tbuckley/cabot-search huggingface dataset:
Genetic Variation in the Leptin Receptor Gene and Obesity in Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study
Authors: Julie A. Ross, Kevin C. Oeffinger, Stella M. Davies, Ann C. Mertens, Erica K. Langer, William R. Kiffmeyer, Charles A. Sklar, Marilyn Stovall, Yutaka Yasui, Leslie L. Robison
Journal: Journal of Clinical Oncology (2004)

Overweight (body mass index [BMI] 25 to 29 kg/m2) and obesity (BMI > or = 30 kg/m2) frequently follow treatment for childhood acute lymphoblastic leukemia (ALL). Recent studies suggest that risk is most apparent in females treated with cranial radiation at a younger age. Because radiation at a young age may affect the hypothalamus causing leptin receptor insensitivity, we hypothesized that a polymorphism in the leptin receptor (LEPR) gene, Gln223Arg, might influence susceptibility to obesity in survivors of childhood ALL.We genotyped 600 non-Hispanic white adult ALL survivors enrolled onto the Childhood Cancer Survivor Study. BMI was compared between those with two copies of the Arg allele to those who had at least one copy of the Gln allele.Female survivors with BMI > or = 25 kg/m2 were more likely Arg homozygous than those with BMI less than 25 kg/m2 (24% v 12%; P =.007). This difference was not observed in males. Moreover, among females treated with > or = 20 Gy cranial radiation, Arg/Arg individuals had six times higher odds of having BMI > or = 25 kg/m2 (95% CI, 2.1 to 22.0) than those with a Gln allele (P =.04 for interaction). CONCLUSION LEPR polymorphism may influence obesity in female survivors of childhood ALL, particularly those exposed to cranial radiation. Because obesity is associated with increased morbidity and mortality in later life, identification of children at high risk might allow for early targeted interventions.
Cancer Risks for BRCA1 and BRCA2 Mutation Carriers: Results From Prospective Analysis of EMBRACE
Authors: Nasim Mavaddat, Susan Peock, Debra Frost, Steve Ellis, Radka Platte, Elena Fineberg, D. Gareth Evans, Louise Izatt, Rosalind A. Eeles, Julian Adlard, Rosemarie Davidson, Diana Eccles, Trevor Cole, Jackie Cook, Carole Brewer, Marc Tischkowitz, Fiona Douglas, Shirley Hodgson, Lisa Walker, Mary E. Porteous, Patrick J. Morrison, Lucy E. Side, M. John Kennedy, Catherine Houghton, Alan Donaldson, Mark T. Rogers, Huw Dorkins, Zosia Miedzybrodzka, Helen Gregory, Jacqueline Eason, Julian Barwell, Emma McCann, Alex Murray, Antonis C. Antoniou, Douglas F. Easton
Journal: JNCI Journal of the National Cancer Institute (2013)

Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles. Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan–Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided. The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02). Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.
Uncoupling protein‐3 content is decreased in peripheral skeletal muscle of patients with COPD
Authors: H.R. Gosker, P. Schrauwen, M.K.C. Hesselink, G. Schaart, G.J. van der Vusse, E.F.M. Wouters, A.M.W.J. Schols
Journal: European Respiratory Journal (2003)

Mechanical efficiency is reduced in patients with chronic obstructive pulmonary disease (COPD). Furthermore, altered fibre-type distribution and metabolic profile has been observed in peripheral skeletal muscle of COPD patients. Since skeletal muscular uncoupling protein‐3 (UCP3) has been implicated in the regulation of energy metabolism, the aim of this study was to assess UCP3 in peripheral skeletal muscle of COPD patients and healthy controls. A total of 16 COPD patients and 11 healthy age-matched control subjects were studied. Mechanical efficiency was measured by means of cycle ergometry. Biopsies were taken from the vastus lateralis, and UCP3 and cytochrome <i>c</i> (as a marker for mitochondrial content) levels were assessed by Western blotting. Muscle fibre types and metabolic profile were examined histochemically. UCP3 levels were markedly decreased in COPD compared to controls. In COPD patients, there was a positive correlation between UCP3 content and the forced expiratory volume in one second. UCP3 content was not related to mechanical efficiency, or other muscular data such as fibre types, markers of oxidative/glycolytic energy metabolism or cytochrome <i>c</i>. The authors of this study conclude that uncoupling protein‐3 content is decreased in peripheral skeletal muscle of patients with chronic obstructive pulmonary disease and is related to disease severity, but not to mechanical efficiency. The low uncoupling protein‐3 content is independent of the loss of oxidative capacity observed in these patients.
Relationship of Echocardiographic Dyssynchrony to Long-Term Survival After Cardiac Resynchronization Therapy
Authors: John Gorcsan, Olusegun Oyenuga, Phillip J. Habib, Hidekazu Tanaka, Evan C. Adelstein, Hideyuki Hara, Dennis M. McNamara, Samir Saba
Journal: Circulation (2010)

