tbuckley/cabot-search huggingface dataset:
The Clinical Sequelae of Intravascular Hemolysis and Extracellular Plasma Hemoglobin
Authors: Russell P Rother, Leonard Bell, Peter Hillmen, Mark T Gladwin
Journal: JAMA (2005)

The efficient sequestration of hemoglobin by the red blood cell membrane and the presence of multiple hemoglobin clearance mechanisms suggest a critical need to prevent the buildup of this molecule in the plasma. A growing list of clinical manifestations attributed to hemoglobin release in a variety of acquired and iatrogenic hemolytic disorders suggests that hemolysis and hemoglobinemia should be considered as a novel mechanism of human disease.Pertinent scientific literature databases and references were searched through October 2004 using terms that encompassed various aspects of hemolysis, hemoglobin preparations, clinical symptoms associated with plasma hemoglobin, nitric oxide in hemolysis, anemia, pulmonary hypertension, paroxysmal nocturnal hemoglobinuria, and sickle-cell disease.Hemoglobin is released into the plasma from the erythrocyte during intravascular hemolysis in hereditary, acquired, and iatrogenic hemolytic conditions. When the capacity of protective hemoglobin-scavenging mechanisms has been saturated, levels of cell-free hemoglobin increase in the plasma, resulting in the consumption of nitric oxide and clinical sequelae. Nitric oxide plays a major role in vascular homeostasis and has been shown to be a critical regulator of basal and stress-mediated smooth muscle relaxation and vasomotor tone, endothelial adhesion molecule expression, and platelet activation and aggregation. Thus, clinical consequences of excessive cell-free plasma hemoglobin levels during intravascular hemolysis or the administration of hemoglobin preparations include dystonias involving the gastrointestinal, cardiovascular, pulmonary, and urogenital systems, as well as clotting disorders. Many of the clinical sequelae of intravascular hemolysis in a prototypic hemolytic disease, paroxysmal nocturnal hemoglobinuria, are readily explained by hemoglobin-mediated nitric oxide scavenging.A growing body of evidence supports the existence of a novel mechanism of human disease, namely, hemolysis-associated smooth muscle dystonia, vasculopathy, and endothelial dysfunction.
IL-12 and type I interferon prolong the division of activated CD8 T cells by maintaining high-affinity IL-2 signaling in vivo
Authors: Gabriel R. Starbeck-Miller, Hai-Hui Xue, John T. Harty
Journal: The Journal of Experimental Medicine (2013)

TCR ligation and co-stimulation induce cellular division; however, optimal accumulation of effector CD8 T cells requires direct inflammatory signaling by signal 3 cytokines, such as IL-12 or type I IFNs. Although in vitro studies suggest that IL-12/type I IFN may enhance T cell survival or early proliferation, the mechanisms underlying optimal accumulation of CD8 T cells in vivo are unknown. In particular, it is unclear if disparate signal 3 cytokines optimize effector CD8 T cell accumulation by the same mechanism and how these inflammatory cytokines, which are transiently produced early after infection, affect T cell accumulation many days later at the peak of the immune response. Here, we show that transient exposure of CD8 T cells to IL-12 or type I IFN does not promote survival or confer an early proliferative advantage in vivo, but rather sustains surface expression of CD25, the high-affinity IL-2 receptor. This prolongs division of CD8 T cells in response to basal IL-2, through activation of the PI3K pathway and expression of FoxM1, a positive regulator of cell cycle progression genes. Thus, signal 3 cytokines use a common pathway to optimize effector CD8 T cell accumulation through a temporally orchestrated sequence of cytokine signals that sustain division rather than survival.
Drug Treatment of Hypertension in Patients With Diabetes Mellitus
Authors: Peter P Stein, Henry R Black
Journal: Diabetes Care (1991)

Patients with diabetes mellitus have an increased prevalence of hypertension and its vascular consequences, including coronary and cerebrovascular disease. Drug treatment of hypertension in diabetic subjects is fraught with potential difficulties, including the altered efficacy of medications, the increased risk of side effects, and the possibility of worsening glycemic control and increasing serum lipid levels. Despite these difficulties, treatment is an important part of reducing morbidity and mortality from vascular events. Antihypertensive therapy may also have the potential to prevent or retard the development of diabetic nephropathy. In this article, we discuss the efficacy and metabolic and nonmetabolic side effects of the various classes of antihypertensive agents in patients with diabetes mellitus and suggest a stepped-care approach to the drug treatment of patients with hypertension and diabetes.
Failures (with some successes) of assisted reproduction and gamete donation programs
Authors: D.T. Baird, S. Bhattacharya, P. Devroey, K. Diedrich, J.L.H. Evers, B.C.J.M. Fauser, P. Jouannet, A. Pellicer, E. Walters, P.G. Crosignani, L. Fraser, J.P.M. Geraedts, L. Gianaroli, A. Glasier, I. Liebaers, A. Sunde, J.S. Tapanainen, B. Tarlatzis, A. Van Steirteghem, A. Veiga
Journal: Human Reproduction Update (2013)

