tbuckley/cabot-search huggingface dataset:
Closing the Gap in Hypertension Control Between Younger and Older Adults
Authors: Brent M. Egan, Jiexiang Li, Ibrahim F. Shatat, J. Michael Fuller, Angelo Sinopoli
Journal: Circulation (2014)

Background— Joint National Committee goal blood pressure for all adults was &lt;140/&lt;90 mm Hg or lower from 1984 to 2013. Adults aged ≥60 years (older) have mainly isolated systolic hypertension, with major trials attaining systolic blood pressure &lt;150 but not &lt;140 mm Hg. The main objective was to assess changes in hypertension control to &lt;140/&lt;90 mm Hg in younger (aged &lt;60 years) and older adults and &lt;150/&lt;90 mm Hg in the latter. Methods and Results— National Health and Nutrition Examination Surveys (NHANES) 1988 to 1994, 1999 to 2004, and 2005 to 2010 were analyzed in adults aged ≥18 years. From 1988 to 1994 to 2005 to 2010, hypertension control to &lt;140/&lt;90 mm Hg improved in older (31.6% to 53.1%; P &lt;0.001) and younger (45.7% to 55.9%; P &lt;0.001) patients. The age gap in control declined from 14.1% ( P &lt;0.01) in 1988 to 1994 to 2.8% ( P =0.13) in 2005 to 2010. Better hypertension control reflected increased percentages of older (55.6% to 77.5%) and younger (34.6% to 54.7%) patients on treatment and treated older (45.7% to 64.9%) and younger (56.8% to 73.4%) patients controlled (all P &lt;0.001). Control to &lt;150/&lt;90 mm Hg rose from 48.8% to 69.9% in older adults. Antihypertensive medication number and percentages on ≥3 medications increased in both age groups but increased more in older patients ( P &lt;0.01). Blood pressure control was higher in both age groups with ≥2 healthcare visits per year and on statin therapy. Conclusions— The age gap in hypertension control to &lt;140/&lt;90 mm Hg was virtually eliminated in 2005 to 2010 as clinicians intensified therapy, especially in older patients in whom isolated systolic hypertension predominates, controlling 70% to &lt;150/&lt;90 mm Hg. More frequent healthcare visits and the use of statin therapy may improve hypertension control in all adults.
Should Sulfonylureas Remain an Acceptable First-Line Add-on to Metformin Therapy in Patients With Type 2 Diabetes? Yes, They Continue to Serve Us Well!
Authors: Martin J. Abrahamson
Journal: Diabetes Care (2014)

Since their introduction to clinical practice in the 1950s, sulfonylureas have been widely prescribed for use in patients with type 2 diabetes. Of all the other medications currently available for clinical use, only metformin has been used more frequently. However, several new drug classes have emerged that are reported to have equal glucose-lowering efficacy and greater safety when added to treatment of patients in whom metformin monotherapy is no longer sufficient. Moreover, current arguments also suggest that the alternative drugs may be superior to sulfonylureas with regard to the risk of cardiovascular complications. Thus, while there is universal agreement that metformin should remain the first-line pharmacologic therapy for those in whom lifestyle modification is insufficient to control hyperglycemia, there is no consensus as to which drug should be added to metformin. Therefore, given the current controversy, we provide a Point-Counterpoint on this issue. In the point narrative presented below, Dr. Abrahamson provides his argument suggesting that avoiding use of sulfonylureas as a class of medication as an add-on to metformin is not appropriate as there are many patients whose glycemic control would improve with use of these drugs with minimal risk of adverse events. In the following counterpoint narrative, Dr. Genuth suggests there is no longer a need for sulfonylureas to remain a first-line addition to metformin for those patients whose clinical characteristics are appropriate and whose health insurance and/or financial resources make an alternative drug affordable.
Brain surgery gets its first live UK broadcast
Authors: Kristina Fister
Journal: BMJ (2004)

