tbuckley/cabot-search huggingface dataset:
Prevention of Uremic Bone Disease Using Calcimimetic Compounds
Authors: Klaus Olgaard, Ewa Lewin
Journal: Annual Review of Medicine (2001)

▪ Abstract The discovery, characterization, and cloning of the calcium-sensing receptor (CaR) in 1993 was soon followed by the creation of a new type of drug, the calcimimetics—NPS R-568 and NPS R-467—which are small phenylalkylamine derivative compounds that act as CaR agonists and increase the sensitivity of the CaR to activation by extracellular calcium (Ca 2+ ). As expected, these compounds turned out to have a significant effect on the Ca 2+ /parathyroid hormone (PTH) relationship, resulting in a dramatically greater suppression of the PTH level than would otherwise occur at the actual extracellular Ca 2+ levels. Renal osteodystrophy (RO) due to secondary hyperparathyroidism (HPT) in chronic renal failure was an obvious target for studying the effects of NPS R-568. In a study on experimental animals, the results clearly showed that this first generation of calcimimetics, NPS R-568, had an acute dose-dependent and short-lived suppressive effect on PTH secretion from the parathyroid glands. A similar effect was found in patients with chronic renal failure and secondary HPT. At the same time, the calcimimetics induced a slight degree of hypocalcemia. Such a significant suppressive effect on PTH secretion would be expected to result in therapeutic potential for a preventive or therapeutic effect on the RO accompanying chronic uremia. Administration would probably be in close concert with present strategies, phosphate binders and vitamin D analogs. A wide distribution of CaRs have now been demonstrated in the body, and an important question is how calcimimetics will affect the function of different tissues and organs when used for long-term treatment or prevention of secondary HPT and RO. Although relatively few experimental and clinical investigations have been completed, they clearly confirm the suppressive effect of calcimimetics on PTH secretion. In rats with experimental chronic renal failure, a significant and beneficial effect on the prevention of RO has been demonstrated. The effect of calcimimetic compounds is presently being evaluated in humans. Besides induction of hypocalcemia, the adverse effects in these mainly short-term studies have been few. Future studies with calcimimetics will further define the physiology and pathophysiology of the CaR and the long-term benefit of calcimimetic compounds in patients with chronic renal failure.
Growing Up with HIV: Children, Adolescents, and Young Adults with Perinatally Acquired HIV Infection
Authors: Rohan Hazra, George K. Siberry, Lynne M. Mofenson
Journal: Annual Review of Medicine (2009)

Tremendous success in the prevention and treatment of pediatric HIV in high-resource countries has changed the face of the epidemic. A perinatally HIV-infected child now faces a chronic disease rather than a progressive, fatal one. However, these successes pose new challenges as perinatally HIV-infected youth survive into adulthood. These include maintaining adherence to long-term, likely life-long therapy; selecting successive antiretroviral drug regimens, given the limited availability of pediatric formulations and the lack of pharmacokinetic and safety data in children; and overcoming extensive drug resistance in multi-drug-experienced children. Pediatric HIV care now focuses on morbidity related to long-term HIV infection and its treatment. Survival into adulthood of perinatally HIV-infected youth in high-resource countries encourages expansion of pediatric treatment programs in low-resource countries, where most HIV-infected children live, and provides important lessons about how the epidemic changes with increasing access to antiretroviral therapy for children.
Risk of Dementia in Seniors With Newly Diagnosed Diabetes: A Population-Based Study
Authors: Nisha Nigil Haroon, Peter C. Austin, Baiju R. Shah, Jianbao Wu, Sudeep S. Gill, Gillian L. Booth
Journal: Diabetes Care (2015)

