correlation between MMSE & 6MWD --- p.141, Chapter 4.5.2.2.2 --- Mean 6MWD by MMSE category --- p.143, Chapter 4.5.2.3 --- Relationship between CSID & VO₂ peak --- p.144, Chapter 4.5.2.3.1 --- Pearson Correlation between CSID & VO₂ peak --- p.144, Chapter 4.5.2.3.2 --- Mean VO₂ peak by CSID Classification --- p.146, Chapter 4.5.2.4 --- Relationship between CSID & 6MWD --- p.147, Chapter 4.5.2.4.1 --- Pearson Correlation between CSID & 6MWD --- p.147, Chapter 4.5.2.4.2 --- Mean 6MWD by CSID Classification --- p.149, Chapter 4.5.2.5 --- Comparison between VO₂ peak & 6MWD relationship with Cognitive Function --- p.150, Chapter 4.5.2.5.1 --- Pearson Correlation between MMSE & 6MWD --- p.151, Chapter 4.5.2.5.2 --- Mean 6MWD by MMSE category --- p.151, Chapter 4.5.2.5.3 --- Pearson Correlation between CSID & 6MWD --- p.152, Chapter 4.5.2.5.4 --- Mean 6MWD by CSID Classification --- p.153, Chapter 4.5.3 --- CRF & Depression --- p.154, Chapter 4.5.3.1 --- Relationship between GDS & VO₂ peak --- p.154, Chapter 4.5.3.1.1 --- Speannan Correlation between GDS & VO₂ peak --- p.154, Chapter 4.5.3.1.2 --- Logistic Regression Analysis --- p.154, Chapter 4.5.3.2. --- Relationship between GDS & 6MWD --- p.156, Chapter 4.5.3.2.1. --- Spearman Correlation between GDS & 6MWD --- p.156, Chapter 4.5.3.2.2. --- Mean 6MWD by depression status. --- p.156, Chapter 4.5.3.3. --- Comparison between VO₂ peak & 6MWD relationship with GDS --- p.158, Chapter 4.5.3.3.1. --- Pears on Correlation between GDS & 6MWD --- p.158, Chapter 4.5.3.3.2. --- Mean 6MWD by depression status --- p.158, Chapter 5 --- DISCUSSION --- p.160, Chapter 5.1 --- INTERPRETATION OF RESULTS --- p.160, Chapter 5.1.1 --- Physical Fitness --- p.160, Chapter 5.1.1.1 --- Cardiorespiratory Fitness --- p.160, Chapter 5.1.1.1.1 --- Mode for CPET --- p.160, Chapter 5.1.1.1.2 --- Criteria for VO₂ peak --- p.161, Chapter 5.1.1.1.3 --- Reference Range of VO₂ peak among HK elderly --- p.164, Chapter 5.1.1.1.4 --- Age Related Decline in VO₂ peak --- p.169, Chapter 5.1.1.1.5 --- Repeatability of Measurements using FitMate[superscript TM] Pro --- p.170, Chapter 5.1.1.1.6 --- Smoking --- p.170, Chapter 5.1.1.2 --- Six Minutes Walk Test --- p.171, Chapter 5.1.1.2.1 --- Reference Range of 6MWD among HK Elderly --- p.172, Chapter 5.1.2 --- How Estimated PA Level Correlated to CRF --- p.173, Chapter 5.1.2.1 --- CRF &PA --- p.174, Chapter 5.1.2.2 --- CRF & Leisure Activities --- p.176, Chapter 5.1.3 --- Elderly CRF of those who met Recommended PA Guidelines --- p.177, Chapter 5.1.4 --- Could Past PA Participation Predict Present CRF --- p.180, Chapter 5.1.5 --- Health --- p.181, Chapter 5.1.5.1 --- Physical Health --- p.181, Chapter 5.1.5.2 --- Dementia --- p.185, Chapter 5.1.5.2.1 --- Community Screening Instrument for Dementia --- p.186, Chapter 5.1.5.2.2 --- Mini-Mental State Examination --- p.188, Chapter 5.1.5.2.3 --- Possible Mechanisms of Cognitive Decline & Benefits ofPA --- p.191, Chapter 5.1.5.3. --- Depression --- p.193, Chapter 5.1.5.3.1 --- Possible Mechanism of Depression & Benefits of PA --- p.197, Chapter 5.1.6 --- 6MWD, a Better Physical Fitness Surrogate than VO₂ peak --- p.200, Chapter 5.2 --- LIMITATIONS AND STRENGTH --- p.205, Chapter 5.3 --- FUTURE STUDIES --- p.210, Chapter 6 --- CONCLUSION --- p.211, Chapter 7 --- REFERENCES --- p.215, APPENDIX --- p.238, http://library.cuhk.edu.hk/record=b5549426, Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/)

The synchrony effect refers to the beneficial impact of temporal matching between the timing of cognitive task administration and preferred time-of-day for diurnal activity. Aging is often associated with an advance in sleep-wake timing and concomitant optimal performance levels in the morning. In contrast, young adults often perform better in the evening hours. So far, the synchrony effect has been tested at fixed clock times, neglecting the individual's sleep-wake schedule and thus introducing confounds, such as differences in accumulated sleep pressure or circadian phase, which may exacerbate synchrony effects. To probe this hypothesis, the authors tested older morning and young evening chronotypes with a psychomotor vigilance and a Stroop paradigm once at fixed morning and evening hours and once adapting testing time to their preferred sleep-wake schedule in a within-subject design. The authors observe a persistence of synchrony effects for overall median reaction times during a psychomotor vigilance task, even when testing time is adapted to the specific individual's sleep-wake schedule. However, data analysis also indicates that time-of-day modulations are weakened under those conditions for incongruent trials on Stroop performance and the slowest reaction times on the psychomotor vigilance task. The latter result suggests that the classically observed synchrony effect may be partially mediated by a series of parameters, such as differences in socio-professional timing constraints, the amount of accumulated sleep need, or circadian phase, all leading to differential arousal levels at testing., Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