Live from Brainworks at the Science Museum's Dana Centre, London NW1 Thursday 28 October www.danacentre.org.uk/ Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img> H ow many non-neurosurgical medical professionals have had the chance to observe a full course of brain surgery during their entire medical training and careers? Probably very few, but about a hundred Londoners witnessed such an operation last week. The British public's first opportunity to see brain surgery live was broadcast from the United States, as Dr Robert Hadosh, medical director of the Neuroscience Institute at Overlook Hospital, New Jersey, removed a recurring meningioma of 3.5 cm in diameter from a 71 year old patient with a history of previous operation and radiation. The … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif
Bile salts induce calcium uptake in vitro by human erythrocytes
Authors: David G. Oelberg, William P. Dubinsky, Jeffrey W. Sackman, Leslie B. Wang, Eugene W. Adcock, Roger Lester
Journal: Hepatology (1987)

At high concentrations, bile salts induce hemolysis by comicellization of lipid components of the cell membrane. However, bile salts are also associated with hemolysis at lower concentrations by mechanisms which have not been characterized. To investigate the possibility that bile salts promote calcium uptake by red blood cells and that bile salt-associated hemolysis is, in part, calcium-mediated, calcium uptake by red blood cells was measured in the presence of individual bile salts, and hemolysis dependence upon calcium availability was examined. Washed human red blood cells with or without ATP depletion were incubated with 1 mM CaCl2 and tracer amounts of 45CaCl2 in the presence of selected bile salts at concentrations (0.01 to 0.3 mM) reported to be below critical micellar concentrations. Calcium uptake (defined for the purposes of this study as 45Ca retained in red blood cells) was monitored over 5 hr, after which hemolysis and membrane phospholipid content were determined. The presence of bile salts stimulated calcium uptake 4- to 25-fold--the magnitude of which was partly related to the lipid solubility of the bile salts. ATP depletion or exposure to trifluoperazine, procedures which inhibit calcium pump activity in red blood cells, enhanced bile salt-induced calcium uptake relative to controls. The percentage of associated hemolysis (2 to 14%) at the end of 5 hr correlated directly with the observed calcium uptake. Removal of calcium from the extracellular space reduced hemolysis in the presence of bile salts to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Dysregulated T cell expression of TIM3 in multiple sclerosis
Authors: Ken Koguchi, David E. Anderson, Li Yang, Kevin C. O'Connor, Vijay K. Kuchroo, David A. Hafler
Journal: The Journal of Experimental Medicine (2006)

T cell immunoglobulin- and mucin domain–containing molecule (TIM)3 is a T helper cell (Th)1–associated cell surface molecule that regulates Th1 responses and promotes tolerance in mice, but its expression and function in human T cells is unknown. We generated 104 T cell clones from the cerebrospinal fluid (CSF) of six patients with multiple sclerosis (MS) (n = 72) and four control subjects (n = 32) and assessed their cytokine profiles and expression levels of TIM3 and related molecules. MS CSF clones secreted higher amounts of interferon (IFN)-γ than did those from control subjects, but paradoxically expressed lower levels of TIM3 and T-bet. Interleukin 12–mediated polarization of CSF clones induced substantially higher amounts of IFN-γ secretion but lower levels of TIM3 in MS clones relative to control clones, demonstrating that TIM3 expression is dysregulated in MS CSF clones. Reduced levels of TIM3 on MS CSF clones correlated with resistance to tolerance induced by costimulatory blockade. Finally, reduction of TIM3 on ex vivo CD4+ T cells using small interfering (si)RNA enhanced proliferation and IFN-γ secretion, directly demonstrating that TIM3 expression on human T cells regulates proliferation and IFN-γ secretion. Failure to up-regulate T cell expression of TIM3 in inflammatory sites may represent a novel, intrinsic defect that contributes to the pathogenesis of MS and other human autoimmune diseases.
Abstract 1463: PARP inhibition reverses radiation resistance conferred by ETS fusions in prostate cancer
Authors: Sumin Han, Chad Brenner, Aaron Sabolch, Kari Wilder-Romans, Karen Knudsen, Theodore Lawrence, Arul Chinnaiyan, Felix Feng
Journal: Cancer Research (2012)