The ability of echocardiographic dyssynchrony to predict response to cardiac resynchronization therapy (CRT) has been unclear.A prospective, longitudinal study was designed with predefined dyssynchrony indexes and outcome variables to test the hypothesis that baseline dyssynchrony is associated with long-term survival after CRT. We studied 229 consecutive class III to IV heart failure patients with ejection fraction ≤35 and QRS duration ≥120 milliseconds for CRT. Dyssynchrony before CRT was defined as tissue Doppler velocity opposing-wall delay ≥65 milliseconds, 12-site SD (Yu Index) ≥32 milliseconds, speckle tracking radial strain anteroseptal-to-posterior wall delay ≥130 milliseconds, or pulsed Doppler interventricular mechanical delay ≥40 milliseconds. Outcome was defined as freedom from death, heart transplantation, or left ventricular assist device implantation. Of 210 patients (89) with dyssynchrony data available, there were 62 events: 47 deaths, 9 transplantations, and 6 left ventricular assist device implantations over 4 years. Event-free survival was associated with Yu Index (P=0.003), speckle tracking radial strain (P=0.003), and interventricular mechanical delay (P=0.019). When adjusted for confounding baseline variables of ischemic origin and QRS duration, Yu Index and radial strain dyssynchrony remained independently associated with outcome (P<0.05). Lack of radial dyssynchrony was particularly associated with unfavorable outcome in those with QRS duration of 120 to 150 milliseconds (P=0.002).The absence of echocardiographic dyssynchrony was associated with significantly less favorable event-free survival after CRT. Patients with narrower QRS duration who lacked dyssynchrony had the least favorable long-term outcome. These observations support the relationship of dyssynchrony and CRT response.
The structure of an alternate form of complement C3 that displays costimulatory growth factor activity for B lymphocytes.
Authors: Y Cahen-Kramer, I L Mårtensson, F Melchers
Journal: The Journal of Experimental Medicine (1994)

In this study, the structure of a novel 1.9-kb transcript coding for complement component 3 (C3) is described. This alternate C3 is identical to the 3' end of the C3 message beginning at position 3300 of the C3 cDNA. Its transcription appears to be driven by an alternate promoter located within intron 8 of the C3 gene. This alternate C3 message contains an open reading frame that may encode a 536-amino acid-long protein identical to the 3' part of the C3 alpha chain. The resulting protein contains the complement receptor CR2 binding site. The suggested 5' end of coding region of the alternate C3 includes information for a potential hydrophobic leader peptide that would allow secretion of the protein. In vitro assays with macrophage-depleted mouse splenic B cells indicate that an activity is secreted from cell lines transfected with the alternate C3 cDNA. Together with Sepharose-bound immunoglobulin M-specific monoclonal antibodies and interleukin 2, it costimulates the proliferation of B cells. Implications for possible in vivo functions are discussed.
D1 Receptors Physically Interact with N-Type Calcium Channels to Regulate Channel Distribution and Dendritic Calcium Entry
Authors: Alexandra E. Kisilevsky, Sean J. Mulligan, Christophe Altier, Mircea C. Iftinca, Diego Varela, Chao Tai, Lina Chen, Shahid Hameed, Jawed Hamid, Brian A. MacVicar, Gerald W. Zamponi
Journal: Neuron (2008)
Hemodynamics of Hypertension in Chronic End-Stage Renal Disease
Authors: KWAN EUN KIM, GADDO ONESTI, ALLAN B. SCHWARTZ, JOEL L. CHINITZ, CHARLES SWARTZ
Journal: Circulation (1972)