This study investigated the modulation of Ia afferent input in young and elderly adults during quiet upright stance in normal and modified visual and proprioceptive conditions. The surface EMG of leg muscles, recruitment curve of the soleus (SOL) Hoffmann (H) reflex and presynaptic inhibition of Ia afferents from SOL, assessed with the D1 inhibition and single motor unit methods, were recorded when young and elderly adults stood with eyes open or closed on two surfaces (rigid vs. foam) placed over a force platform. The results showed that elderly adults had a longer path length for the centre of pressure and larger antero-posterior body sway across balance conditions (P < 0.05). Muscle EMG activities were greater in elderly compared with young adults (P < 0.05), whereas the H(max) expressed as a percentage of the H(max) was lower (P = 0.048) in elderly (38 ± 16%) than young adults (58 ± 16%). The conditioned H reflex/test H reflex ratio (D1 inhibition method) increased with eye closure and when standing on foam (P < 0.05), with greater increases for elderly adults (P = 0.019). These changes were accompanied by a reduced peak motor unit discharge probability when standing on rigid and foam surfaces (P 0.001), with a greater effect for elderly adults (P = 0.026). Based on these latter results, the increased conditioned H reflex/test H reflex ratio in similar sensory conditions is likely to reflect occlusion at the level of presynaptic inhibitory interneurones. Together, these findings indicate that elderly adults exhibit greater modulation of Ia presynaptic inhibition than young adults with variation in the sensory conditions during upright standing., Journal Article, Research Support, Non-U.S. Gov't, FLWIN, SCOPUS: ar.j, info:eu-repo/semantics/published

We hypothesized that occupational exposure to polychlorinated biphenyls (PCBs) reduces dopamine (DA) terminal densities in the basal ganglia. We found, using beta-CIT imaging, a significant negative relationship between current serum PCB concentrations and the density of beta-CIT binding only in women. We also determined that bone lead, measured using XRF fluorescent techniques, is associated with greater decrements in memory, executive function and motor function in women compared to similarly aged men with similar bone lead levels. These latter findings are the first to demonstrate a sexual dimorphism in these behaviors associated with low to moderate bone lead concentrations. We are writing a manuscript describing changes in these behaviors with bone lead and have previously published two manuscripts describing: (i) the effects of PCB exposure on beta-CIT and (ii) the half lives of PCB congeners over a 28 year interval., The original document contains color images.

The goals of this synergistic project are to establish the mitochondria localized sirtuin protein SIRT3 as a tumor suppresso breast cancer and to define its role as a molecular link between aging and breast cancer. Sirt3 knockout mice develop ER/P positive breast tumors later in life. These ER/PR-positive tumors are histologically similar to breast tumors common in old women. In humans, loss of SIRT3 is seen in a significant fraction of breast cancers and may serve as a molecular biomark Molecular targets of SIRT3 deacetylation have been identified, including MnSOD and OSCP. Antibodies that recognize specific acetylated lysine residues targeted by SIRT3 in these molecules have been identified and validated and are being developed as potential novel biomarkers in breast cancer. These studies have enhanced our understanding of the molecula links between aging and breast cancer and provide novel potential biomarkers of breast cancer in humans., The original document contains color images.

Thermal stress can have a significant impact on normal physiological functioning if precipitous increases in core temperature are not adequately controlled with behavioral and autonomic mechanisms of body cooling. The United States experiences approximately 200 heat stroke deaths per year with the incidence of heat illness expected to rise as the average life span increases, the rate of obesity is accelerated, and global warming is realized. Heat illness affects all segments of society, although the etiological factors predisposing to heat stroke differ between young adults and the elderly population. The majority of heat illnesses are preventable with improved understanding of the basic thermoregulatory mechanisms of the body's response to heat stress and the development of novel intervention/treatment strategies to mitigate the adverse consequences of this syndrome.

Europe is experiencing a steady population decline, which is sharpened by the aging of its population. Nothing is more determinant for Europe's future than the question of whether the Old Continent will be able to solve this acute demographic problem, and if so, how. This project will examine this issue through the lens of critical thinking, explain the main problems related to the issue, and propose policy options. In the near- to mid-term, the most promising solution to Europe's population decline is immigration. This should be supported by a concerted effort to make the European Union a more attractive destination for immigrants through a fair and proactive integration policy. The migration context in Europe has changed significantly over the last few decades and many Member States have converted from countries of emigration to countries of immigration. Immigration alone will not resolve Europe's demographic and economic problems, but it may help mitigate the phenomenon. If European citizens perceive immigration as an opportunity to be seized, rather than a burden to be shouldered and a threat to their security and culture, Europe will have a greater chance of maintaining its economic power and its relative geopolitical status., Strategy Research Project.

The goal of this proposal was to examine the induction of senescence by common effective treatments for prostate cancer, and to further identify and target senescence-associated factors which might mediate resistance to these therapies in the neoplastic epithelium. Senescence cell biomarkers (p16 and DcR2) were correlated with aging and prostate cancer. The senescence-associated factors GDF15 and STC1 were found to correlate with neoplasia, but not aging. Stressful environmental conditions leading to altered secretion of STC1 were defined, but multiple studies seeking to define the function of STC1 in the prostate were uniformly negative. A clinical trial testing the effects of neoadjuvant anti-IGF-1R (IMC-A12) treatment in combination with androgen deprivation was completed and a panel of serum biomarkers were evaluated. We find biomarker evidence for good on-target efficacy and an intriguing correlation of PSA response with A12-induced insulin resistance that is not fully accounted for by pre-treatment factors such as body mass index., The original document contains color images.

In the first year of the grant we addressed tasks 1, 2 and 3. Specifically we demonstrated that Hsf1 controls development of Her2-positive cancer both at the stage of initiation, where is affects the oncogene-induced senescence, and later at the stage of progression, where it affects tumor angiogenesis. We also dissected the mechanism of effects of Hsf1 on tumor angiogenesis, and demonstrated that Hsf1 regulates expression of the major angiogenesis factor HIF-1., The original document contains color images.

