tbuckley/cabot-search huggingface dataset:
Albumin absorption and catabolism by isolated perfused proximal convoluted tubules of the rabbit.
Authors: C H Park, T Maack
Journal: Journal of Clinical Investigation (1984)

Overall characteristics and kinetics of tubular absorption of albumin (Alb) were studied in isolated perfused proximal convoluted tubules of the rabbit. The fate of absorbed Alb was determined in tubules perfused with low [Alb]. Alb was labeled with tritium by reductive methylation ( [3H3C]Alb). At [Alb] = 0.03 mg/ml, approximately 80% of the absorbed [3H3C]Alb was released to the peritubular bathing solution as catabolic products. Transcellular transport of intact [3H3C]Alb was negligible. Iodoacetate (IAA, 4 mM) inhibited albumin absorption (JAlb) by greater than 95% and fluid reabsorption (JV) by 55%. At [Alb] = 0.1 mg/ml the absorption rate of a derivatized cationic Alb (pI = 8.4) was fivefold greater (P less than 0.01) than that of anionic Alb. Higher cationic [Alb] had deleterious effects on tubular functions. Overall Alb absorption was of high capacity and low affinity (JmaxAlb = 3.7 ng/min per mm tubule length, apparent Michaelis constant (Km) = 1.2 mg/ml). A low capacity system that saturates at near physiological loads was also detected (JmaxAlb = 0.064 ng/min per mm, apparent Km = 0.031 mg/ml). High [Alb] did not alter the rate of endocytic vesicle formation as determined by the tubular uptake of [14C]inulin. Results show that Alb absorption is a saturable process that is inhibited by high IAA concentrations and is affected by the charge of the protein. Absorbed Alb is hydrolyzed by tubular cells and catabolic products are readily released to the peritubular side. The dual kinetics of Alb absorption may be due to a combination of adsorptive endocytosis (low capacity system) and fluid endocytosis of albumin aggregates (high capacity system). Results indicate that albuminuria occurs much before albumin absorption is saturated. The kinetic characteristics of the process of tubular absorption of albumin helps to explain the concomitance of albuminuria, increased renal catabolic rates of albumin, and renal cell deposition of protein absorption droplets in severe glomerular proteinurias.
Underexpression of RhoH in Hairy Cell Leukemia
Authors: Sylvie Galiègue-Zouitina, Laure Delestré, Caroline Dupont, Xavier Troussard, Carl Simon Shelley
Journal: Cancer Research (2008)

Abstract The cause of hairy cell leukemia (HCL) is unknown. Current treatments seem effective only for a limited period of time. In addition, a significant proportion of patients remain refractive to all treatment options. These considerations indicate the need to develop alternative therapeutic strategies for HCL. Here, we report that HCL is characterized by underexpression of RhoH. In vitro reconstitution of RhoH expression inhibits the aberrant adhesion and transendothelial migration that drives disease pathogenesis. In an in vivo model of HCL, RhoH reconstitution limits malignant progression and protects against mortality. These findings provide the proof of principle that RhoH reconstitution represents a potential new approach to the treatment of HCL. [Cancer Res 2008;68(12):4531–40]
Feedback-Driven Trial-by-Trial Learning in Autism Spectrum Disorders
Authors: Marjorie Solomon, Michael J. Frank, J. Daniel Ragland, Anne C. Smith, Tara A. Niendam, Tyler A. Lesh, David S. Grayson, Jonathan S. Beck, John C. Matter, Cameron S. Carter
Journal: American Journal of Psychiatry (2014)

Objective: Impairments in learning are central to autism spectrum disorders. The authors investigated the cognitive and neural basis of these deficits in young adults with autism spectrum disorders using a well-characterized probabilistic reinforcement learning paradigm. Method: The probabilistic selection task was implemented among matched participants with autism spectrum disorders (N=22) and with typical development (N=25), aged 18–40 years, using rapid event-related functional MRI. Participants were trained to choose the correct stimulus in high-probability (AB), medium-probability (CD), and low-probability (EF) pairs, presented with valid feedback 80%, 70%, and 60% of the time, respectively. Whole-brain voxel-wise and parametric modulator analyses examined early and late learning during the stimulus and feedback epochs of the task. Results: The groups exhibited comparable performance on medium- and low-probability pairs. Typically developing persons showed higher accuracy on the high-probability pair, better win-stay performance (selection of the previously rewarded stimulus on the next trial of that type), and more robust recruitment of the anterior and medial prefrontal cortex during the stimulus epoch, suggesting development of an intact reward-based working memory for recent stimulus values. Throughout the feedback epoch, individuals with autism spectrum disorders exhibited greater recruitment of the anterior cingulate and orbito-frontal cortices compared with individuals with typical development, indicating continuing trial-by-trial activity related to feedback processing. Conclusions: Individuals with autism spectrum disorders exhibit learning deficits reflecting impaired ability to develop an effective reward-based working memory to guide stimulus selection. Instead, they continue to rely on trial-by-trial feedback processing to support learning dependent upon engagement of the anterior cingulate and orbito-frontal cortices.
Efficacy Studies to Large-Scale Transport: The Development and Validation of Multisystemic Therapy Programs
Authors: Scott W. Henggeler
Journal: Annual Review of Clinical Psychology (2011)