This study was undertaken to define the hemodynamic changes in hypertension of chronic end-stage renal disease. Mean cardiac index in 75 uremic patients was higher ( P &lt; 0.001) than that of 42 normal volunteers while stroke index was not different from normals. The higher cardiac indices of uremic patients were accounted for by increased heart rates. Despite the significantly higher blood pressure in the uremics, their mean total peripheral resistance index was not different from that of normals. The total group of 75 patients included 52 hypertensive and 23 normotensive uremics. Cardiac index, heart rate, and stroke index were the same in 52 hypertensive and 23 normotensive uremics while mean total peripheral resistance index of hypertensive uremics was higher ( P &lt; 0.001) than normotensive uremics. Therefore, the hypertension in end-stage renal disease is sustained by a high total peripheral resistance. Bilateral nephrectomy in 12 hypertensive uremics resulted in no changes in cardiac index; a consistent decrease in blood pressure ( P &lt; 0.001) and a decrease in total peripheral resistance index ( P &lt; 0.001) occurred. Bilateral nephrectomy in eight additional uremics with malignant hypertension resulted in an actual increase in cardiac index ( P &lt; 0.001) with a consistent reduction in blood pressures ( P &lt; 0.001) and an even more dramatic decrease in total peripheral resistance ( P &lt; 0.001). These findings imply that a vasopressor substance of renal origin increasing peripheral resistance is the major factor in the pathophysiology of renal hypertension in the late stage of its natural history.
Old Versus New Oral Anticoagulants: Focus on Pharmacology
Authors: Jawed Fareed, Indermohan Thethi, Debra Hoppensteadt
Journal: The Annual Review of Pharmacology and Toxicology (2011)

Since the discovery of heparin nearly a century ago, there have been large gaps in the development of anticoagulants. The discovery of warfarin was the first step toward using oral anticoagulants, but warfarin use has been associated with its own challenges from the perspectives of the prescribing physician and the patient. Warfarin, along with other coumarins, has a narrow therapeutic index, requires frequent monitoring, exhibits interindividual response variations, and is associated with several adverse effects. Frequent drug and food interactions contribute to potential safety and efficacy compromise. The indications for use of oral anticoagulants have increased, as these drugs are used not only for thrombosis management but also for cardiovascular indications, producing more challenges for oral anticoagulant use. Factor Xa and thrombin targeting has provided a rational approach to develop new oral anticoagulants with improvements over warfarin. In this review, the pharmacology of warfarin and the pharmacology of the newly developed oral anti-Xa and antithrombin agents are discussed.
BLOOD COAGULATION INITIATION BY A COMPLEMENT-MEDIATED PATHWAY
Authors: Theodore S. Zimmerman, Hans J. Müller-Eberhard
Journal: The Journal of Experimental Medicine (1971)

A variety of complement-activating substances, including inulin, immunoglobulin aggregates, bacterial endotoxins, and staphylococcal protein A, were found to initiate blood coagulation through a complement-mediated pathway. These substances markedly accelerated blood coagulation in normal rabbit blood. That this clot-promoting activity requires an intact complement system was demonstrated by an almost total lack of effect on blood from rabbits with an inherited deficiency of the sixth component of complement (C6). Small amounts of isolated C6 conferred to C6-deficient blood the ability to respond with accelerated coagulation upon activation of the complement system. In addition, it was determined that activation of complement through the previously described C3 activator system resulted in the initiation of blood coagulation. The participation of C1, C2, and C4 was not necessary.
Oxidised proteins and superoxide anion production in the diaphragm of severe COPD patients
Authors: J. Marin-Corral, J. Minguella, A. L. Ramírez-Sarmiento, S. N. A. Hussain, J. Gea, E. Barreiro
Journal: European Respiratory Journal (2009)