Little information exists on the health-related quality of life (HRQL) of U.S. veterans based on rural (versus urban) status, especially those in younger age groups, and whether deployment influences this outcome. We addressed these questions in the Millennium Cohort Study, a prospective investigation of U.S. military personnel assessed first in 2001 and then subsequently every three years via self-administered questionnaires. Participants separated from the military at the time of the most recent survey were eligible (n = 10,738). HRQL was assessed using the SF-36V Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. Rural status was assigned from zip codes using the Rural-Urban Commuting Area classification. The mean age of participants was 35 years (SD = 8.98). Compared with urban dwellers, rural residents reported significantly lower unadjusted mean PCS (49.80 vs. 50.42) and MCS (49.97 vs. 50.81) scores, but differences became nonsignificant after covariate adjustment. No interaction was seen between deployment and rural status. Rural status is not independently associated with HRQL among recent U.S. veterans., Pub. in Journal of Rural Social Sciences, v26 n3 p32-56, 2011. Government or Federal Purpose Rights License. Supported in part by VA.

Ovarian cancer ranks first as the cause of death for gynecological cancers. Obviously, there is an urgent need to develop novel treatment methods for ovarian cancer. To do this, we must better understand key events associated with ovarian cancer development. In order to combat cancer, a normal cell's typical response to a tumor-promoting genetic alteration is irreversible growth arrest, consequently preventing the normal human cell from progressing towards becoming a cancer cell. This process is termed senescence. When this process fails, those cells containing tumor-promoting genetic alterations can grow without control and become a tumor. The potential use of cellular senescence for cancer therapy would rely on reactivation of this process in cancer cells. We have previously discovered a pathway that opposes the beneficial process of senescence. This pathway is referred to as the canonical Wnt signaling pathway. Therefore, we hypothesize that canonical Wnt signaling pathway contributes to the development of ovarian cancer through bypassing senescence. The proposed studies may lead to development of strategies for ovarian cancer treatment using reactivation of cellular senescence as a novel mechanism by targeting ovarian cancer promoting canonical Wnt signaling.

The love of flying seldom diminishes throughout a pilot's career. It is often the primary motivation for investing the time and expense necessary to attain and maintain a valid pilot license and medical certificate. However, a pilot's ability to meet the physical requirements for aeromedical certification may become compromised by advancing age or impairments. Individuals with physical limitations or the elderly in a number of states must pass a vision test to renew their driver's license. These individuals may resort to extraordinary measures to avoid losing the privilege of operating a motor vehicle and maintain a sense of independence. Similarly, pilots with physical limitations may attempt to circumvent the Federal Aviation Administration's aeromedical certification process to retain a valid medical certificate. In an investigation of a fatal accident, the National Transportation Safety Board (NTSB) concluded that the aviation medical examiner who issued an airman medical certificate to a visually impaired pilot failed to perform the appropriate procedures to verify the validity of medical information provided by the pilot. The airman subsequently crashed his aircraft, resulting in his death and the deaths of five others onboard. The NTSB report stated that the pilot's failure to maintain airplane control for an undetermined reason resulted in an inadvertent stall. The report also stated that either the pilot's macular degeneration or his unrecognized coronary artery disease could have contributed to his failure to maintain control of the airplane. The report discusses this case study in depth, including the details of the accident, the pilot's medical history, clinical signs and symptoms of macular degeneration, FAA vision standards for the Airman Medical Certificate by class of certificate, macular degeneration clinical sequelae and treatment, and clinical considerations of this accident.

A small subpopulation of drug- and radiation-resistant leukemia is an immediate concern for leukemia patients as this subtype remains the actual cause of morbidity and mortality. Our preliminary results showed that P2Y14 functions in bone marrow to preserve stem progenitor cells from premature senescence/cell death induced by genotoxic stress. As P2Y14 is highly expressed in differentiation resistant leukemia cells, P2Y14 expression in leukemia cells may function in preserving regenerative capacity by constraining cell death/senescence induction. We also found that P2Y14 axis is associated with stem cell mobilization. By providing a mechanistic insight for the roles of P2Y14 in the genotoxic stress-induced injury, directly documenting the effects of P2Y14/UDP-Glc axis on stem cell mobilization, our preliminary results are expected to provide the foundation for an effective treatment to destroy therapy resistant leukemia cells., The original document contains color images.

Our application seeks to develop myostatin inhibitors as novel therapeutic agents for improving muscle and bone strength, and preventing falls and fractures for aging veterans. Our goals for year 1 of the project were to determine how the expression of myostatin, its receptor, and the myostatin antagonist follistatin change with age in musculoskeletal tissues from aged mice and bone marrow samples obtained from young (18-30) and older (50-70) patients in the orthopaedic clinic. Our findings so far demonstrate that, in skeletal muscles from mice, myostatin expression does not change with age but expression of the myostatin antagonist follistatin decreases significantly with age. Data from bone marrow samples show that while myostatin shows a moderate increase with age, and follistatin levels show no change, levels of activin A increase significantly with age. Activin binds the same receptor as myostatin, and inhibits bone mineralization. These data suggest that a decoy receptor that binds both myostatin and activin A may prevent loss of muscle and bone mass with age., The original document contains color images.

Hormesis describes a phenomenon where low doses of toxic substances or radiation stimulate responses that might counteract the harmful effects of a subsequent high level of stress. We hypothesized that low doses of radiation received through mammography could be beneficial for patients. We therefore treated human breast epithelial cells with X-rays at low doses, high doses, or at low doses followed by high doses. We then scored cells for the effects of these various doses on the number of DNA damage 53BP1 foci and on the ability to trigger cell senescence. Based on the results we have obtained so far, there was no significant change in the amount of DNA damage foci generated nor in the induction of senescence when cells were pre-treated with low doses of ionizing radiation and subsequently challenged by a high dose of ionizing radiation. Moreover, there was no effect on chromatin modifications in mammary epithelial cells, whereas low doses of radiation appeared to have some effects in human fibroblasts. In conclusion, our data suggest that low doses of radiation are not protective, nor detrimental, in mammary epithelial cells, whereas in other cell types, such as fibroblasts, these low doses of radiation appear to be protective., The original document contains color images.

