tbuckley/cabot-search huggingface dataset:
Randomized Clinical Trial of 3 Types of Physical Exercise for Patients With Parkinson Disease
Authors: Lisa M. Shulman, Leslie I. Katzel, Frederick M. Ivey, John D. Sorkin, Knachelle Favors, Karen E. Anderson, Barbara A. Smith, Stephen G. Reich, William J. Weiner, Richard F. Macko
Journal: JAMA Neurology (2012)

<h3>Objective</h3>To compare the efficacy of treadmill exercises and stretching and resistance exercises in improving gait speed, strength, and fitness for patients with Parkinson disease.<h3>Design</h3>A comparative, prospective, randomized, single-blinded clinical trial of 3 types of physical exercise.<h3>Setting</h3>The Parkinson's Disease and Movement Disorders Center at the University of Maryland and the Baltimore Veterans Affairs Medical Center, Geriatric Research Education and Clinical Center.<h3>Patients</h3>A total of 67 patients with Parkinson disease who had gait impairment were randomly assigned to 1 of 3 arms of the trial.<h3>Interventions</h3>(1) A higher-intensity treadmill exercise (30 minutes at 70%-80% of heart rate reserve), (2) a lower-intensity treadmill exercise (50 minutes at 40%-50% of heart rate reserve), and (3) stretching and resistance exercises (2 sets of 10 repetitions on each leg on 3 resistance machines [leg press, leg extension, and curl]). These exercises were performed 3 times a week for 3 months.<h3>Main Outcome Measures</h3>The primary outcome measures were gait speed (6-minute walk), cardiovascular fitness (peak oxygen consumption per unit time [$$⋅VO<sub>2</sub>], and muscle strength (1-repetition maximum strength).<h3>Results</h3>All 3 types of physical exercise improved distance on the 6-minute walk: lower-intensity treadmill exercise (12% increase; P = .001), stretching and resistance exercises (9% increase; P &lt; .02), and higher-intensity treadmill exercise (6% increase; P = .07), with no between-group differences. Both treadmill exercises improved peak $$⋅VO<sub>2</sub> (7%-8% increase; P &lt; .05) more than did the stretching and resistance exercises. Only stretching and resistance improved muscle strength (16% increase; P &lt; .001).<h3>Conclusions</h3>The effects of exercise were seen across all 3 exercise groups. The lower-intensity treadmill exercise resulted in the greatest improvement in gait speed. Both the higher- and lower-intensity treadmill exercises improved cardiovascular fitness. Only the stretching and resistance exercises improved muscle strength. Therefore, exercise can improve gait speed, muscle strength, and fitness for patients with Parkinson disease. The combination of treadmill and resistance exercises may result in greater benefit and requires further investigation.
TIMP-1 Alters Susceptibility to Carcinogenesis
Authors: Jin-Sae Rhee, Robert Diaz, Lidiya Korets, J. Graeme Hodgson, Lisa M. Coussens
Journal: Cancer Research (2004)

Abstract Tissue inhibitors of metalloproteinases (TIMPs) are a family of multifunctional proteins known to possess a broad range of biological activities, including inhibition of metalloproteinase activity, regulation of proliferation and apoptosis of a variety of cell types, and, depending on the context, differential regulation of angiogenic and inflammatory responses. Elevated mRNA expression of TIMP family members correlates with malignancy and clinical outcome in many human cancer types; however, a protective role for TIMPs also has been observed in various mouse models of human cancer. In the current study, we found distinct spatial-temporal expression patterns for the mRNA of TIMP family members in a mouse model of epithelial carcinogenesis [i.e., keratin 14-human papillomavirus 16 (K14-HPV16) transgenic mice]. To test the hypothesis that elevated expression of TIMP-1 functionally regulates epithelial carcinogenesis, we introduced a human TIMP-1 transgene into K14-HPV16 transgenic mice and assessed neoplastic progression. Results from these studies suggest that TIMP-1 enhances tumorgenicity by potentiating keratinocyte hyperproliferation and appearance of chromosomal aberrations in premalignant cells, thereby increasing their risk to undergo malignant conversion. In addition, TIMP-1 inhibits tissue gelatinolytic activity in tumor stroma, affects stabilization of collagen fibrils, but does not inhibit malignant conversion of dysplasias into carcinomas or development of metastases. The combined implications of these studies suggest that TIMP-1 is an important contributor to epithelial neoplastic progression and supports the concept that TIMP-1 exerts differential regulation on tissues in a stage-dependent manner.
Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI): a modified outcome instrument for cutaneous lupus erythematosus
Authors: A. Kuhn, S. Amler, S. Beissert, M. Böhm, R. Brehler, J. Ehrchen, S. Grundmann, M. Haust, V. Ruland, M. Schiller, P. Schulz, S. Ständer, C. Sauerland, T.A. Luger, G. Bonsmann
Journal: British Journal of Dermatology (2010)