In the diaphragms of chronic obstructive pulmonary disease (COPD) patients, the nature of oxidatively modified proteins and superoxide anion production were explored. Diaphragm specimens were obtained through thoracotomy because of localised lung lesions in COPD patients (16 severe and eight moderate) and 10 control subjects. Lung and respiratory muscle functions were evaluated. Oxidised proteins were identified using immunoblotting and mass spectrometry. Protein and activity levels of the identified proteins were determined using immunoblotting and activity assays. Lucigenin-derived chemiluminescence signals in a luminometer were used to determine superoxide anion levels in muscle compartments (mitochondria, membrane and cytosol) using selective inhibitors. In severe COPD patients compared with controls, respiratory muscle function was impaired; creatine kinase, carbonic anhydrase III, actin and myosin were oxidised; myosin carbonylation levels were increased five-fold; creatine kinase content and activity and myosin protein were reduced; superoxide anion levels were increased in both mitochondria and membrane compartments; and the percentage of superoxide anion inhibition achieved by rotenone was significantly greater. In severe COPD patients, oxidation of diaphragm proteins involved in energy production and contractile performance is likely to partially contribute to the documented respiratory muscle dysfunction. Furthermore, generation of the superoxide anion was increased in the diaphragms of these patients.
Concealed Air Leak Associated with Large Tidal Volumes in Partial Liquid Ventilation
Authors: PETER N. COX, HELENA FRNDOVA, PATRICK S. K. TAN, TOMOHIKO NAKAMURA, KEIKO MIYASAKA, YOSHIO SAKURAI, WILLIAM MIDDLETON, DAVID MAZER, A. CHARLES BRYAN
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Current ventilator strategies aim at maintaining an open lung and limiting both peak inspiratory pressures and tidal volumes to avoid alveolar distension. Perfluorocarbons, as well as being excellent solvents for oxygen and carbon dioxide, have the unique properties of being able to recruit dependent lung regions and improve pulmonary mechanics. Optimal ventilator strategies for partial liquid ventilation (PLV) have not yet been clearly defined. In the surfactant-depleted rabbit model, an approach involving a large tidal volume (Vt) (15 ml/kg) and lung filled to FRC with perfluorocarbon (PFC) was compared with strategies involving a moderate Vt (9 ml/kg) and partially filled lung (6 ml/ kg), a moderate Vt (9 ml/kg) and lung filled to FRC with PFC, and a large Vt (15 ml/kg) and partially filled lung (6 ml/kg). PEEP was maintained at 5 cm H2O except in the moderate Vt, partial-filling group, in which a PEEP of 9 cm H2O was used to maintain the rabbits for the duration of the experiment. Oxygenation was satisfactory in all groups, and peak inspiratory pressures were not significantly different. However, five of the 13 animals in the large-Vt, PFC-filled lung group died of a pneumothorax prior to completion of the experiment. Of the eight animals in this group surviving the experiment, two had radiographic evidence of pneumothoraces, with an additional three animals having autopsy evidence of air leak. Of the 22 animals in the other groups, all survived with the exception of a single rabbit in the large Vt, partial-filling group, which had both radiographic and autopsy evidence of air leak. We conclude that there is a significant risk of barotrauma in a PLV strategy in which a large Vt is used in association with a lung filled to FRC with perfluorocarbon. Adequate gas exchange can be achieved with alternative ventilation strategies in combination with PLV.
From genetic association studies to the biology of interleukin-28B in hepatitis C virus infection and beyond
Authors: Christian M Lange
Journal: Gut (2012)

<h3>Abstract</h3> Rapid transmission of coronavirus disease 2019 (COVID-19) was observed in the Shincheonji Church of Jesus, a religious sect in South Korea. The index case was confirmed on February 18, 2020 in Daegu City, and within two weeks, 3,081 connected cases were identified. Doubling times during the initial stages of the outbreak were less than 2 days. A stochastic model fitted to the time series of confirmed cases suggests that the basic reproduction number (<i>R</i><sub>0</sub>) of COVID-19 was 8.5 [95% credible interval (CrI): 6.3, 10.9] among the church members, whereas (<i>R</i><sub>0</sub> = 1.9 [95% CrI: 0.4, 4.4]) in the rest of the population of Daegu City. The model also suggests that there were 4 [95% CrI: 2, 11] undetected cases when the first case reported symptoms on February 7. The Shincheonji Church cluster is likely to be emblematic of other outbreak-prone populations where <i>R</i><sub>0</sub> of COVID-19 is higher. Understanding and subsequently limiting the risk of transmission in such high-risk places is key to effective control.
Long-Term Colorectal-Cancer Incidence and Mortality after Lower Endoscopy
Authors: Reiko Nishihara, Kana Wu, Paul Lochhead, Teppei Morikawa, Xiaoyun Liao, Zhi Rong Qian, Kentaro Inamura, Sun A. Kim, Aya Kuchiba, Mai Yamauchi, Yu Imamura, Walter C. Willett, Bernard A. Rosner, Charles S. Fuchs, Edward Giovannucci, Shuji Ogino, Andrew T. Chan
Journal: New England Journal of Medicine (2013)