OBJECTIVE To study whether diabetes onset in late life is a risk factor for dementia. RESEARCH DESIGN AND METHODS We conducted a population-based matched cohort study using provincial health data from Ontario, Canada. Seniors with (n = 225,045) and without newly diagnosed diabetes (n = 668,070) between April 1995 and March 2007 were followed until March 2012 for a new diagnosis of dementia. Cox proportional hazards modeling was used to compare the risk of dementia between groups after adjusting for baseline cardiovascular disease, chronic kidney disease (CKD), hypertension, and other risk factors. RESULTS Over this period, we observed 169,114 new cases of dementia. Individuals with diabetes had a modestly higher incidence of dementia (2.68 vs. 2.62 per 100 person-years) than those without diabetes. In the fully adjusted Cox model, the risk of dementia was 16% higher among our subgroup with diabetes (hazard ratio [HR] 1.16 [95% CI 1.15–1.18]). Adjusted HRs for dementia were 1.20 (95% CI 1.17–1.22) and 1.14 (95% CI 1.12–1.16) among men and women, respectively. Among seniors with diabetes, the risk of dementia was greatest in those with prior cerebrovascular disease (HR 2.03; 95% CI 1.88–2.19), peripheral vascular disease (HR 1.47; 95% CI 1.19–1.82), and CKD (HR 1.44; 95% CI 1.38–1.51), and those with one or more hospital visits for hypoglycemia (HR 1.73; 95% CI 1.62–1.84). CONCLUSIONS In this population-based study, newly diagnosed diabetes was associated with a 16% increase in the risk of dementia among seniors. Preexisting vascular disease and severe hypoglycemia were the greatest risk factors for dementia in seniors with diabetes.
Commentaries on the end of year editorial on the definition of ischaemia in last December's issue
Authors: G. A Elgavish
Journal: Cardiovascular Research (1995)

Journal Article Commentaries on the end of year editorial on the definition of ischaemia in last December's issue Get access Gabriel A Elgavish, Dr Gabriel A Elgavish, Dr Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 29, Issue 2, February 1995, Pages 285–286, https://doi.org/10.1016/S0008-6363(95)90007-1 Published: 01 February 1995
The Detection and Treatment of Psychiatric Disorders and Substance Use Among Pregnant Women Cared for in Obstetrics
Authors: Rosemary H. Kelly, Douglas F. Zatzick, Thomas F. Anders
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: This investigation assessed the detection and treatment of psychiatric disorders and at-risk substance use among pregnant women in the obstetric sector. METHOD: The Primary Care Evaluation of Mental Disorders Patient Health Questionnaire and modified CAGE questionnaires were used to assess current psychiatric disorders and at-risk substance use among 186 women receiving prenatal care. Medical records were reviewed for evidence of obstetrical providers' recognition of psychiatric and substance use symptoms and diagnoses and initiation of evaluations and treatments. The associations between patient characteristics and chart-documented evaluations and treatments were ascertained. RESULTS: Seventy (38%) of the women met screening criteria for psychiatric disorders or substance use. Among women who screened positive, symptoms were recorded in 43% of the charts, diagnoses in 18%, evaluations in 35%, and treatments in only 23% Patients who screened positive for psychiatric disorders and/or substance use were significantly more likely to have a documented mental health evaluation if they were less well educated, had inadequate prenatal care, or had longer hospital stays at delivery. CONCLUSIONS: A substantial number of women treated in obstetrics have unrecognized and untreated psychiatric disorders and substance use. Given the potential impact of antenatal mental disturbances on maternal and infant outcomes, further investigations into the psychiatric evaluation and treatment of pregnant women in the obstetrical sector are required.
Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis
Authors: F Gerald R Fowkes, Diana Rudan, Igor Rudan, Victor Aboyans, Julie O Denenberg, Mary M McDermott, Paul E Norman, Uchechukwe KA Sampson, Linda J Williams, George A Mensah, Michael H Criqui
Journal: The Lancet (2013)
Nitrostyrene Derivatives Act as RXRα Ligands to Inhibit TNFα Activation of NF-κB
Authors: Zhiping Zeng, Zhe Sun, Mingfeng Huang, Weidong Zhang, Jie Liu, Liqun Chen, Fan Chen, Yuqi Zhou, Jiacheng Lin, Fengyu Huang, Lin Xu, Zixing Zhuang, Shangjie Guo, Gulimiran Alitongbieke, Guobin Xie, Yang Xu, Bingzhen Lin, Xihua Cao, Ying Su, Xiao-kun Zhang, Hu Zhou
Journal: Cancer Research (2015)