The 35-year progression of multisystemic therapy (MST) from modest university-based efficacy studies to large-scale transport to community practice settings is described in this review. The success of early efficacy research led to effectiveness trials, and their success in decreasing rates of youth rearrest and incarceration led to multisite transportability trials and adaptations of the MST model for treating youth presenting other types of challenging clinical problems. To support the transport of MST programs to community settings, an intensive quality improvement system modeled after that used in clinical trials has been implemented in community-based MST programs for the past 15 years. With the association between therapist treatment fidelity and youth outcomes well established, transportability research has demonstrated the significant roles played by clinical supervisors, expert consultants, and provider organizations in supporting therapist adherence and youth outcomes. This body of work has been facilitated by federal and state initiatives to support evidence-based services.
Plasma somatomedin-C levels in systemic sclerosis
Authors: M.J. ROTHE, R.D. ALTMAN, V. FALANGA
Journal: British Journal of Dermatology (1988)

We have measured the plasma levels of somatomedin-C (SM-C) or insulin-like growth factor I (IGF-I) in 13 patients with progressive systemic sclerosis (PSS) and age and sex matched healthy controls. We found the plasma SM-C levels to be within normal limits in all the patients. Thus, if somatomedin-C plays a role in the pathogenesis of PSS, it is more likely to be at the fibroblast receptor level or in the synthetic response of fibroblasts to SM-C.
The Immunological Synapse
Authors: Shannon K. Bromley, W. Richard Burack, Kenneth G. Johnson, Kristina Somersalo, Tasha N. Sims, Cenk Sumen, Mark M. Davis, Andrey S. Shaw, Paul M. Allen, Michael L. Dustin
Journal: Annual Review of Immunology (2001)

The adaptive immune response is initiated by the interaction of T cell antigen receptors with major histocompatibility complex molecule-peptide complexes in the nanometer scale gap between a T cell and an antigen-presenting cell, referred to as an immunological synapse. In this review we focus on the concept of immunological synapse formation as it relates to membrane structure, T cell polarity, signaling pathways, and the antigen-presenting cell. Membrane domains provide an organizational principle for compartmentalization within the immunological synapse. T cell polarization by chemokines increases T cell sensitivity to antigen. The current model is that signaling and formation of the immunological synapse are tightly interwoven in mature T cells. We also extend this model to natural killer cell activation, where the inhibitory NK synapse provides a striking example in which inhibition of signaling leaves the synapse in its nascent, inverted state. The APC may also play an active role in immunological synapse formation, particularly for activation of naïve T cells.
THE CRITICAL ROLE OF THE MELANOCORTIN SYSTEM IN THE CONTROL OF ENERGY BALANCE
Authors: Randy J. Seeley, Deborah L. Drazen, Deborah J. Clegg
Journal: Annual Review of Nutrition (2004)

Animals have developed highly adaptive and redundant mechanisms to maintain energy balance by matching caloric intake to caloric expenditure. Recent evidence has pointed to a variety of peripheral signals that inform specific central nervous system (CNS) circuits about the status of peripheral energy stores as critical to the maintenance of energy balance. A critical component of these CNS circuits is the melanocortin system. Regulation of signaling by melanocortin 3 and melanocortin 4 receptors in the CNS is controlled via neuronal cell bodies in the arcuate nucleus of the hypothalamus that synthesize melanocortin receptor agonists such as alpha-melanocyte-stimulating hormone (alpha-MSH) or antagonists such as agouti-related protein (AgRP). The activity of these two populations of neurons is reciprocally regulated by a number of peripheral and central systems that influence energy balance. Further, increased melanocortin signaling via pharmacological or genetic means in the CNS causes potent reductions in food intake and weight loss. Decreased melanocortin signaling via pharmacological or genetic means results in increased food intake and weight gain. Reviewed here is the wide range of evidence that points to the melanocortin system as a critical node in the diverse neurocircuitry that regulates food intake and body weight.
Temporal Changes in Incidence of Dialysis-Requiring AKI
Authors: Raymond K. Hsu, Charles E. McCulloch, R. Adams Dudley, Lowell J. Lo, Chi-yuan Hsu
Journal: Journal of the American Society of Nephrology (2012)

