tbuckley/cabot-search huggingface dataset:
Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model
Authors: Thomas J. Hund, Yoram Rudy
Journal: Circulation (2004)

Computational biology is a powerful tool for elucidating arrhythmogenic mechanisms at the cellular level, where complex interactions between ionic processes determine behavior. A novel theoretical model of the canine ventricular epicardial action potential and calcium cycling was developed and used to investigate ionic mechanisms underlying Ca2+ transient (CaT) and action potential duration (APD) rate dependence.The Ca2+/calmodulin-dependent protein kinase (CaMKII) regulatory pathway was integrated into the model, which included a novel Ca2+-release formulation, Ca2+ subspace, dynamic chloride handling, and formulations for major ion currents based on canine ventricular data. Decreasing pacing cycle length from 8000 to 300 ms shortened APD primarily because of I(Ca(L)) reduction, with additional contributions from I(to1), I(NaK), and late I(Na). CaT amplitude increased as cycle length decreased from 8000 to 500 ms. This positive rate-dependent property depended on CaMKII activity.CaMKII is an important determinant of the rate dependence of CaT but not of APD, which depends on ion-channel kinetics. The model of CaMKII regulation may serve as a paradigm for modeling effects of other regulatory pathways on cell function.
Virus- and Bradykinin-Induced Airway Hyperresponsiveness in Guinea Pigs
Authors: GERT FOLKERTS, JANNEKE WESTRA-de VLIEGER, ANNICK de VRIES, STEPHAN FAAS, HENK van der LINDE, FERDI ENGELS, JAN C. de JONG, FONS A. K. C. P. VERHEYEN, DICKY VAN HEUVEN-NOLSEN, FRANS P. NIJKAMP
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The involvement of bradykinin in virus-induced airway hyperresponsiveness (AHR) in guinea pig airways in vivo was determined with the B(2)-receptor antagonist Hoe 140. The efficacy of Hoe 140 treatment was assessed through its effect on the bradykinin-induced (up to 2.5 microgram/100 g B.W. administered intravenously) decrease in blood pressure (BP). Hoe 140 (0.1 micromol/kg), administered subcutaneously twice a day for 5 d almost completely blocked bradykinin-induced changes in BP. Four days after parainfluenza-3 (PI-3) virus infection, guinea pigs showed AHR; excessive airway contraction was found with histamine-receptor stimulation. This hyperresponsiveness was completely inhibited by pretreatment with Hoe 140 (0.1 micromol/kg) administered subcutaneously twice a day for five consecutive days, starting 1 d before virus inoculation. Interestingly, nebulized delivery of bradykinin itself to captopril-treated animals induced an AHR comparable to that observed in virus-treated guinea pigs. Viral infection also caused influx of bronchoalveolar cells into the lungs. Both histologic examinations and lung lavage experiments showed that this cell influx could not be inhibited by pretreatment with Hoe 140. In summary, the results of the study show that bradykinin is involved in a cascade of events leading to AHR after a viral infection in guinea pigs, without affecting bronchoalveolar cell influx.
Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide
Authors: Jean-Pierre Lévesque, Jean Hendy, Yasushi Takamatsu, Paul J. Simmons, Linda J. Bendall
Journal: Journal of Clinical Investigation (2003)

Hematopoietic progenitor cells (HPCs) normally reside in the bone marrow (BM) but can be mobilized into the peripheral blood (PB) after treatment with GCSF or chemotherapy. In previous studies, we showed that granulocyte precursors accumulate in the BM during mobilization induced by either GCSF or cyclophosphamide (CY), leading to the accumulation of active neutrophil proteases in this tissue. We now report that mobilization of HPCs by GCSF coincides in vivo with the cleavage of the N-terminus of the chemokine receptor CXCR4 on HPCs resident in the BM and mobilized into the PB. This cleavage of CXCR4 on mobilized HPCs results in the loss of chemotaxis in response to the CXCR4 ligand, the chemokine stromal cell–derived factor-1 (SDF-1/CXCL12). Furthermore, the concentration of SDF-1 decreased in vivo in the BM of mobilized mice, and this decrease coincided with the accumulation of serine proteases able to directly cleave and inactivate SDF-1. Since both SDF-1 and its receptor, CXCR4, are essential for the homing and retention of HPCs in the BM, the proteolytic degradation of SDF-1, together with that of CXCR4, could represent a critical step leading to the mobilization of HPCs into the PB in response to GCSF or CY.
Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease.
Authors: C E Hollak, S van Weely, M H van Oers, J M Aerts
Journal: Journal of Clinical Investigation (1994)

Gaucher disease (GD; glucosylceramidosis) is caused by a deficient activity of the enzyme glucocerebrosidase (GC). Clinical manifestations are highly variable and cannot be predicted accurately on the basis of the properties of mutant GC. Analysis of secondary abnormalities, such as elevated plasma levels of some hydrolases, may help to increase insight into the complicated pathophysiology of the disease and could also provide useful disease markers. The recent availability of enzyme supplementation therapy for GD increases the need for markers as early predictors of the efficacy of treatment. We report the finding of a very marked increase in chitotrisidase activity in plasma of 30 of 32 symptomatic type 1 GD patients studied: the median activity being > 600 times the median value in plasma of healthy volunteers. In three GC-deficient individuals without clinical symptoms, only slight increases were noted. Chitotriosidase activity was absent in plasma of three control subjects and two patients. During enzyme supplementation therapy, chitotriosidase activity declined dramatically. We conclude that plasma chitotriosidase levels can serve as a new diagnostic hallmark of GD and should prove to be useful in assessing whether clinical manifestations of GD are present and for monitoring the efficacy of therapeutic intervention.
Hazards to Health Workers from Antineoplastic Drugs
Authors: Eula Bingham
Journal: New England Journal of Medicine (1985)