The investigator has shown that moderate telomere shortening occurs specifically in luminal epithelial cells, but not in myoepithelial cells, in the majority of histologically normal terminal ductal lobular units analyzed from patients undergoing reduction mammoplasty and in women at time of autopsy. However, the extent and degree of telomere shortening varies by the individual. These data imply that there is a reservoir of genetically altered, yet histologically normal, cells within normal breast tissues that may represent fertile ground for tumor development. Since telomere shortening has been associated with cellular senescence and dysfunctional telomeres have been linked to the DNA damage response pathway in cancerous tissues, ongoing experiments are designed to assess the senescence-associated markers and DNA damage response pathway markers in histologically normal human breast tissues that display either normal or short telomeres (i.e. prior to tumor formation). In addition, the proposed investigation has provided grounding in both basic and translational breast cancer research for the trainee. The interactive, multidisciplinary research environment has provided the investigator opportunities to interact with pathologists and oncologists, thus fostering future success as an independent breast cancer researcher. To date, all tasks, as outlined in the Statement of Work, are on schedule., The original document contains color images.

Bone is the most common metastatic site for prostate cancer. The growth of the tumor cells in the bone is generally slow and they often become dormant until an appropriate microenviroment is established for their re-growth. The recent stem cell theory predicts that the metastatic cells are a small population of stem-like cells in the primary tumor. However, the precise mechanism of dormancy is virtually unknown, and identifying the responsible factors and understanding their underlining mechanism are crucial for developing a novel therapeutic approach. Our preliminary data indicate that (i) bone morphogenetic protein 7 (BMP7) which is secreted from bone marrow stromal cells is able to induce senescence to prostate tumor cell and (ii) this induction is mediated by activation of the tumor metastasis suppressor gene, N-myc downstream regulated gene 1 (NDRG1). These results strongly suggest that the BMP7-NDRG1axis plays a critical role in dormancy of prostate tumor cells in the bone. The overall goal of this proposal is to elucidate the mechanism of BMP7-induced dormancy in tumor stem cells and explore a possibility of using BMP7 as an anti-metastatic drug for prostate cancer., The original document contains color images.

Choroid plexus carcinoma (CPC) is a rare malignant brain tumor originating from the epithelial cells lining the cerebral ventricles. CPC represents less than 0.6% of brain tumors in all age groups, yet is more frequent in children (2-4%), especially in infants under the age of 1, accounting for over 20% of brain tumors in this age group (1). The molecular events that drive the malignant progression of this tumor are not well understood, yet this knowledge is crucial to improve patient survival. Surgical resection combined with neo-adjuvant and/or adjuvant therapy remain the primary methods of treatment for CPC; however tumor progression and relapse is observed in 70% of cases (2). Despite improvements on the most current treatment protocols, long-term survival of CPC patients remains under 30% and survivors display significant neurocognitive and/or sensory deficits. (2,3). Identifying altered genes that drive the progression of CPC will refine current diagnostic and prognostic classifications of CPC patients, and promote the implementation of targeted therapies to improve patient survival and reduce long-term side effects. The proposed research aims to identify genetic lesions involved in CPC tumorigenesis in order to implement their use as unique markers for diagnostic and prognostic classification of choroid plexus tumor patients, as well as to promote the creation of personalized molecular targeted therapies. I hypothesize that recurrent genetic lesions accompanied by a significant change in gene expression in CPC, will be drivers of tumorigenesis in this malignant brain tumor. Consequently, this research project will seek to answer the following question: What genes may be used as molecular markers for diagnostic and prognostic classification of CPC, and for which tumor-promoting alterations could CPC therapies be created?, The original document contains color images.

There is abundant evidence to suggest that epigenetic DNA methylation changes may appear early during prostate cancer (PCa) development than genetic changes, and are more common and consistent. The purpose of this study is to investigate whether aberrant DNA methylation occurs as a function of age and if it accompanies neoplastic transformation of the human prostate. RESULTS: Using methylated CpG island amplification coupled with promoter microarray and also genome-wide DNA methylation analysis, I have identified several novel genes that are differentially methylated in normal and PCa tissues. In addition, I have also identified novel methylated patterns among preinvasive and cancerous lesions of the prostate. Quantitative methylation analysis revealed significant differences (p 0.05) in methylation level for several genes in African-American (AA) samples versus Caucasian (Cau) samples. Furthermore, regression analysis revealed significantly higher methylation for NKX2-5 (p = 0.008) and TIMP3 (p = 0.039) genes in normal prostate tissue samples from AA versus Cau, and a statistically significant association of methylation with age for NKX2-5 (p = 0.03) in AA versus Cau. In addition, functional studies demonstrate that NKX2-5 may have tumor suppressor function in PCa cells. CONCLUSION: I have identified several novel methylated genes as potential (ethnic sensitive) biomarkers for early disease detection and for distinguishing indolent from aggressive PCa., The original document contains color images.

In this randomized controlled study, we evaluated the effect of assessment and intervention for age-specific barriers, on the glycemic control and other clinical, functional and psychosocial parameters in 100 subjects over the age of 69 years with poorly controlled diabetes. The intervention group had an assessment of age-specific barriers followed by designing strategies to improve their ability to follow diabetes management plans as prescribed by their providers. The interventions were implemented by a care manager in half subjects and via phone calls from the office in the other half of the group. The attention control subjects received equal number of courtesy phone calls by an educator. All subjects underwent measurement of glycemic control (A1C) and other outcome measures at baseline and 6-months. Second assessment of outcome measures was performed in all patients at 12-months from baseline (after 6 months of no contact with study team) to assess if changes during intervention were sustained. The important results show 1) there are many barriers to self-care in older adults. 2) Phone communication between clinic visits by an educator improves glycemic control and lowers diabetes-related distress 3) Communication with an educator cognizant of age-specific barriers may improve glycemic control more and help maintain functionality 4) Hypoglycemic episodes are common in even in poorly controlled older patients on insulin regimen., The original document contains color images.