Abstract Background: ETS gene fusions, which are found in approximately half of all prostate cancers, result in overexpression of ETS transcription factors, of which ERG is the prototype. We previously discovered that ERG interacts with the DNA damage response protein poly (ADP-ribose) polymerase 1 (PARP1). Therefore, we hypothesized that the ERG-PARP1 interaction may confer radiation resistance by increasing DNA repair efficiency, and this radioresistance can be reversed with PARP1 inhibition. Methods: We used lentiviral approaches to establish isogenic models of ERG overexpression in PC3 and DU145 prostate cancer cell lines. We then assessed the role of ERG overexpression on 1) PARP1 activity (via immunoblots for poly ADP-ribose (PAR) formation), 2) DNA repair (via COMET assays and immunofluorescent microscopy for gamma-H2aX foci), and 3) clonogenic survival, before and following radiation +/− the PARP1 inhibitor olaparib. We also created ERG mutants with a point mutation (Y373) which disrupted the ERG-PARP interaction, and assessed the role of this interaction on radiation response. Finally, we established xenografts from ERG-overexpressing and control PC3 cells, and treated these xenografts with radiation +/− PARP1 inhibition. Results: In both PC3 and DU145 cells, ERG overexpression resulted in increased PARP1 activity and quicker repair of DNA damage, both of which were reversed with olaparib. ERG overexpression resulted in a 1.3 fold increase in clonogenic survival following radiation, consistent with radioresistance. PARP1 inhibition with olaparib preferentially radiosensitized ERG-positive cells, by a factor of 1.5 relative to ERG-negative cells (p&amp;lt;0.05). Additionally, disruption of ERG-PARP interaction via point mutation reversed the ERG-mediated increase in clonogenic survival following radiation. Within PC3 xenografts, ERG overexpression also conferred radioresistance which was reversed with PARP1 inhibition. Conclusions: In these prostate cancer cell models, ERG overexpression confers radiation resistance via increased efficiency of DNA repair following radiation. This radioresistance is dependent on the ERG-PARP1 interaction, and can be reversed via inhibition of PARP1 both in vitro and in vivo. These novel findings motivate the use of PARP1 inhibitors as radiosensitizers in patients with localized ETS fusion-positive prostate cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1463. doi:1538-7445.AM2012-1463
Effects of Smoking on the Pharmacokinetics of Erlotinib
Authors: Marta Hamilton, Julie L. Wolf, Jason Rusk, Shannon E. Beard, Gary M. Clark, Karsten Witt, Pablo J. Cagnoni
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To compare the pharmacokinetic variables of erlotinib in current smokers with nonsmokers after receiving a single oral 150 or 300 mg dose of erlotinib. Experimental Design: This was a single-center, open-label pharmacokinetic study in healthy male subjects. Subjects were enrolled into two treatment cohorts based on smoking status (current smokers and nonsmokers). The pharmacokinetic profile for erlotinib and its metabolite, OSI-420, was determined for each subject following each treatment. Results: Current smokers achieved significantly less erlotinib exposure following a single 150 or 300 mg dose than nonsmokers. Following the 150 mg dose, the geometric mean erlotinib AUC0-∞ in smokers was 2.8-fold lower than in nonsmokers and similar to that of nonsmokers at the 300 mg dose. Cmax in smokers was two-thirds of that in nonsmokers, and C24h in smokers was 8.3-fold lower than in nonsmokers. The median C24h of smokers at the 300 mg dose was slightly less than the C24h of smokers at the 150 mg dose. The median Cmax was greater in smokers at the 300 mg dose than in nonsmokers at the 150 mg dose. Conclusion: This study confirms that the pharmacokinetics of erlotinib is different in current smokers and nonsmokers. The observation that AUC0-∞ and C24h were significantly decreased in smokers compared with nonsmokers, and a smaller decrease in Cmax was observed, is consistent with increased metabolic clearance of erlotinib in current smokers.
Exercise training in COPD patients: the basic questions
Authors: R Gosselink, T Troosters, M Decramer
Journal: European Respiratory Journal (1997)