Abstract Retinoid X receptor alpha (RXRα) and its N-terminally truncated version, tRXRα, are widely implicated in cancer development and represent intriguing targets for cancer prevention and treatment. Successful manipulation of RXRα and tRXRα requires the identification of their modulators that could produce therapeutic effects. Here, we report that a class of nitrostyrene derivatives bind to RXRα by a unique mechanism, of which the nitro group of nitrostyrene derivatives and Cys432 of RXRα are required for binding. The binding results in the potent activation of Gal4-DBD-RXRα-LBD transactivation. However, the binding inhibits the transactivation of RXRα homodimer, which might be due to the distinct conformation of RXRα homodimer induced by these nitrostyrene derivatives. Two RXRα point mutants with Cys432 substituted with Tyr and Trp, respectively, could mimic the bindings of two nitrostyrene derivatives and have the ability of autotransactivation. In studying the functional consequences of the binding, we show that these nitrostyrene derivatives could potently inhibit the TNFα/NFκB signaling pathway in a tRXRα-dependent manner. tRXRα promotes TNFα-induced NF-κB activation through its interaction with TRAF2 and enhances TNFα-induced ubiquitination of RIP1, which is strongly inhibited by nitrostyrene derivatives. The inhibition of TNFα-induced NF-κB activation results in the synergistic effect of the combination of nitrostyrene derivatives and TNFα on the induction of cancer cell apoptosis. Together, our results show a new class of RXRα modulators that induce apoptosis of cancer cells through their unique binding mode and new mechanism of action. Cancer Res; 75(10); 2049–60. ©2015 AACR.
Ovarian Cancer: Is Dose Intensity Dead?
Authors: Robert F. Ozols
Journal: Journal of Clinical Oncology (2007)

Dose Intensity Analysis of Chemotherapy Regimens in Ovarian Cancer."This retrospective analysis of the relationship between outcome and dose intensity in advanced ovarian cancer suggested that dose intensity was a major determinant of survival.While this was not the first article to suggest that high-dose therapy was important in ovarian cancer, the careful and detailed analysis of Levin and Hryniuk provided a persuasive rationale for prospective trials of dose intensity in ovarian cancer.Two decades later, we can conclude that increasing the dose intensity of currently available cytotoxic agents in ovarian cancer is a strategy that has failed to improve survival compared with conventional intravenous chemotherapy with carboplatin plus paclitaxel.The randomized trial comparing high-dose sequential chemotherapy with standard intravenous chemotherapy by Möbus et al in this issue of the Journal of Clinical Oncology 2 is the last nail in the coffin of this once important concept.After the report by Levin and Hryniuk, 1 investigators explored the role of dose intensity in two distinct strategies.The first was to perform randomized trials comparing regimens in which the dose intensities were essentially doubled.While the higher dose regimens were associated with increased toxicity, they could be administered with standard supportive care.Other investigators explored the role of high-dose chemotherapy, which required autologous support, initially in the form of bone marrow transplantations and, more recently, with peripheral blood stem cell (PBSC) transfusions.Eight randomized trials were conducted comparing doseintensity regimens of platinum compounds without autologous support, and Thigpen 3 summarized the results of those trials.Some of these trials increased the dose of cisplatin, others doubled the dose of carboplatin, and some trials combined cisplatin and carboplatin in the same regimen.Furthermore, some trials increased dose intensity as well as total doses of platinum compounds in the experimental arm.The Gynecologic Oncology Group (GOG) trial was perhaps the most definitive test of doubling dose intensity over a clinically relevant range. 4Patients with large-volume advanced disease were randomly assigned to either eight cycles of cisplatin (50 mg/m 2 ) plus cyclophosphamide (500 mg/m 2 ) or to four cycles of twice as much of each drug every 3 weeks.There were no differences in response, complete response, progression-free survival, or overall survival.Thigpen concluded that the weight of evidence from these eight trials suggested that increasing the dose intensity of carboplatin beyond an area under the curve (AUC) of 4 or a cisplatin dose greater than 25 mg/m 2 per week was not likely to result in increased efficacy.
Parents as equal partners in the paediatric cystic fibrosis multidisciplinary team
Authors: Mandy Bryon, Colin Wallis
Journal: Journal of the Royal Society of Medicine (2011)

There is currently no cure for cystic fibrosis (CF). Notwithstanding that, over the past 10 years there have been great improvements in the health status, life expectancy and therefore quality of life for people with CF. There is no single breakthrough in care that has made this difference but rather the introduction of small incremental changes and a new ethos of care. These include better surveillance of lung disease, better recognition of symptoms, tailored antibiotic therapy, a better understanding of the role of inflammation and infection on the lung and improved nutrition. The importance of caring for the vital childhood years to secure a better longterm future has mobilized CF teams to adopt programmes of early intervention and vigilance. There is good reason to maintain optimism with genetic and specific mutation research gathering pace and offering opportunity to halt deteriorating lung disease. But it is hard work for all involved.
P08.12 * WHOLE BRAIN RADIATION THERAPY OR GAMMA KNIFE RADIOSURGERY IN PATIENTS WITH &gt;=3 BRAIN METASTASES? RESULTS BASED ON A STUDY OF MORE THAN 600 DUTCH PATIENTS AND A REVIEW OF THE LITERATURE
Authors: B. Karlsson, P. E. J. Hanssens, M. Yamamoto, G. Beute, T. Kawabe, S. Watanabe, M. Soderman, K. LIm, T. Yeo
Journal: Neuro-Oncology (2014)