We present an unusual neurologic emergency in an elderly male patient. Given his presentation and risk factors, we presumed the initial symptoms to be secondary to a cerebrovascular accident. As the case evolved, however, it became apparent that a more unusual pathology was present. This case report showcases a rare condition masquerading as a common neurologic emergency., Pub in the Western Jnl of Emergency Medicine V12 ni pp87-89 2011.

Emi-1 has been known as an inhibitor of APC (anaphase promoting complex). The depletion of Emi-1 would prematurely activate APC, lead to simultaneous degradation of geminin and cyclin A, and induce re-replication at least in colon cancer cell lines and breast epithelial cell MCF10A. We proposed Emi-1 depletion can induce re-replication in breast cancer cells, lead to gene amplification and stimulate tumor growth. We showed earlier that the depletion of Emi-1 induced re-replication and activated the checkpoint pathway in several breast cancer cell lines. However, we didn't observe any difference on cell growth after methotrexate (MTX) inhibition, as an indicator of gene amplification, between control and re-replicated cells, with or without the inhibition of checkpoint and apoptosis pathways. We didn't observe significant difference in tumor growth in xenograft experiments using those cells. In a separate study, we found that re-replication in colon cancer cells could activate not only apoptosis but also cellular senescence. So we hypothesize that re-replicated cells underwent senescence before we could detect any gene amplification phenotype. To test this hypothesis, we tried to inhibit the senescence pathway by depleting several known important genes. However, those genes are not essential for senescence activation. Further studies are necessary to address the issue., The original document contains color images.

This research focuses on the smoking rates among the Active Duty Air Force (ADAF) personnel and the association of smoking and cost of hospitalization because of diseases related to smoking. The analysis of the data taken from the Air Force Web HA questionnaire provides information about the relationship between the smoking rates of the ADAF personnel and specific socio-demographic characteristics. The analysis of a second dataset associated with the cost of hospitalization, provides a list with the most prevalent diseases related to smoking with the highest cost. Moreover, a Regression Analysis tries to explore potential predictors that could anticipate the cost of the most prevalent diseases related to smoking. The Contingency Analysis showed that smoking in the U.S. Air Force is more prevalent among the enlisted, males, and the younger age groups. The Pivot Table Analysis demonstrated that ischemic heart disease and cerebrovascular disease present the highest cost. In addition, the enlisted personnel exhibit higher total cost compared to the officers, but the situation is reversed when referring to the average cost. Furthermore, while smoking is more prevalent among the younger age groups, the cost consequences of smoking are more intense in the older age groups. The Regression Analysis exhibited that the variables, related to socio-demographic characteristics, that explain better the cost of hospitalization are the age group of 45- 60, the enlisted personnel, and all the pay ranks of the officers, while the diseases that affect more the cost of hospitalization are ischemic heart disease, cerebrovascular disease, malignant neoplasms of the urinary bladder, and other arterial diseases., The original document contains color images.

To project TRICARE savings resulting from section 707, DOD, in April 2010, developed two baseline estimates. One baseline estimate was of the number of retirees and their dependents under age 65 that DOD expected would not participate in TRICARE in fiscal year 2009 in the absence of employer incentives. The other baseline estimate was of the average TRICARE cost per participating retiree and dependent under age 65 for fiscal year 2009. DOD then calculated adjustments to both of the baseline estimates to account for anticipated changes in fiscal years 2010 through 2015. Specifically, DOD projected that there would be no change in the number of retirees and their dependents under age 65 in fiscal year 2010, but a 2 percent annual decrease in fiscal years 2011 through 2015. Additionally, DOD projected that average TRICARE costs would increase by 8 percent in fiscal year 2010 and 7 percent in fiscal years 2011 through 2015 as a result of medical inflation. DOD applied these adjustments to its baseline estimates to project savings for fiscal years 2010 through 2015. DOD reported that it was not able to determine the effects of section 707 on TRICARE participation and costs after the law went into effect because of data limitations and multiple factors affecting the health insurance choices of retirees and their dependents under age 65. DOD reported that it was unable to link data on TRICARE enrollment to beneficiary survey data on why beneficiaries choose one health insurance plan over another. DOD also reported that many factors affect health insurance choices, such as the costs of participating in TRICARE (compared to the costs of participating in employer-sponsored health insurance), making it difficult to attribute any single factor to changes in TRICARE participation. In commenting on a draft of this report, DOD indicated that it concurred with our report.

Senescence marker protein (SMP30), also known as regucalcin, is a 34 kDa cytosolic marker protein of aging which plays an important role in intracellular Ca2+ homeostasis, ascorbic acid biosynthesis, oxidative stress, and detoxification of chemical warfare nerve agents. In our goal to investigate the activity of SMP30 for the detoxification of nerve agents, we have produced a recombinant adenovirus expressing human SMP30 as a fusion protein with a hemaglutinin tag (Ad-SMP30-HA). Ad-SMP30-HA transduced the expression of SMP30-HA and two additional forms of SMP30 with molecular sizes ,28 kDa and 24 kDa in HEK-293A and C3A liver cells in a dose and time-dependent manner. Intravenous administration of Ad-SMP30-HA in mice results in the expression of all the three forms of SMP30 in the liver and diaphragm. LC-MS/MS results confirmed that the lower molecular weight 28 kDa and 24 kDa proteins are related to the 34 kDa SMP30. The 28 kDa and 24 kDa SMP30 forms were also detected in normal rat liver and mice injected with Ad-SMP30-HA suggesting that SMP30 does exist in multiple forms under physiological conditions. Time course experiments in both cell lines suggest that the 28 kDa and 24 kDa SMP30 forms are likely generated from the 34 kDa SMP30. Interestingly, the 28 kDa and 24 kDa SMP30 forms appeared initially in the cytosol and shifted to the particulate fraction. Studies using small molecule inhibitors of proteolytic pathways revealed the potential involvement of b and c-secretases but not calpains, lysosomal proteases,proteasome and caspases. This is the first report describing the existence of multiple forms of SMP30, their preferential distribution to membranes and their generation through proteolysis possibly mediated by secretase enzymes., Pub. in PLoS ONE, v6 n2, p1-10, Feb 2011. The original document contains color images.