The population epidemiology of AKI is not well described. Here, we analyzed data from the Nationwide Inpatient Sample, a nationally representative dataset, to identify cases of dialysis-requiring AKI using validated International Classification of Diseases, Ninth Revision (ICD-9) codes. From 2000 to 2009, the incidence of dialysis-requiring AKI increased from 222 to 533 cases per million person-years, averaging a 10% increase per year (incidence rate ratio=1.10, 95% CI=1.10-1.11 per year). Older age, male sex, and black race associated with higher incidence of dialysis-requiring AKI. The rapid increase in incidence was evident in all age, sex, and race subgroups examined. Temporal changes in the population distribution of age, race, and sex as well as trends of sepsis, acute heart failure, and receipt of cardiac catheterization and mechanical ventilation accounted for about one third of the observed increase in dialysis-requiring AKI among hospitalized patients. The total number of deaths associated with dialysis-requiring AKI rose from 18,000 in 2000 to nearly 39,000 in 2009. In conclusion, the incidence of dialysis-requiring AKI increased rapidly in all patient subgroups in the past decade in the United States, and the number of deaths associated with dialysis-requiring AKI more than doubled.
Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor
Authors: Richard Rozmahe, Michael Wilschanski, Angabin Matin, Suzanne Plyte, Mary Oliver, Wojtek Auerbach, Aideen Moore, Janet Forstner, Peter Durie, Joseph Nadeau, Christine Bear, Lap-Chee Tsui
Journal: Nature Genetics (1996)
How Cardiologists Present the Benefits of Percutaneous Coronary Interventions to Patients With Stable Angina
Authors: Sarah L. Goff, Kathleen M. Mazor, Henry H. Ting, Reva Kleppel, Michael B. Rothberg
Journal: JAMA Internal Medicine (2014)

<h3>Importance</h3> Patients with stable coronary artery disease (CAD) attribute greater benefit to percutaneous coronary interventions (PCI) than indicated in clinical trials. Little is known about how cardiologists’ presentation of the benefits and risks may influence patients’ perceptions. <h3>Objectives</h3> To broadly describe the content of discussions between patients and cardiologists regarding angiogram and PCI for stable CAD, and to describe elements that may affect patients’ understanding. <h3>Design, Setting, and Participants</h3> Qualitative content analysis of encounters between cardiologists and patients with stable CAD who participated in the Verilogue Point-of-Practice Database between March 1, 2008, and August 31, 2012. Transcripts in which angiogram and PCI were discussed were retrieved from the database. Patients were aged 44 to 88 years (median, 64 years); 25% were women; 50% reported symptoms of angina; and 6% were taking more than 1 medication to treat angina. <h3>Main Outcomes and Measures</h3> Results of conventional and directed qualitative content analysis. <h3>Results</h3> Forty encounters were analyzed. Five major categories and subcategories of factors that may affect patients’ understanding of benefit were identified: (1) rationale for recommending angiogram and PCI (eg, stress test results, symptoms, and cardiologist’s preferences); (2) discussion of benefits (eg, accurate discussion of benefit [5%], explicitly overstated benefit [13%], and implicitly overstated benefit [35%]); (3) discussion of risks (eg, minimization of risk); (4) cardiologist’s communication style (eg, humor, teach-back, message framing, and failure to respond to patient questions); and (5) patient and family member contributions to the discussion. <h3>Conclusions and Relevance</h3> Few cardiologists discussed the evidence-based benefits of angiogram and PCI for stable CAD, and some implicitly or explicitly overstated the benefits. The etiology of patient misunderstanding is likely multifactorial, but if future quantitative studies support the findings of this hypothesis-generating analysis, modifications to cardiologists’ approach to describing the risks and benefits of the procedure may improve patient understanding.
Asymptomatic Autoantibodies Associate with Future Anti-glomerular Basement Membrane Disease
Authors: Stephen W. Olson, Charles B. Arbogast, Thomas P. Baker, David Owshalimpur, David K. Oliver, Kevin C. Abbott, Christina M. Yuan
Journal: Journal of the American Society of Nephrology (2011)