OBJECTIVES: The role of Gamma Knife Radiosurgery (GKRS) in the management of patients with ≥3 brain metastases (BM) is still controversial. Should GKRS, whole brain radiation therapy (WBRT) or both be given to these patients? A study was performed comparing the survival times in two Dutch patient populations with ≥3 BM managed with either WBRT or GKRS to try to find answers to these questions. MATERIAL AND METHODS: Data from patients with ≥3 BM treated with GKRS or WBRT were retrospectively analyzed. Patients with a Karnofsky score of <70 were excluded from the analysis. The survival times were compared to a number of patient and treatment parameters. The survival times following GKRS were also compared to those from patients with ≥3 BM treated with GKRS in Stockholm, Sweden and in Ibaraki, Japan. RESULTS: The median survival time among the 210 patients treated with WBRT was 3.6 months as compared to 6.5 months among the 481 patients treated with GKRS, P < 0.0001. Thirty percent of the patients treated with GKRS lived one year, 14% two and 5% five years following GKRS as compared to 7%, 1% and 0%, respectively, following WBRT. The median survival times were 4.9 months in the Stockholm and 7.0 months in the Ibaraki patient populations. There was no significant difference in survival times between patients with 3-4 and >4 BM in any of the centers neither following GKRS nor following WBRT. CONCLUSIONS: The survival times were significantly longer following GKRS as compared to following WBRT. Longer survival among the more recently treated patients and salvage treatment of recurrences in the GKRS group both contributed to this difference. The number of BM had no predictive power in this study. Almost a third of the patients survived a year or more in the GKRS group, suggesting that their prognosis is better nowadays than previously assumed.
Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study
Authors: D. N Juurlink, T. Gomes, L. L Lipscombe, P. C Austin, J. E Hux, M. M Mamdani
Journal: BMJ (2009)

To compare the risk of acute myocardial infarction, heart failure, and death in patients with type 2 diabetes treated with rosiglitazone and pioglitazone.Retrospective cohort study.Ontario, Canada.Outpatients aged 66 years and older who were started on rosiglitazone or pioglitazone between 1 April 2002 and 31 March 2008.Composite of death or hospital admission for either acute myocardial infarction or heart failure. In a secondary analysis, each outcome was also examined individually.39 736 patients who started on either pioglitazone or rosiglitazone were identified. During the six year study period, the composite outcome was reached in 895 (5.3%) of patients taking pioglitazone and 1563 (6.9%) of patients taking rosiglitazone. After extensive adjustment for demographic and clinical factors and drug doses, pioglitazone treated patients had a lower risk of developing the primary outcome than did patients treated with rosiglitazone (adjusted hazard ratio 0.83, 95% confidence interval 0.76 to 0.90). Secondary analyses revealed a lower risk of death (adjusted hazard ratio 0.86, 0.75 to 0.98) and heart failure (0.77, 0.69 to 0.87) with pioglitazone but no significant difference in the risk of acute myocardial infarction (0.95, 0.81 to 1.11). One additional composite outcome would be predicted to occur annually for every 93 patients treated with rosiglitazone rather than pioglitazone.Among older patients with diabetes, pioglitazone is associated with a significantly lower risk of heart failure and death than is rosiglitazone. Given that rosiglitazone lacks a distinct clinical advantage over pioglitazone, continued use of rosiglitazone may not be justified.
Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up
Authors: Linda Douw, Martin Klein, Selene SAA Fagel, Josje van den Heuvel, Martin JB Taphoorn, Neil K Aaronson, Tjeerd J Postma, W Peter Vandertop, Jacob J Mooij, Rudolf H Boerman, Guus N Beute, Jasper D Sluimer, Ben J Slotman, Jaap C Reijneveld, Jan J Heimans
Journal: The Lancet Neurology (2009)
CaM Kinase Kinase β-Mediated Activation of the Growth Regulatory Kinase AMPK Is Required for Androgen-Dependent Migration of Prostate Cancer Cells
Authors: Daniel E. Frigo, Matthew K. Howe, Bryan M. Wittmann, Abigail M. Brunner, Ian Cushman, Qianben Wang, Myles Brown, Anthony R. Means, Donald P. McDonnell
Journal: Cancer Research (2010)