Pancreatic islet cell regeneration is considered to be important in the onset and progression of diabetes and as a potential cell therapy. Current hypotheses, largely based on rodent studies, indicate continuous turnover and plasticity of α- and β-cells in adults; cell populations in rodents respond to increased secretory demand in obesity (30-fold β-cell increase) and pregnancy. Turnover and plasticity of islet cells decrease in mice within >1 year. In man, morphometric observations on postmortem pancreas have indicated that the cellular expansion is much smaller than the increased insulin secretion that accompanies obesity. Longevity of β-cells in humans >20-30 years has been shown by (14) C measurements and bromo-deoxyuridine (BrdU) incorporation and there is an age-related decline in the expression of proteins associated with cell division and regeneration including cyclin D3 and PDX-1. Quantitative estimation and mathematical modelling of the longevity marker, cellular lipofuscin body content, in islets of subjects aged 1-84 years indicated an age-related increase and that 97% of the human β-cell population was established by the age of 20. New data show that human α-cell lipofuscin content is less than that seen in β-cells, but the age-related accumulation is similar; lipofuscin-positive (aged) cells form ≥ 95% of the population after 20 years. Increased turnover of cellular organelles such as mitochondria and endoplasmic reticulum could contribute to lipofuscin accumulation with age in long-lived cells. Induction of regeneration of human islet cells will require understanding of the mechanisms associated with age-related senescence., Journal Article, Research Support, Non-U.S. Gov't, Review, FLWIN, SCOPUS: re.j, info:eu-repo/semantics/published

Adult neurogenesis within the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ) of the lateral ventricle (LV) has been most intensely studied within the brains of rodents such as mice and rats. However, little is known about the cell types and processes involved in adult neurogenesis within primates such as the common marmoset (Callithrix jacchus). Moreover, substantial differences seem to exist between the neurogenic niche of the LV between rodents and humans. Here, we set out to use immunohistochemical and autogradiographic analysis to characterize the anatomy of the neurogenic niches and the expression of cell type-specific markers in those niches in the adult common marmoset brain. Moreover, we demonstrate significant differences in the activity of neurogenesis in the adult marmoset brain compared to the adult mouse brain. Finally, we provide evidence for ongoing proliferation of neuroblasts within both the SGZ and SVZ of the adult brain and further show that the age-dependent decline of neurogenesis in the hippocampus is associated with a decrease in neuroblast cells.

Starenje uzrokuje brojne tjelesne i psihološke promjene koje mogu utjecati na nutritivne potrebe i nutritivni status. Prisutnost kroničnih bolesti i uzimanje lijekova mogu uzrokovati neravnotežu između potrebe za nutrijentima i prehrambenog unosa, što vodi nastanku malnutricije ili lošeg statusa uhranjenosti. Brojna istraživanja pokazuju da je malnutricija učestali problem među osobama starije dobi. Stoga redovita procjena nutritivnog statusa čini bitan dio zdravstvene skrbi za osobe starije dobi. Pritom je važno uzeti u obzir odrednice geroantropometrije. Fiziološke promjene vezane uz starenje utječu na potrebe za nutrijentima. Energetske potrebe i potrebe za makronutrijentima smanjuju se, međutim potrebe za mikronutrijentima jednake su ili veće nego tijekom zrele dobi. Dodatno, brojne psihosocijalne i socioekonomske promjene koje prate starenje mogu utjecati na prehrambeni unos. Planiranje obroka važan je dio nutritivne njege osoba starije dobi, a veoma važni mogu biti i dodaci prehrani te oralni nutritivni dodaci (enteralni pripravci) koji se propisuju kod dijagnosticirane ili prijeteće malnutricije. Radna skupina koju su činili internisti, gerontolozi, antropolozi, nutricionisti i ostali stručnjaci, posebno upućeni u liječenje gerijatrijskih bolesnika izradila je Hrvatske smjernice za prehranu osoba starije dobi. Izrada smjernica temeljena je na dokazima iz relevantne medicinske literature te kliničkim iskustvima članova radne skupine., Aging produces numerous physical and physiologic changes, which in turn alter nutritional requirements and affect nutritional status. The presence of chronic disease, and/or medications can enhance potential disparities between nutrient needs and dietary intake, leading to malnutrition. Indeed, research suggests that malnutrition is a common condition among the elderly. Therefore, regular nutritional assessment should be done as an integral part of healthcare for elderly. Also, it is important to take in consideration all determinants of geroanthropometry. The physiologic changes associated with aging affect requirement for several essential nutrients. In general, the requirement for many nutrients decreases, concomitant with the decrease in energy needs. However, some nutrients are needed in higher amounts. Additionally, various psychosocial and socioeconomic changes that often attend aging may also alter dietary intake. Dietary planning is important part of nutritional care in the elderly. Also, some elderly persons can benefit with dietary supplements and oral nutritional supplements (enteral formulas) which can be prescribed by diagnosed or threatening malnutrition. Croatian guidelines for nutrition in the elderly have been developed by interdisciplinary expert group of Croatian clinicians, gerontologists, anthropologists, nutritionists and other professionals involved with care for elderly population. The guidelines are based on evidence from relevant medical literature and clinical experience of working group.

Comment, Letter, SCOPUS: le.j, info:eu-repo/semantics/published

We study a population model in which there are two species, one of which has a juvenile and adult life stage. The adults of the first species prey on the second species which in turn preys on the juveniles of the first. One version of the model represents systems where neither species can survive on its own, although we find that both can survive through mutual predation. To avoid extinction, the two types of predation must be of sufficient strength and in appropriate proportion to one another. Another version of the model represents systems where each species can survive without the other, and there we find that mutual predation is capable of increasing both of their equilibrium populations or creating stable limit cycles., See also ADA544302. The original document contains color images.