Summary Background In 2005, a scoring system (CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index) was developed for patients with cutaneous lupus erythematosus (CLE) to assess disease 'activity' and 'damage'. However, the CLASI does not give an accurate assessment of the severity in all disease subtypes. Objectives The main objective of this study was to analyse critically the included parameters of the CLASI and to revise the activity and damage score taking into account various clinical features of the different subtypes of CLE. The revised CLASI (RCLASI) was also validated for use in clinical trials. Patients and methods A RCLASI was designed with regard to the anatomical region (i.e. face, chest, arms) and morphological aspects (i.e. erythema, scaling/hyperkeratosis, oedema/infiltration, scarring/atrophy) of skin lesions and evaluated by nine dermatologists who scored 12 patients with different subtypes of CLE to estimate inter- and intrarater reliability. Results Reliability studies demonstrated an intraclass correlation coefficient (ICC) for an inter-rater reliability of 0·89 for the activity score [95% confidence interval (CI) 0·79–0·96] and of 0·79 for the damage score (95% CI 0·62–0·92). The ICC for intrarater reliability for the activity score was 0·92 (95% CI 0·89–0·95) and the ICC for the damage score was 0·95 (95% CI 0·92–0·98). Conclusions In the present study, a RCLASI was developed by experts, and reliability studies supported the validity and applicability of the revised scoring instrument for CLE. Thus, the RCLASI is a valuable instrument in multicentre studies and for the clinical evaluation of activity and damage in different disease subtypes.
A Single Vaccination with Polyomavirus VP1/VP2Her2 Virus-Like Particles Prevents Outgrowth of HER-2/<i>neu</i>–Expressing Tumors
Authors: Karin Tegerstedt, Jan Alvar Lindencrona, Claudia Curcio, Kalle Andreasson, Carl Tullus, Guido Forni, Tina Dalianis, Rolf Kiessling, Torbjörn Ramqvist
Journal: Cancer Research (2005)

Abstract Murine polyomavirus (MPyV) VP1 virus-like particles (VLPs), containing a fusion protein between MPyV VP2 and the extracellular and transmembrane domain of HER-2/neu (Her2), Her21-683PyVLPs, were tested for their ability to vaccinate against Her2-expressing tumors in two different in vivo models. Protection was assessed both against a lethal challenge with a BALB/c mammary carcinoma transfected with human Her2 (D2F2/E2) and against the outgrowth of autochthonous mammary carcinomas in BALB-neuT mice, transgenic for the activated rat Her2 oncogene. A single injection of Her21-683PyVLPs before tumor inoculation induced a complete rejection of D2F2/E2 tumor cells in BALB/c mice. Similarly, a single injection of Her21-683PyVLPs at 6 weeks of age protected BALB-neuT mice with atypical hyperplasia from a later outgrowth of mammary carcinomas, whereas all controls developed palpable tumors in all mammary glands. VLPs containing only VP1 and VP2 did not induce protection. The protection elicited by Her21-683PyVLPs vaccination was most likely due to a cellular immune response because a Her2-specific response was shown in an ELISPOT assay, whereas antibodies against Her2 were not detected in any of the two models. The results show the feasibility of using MPyV-VLPs carrying Her2 fusion proteins as safe and efficient vaccines against Her2-expressing tumors.
Pretreatment with DNA-damaging agents permits selective killing of checkpoint-deficient cells by microtubule-active drugs
Authors: Mikhail V. Blagosklonny, Robert Robey, Susan Bates, Tito Fojo
Journal: Journal of Clinical Investigation (2000)