BACKGROUNDAlthough the possibilities for the treatment of infertility have been improved tremendously, not every couple will be treated successfully.
Urticarial reaction following the inhalation of nicotine in tobacco smoke
Authors: None Lee, None Ahn, None Choi, None Lee
Journal: British Journal of Dermatology (1998)

We report a patient with recurrent generalized itching and urticaria due to inhalation of nicotine in tobacco smoke. A skin prick test with nicotine base (1:10 w/v) was negative but an intradermal test with nicotine base (1:100 w/v) was strongly positive. Intradermal tests with nicotine base (1:100 w/v) performed on 10 healthy controls were negative. A provocation test with a nicotine patch showed the same symptoms and signs including generalized itching, weals and flares, and mild dyspnoea, which occurred when he was exposed to tobacco smoke. Nicotine in tobacco smoke can act as an inhalant allergen and induce urticaria in hypersensitive persons.
Feasibility of Withholding Antibiotics in Selected Febrile Neutropenic Cancer Patients
Authors: Claudi Oude Nijhuis, Willem A. Kamps, Simon M.G. Daenen, Jourik A. Gietema, Winette T.A. van der Graaf, Harrie J.M. Groen, Edo Vellenga, Els M. ten Vergert, Karin M. Vermeulen, Hillie G. de Vries-Hospers, Eveline S.J.M. de Bont
Journal: Journal of Clinical Oncology (2005)

Purpose To investigate the feasibility of withholding antibiotics and early discharge for patients with chemotherapy-induced neutropenia and fever at low risk of bacterial infection by a new risk assessment model. Patients and Methods Outpatients with febrile neutropenia were allocated to one of three groups by a risk assessment model combining objective clinical parameters and plasma interleukin 8 level. Patients with signs of a bacterial infection and/or abnormal vital signs indicating sepsis were considered high risk. Based on their interleukin-8 level, remaining patients were allocated to low or medium risk for bacterial infection. Medium-risk and high-risk patients received standard antibiotic therapy, whereas low-risk patients did not receive antibiotics and were discharged from hospital after 12 hours of a febrile observation. End points were the feasibility of the treatment protocol. Results Of 196 assessable episodes, 76 (39%) were classified as high risk, 84 (43%) as medium risk, and 36 (18%) as low risk. There were no treatment failures in the low-risk group (95% CI, 0% to 10%). Therefore, sensitivity of our risk assessment model was 100% (95% CI, 90% to 100%), the specificity, positive, and negative predictive values were 21%, 13%, and 100%, respectively. Median duration of hospitalization was 3 days in the low-risk group versus 7 days in the medium- and high-risk groups (P &lt; .0001). The incremental costs of the experimental treatment protocol amounted to a saving of €471 (US $572) for every potentially low-risk patient. Conclusion This risk assessment model appears to identify febrile neutropenic patients at low risk for bacterial infection. Antibiotics can be withheld in well-defined neutropenic patients with fever.
Pre-referral rectal artesunate to prevent death and disability in severe malaria: a placebo-controlled trial
Authors: MF Gomes, MA Faiz, JO Gyapong, M Warsame, T Agbenyega, A Babiker, F Baiden, EB Yunus, F Binka, C Clerk, P Folb, R Hassan, MA Hossain, O Kimbute, A Kitua, S Krishna, C Makasi, N Mensah, Z Mrango, P Olliaro, R Peto, TJ Peto, MR Rahman, I Ribeiro, R Samad, NJ White
Journal: The Lancet (2008)
Rule-based induction method for haplotype comparison and identification of candidate disease loci
Authors: Sirkku Karinen, Silva Saarinen, Rainer Lehtonen, Pasi Rastas, Pia Vahteristo, Lauri A Aaltonen, Sampsa Hautaniemi
Journal: Genome Medicine (2012)

There is a need for methods that are able to identify rare variants that cause low or moderate penetrance disease susceptibility. To answer this need, we introduce a rule-based haplotype comparison method, Haplous, which identifies haplotypes within multiple samples from phased genotype data and compares them within and between sample groups. We demonstrate that Haplous is able to accurately identify haplotypes that are identical by descent, exclude common haplotypes in the studied population and select rare haplotypes from the data. Our analysis of three families with multiple individuals affected by lymphoma identified several interesting haplotypes shared by distantly related patients.
Playing with metal: fracture implants and contact sport.
Authors: N A Evans, R O Evans
Journal: British Journal of Sports Medicine (1997)