Recently, it has been recognized that a distinct mechanism of terminal proliferation arrest after chemotherapy involves the reactivation of senescence. However, whether this phenotype occurs in vivo is unclear, as is the biological impact of senescence induction. We have previously identified pathways and genes involved in human senescence that may serve as senescence markers, and have demonstrated that senescence occurs in prostate cancer cell lines after chemotherapy. In this proposal, we will: a) determine whether senescent tumor cells alter the proliferation and invasion of surrounding prostate cancer cells in vitro and in vivo, b) assess for and augment senescence in prostate cancer xenograft models and human tumors, and c) identify novel small molecules that induce senescence in prostate cancer cells. Both in vitro and in vivo approaches using human prostate cancer cells will be utilized to identify and determine the mechanisms underlying senescence. With this data, our understanding of cellular senescence will undergo a quantum leap and permit the translation of this entity both as a marker of response and for directing therapy., The original document contains color images.

During this research period, we have nearly completed recruitment of patients over age 70 with diabetes and poor glycemic control as defined by A1c>8%, and have started analysis of the data. We have now recruited 50 subjects for the study and have additional data on 16 patients who are in the control arm of the parallel study for better sample size and analysis. We are also performing interim analysis of the results of the cerebral blood flow study. Our baseline data was presented at the annual scientific meeting of the American Diabetes Association last year. This year we have interim data to show effect of interventions. We also have novel data gained by continuous glucose monitoring that will be oral paper presentation at the annual meeting of the American Diabetes Association. The important results show 1) Frequent hypoglycemic episodes were detected by continuous glucose monitoring in older adults even with poor glycemic control. 2) Self-management interventions to overcome barriers to diabetes improved self-care frequency and functionality in older adults 3) different methods of measuring executive dysfunction identifies different deficiencies in older patients with diabetes. Based on our continuous monitoring data, we have received a pilot funding to assess cardiac autonomic dysfunction in older adults with diabetes during continuous glucose monitoring., The original document contains color images.

We developed an injury model to bone marrow stroma cultured in vitro from bone marrow samples from mice and human donors. We demonstrated that oxidative injury with H2O2 induces a reproducible time- and dose-dependent secretory senescence profile that consists of export of interleukin 6 (IL-6) by murine and human stroma and IL-8 by murine stroma and activation of TGF beta signaling. Using oxidative injury as a positive control, we demonstrated that estrogen deprivation induces secretory senescence in bone marrow stroma both in female mice and a premenopausal human female volunteer and activation of TGF beta signaling in mice. We defined the parameters for estrogen-induced secretory senescence in mouse and human marrow. Preliminary observations suggest that human marrow is more sensitive to estrogen deprivation-induced secretory senescence resulting in a greater and more sustained response. These data will be expanded to define the relationship between post menopausal status and secretory senescence and the effect on this stromal response on the capacity to support micrometastatic breast cancer cell dormancy., The original document contains color images.

A novel A/H1N1 virus is the cause of the present influenza pandemic; vaccination is a key countermeasure however, few data assessing prior seasonal vaccine effectiveness (VE) against the pandemic strain of H1N1 (pH1N1) virus are available. Materials and Methods: Surveillance of influenza-related medical encounter data of active duty military service members stationed in the United States during the period of April-October 2009 with comparison of pH1N1-confirmed cases and location and date-matched controls. Crude odds ratios (OR) and VE estimates for immunized versus non-immunized were calculated as well as adjusted OR (AOR) controlling for sex, age group, and history of prior influenza vaccination. Separate stratified VE analyses by vaccine type (trivalent inactivated [TIV] or live attenuated [LAIV]), age groups and hospitalization status were also performed. For the period of April 20 to October 15, 2009, a total of 1,205 cases of pH1N1-confirmed cases were reported, 966 (80%) among males and over one-half (58%) under 25 years of age. Overall VE for service members was found to be 45% (95% CI, 33 to 55%). Immunization with prior season's TIV (VE = 44%, 95% CI, 32 to 54%) as well as LAIV (VE = 24%, 95% CI, 6 to 38%) were both found to be associated with protection. Of significance, VE against a severe disease outcome was higher (VE = 62%, 95% CI, 14 to 84%) than against milder outcomes (VE = 42%, 95% CI, 29 to 53%). Conclusion: A moderate association with protection against clinically apparent, laboratory-confirmed Pandemic (H1N1) 2009-associated illness was found for immunization with either TIV or LAIV 2008-09 seasonal influenza vaccines. This association with protection was found to be especially apparent for severe disease as compared to milder outcome, as well as in the youngest and older populations., Pub. in PLoS one, v5 n5, p1-7, May 2010.

This project examines the relationship between PPAR-gamma and carcinogenesis. PPAR-GAMMA sits at a critical juncture in cellular differentiation and metabolism being involved in both differentiation and in the regulation of stress responses mediated through the cyclooxygenase (COX) and lipoxygenase (LOX) pathways of fatty acid metabolism. The basis for this project was the observation that in human prostate cancer there is an early loss of enzymes responsible for the production of the putative endogenous ligands for PPAR-GAMMA, presumed to result in a decrease in receptor function. We have found that loss of PPARGAMMA function can result in the generation of premalignant prostatic lesions in mice (Jiang et al 2010). We have also shown that there is an associated upregulation of COX pathways which would generate increases in prostaglandin production and oxidative stress, which could underlie such pathology. This project sets out to examine interactions between the PPARGAMMA, COX and LOX pathways and their role in carcinogenesis. We are using predominantly tissue recombination models involving human prostatic epithelial cells. The use of human cells is important in that there are significant differences between the fatty acid metabolic pathways between humans and mice. However we have also generated mouse epithelial cell lines from the transgenic animals and as a result have been able to use their accelerated aging and metabolism as compared to human cells to illustrate malignant transformation in a recombination model. These data provide a strong basis for future studies, The original document contains color images.