While patients with advanced prostate cancer initially respond favorably to androgen ablation therapy, most experience a relapse of the disease within 1-2 years. Although hormone-refractory disease is unresponsive to androgen-deprivation, androgen receptor (AR)-regulated signaling pathways remain active and are necessary for cancer progression. Thus, both AR itself and the processes downstream of the receptor remain viable targets for therapeutic intervention. Microarray analysis of multiple clinical cohorts showed that the serine/threonine kinase Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) is both highly expressed in the prostate and further elevated in prostate cancers. Using cellular models of prostate cancer, we have determined that androgens (a) directly increase the expression of a CaMKKβ splice variant and (b) increase functional CaMKKβ protein levels as determined by the phosphorylation of both CaMKI and AMP-activated protein kinase (AMPK), two of CaMKKβ's primary substrates. Importantly, inhibition of the CaMKKβ-AMPK, but not CaMKI, signaling axis in prostate cancer cells by pharmacological inhibitors or siRNA-mediated knockdown blocks androgen-mediated migration and invasion. Conversely, overexpression of CaMKKβ alone leads to both increased AMPK phosphorylation and cell migration. Given the key roles of CaMKKβ and AMPK in the biology of prostate cancer cells, we propose that these enzymes are potential therapeutic targets in prostate cancer.
Human Postmeiotic Segregation 2 Exhibits Biased Repair at Tetranucleotide Microsatellite Sequences
Authors: Sandeep N. Shah, Kristin A. Eckert
Journal: Cancer Research (2009)

The mismatch repair (MMR) system plays a major role in removing DNA polymerization errors, and loss of this pathway results in hereditary cancers characterized by microsatellite instability. We investigated microsatellite stability during DNA replication within human postmeiotic segregation 2 (hPMS2)-deficient and proficient human lymphoblastoid cell lines. Using a shuttle vector assay, we measured mutation rates at reporter cassettes containing defined mononucleotide, dinucleotide, and tetranucleotide microsatellite sequences. A mutator phenotype was observed in the hPMS2-deficient cell line. The mutation rate of vectors containing [G/C](10) or [GT/CA](10) alleles was elevated 20-fold to 40-fold in hPMS2-deficient cells, relative to an hPMS2-expressing cell line. We observed a 6-fold and 12-fold relative increase in mutation rate of [TTTC/AAAG](9) and [TTCC/AAGG](9) sequences, respectively, in hPMS2-deficient cells. Mutational specificity analyses suggested that repair by hPMS2 is biased. In the absence of hPMS2, a greater number of microsatellite expansion versus deletion mutations was observed, and expansion rates of the tetranucleotide alleles were similar. In the presence of hPMS2, we observed a 29-fold decrease in the [TTCC/AAGG](9) expansion rate but only a 6-fold decrease for the [TTTC/AAAG](9) allele. Our data indicate that hPMS2 is more protective of tetranucleotide expansions than deletions and that hPMS2 displays a sequence bias, wherein [TTCC/AAGG] sequences are stabilized to a greater extent than [TTTC/AAAG]. Our results allow for greater accuracy during identification of MMR defects by providing a mutational signature characteristic of hPMS2 defect. This study also provides clues to possible mechanisms of repair by hPMS2 in the context of the MMR system.
Prokaryotic Evolution in Light of Gene Transfer
Authors: J. Peter Gogarten, W. Ford Doolittle, Jeffrey G. Lawrence
Journal: Molecular Biology and Evolution (2002)

Accumulating prokaryotic gene and genome sequences reveal that the exchange of genetic information through both homology-dependent recombination and horizontal (lateral) gene transfer (HGT) is far more important, in quantity and quality, than hitherto imagined. The traditional view, that prokaryotic evolution can be understood primarily in terms of clonal divergence and periodic selection, must be augmented to embrace gene exchange as a creative force, itself responsible for much of the pattern of similarities and differences we see between prokaryotic microbes. Rather than replacing periodic selection on genetic diversity, gene loss, and other chromosomal alterations as important players in adaptive evolution, gene exchange acts in concert with these processes to provide a rich explanatory paradigm—some of whose implications we explore here. In particular, we discuss (1) the role of recombination and HGT in giving phenotypic "coherence" to prokaryotic taxa at all levels of inclusiveness, (2) the implications of these processes for the reconstruction and meaning of "phylogeny," and (3) new views of prokaryotic adaptation and diversification based on gene acquisition and exchange.