To assess the outcome of athletes returning to contact sport with indwelling fracture implants.A retrospective analysis of professional rugby union players competing in the South Wales premier league.Fifteen athletes were identified who had returned to competitive rugby union with retained fracture implants during the period 1990-97. After fracture fixation, the players resumed their preinjury level of contact sport within one to 12 months. Only two athletes suffered complications in relation to the retained implant, whereas the other 13 athletes played for up to six years without symptoms.The results from this preliminary series suggest that an early return to contact sport is feasible in selected cases. Avoiding the extended delay associated with implant removal affords not only minimal disruption to competitive participation, but also prevents prolonged financial losses for the professional player.
Influence of Biospecimen Variables on Proteomic Biomarkers in Breast Cancer
Authors: Funda Meric-Bernstam, Argun Akcakanat, Huiqin Chen, Aysegul Sahin, Emily Tarco, Selin Carkaci, Beatriz E. Adrada, Gopal Singh, Kim-Anh Do, Zerzhinski M. Garces, Elizabeth Mittendorf, Gildy Babiera, Isabelle Bedrosian, Rosa Hwang, Savitri Krishnamurthy, William F. Symmans, Ana Maria Gonzalez-Angulo, Gordon B. Mills
Journal: Clinical Cancer Research (2014)

PI3K/Akt/mTOR signaling is being actively pursued as a therapeutic target for breast cancer. We sought to determine if tumor heterogeneity and biospecimen variables affect the evaluation of PI3K/Akt/mTOR pathway markers.Intraoperative image-guided core-needle biopsies (CNB), and central and peripheral surgical tumor specimens were prospectively collected in 53 patients with invasive breast cancer. Specimens were assessed with reverse-phase protein arrays (RPPA) and immunohistochemistry (IHC).There was a moderate or strong correlation between the expression of 149 (97%) of the 154 different RPPA markers in the center and periphery. Correlation was higher for smaller tumors, in patients who did not undergo neoadjuvant therapy, and with shorter cold ischemia time. Of 154 markers, 132 (86%) were not statistically different between the center and periphery, and 97 (63%) were not different between the CNB and the surgical specimen (average of the central and peripheral specimen). pAkt S473 and PTEN had a significant correlation between central and peripheral specimens, and between CNB and surgical specimen. However, pAkt S473, pS6 S235/236, and pS6 240/244 levels were significantly higher in CNB than the central specimens both by RPPA and by IHC.Most individual proteomic biomarkers studied do not have significant intratumoral heterogeneity. However, protein and phosphoprotein levels are affected by biospecimen type and other preanalytic variables. PI3K pathway activation is greater in CNB compared with postexcision surgical samples suggesting a potential loss of phosphorylation during surgical manipulation, or with cold ischemia of surgical specimens.
Response to Letter Regarding Article, “Randomized Trial of Acupuncture to Lower Blood Pressure”
Authors: Frank A. Flachskampf, Alois Wortmann, Lutz Klinghammer, Werner G. Daniel, Joachim Gallasch, Wolfgang Pflederer, Olaf Gefeller, Annette B. Pfahlberg, Junxue Gan, Juntong Mao
Journal: Circulation (2008)
Gene Identification for the cblD Defect of Vitamin B<sub>12</sub>Metabolism
Authors: David Coelho, Terttu Suormala, Martin Stucki, Jordan P. Lerner-Ellis, David S. Rosenblatt, Robert F. Newbold, Matthias R. Baumgartner, Brian Fowler
Journal: New England Journal of Medicine (2008)