Cancer is aberrant, uncontrolled cellular proliferation arising from an accumulation of mutations in growth regulatory genes. Two mammalian DNA damage checkpoint pathways, the Atm and Atr pathways, act to suppress tumor formation by preventing mutation accumulation and inducing senescence in response to oncogenic stimuli. Roles for the Atr pathway in tumor suppression are less understood, as deletion of any member of this pathway, including Hus1, results in embryonic lethality. To understand roles for Hus1 in breast cancer suppression, we developed mouse models featuring partial Hus1 impairment and are testing how Hus1 dysfunction affects cellular responses to activated oncogenes. Proliferation, immortalization, focus formation, soft agar, and transplantation assays suggest that cultured cells with reduced Hus1 levels are less able to be transformed. To elucidate roles for Hus1 as a tumor suppressor in vivo, mice expressing reduced levels of Hus1 were crossed to mice overexpressing ErbB2 in the mammary gland to generate a cohort of mice. Our preliminary results indicate that reduced Hus1 levels may decrease the capacity of cells to undergo transformation, suggesting that Hus1, or the Atr pathway, may be a possible target for breast cancer treatment., The original document contains color images.

We recently demonstrated that telomere lengths were shorter in more aggressive breast cancer subtypes, such as luminal B, HER-2 positive and triple-negative tumors, suggesting tumor telomere length may have clinical utility as a prognostic and/or risk marker for breast cancer. Interestingly, the investigator has shown that moderate telomere shortening occurs specifically in luminal epithelial cells, but not in myoepithelial cells, in the majority of histologically normal terminal ductal lobular units analyzed from patients undergoing reduction mammoplasty, but the extent and degree of shortening varies by the individual. These data imply that there is a reservoir of genetically altered, yet histologically normal, cells within normal breast tissues that may represent fertile ground for tumor development. Since telomere shortening has been associated with cellular senescence and dysfunctional telomeres have been linked to the DNA damage response pathway in cancerous tissues, future planned experiments will assess senescence-associated markers and DNA damage response pathway markers in histologically normal human breast tissues that display either normal or short telomeres (i.e. prior to tumor formation). In addition, the proposed investigation has provided grounding in both basic and translational breast cancer research. The interactive, multidisciplinary research environment has provided the investigator opportunities to interact with pathologists and oncologists, thus fostering future success as an independent breast cancer researcher. To date, all tasks, as outlined in the Statement of Work, are on schedule.

1-alpha, 25-dihydroxy vitamin D(sub 3) (1,25(OH)2D3) inhibits proliferation of multiple cancer cell types including prostate cells and upregulates p21 and/or p27, while loss of Pten and PI3K/AKT activation stimulates survival and downregulates p21 and p27. We hypothesized that inhibition of the PI3K/AKT pathway synergizes with the antiproliferative signaling of 1,25(OH)(sub 2)D(sub 3). Viability, cell cycle and senescence of cells were evaluated upon combinational treatment with 1,25(OH)(sub 2)D(sub 3) and pharmacological PI3K/AKT inhibitors. Pharmacological inhibitors of PI3K or Akt and 1,25(OH)(sub 2)D(sub 3) synergistically inhibited growth of DU145, LNCaP, primary human prostate cancer cell strains and Pten null mouse prostatic epithelial cells (MPEC). The inhibitors used included API-2 (Triciribine) and GSK690693 which are currently in clinical trials for treatment of cancer. A novel mechanism for antiproliferative effects of 1,25(OH)(sub 2)D(sub 3) in prostate cells, induction of senescence, was discovered. Combination of 1,25(OH)(sub 2)D(sub 3) and AKT inhibitor cooperated to induce G1 arrest, senescence, and p21 levels in prostate cancer cells. As AKT is commonly activated by PTEN loss, we evaluated the role of Pten in responsiveness to 1,25(OH)(sub 2)D(sub 3) using shRNA knockdown and by in vitro knockout of Pten. MPEC that lost Pten expression remained sensitive to the antiproliferative action of 1,25(OH)(sub 2)D(sub 3), and showed higher degree of synergism between AKT inhibitor and 1,25(OH)(sub 2)D(sub 3) compared to Pten-expressing counterparts. CONCLUSIONS: These findings provide the rationale for the development of therapies utilizing 1,25(OH)(sub 2)D(sub 3) or its analogs combined with inhibition of PI3K/AKT for the treatment of prostate cancer., The original document contains color images.

Influenza-like illness (ILI) is often defined as fever (>38.0C) with cough or sore throat. In this study, we tested the sensitivity, specificity, and positive and negative predictive values of this case definition in a Cambodia patient population. Methods: Passive clinic-based surveillance was established at nine healthcare centers to identify the causes of acute undifferentiated fever in patients aged two years and older seeking treatment. Fever was defined as tympanic membrane temperature >38?C lasting more than 24 hours and less than 10 days. Influenza virus infections were identified by polymerase chain reaction. Results: From July 2008 to December 2008, 2,639 patients were enrolled. From 884 (33%) patients positive for influenza, 652 presented with ILI and 232 acute fever patients presented without ILI. Analysis by age group identified no significant differences between influenza positive patients from the two groups. Positive predictive values (PPVs) varied during the course of the influenza season and among age groups. Conclusion: The ILI case definition can be used to identify a significant percentage of patients with influenza infection during the influenza season in Cambodia, assisting healthcare providers in its diagnosis and treatment. However, testing samples based on the criteria of fever alone increased our case detection by 34%., Pub. in Kasper et al. BMC Infectious Diseases, v10, p1-5, 2010.

The Purpose of this proposal is to examine how senescence in the prostate may be caused by medical treatments for prostate cancer, and to identify senescence-associated factors which may mediate resistance of neoplastic epithelium. To date, our major findings present a mixed picture of chemotherapy-induced senescence. Senescence-associated Beta-galactosidase staining has not identified significant chemotherapy-induced senescence, but quantitation of gene expression changes reveal a pervasive pattern of senescence changes. Correlation of chronological aging and senescence is seen. Detailed investigations into a putative secreted marker of senescence, STC1, find significant decreases in cancer compared to benign prostate glands, establish STC1 secretion as a response to numerous microenvironmental stressors including chemotherapy, and find increased STC1 expression in human prostate tissue after neoadjuvant chemotherapy. Finally, abrogation of the senescence-associated IGF pathway is being tested in a clinical trial of neoadjuvant anti-IGF-1R antibody therapy with combined androgen deprivation prior to prostatectomy., The original document contains color images.