The pathophysiology of anti-glomerular basement membrane (anti-GBM) disease before clinical presentation is unknown. The presence of anti-GBM, anti-proteinase 3 (PR3), and anti-myeloperoxidase (MPO) antibodies associate with the disease at the time of diagnosis, but little is known about the presence of these autoantibodies before diagnosis. We used serum samples from the Department of Defense Serum Repository to conduct a case-control study involving 30 patients diagnosed with anti-GBM disease and 30 healthy controls matched for the age, gender, race, and age of the serum samples. We analyzed a maximum of three samples from each subject: the most recent sample before diagnosis, the penultimate sample before diagnosis, and the oldest sample available; the average time between the most recent sample and diagnosis was 195 days (range, 4 to 1346 days). Elevated anti-GBM levels (≥3 U/ml) were present in four patients, all less than 1 year before diagnosis but in no controls. Detectable anti-GBM antibody levels (≥1 U/ml but <3 U/ml) in a single serum sample before diagnosis were more frequent in cases than controls (70% versus 17%, P < 0.001). Only study patients had detectable anti-GBM levels in multiple samples before diagnosis (50% versus 0%, P < 0.001). Almost all patients had detectable anti-PR3 and/or anti-MPO that preceded the onset of disease. Among patients with a clear antecedent antibody, anti-PR3 or anti-MPO always became detectable before the anti-GBM antibody. In summary, our data describe the subclinical formation of autoantibodies, which improves our understanding of the pathophysiology of anti-GBM disease.
Cervical Cancer Screening in Older Women: New Evidence and Knowledge Gaps
Authors: Anne F. Rositch, Michelle I. Silver, Patti E. Gravitt
Journal: PLoS Medicine (2014)

Anne Rositch and colleagues discuss the study by Peter Sasieni and colleagues on cervical cancer screening in older women and describe the further information needed to help inform decisions about whether to extend screening programs beyond 65 years for women with adequate negative screening. Please see later in the article for the Editors' Summary
Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice
Authors: Katerina Vlantis, Andy Wullaert, Yoshiteru Sasaki, Marc Schmidt-Supprian, Klaus Rajewsky, Tania Roskams, Manolis Pasparakis
Journal: Journal of Clinical Investigation (2011)

Many cancers display increased NF-κB activity, and NF-κB inhibition is known to diminish tumor development in multiple mouse models, supporting an important role of NF-κB in carcinogenesis. NF-κB activation in premalignant or cancer cells is believed to promote tumor development mainly by protecting these cells from apoptosis. However, it remains unclear to what extent NF-κB activation exhibits additional protumorigenic functions in premalignant cells that could be sufficient to induce spontaneous tumor development. Here we show that expression of constitutively active IκB kinase 2 (IKK2ca) in mouse intestinal epithelial cells (IECs) induced spontaneous tumors in aged mice and also strongly enhanced chemical- and Apc mutation-mediated carcinogenesis. IECs expressing IKK2ca displayed altered Wnt signaling and increased proliferation and elevated expression of genes encoding intestinal stem cell-associated factors including Ascl2, Olfm4, DLK1, and Bmi-1, indicating that increased IKK2/NF-κB activation synergized with Wnt signaling to drive intestinal tumorigenesis. Moreover, IECs expressing IKK2ca produced cytokines and chemokines that induced the recruitment of myeloid cells and activated stromal fibroblasts to become myofibroblasts, thus creating a tumor-promoting microenvironment. Taken together, our results show that constitutively increased activation of IKK2/NF-κB signaling in the intestinal epithelium is sufficient to induce the full spectrum of cell-intrinsic and stromal alterations required for intestinal tumorigenesis.
Financial Crisis in Medical Education Support
Authors: E. N. Goren
Journal: JAMA (1970)