Cell-cycle checkpoint mechanisms, including the p53- and p21-dependent G(2) arrest that follows DNA damage, are often lost during tumorigenesis. We have exploited the ability of DNA-damaging drugs to elicit this checkpoint, and we show here that such treatment allows microtubule drugs, which cause cell death secondary to mitotic arrest, to kill checkpoint-deficient tumor cells while sparing checkpoint-competent cells. Low doses of the DNA-damaging drug doxorubicin cause predominantly G(2) arrest without killing HCT116 cells that harbor wt p53. Doxorubicin treatment prevented mitotic arrest, Bcl-2 phosphorylation, and cell death caused by paclitaxel, epothilones, and vinblastine. In contrast, doxorubicin enhanced cytotoxicity of FR901228, an agent that does not affect microtubules. Low doses of doxorubicin did not arrest p21-deficient clones of HCT116 cells and did not protect these cells from cytotoxicity caused by microtubule drugs, but cells in which p21 expression was restored enjoyed partial protection under these conditions. Moreover, in p53-deficient clones of HCT116 cells doxorubicin did not induce either p53 or p21 and provided no protection against paclitaxel-induced cytotoxicity. Therefore, (a) p53-dependent p21 induction caused by doxorubicin protects from microtubule drug-induced cytotoxicity, and (b) pretreatment with cytostatic doses of DNA-damaging drugs before treatment with microtubule drugs results in selective cytotoxicity to cancer cells with defective p53/p21-dependent checkpoint.
BP Control and Left Ventricular Hypertrophy Regression in Children with CKD
Authors: Juan C. Kupferman, Lisa Aronson Friedman, Christopher Cox, Joseph Flynn, Susan Furth, Bradley Warady, Mark Mitsnefes
Journal: Journal of the American Society of Nephrology (2013)

In adult patients with CKD, hypertension is linked to the development of left ventricular hypertrophy, but whether this association exists in children with CKD has not been determined conclusively. To assess the relationship between BP and left ventricular hypertrophy, we prospectively analyzed data from the Chronic Kidney Disease in Children cohort. In total, 478 subjects were enrolled, and 435, 321, and 142 subjects remained enrolled at years 1, 3, and 5, respectively. Echocardiograms were obtained 1 year after study entry and then every 2 years; BP was measured annually. A linear mixed model was used to assess the effect of BP on left ventricular mass index, which was measured at three different visits, and a mixed logistic model was used to assess left ventricular hypertrophy. These models were part of a joint longitudinal and survival model to adjust for informative dropout. Predictors of left ventricular mass index included systolic BP, anemia, and use of antihypertensive medications other than angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Predictors of left ventricular hypertrophy included systolic BP, female sex, anemia, and use of other antihypertensive medications. Over 4 years, the adjusted prevalence of left ventricular hypertrophy decreased from 15.3% to 12.6% in a systolic BP model and from 15.1% to 12.6% in a diastolic BP model. These results indicate that a decline in BP may predict a decline in left ventricular hypertrophy in children with CKD and suggest additional factors that warrant additional investigation as predictors of left ventricular hypertrophy in these patients.
Hereditary Peripheral Neuropathies: Clinical Forms, Genetics, and Molecular Mechanisms
Authors: Laura E. Warner, Carlos A. Garcia, MD, James R. Lupski, MD, PhD
Journal: Annual Review of Medicine (1999)

Hereditary peripheral neuropathies, among the most common genetic disorders in humans, are a complex, clinically and genetically heterogeneous group of disorders that produce progressive deterioration of the peripheral nerves. This group of disorders includes hereditary neuropathy with liability to pressure palsies, Charcot-Marie-Tooth disease, Dejerine-Sottas syndrome, and congenital hypomyelinating neuropathy. Our understanding of these disorders has progressed from the description of the clinical phenotypes and delineation of the electrophysiologic and pathologic features to the identification of disease genes and elucidation of the underlying molecular mechanisms.
Current hydration guidelines are erroneous: dehydration does not impair exercise performance in the heat
Authors: Bradley A Wall, Greig Watson, Jeremiah J Peiffer, Chris R Abbiss, Rodney Siegel, Paul B Laursen
Journal: British Journal of Sports Medicine (2013)