Vitamin B12 (cobalamin) is an essential cofactor in several metabolic pathways. Intracellular conversion of cobalamin to its two coenzymes, adenosylcobalamin in mitochondria and methylcobalamin in the cytoplasm, is necessary for the homeostasis of methylmalonic acid and homocysteine. Nine defects of intracellular cobalamin metabolism have been defined by means of somatic complementation analysis. One of these defects, the cblD defect, can cause isolated methylmalonic aciduria, isolated homocystinuria, or both. Affected persons present with multisystem clinical abnormalities, including developmental, hematologic, neurologic, and metabolic findings. The gene responsible for the cblD defect has not been identified.We studied seven patients with the cblD defect, and skin fibroblasts from each were investigated in cell culture. Microcell-mediated chromosome transfer and refined genetic mapping were used to localize the responsible gene. This gene was transfected into cblD fibroblasts to test for the rescue of adenosylcobalamin and methylcobalamin synthesis.The cblD gene was localized to human chromosome 2q23.2, and a candidate gene, designated MMADHC (methylmalonic aciduria, cblD type, and homocystinuria), was identified in this region. Transfection of wild-type MMADHC rescued the cellular phenotype, and the functional importance of mutant alleles was shown by means of transfection with mutant constructs. The predicted MMADHC protein has sequence homology with a bacterial ATP-binding cassette transporter and contains a putative cobalamin binding motif and a putative mitochondrial targeting sequence.Mutations in a gene we designated MMADHC are responsible for the cblD defect in vitamin B12 metabolism. Various mutations are associated with each of the three biochemical phenotypes of the disorder.
Heart rate and estimated energy expenditure during ballroom dancing.
Authors: B A Blanksby, P W Reidy
Journal: British Journal of Sports Medicine (1988)

Ten competitive ballroom dance couples performed simulated competitive sequences of Modern and Latin American dance. Heart rate was telemetered during the dance sequences and related to direct measures of oxygen uptake and heart rate obtained while walking on a treadmill. Linear regression was employed to estimate gross and net energy expenditures of the dance sequences. A multivariate analysis of variance with repeated measures on the dance factor was applied to the data to test for interaction and main effects on the sex and dance factors. Overall mean heart rate values for the Modern dance sequence were 170 beats.min-1 and 173 beats.min-1 for males and females respectively. During the Latin American sequence mean overall heart rate for males was 168 beats.min-1 and 177 beats.min-1 for females. Predicted mean gross values of oxygen consumption for the males were 42.8 +/- 5.7 ml.kg-1 min-1 and 42.8 +/- 6.9 ml.kg-1 min-1 for the Modern and Latin American sequences respectively. Corresponding gross estimates of oxygen consumption for the females were 34.7 +/- 3.8 ml.kg-1 min-1 and 36.1 +/- 4.1 ml.kg-1 min-1. Males were estimated to expand 54.1 +/- 8.1 kJ.min-1 of energy during the Modern sequence and 54.0 +/- 9.6 kJ.min-1 during the Latin American sequence, while predicted energy expenditure for females was 34.7 +/- 3.8 kJ.min-1 and 36.1 +/- 4.1 kJ.min-1 for Modern and Latin American dance respectively. The results suggested that both males and females were dancing at greater than 80% of their maximum oxygen consumption. A significant difference between males and females was observed for predicted gross and net values of oxygen consumption (in L.min-1 and ml.kg-1 min-1).
CSPG4 Protein as a New Target for the Antibody-Based Immunotherapy of Triple-Negative Breast Cancer
Authors: Xinhui Wang, Takuya Osada, Yangyang Wang, Ling Yu, Koichi Sakakura, Akihiro Katayama, James B. McCarthy, Adam Brufsky, Mamatha Chivukula, Thaer Khoury, David S. Hsu, William T. Barry, H. Kim Lyerly, Timothy M. Clay, Soldano Ferrone
Journal: JNCI Journal of the National Cancer Institute (2010)

The cell surface proteoglycan, chondroitin sulfate proteoglycan 4 (CSPG4), is a potential target for monoclonal antibody (mAb)-based immunotherapy for many types of cancer. The lack of effective therapy for triple-negative breast cancer (TNBC) prompted us to examine whether CSPG4 is expressed in TNBC and can be targeted with CSPG4-specific mAb.CSPG4 protein expression was assessed in 44 primary TNBC lesions, in TNBC cell lines HS578T, MDA-MB-231, MDA-MB-435, and SUM149, and in tumor cells in pleural effusions from 12 metastatic breast cancer patients. The effect of CSPG4-specific mAb 225.28 on growth, adhesion, and migration of TNBC cells was tested in vitro. The ability of mAb 225.28 to induce regression of tumor metastases (n = 7 mice) and to inhibit spontaneous metastasis and tumor recurrence (n = 12 mice per group) was tested in breast cancer models in mice. The mechanisms responsible for the antitumor effect of mAb 225.28 were also investigated in the cell lines and in the mouse models. All statistical tests were two-sided.CSPG4 protein was preferentially expressed in 32 of the 44 (72.7%) primary TNBC lesions tested, in TNBC cell lines, and in tumor cells in pleural effusions from 12 metastatic breast cancer patients. CSPG4-specific mAb 225.28 statistically significantly inhibited growth, adhesion, and migration of TNBC cells in vitro. mAb 225.28 induced 73.1% regression of tumor metastasis in a TNBC cell-derived experimental lung metastasis model (mAb 225.28 vs control, mean area of metastatic nodules = 44590.8 vs 165950.8 μm(2); difference of mean = 121360.0 μm(2), 95% confidence interval = 91010.7 to 151709.4 μm(2); P < .001). Additionally, mAb 225.28 statistically significantly reduced spontaneous lung metastases and tumor recurrences in an orthotopic xenograft mouse model. The mechanisms responsible for antitumor effect included increased apoptosis and reduced mitotic activity in tumor cells, decreased blood vessel density in the tumor microenvironment, and reduced activation of signaling pathways involved in cell survival, proliferation and metastasis.This study identified CSPG4 as a new target for TNBC. The antitumor activity of CSPG4-specific mAb was mediated by multiple mechanisms, including the inhibition of signaling pathways crucial for TNBC cell survival, proliferation, and metastasis.
Private practice: Bevan's bogey
Authors: J Mark Aitken
Journal: Journal of the Royal Society of Medicine (2008)