Pulmonary rehabilitation programmes aim at improving exercise capacity, activities of daily living, quality of life and perhaps survival in patients with chronic obstructive pulmonary disease (COPD). Recently, well-designed studies investigated and confirmed the efficacy of comprehensive pulmonary rehabilitation programmes, including exercise training, breathing exercises, optimal medical treatment, psychosocial support and health education. In the present overview, the contribution of exercise training in clinical practice to the demonstrated effects of pulmonary rehabilitation is discussed by means of six basic questions. These include: 1) the significance of exercise training; 2) the optimal intensity for exercise training; 3) prescribing training modalities; 4) the effects of exercise training combined with medication, nutrition or oxygen; 5) how training effects should be maintained; and 6) where the rehabilitation programme should be performed: in-patient, out-patient or homecare? First, exercise training has been proven to be an essential component of pulmonary rehabilitation. Training intensity is of key importance. High-intensity training (&gt;70% maximal workload) is feasible even in patients with more advanced COPD. In addition, the effects on peripheral muscle function and ventilatory adaptations are superior to low-intensity training. There is, however, no consensus on the optimal training modalities. Both walking and cycling improved exercise performance. Since peripheral muscle function has been recognized as an important contributor to exercise performance, specific peripheral muscle training recently gained interest. Improved submaximal exercise performance and increased quality of life were found after muscle training. The optimal training regimen (strength or endurance) and the muscle groups to be trained, remain to be determined. Training of respiratory muscles is recommended in patients with ventilatory limitation during exercise. The additional effects of anabolic-androgenic drugs, oxygen and nutrition are not well-established in COPD patients and need further research. In order to maintain training effects, close attention of the rehabilitation team is required. The continuous training frequency necessary to maintain training effects remains to be defined. At this point in time, out-patient-based programmes show the best results and guarantee the best supervision and a multidisciplinary approach. Future research should focus on the role of homecare programmes to maintain improvements.
Management of Metastatic Cervical Cancer: Should We Ignore Lessons Learned From Treating Other Advanced Squamous Cell Cancers?
Authors: Joel S. Grossman
Journal: Journal of Clinical Oncology (2015)