Background Laboratory studies that support the hydration guidelines of leading governing bodies have shown that dehydration to only −2% of body mass can lead to increase in body temperature and heart rate during exercise, and decrease in performance. These studies, however, have been conducted in relatively windless environments (ie, wind speed &lt;12.9 km/h), without participants being blinded to their hydration status. Aim To investigate the effect of blinded hydration status on cycling time-trial performance in the heat with ecologically valid facing wind speed conditions. Methods During three experimental trials, 10 cyclists were dehydrated to −3% body mass by performing 2 h of submaximal exercise (walking and cycling) in the heat, before being reinfused with saline to replace 100%, 33% or 0% of fluid losses, leaving them 0%, −2% or −3% hypohydrated, respectively. Participants then completed a 25 km time trial in the heat (33°C, 40% relative humidity; wind speed 32 km/h) during which their starting hydration status was maintained by infusing saline at a rate equal to their sweat rate. The treatment was participant-blinded and the order was randomised. Completion time, power output, heart rate, rectal temperature and perceptual variables were measured. Results While rectal temperature was higher beyond 17 km of the time trial in the −3% vs 0% conditions (38.9±0.3°C vs 38.6±0.3°C; p&lt;0.05), no other differences between trials were shown. Conclusion When well-trained cyclists performed a 25 km cycling time trial under ecologically valid conditions and were blinded to their hydration status, performance, physiological and perceptual variables were not different between trials. These data do not support the residing basis behind many of the current hydration guidelines.
FURTHER STUDIES ON THE ETIOLOGICAL RÔLE OF VIBRIO FETUS
Authors: Theobald Smith, Ralph B. Little, Marian S. Taylor
Journal: The Journal of Experimental Medicine (1920)

The data bearing on these three cases are quite sufficient to rule out Bacillus abortus as the agent. Not only the cultures and guinea pig tests of fetal tissues and contents of the digestive tract, but also the agglutination and guinea pig tests of the milk, were negative. The same is true of the agglutination tests of the blood serum. Only in one case was the placenta obtained in part. The stained films and the sections from various regions showed no abortion bacilli. Guinea pig tests of placental tissue were negative for Bacillus abortus. On the other hand) minute organisms resembling vibrios were detected in the cytoplasm of endothelial cells within capillaries in the edematous subchorionic tissue. Subsequently the agglutination titer of the blood serum of one of these cases rose to a level indicating infection with Bacillus abortus during the second pregnancy. The peculiar distribution of abortions due to Vibrio fetus among older cows and heifers in this herd, resulting at first in cases among older cows and latterly passing to young stock, may be explained by certain occurrences in the herd itself. It may be assumed that the infection was originally brought in by purchased cows. The young stock is kept segregated from these in a special barn, and when 6 months old it is pastured on outlying farms until returned in an advanced stage of pregnancy. The heifers during the first pregnancy were thus kept away from vibrio carriers until after the first calf was born. In June and July, 1919, 55 older cows, purchased and native, were placed on the young stock pasture. The three cases of abortion in heifers due to Vibrio fetus occurred October 24, November 9, and December 2, 1919. The age and condition of the fetuses accord very well with the assumption that Vibrio fetus was introduced among the young stock in June or July of the same year. The information gathered thus far concerning vibrionic abortion in this herd enables us to formulate a tentative hypothesis subject to modification with increasing knowledge of this type of infectious abortion. The infectious agent was probably introduced by purchased cows in 1917 or earlier. It gained a certain headway up to 1919, then the number of cases declined so that between May, 1919, and May, 1920, only the above three cases in heifers, and one case of mixed infection with Bacillus abortus in an older cow, were detected. During the same period cases due to Bacillus abortus continued undiminished. The greater resistance of Bacillus abortus manifested in cultures as compared with Vibrio fetus is thus reflected in its behavior in nature. The temporary dying out of the infection indicates that natural immunization of a herd to Vibrio fetus proceeds quite rapidly. Another outbreak may be expected when the immunity of the herd has declined in the absence of the infecting agent and the latter is reintroduced from without, or it may reappear at any time when a vibrio of higher virulence is brought in.
Recurrence and Survival After Random Assignment to Laparoscopy Versus Laparotomy for Comprehensive Surgical Staging of Uterine Cancer: Gynecologic Oncology Group LAP2 Study
Authors: Joan L. Walker, Marion R. Piedmonte, Nick M. Spirtos, Scott M. Eisenkop, John B. Schlaerth, Robert S. Mannel, Richard Barakat, Michael L. Pearl, Sudarshan K. Sharma
Journal: Journal of Clinical Oncology (2012)