To the Editor:—  As students in several Medical Scientist Training Programs, some of which are supported by the National Institutes of Health, our own support has been assured despite the current scientific fiscal crisis. Nonetheless, we are most concerned with the tightening financial noose that is undermining and threatening the scientific institutions that have provided this country with both major medical advances and highly skilled physicians.  Our programs train us for both the MD and PhD degrees. It would be quite easy to ignore these current financial problems and choose the more lucrative role of a practicing physician. Our programs commit us to a longer training period and lesser future financial benefits than the conventional medical training program. We desire to be part of the medical science community that is responsible for training new physicians, caring for patients in municipal hospitals, and making new advances in medical science.  The recent
Complexity in Non-Pharmacological Caregiving Activities at the End of Life: An International Qualitative Study
Authors: Olav Lindqvist, Carol Tishelman, Carina Lundh Hagelin, Jean B. Clark, Maria L. Daud, Andrew Dickman, Franzisca Domeisen Benedetti, Maren Galushko, Urska Lunder, Gunilla Lundquist, Guido Miccinesi, Sylvia B. Sauter, Carl Johan Fürst, Birgit H. Rasmussen
Journal: PLoS Medicine (2012)

In late-stage palliative cancer care, relief of distress and optimized well-being become primary treatment goals. Great strides have been made in improving and researching pharmacological treatments for symptom relief; however, little systematic knowledge exists about the range of non-pharmacological caregiving activities (NPCAs) staff use in the last days of a patient's life.Within a European Commission Seventh Framework Programme project to optimize research and clinical care in the last days of life for patients with cancer, OPCARE9, we used a free-listing technique to identify the variety of NPCAs performed in the last days of life. Palliative care staff at 16 units in nine countries listed in detail NPCAs they performed over several weeks. In total, 914 statements were analyzed in relation to (a) the character of the statement and (b) the recipient of the NPCA. A substantial portion of NPCAs addressed bodily care and contact with patients and family members, with refraining from bodily care also described as a purposeful caregiving activity. Several forms for communication were described; information and advice was at one end of a continuum, and communicating through nonverbal presence and bodily contact at the other. Rituals surrounding death and dying included not only spiritual/religious issues, but also more subtle existential, legal, and professional rituals. An unexpected and hitherto under-researched area of focus was on creating an aesthetic, safe, and pleasing environment, both at home and in institutional care settings.Based on these data, we argue that palliative care in the last days of life is multifaceted, with physical, psychological, social, spiritual, and existential care interwoven in caregiving activities. Providing for fundamental human needs close to death appears complex and sophisticated; it is necessary to better distinguish nuances in such caregiving to acknowledge, respect, and further develop end-of-life care.
Therapeutic Cure against Human Tumor Xenografts in Nude Mice by a Microtubule Stabilization Agent, Fludelone, via Parenteral or Oral Route
Authors: Ting-Chao Chou, Huajin Dong, Xiuguo Zhang, William P. Tong, Samuel J. Danishefsky
Journal: Cancer Research (2005)

Abstract Epothilones, 16-membered macrolides isolated from a myxobacterium in soil, exert their antitumor effect, like Taxol, by induction of microtubule polymerization and microtubule stabilization. They are effective against tumor cells that are resistant to Taxol or vinblastine. We recently designed, via molecular editing and total synthesis, a new class of epothilones represented by 26-trifluoro-(E)-9,10-dehydro-12,13-desoxy-epothilone B (Fludelone), which has emerged as a lead candidate for clinical development. Treatment of nude mice bearing MX-1 human mammary carcinoma xenografts (as large as 3.4% body weight) with Fludelone (6-hour i.v. infusion, 25 mg/kg, q3d × 5, q3d × 4) led to complete disappearance and de facto “cure” (i.e., remission without a relapse for over 15% of the average life span of 2 years). The toxicities induced by bolus i.v. injection could be avoided through prolonged i.v. infusion, which allowed for a 10-fold increase in maximal tolerated dose. Complete remission of MX-1 xenografts was achieved with only one third of this maximal tolerated dose. Parallel studies with Taxol and Fludelone [20 mg/kg, 6-hour i.v. infusion (q2d × 4) ×3] against HCT-116 human colon carcinoma xenografts revealed that both drugs achieved tumor remission; however, all Taxol-treated mice relapsed in ∼1.3 months, whereas the Fludelone-treated mice were cured without any relapse for over 7 months. Furthermore, tumor remission was achieved by Fludelone against SK-OV-3 (ovary), PC-3 (prostate), and the Taxol-resistant CCRF-CEM/Taxol (leukemia) xenograft tumors. Most remarkably, p.o. administration of Fludelone (30 mg/kg, q2d × 7, q2d × 9, q2d × 5) against MX-1 xenografts achieved a nonrelapsing cure for as long as 8.4 months. The above results indicate that Fludelone is a highly promising compound for cancer chemotherapeutics.