TO THE EDITOR: The study by Miller et al and its accompanying editorial by Monk et al have raised some important issues. After reviewing the National Comprehensive Cancer Network guidelines and other literature on metastatic cervical cancer, I have become concerned that the division of labor in subspecialty oncology has led to an unsettling situation in which general and important medical oncology information is seriously underappreciated or even lacking. This is highlighted by the statement in the Discussion section of the Miller et al article in which the authors explain that the trial was pursued “on the basis of the biologic rationale as well as its activity in other squamous cell cancers.” In fairness, this would have been a reasonable assertion in 2008 when this trial started; however, I find it disturbing that there is no mention in the article or accompanying editorial of what we have learned about pemetrexed in other squamous cell cancers between when the trial started and when the Miller et al article was submitted for publication. Specifically, in squamous cell lung cancer, pemetrexed has completely fallen out of favor and has lost its indication for treating that far more common disease. Differences in outcomes based on histology were first delineated in an article by Scagliotti et al. Shortly after publication of that article, Ciuleanu et al reported that for squamous cell lung cancer, in contrast to other histologic subtypes, pemetrexed had no benefit greater than placebo with respect to progression-free survival, overall survival, or disease control rate. Similarly, pemetrexed offers no benefit to those with head and neck cancer, the second most common squamous cell cancer treated by medical oncologists. Eli Lilly announced in 2010 they would not seek approval for the use of pemetrexed in head and neck cancer. More concerning, in the editorial written about a case of metastatic cervical cancer to the pelvic sidewall, para-aortic and pelvic nodes, and bilateral pulmonary nodules, the authors recommend paclitaxel, carboplatin, and high-dose bevacizumab. Although this is perfectly in line with National Comprehensive Cancer Network guidelines and published disease-specific data, it is important to point out the potential for life-threatening pulmonary hemorrhage based on data for treating squamous cell lung cancer with bevacizumab. If the authors’ position is that the lack of either cavitation, existing hemoptysis, or central location renders bevacizumab a favorable choice in the case presented, this rationale would be instructive for the reader to know. We should all share a fear for a possible future in which oncology treatment is largely conducted by overworked and undersupervised midlevel providers who guide patients along established, financially driven pathways. Now, more than ever, we need to use all the knowledge available to us to ensure that our recommendations are both effective and safe.
Phosphorylation/Cytoplasmic Localization of p21Cip1/WAF1 Is Associated with HER2/<b> <i>neu</i> </b> Overexpression and Provides a Novel Combination Predictor for Poor Prognosis in Breast Cancer Patients
Authors: Weiya Xia, Jin-Shing Chen, Xian Zhou, Pei-Rong Sun, Dung-Fang Lee, Yong Liao, Binhua P. Zhou, Mien-Chie Hung
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The diversity of biological functions makes p21Cip1/WAF1 (p21) a controversial marker in predicting the prognosis of breast cancer patients. Recent laboratory studies revealed that the regulation of p21 function could be related to different subcellular localizations of p21 by Akt-induced phosphorylation at threonine 145 in HER2/neu-overexpressing breast cancer cells. The purpose of this study was to verify these findings in clinical settings. Experimental Design: The expression status of the key biological markers in the HER2/neu-Akt-p21 pathway in 130 breast cancer specimens was evaluated by immunohistochemical staining and correlated with patients’ clinical parameters and survival. In addition, an antibody against phospho-p21 at threonine 145 [phospho-p21 (T145)] was also used for better validation of these findings. Results: Cytoplasmic localization of p21 is highly correlated with overexpression of phospho-p21 (T145). Both cytoplasmic p21 and overexpression of phospho-p21 (T145) are associated with high expression of HER2/neu and phospho-Akt. Cytoplasmic localization of p21 and overexpression of phospho-p21 (T145), HER2/neu, and phospho-Akt are all associated with worse overall survival. Multivariate analysis of the Cox proportional hazard regression model revealed that cytoplasmic p21 and overexpression of HER2/neu are independently associated with increased risk of death. Combining these two factors stratified patients’ survival into four distinct groups, with a 5-year survival rate of 79% in low HER2/neu and negative/nuclear p21 patients, 60% in high HER2/neu and negative/nuclear p21 patients, 29% in low HER2/neu and cytoplasmic p21 patients, and 16% in high HER2/neu and cytoplasmic p21 patients. Conclusions: The present study, in addition to supporting the mechanisms of p21 regulation derived from laboratory investigation, demonstrates the prognostic importance of phospho-p21 (T145) for the first time and also provides a novel combination of p21 and HER2/neu for better stratification of patients’ survival than any single clinicopathological or biological marker that may play important diagnostic and therapeutic roles for breast cancer patients.
The rational clinical examination. Physical examination of the liver
Authors: C D Naylor
Journal: JAMA (1994)

<h3>CLINICAL SCENARIO</h3> The patient in your examining room is new to the practice. He is 52 years old, emigrated from Southeast Asia about 10 years ago, and has no specific complaints except fatigue. On examination you find little of note except that his liver edge is firm, easily felt, and extends about 6 cm below the costal margin across much of the right upper quadrant. The span, by light percussion, is 17 or 18cm. Should you be concerned? What does the research literature tell us about the meaning of these findings? Ideally, the clinical meaning of physical examination findings should be established in research studies that account for the overall context, including other signs and details from the medical history. This approach is difficult in liver disease, because the physical manifestations of hepatic dysfunction are protean and many multisystem diseases affect the liver. Our focus, therefore, is on physical examination
Psychotogenic Properties of Cyclopentolate
Authors: Harry H. Mark
Journal: JAMA (1963)

IT IS ALWAYS unpleasant for the physician and patient to be confronted with peculiar, unexpected reactions to a drug which was administered for its beneficial effects. The drug in this case is cyclopentolate (Cyclogyl) hydrochloride, an anticholinergic agent used in eye drop form. In customary use of aqueous solutions of 0.5% to 2.0%, cycloplegia and mydriasis occur within 30 min of instillation of one drop into the conjunctival cul-de-sac. Since its introduction some 10 years ago, cyclopentolate gained wide popularity, particularly among ophthalmologists. The rapid onset and short duration of its action made the drug almost ideal for ophthalmoscopy and refraction in children. Furthermore, serious side effects had not been encountered until the recent publication of two such cases.<sup>1,2</sup> It is the purpose of this report to illustrate, by way of four cases, the psychotogenic properties of cyclopentolate, and to point out the chemical similarity of the drug to