The primary objective was to establish noninferiority of laparoscopy compared with laparotomy for recurrence after surgical staging of uterine cancer.Patients with clinical stages I to IIA disease were randomly allocated (two to one) to laparoscopy (n = 1,696) versus laparotomy (n = 920) for hysterectomy, salpingo-oophorectomy, pelvic cytology, and pelvic and para-aortic lymphadenectomy. The primary study end point was noninferiority of recurrence-free interval defined as no more than a 40% increase in the risk of recurrence with laparoscopy compared with laparotomy.With a median follow-up time of 59 months for 2,181 patients still alive, there were 309 recurrences (210 laparoscopy; 99 laparotomy) and 350 deaths (229 laparoscopy; 121 laparotomy). The estimated hazard ratio for laparoscopy relative to laparotomy was 1.14 (90% lower bound, 0.92; 95% upper bound, 1.46), falling short of the protocol-specified definition of noninferiority. However, the actual recurrence rates were substantially lower than anticipated, resulting in an estimated 3-year recurrence rate of 11.4% with laparoscopy and 10.2% with laparotomy, or a difference of 1.14% (90% lower bound, -1.28; 95% upper bound, 4.0). The estimated 5-year overall survival was almost identical in both arms at 89.8%.This study previously reported that laparoscopic surgical management of uterine cancer is superior for short-term safety and length-of-stay end points. The potential for increased risk of cancer recurrence with laparoscopy versus laparotomy was quantified and found to be small, providing accurate information for decision making for women with uterine cancer.
Spontaneous Aortic Cusp Rupture Associated with Valvular Myxomatous Transformation
Authors: KEVIN P. O'BRIEN, GEORGE C. HITCHCOCK, BRIAN G. BARRATT-BOYES, JAMES B. LOWE
Journal: Circulation (1968)

Two adult male patients are presented with sudden onset of aortic incompetence secondary to rupture of an aortic valve cusp. Histological examination of these leaflets revealed myxomatous changes. Operation was undertaken on both patients, and an aortic homograft valve was inserted in each with a very satisfactory result. The relationship between medionecrosis of the aorta and myxomatous valvular transformation is discussed.
Regulation of Survivin by ErbB2 Signaling: Therapeutic Implications for ErbB2-Overexpressing Breast Cancers
Authors: Wenle Xia, John Bisi, Jay Strum, Leihua Liu, Kevin Carrick, Katherine M. Graham, Amanda L. Treece, Mary Ann Hardwicke, Michael Dush, Qiaoyin Liao, Ron E. Westlund, Sumin Zhao, Sarah Bacus, Neil L. Spector
Journal: Cancer Research (2006)

Abstract In breast cancer, overexpression of ErbB2 or aberrant regulation of survivin, a member of the inhibitor of apoptosis family, is associated with resistance to chemo/hormone therapy and predicts for a poor clinical outcome. A functional link between the two predictive factors has not been previously shown. Here, using genetic and pharmacologic approaches to block ErbB2 signaling, we show that ErbB2 regulates survivin protein expression in ErbB2-overexpressing breast cancer cells. Selective knockdown of ErbB2 using small interfering RNA markedly reduced survivin protein, resulting in apoptosis of ErbB2-overexpressing breast cancer cell lines such as BT474. Alternatively, inhibition of ErbB2 signaling using lapatinib (GW572016), a reversible small-molecule inhibitor of ErbB1/ErbB2 tyrosine kinases, at pharmacologically relevant concentrations, leads to marked inhibition of survivin protein with subsequent apoptosis. The effect of lapatinib on survivin seems to be predominantly posttranslational, mediated by ubiquitin-proteosome degradation as lactacystin, a proteosome inhibitor, reverses these effects. Furthermore, lapatinib down-regulated the expression of His-tagged survivin, which was under the transcriptional control of a heterologous promoter, providing additional evidence supporting a posttranslational mechanism of regulation. In contrast, trastuzumab and gefitinib failed to down-regulate survivin in ErbB2-overexpressing breast cancer cells. Importantly, the clinical relevance of these findings was illustrated in patients with ErbB2-overexpressing breast cancer whose clinical response to lapatinib was associated with marked inhibition of survivin in their tumors. These findings shed new light on the mechanism by which ErbB2 overexpression protects against apoptotic stimuli in breast cancer and identifies therapeutic interventions to improve clinical outcomes in these aggressive tumors. (Cancer Res 2006; 66(3): 1640-7)