Aneurin Bevan's unswerving determination to see a National Health Service established by parliamentary law and Lord Moran's desire to be re-elected as President of the Royal College of Physicians played a significant part in the evaluation of consultants' remuneration. Previously, consultants had been paid a pittance for their work in the public sector but could make small fortunes from private patients. Who would turn down an offer which greatly enhanced their earnings from the public sector (justified by a probable increase in patient demand) whilst being allowed to continue to make a killing from private practice? Consequently, the NHS was born and Lord Moran was duly re-elected. Furthermore, consultants were given an internally regulated mechanism by which they could negotiate even greater rewards from the public sector by what were described as merit awards. This was intended to compensate teaching hospital consultants and associated university appointees for their diminished exposure to private practice, but quickly became another bonus open to all consultants and unrelated to clinical input. Once this gravy train had been set in motion there was little that could stop it short of a government that would both appeal to the conscience of the medical profession and match that with salaries commensurate with those earned by, for example, lawyers. After working for over 40 years in general medicine I was recently paid at a rate of £52 per hour for an eight-hour shift in our emergency department. A solicitor in the town charges £195 per hour but is unlikely to be exposed to mental or physical abuse or risk of contagion! Do aspiring doctors today see the medical profession as a humanitarian vocation or a means to a potentially substantial income? Inspecting the tables produced by Morris et al.1 might encourage prospective medics wishing to engage in a lucrative career to see Essex as the county of choice and; those with surgical inclinations might be encouraged to choose orthopaedics, whereas those with a non-surgical leaning and no wish to engage in emergency work might select dermatology (JRSM 2008;101;372–380). Their paper suggested that working in both the public and private sectors ‘might’ cause a conflict of interest. Let's not pussyfoot about: it does cause a conflict of interest. Doctors must choose between God and Mammon, as recommended by the Parliamentary Select Committee of 2000,2 but a full-time NHS commitment would require a level of remuneration which made private practice financially unattractive and illegal.
Nucleotide Receptors Involved in UTP-Induced Rat Arterial Smooth Muscle Cell Migration
Authors: Xavier Pillois, Hervé Chaulet, Isabelle Belloc, Françoise Dupuch, Claude Desgranges, Alain-Pierre Gadeau
Journal: Circulation Research (2002)

Many factors have been shown to be involved in the development of hyperplasic lesions of vessels, but the role of extracellular nucleotides remains largely unknown. The presence of P2Y and P2X nucleotide receptors on arterial endothelial and smooth muscle cells suggests a potential role for nucleotides in the vessel pathophysiology. Although the role of P2X in physiology of vessels is well documented, that of P2Y is not completely understood. We recently demonstrated that extracellular nucleotides, and particularly UTP, induced migration of cultured arterial smooth muscle cells (ASMCs). This migration is dependent on osteopontin expression and involves the Rho and mitogen-activated protein (MAP) kinase pathways. An important question is to determine the specific role of the different P2Y receptors of rat ASMCs in the UTP-induced migration process. Therefore, we first quantified mRNA levels of P2Y 2 , P2Y 4 , and P2Y 6 nucleotide receptors in cultured rat ASMCs by a competitive RT-PCR approach and demonstrated that P2Y 2 is the most highly expressed among these receptors potentially involved in the UTP-mediated response. In addition to UTP, UDP also induced ASMC migration even when UTP regeneration was inhibited, suggesting the involvement of UDP receptor P2Y 6 . Moreover, suramin, a specific antagonist of rat P2Y 2 receptor, acted as an inhibitor of UTP-induced migration. Taken together, these results suggest a prominent role for the UTP receptor, P2Y 2 , and for the UDP receptor, P2Y 6 , in UTP-induced rat ASMC migration.