Colonoscopy and sigmoidoscopy provide protection against colorectal cancer, but the magnitude and duration of protection, particularly against cancer of the proximal colon, remain uncertain.We examined the association of the use of lower endoscopy (updated biennially from 1988 through 2008) with colorectal-cancer incidence (through June 2010) and colorectal-cancer mortality (through June 2012) among participants in the Nurses' Health Study and the Health Professionals Follow-up Study.Among 88,902 participants followed over a period of 22 years, we documented 1815 incident colorectal cancers and 474 deaths from colorectal cancer. With endoscopy as compared with no endoscopy, multivariate hazard ratios for colorectal cancer were 0.57 (95% confidence interval [CI], 0.45 to 0.72) after polypectomy, 0.60 (95% CI, 0.53 to 0.68) after negative sigmoidoscopy, and 0.44 (95% CI, 0.38 to 0.52) after negative colonoscopy. Negative colonoscopy was associated with a reduced incidence of proximal colon cancer (multivariate hazard ratio, 0.73; 95% CI, 0.57 to 0.92). Multivariate hazard ratios for death from colorectal cancer were 0.59 (95% CI, 0.45 to 0.76) after screening sigmoidoscopy and 0.32 (95% CI, 0.24 to 0.45) after screening colonoscopy. Reduced mortality from proximal colon cancer was observed after screening colonoscopy (multivariate hazard ratio, 0.47; 95% CI, 0.29 to 0.76) but not after sigmoidoscopy. As compared with colorectal cancers diagnosed in patients more than 5 years after colonoscopy or without any prior endoscopy, those diagnosed in patients within 5 years after colonoscopy were more likely to be characterized by the CpG island methylator phenotype (CIMP) (multivariate odds ratio, 2.19; 95% CI, 1.14 to 4.21) and microsatellite instability (multivariate odds ratio, 2.10; 95% CI, 1.10 to 4.02).Colonoscopy and sigmoidoscopy were associated with a reduced incidence of cancer of the distal colorectum; colonoscopy was also associated with a modest reduction in the incidence of proximal colon cancer. Screening colonoscopy and sigmoidoscopy were associated with reduced colorectal-cancer mortality; only colonoscopy was associated with reduced mortality from proximal colon cancer. Colorectal cancer diagnosed within 5 years after colonoscopy was more likely than cancer diagnosed after that period or without prior endoscopy to have CIMP and microsatellite instability. (Funded by the National Institutes of Health and others.).
Human Mesangial Cells in Culture and in Kidney Sections Fail to Express Fc Alpha Receptor (CD89)
Authors: RALF WESTERHUIS, GER VAN ZANDBERGEN, NICOLE A. M. VERHAGEN, N. KLAR-MOHAMAD, MOHAMED R. DAHA, CEES VAN KOOTEN
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The mechanism of deposition of IgA in the renal mesangium in primary IgA-nephropathy is poorly understood. It has been suggested that membrane receptors for IgA on mesangial cells (MC) of the kidney may be involved. To obtain more insight in the occurrence of the myeloid receptor for IgA (CD89) on MC, both in situ and in culture, rabbit and goat polyclonal antibodies and mouse monoclonal antibody against recombinant CD89 were raised. Kidney sections from five control subjects and five patients with primary IgA-nephropathy failed to be positive for CD89 in the mesangium, using our polyclonal and monoclonal antibodies. Also, five primary human MC cultures assessed for CD89 expression showed no protein expression of CD89. Furthermore, reverse transcription-PCR failed to detect mRNA expression of CD89 in the cultured MC. It was demonstrated that all five human primary MC bound human IgA in a dose-dependent manner, which was not inhibitable by blocking monoclonal anti-CD89 antibody (My43). In contrast, binding of IgA to U937 cells was blocked efficiently by My43. Finally, incubation of human MC with either human or rat IgA led to increased interleukin-6 production, whereas only human IgA, but not rat IgA, was able to bind to human CD89. Therefore, it is concluded that human MC do not express CD89 (to a significant extent). These results strongly suggest that binding of IgA to human MC occurs via an IgA receptor distinct from CD89.