The study by Selevan et al. in this issue of the Journal 1 provides documentation that nurses exposed to antineoplastic drugs are at risk of adverse effects on reproduction. Thus, an outcome that could be predicted from the vast amount of research on the biochemical mechanisms of action of these drugs, both in vitro and in vivo, has been demonstrated by the meticulous and arduous techniques of epidemiologists.The story began with the development of chemicals designed to produce cytotoxic effects (hence their efficacy as antineoplastic agents). Next, there were troubling reports in the toxicologic literature on the specific mechanisms of . . .
Very long-chain acyl-CoA dehydrogenase deficiency presenting as acute hypercapnic respiratory failure
Authors: M. K. H. Tong, C-S. Lam, T. W. L. Mak, M. Y. P. Fu, S-H. Ng, R. J. A. Wanders, N. L. S. Tang
Journal: European Respiratory Journal (2006)

Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) is a key enzyme catalysing the dehydrogenation of long-chain fatty acids in mitochondrial β-oxidation. VLCAD deficiency is a genetic disorder that commonly presents in infancy or childhood with episodes of hypoketotic hypoglycaemia, cardiomyopathy and liver dysfunction. The present study reports an 18-yr-old Chinese female who presented with acute hypercapnic respiratory failure and rhabdomyolysis after a period of prolonged fasting and exertion. VLCAD deficiency was confirmed with decreased VLCAD activity in cultured fibroblasts. The patient completely recovered with supportive care. Pulmonary function tests after the acute episode showed evidence of chronic subclinical respiratory muscle weakness. In conclusion, this rare metabolic disorder should be considered in patients presenting with unexplained acute respiratory paralysis and failure.
Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer
Authors: S. Ogino, T. Kawasaki, G. J Kirkner, Y. Suemoto, J. A Meyerhardt, C. S Fuchs
Journal: Gut (2007)

<h3>Background:</h3> The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct epigenetic phenotype in colorectal cancer. In contrast, a phenotype with less widespread promoter methylation (CIMP-low) has not been well characterised. O-6-methylguanine-DNA methyltransferase (<i>MGMT</i>) promoter methylation and silencing have been associated with G&gt;A mutations and microsatellite instability-low (MSI-low). <h3>Aim:</h3> To examine molecular correlates with <i>MGMT</i> methylation/silencing in colorectal cancer. <h3>Methods:</h3> Utilising MethyLight technology, we quantified DNA methylation in <i>MGMT</i> and eight other markers (a CIMP-diagnostic panel; <i>CACNA1G</i>, <i>CDKN2A (p16)</i>, <i>CRABP1</i>, <i>IGF2</i>, <i>MLH1</i>, <i>NEUROG1</i>, <i>RUNX3</i> and <i>SOCS1</i>) in 920 population-based colorectal cancers. <h3>Results:</h3> Tumours with both <i>MGMT</i> methylation and loss were correlated positively with MSI-low (p = 0.02), CIMP-high (⩾6/8 methylated CIMP markers, p = 0.005), CIMP-low (1/8–5/8 methylated CIMP markers, p = 0.002, compared to CIMP-0 with 0/8 methylated markers), <i>KRAS</i> G&gt;A mutation (p = 0.02), and inversely with 18q loss of heterozygosity (p = 0.0002). Tumours were classified into nine MSI/CIMP subtypes. Among the CIMP-low group, tumours with both <i>MGMT</i> methylation and loss were far more frequent in MSI-low tumours (67%, 12/18) than MSI-high tumours (5.6%, 1/18; p = 0.0003) and microsatellite stable (MSS) tumours (33%, 52/160; p = 0.008). However, no such relationship was observed among the CIMP-high or CIMP-0 groups. <h3>Conclusion:</h3> The relationship between <i>MGMT</i> methylation/silencing and MSI-low is limited to only CIMP-low tumours, supporting the suggestion that CIMP-low in colorectal cancer may be a different molecular phenotype from CIMP-high and CIMP-0. Our data support a molecular difference between MSI-low and MSS in colorectal cancer, and a possible link between CIMP-low, MSI-low, <i>MGMT</i> methylation/loss and <i>KRAS</i> mutation.
Polo-like kinase 1 inhibition suppresses hepatitis B virus X protein-induced transformation in an in vitro model of liver cancer progression
Authors: Leo L. Studach, Lova Rakotomalala, Wen‐Horng Wang, Ronald L. Hullinger, Stefano Cairo, Marie‐Annick Buendia, Ourania M. Andrisani
Journal: Hepatology (2009)

Chronic hepatitis B virus (HBV) infection is linked to development of hepatocellular carcinoma (HCC). The HBV X protein (pX) is implicated in HCC pathogenesis acting as a weak oncogene or a cofactor in hepatocarcinogenesis. pX induces DNA re-replication, DNA damage, and partial polyploidy in a poorly differentiated, immortalized hepatocyte cell line. In this study we employed sorted, pX-induced polyploid cells to investigate their growth and oncogenic transformation potential over the course of 70 cell doublings. Immediately after live cell-sorting, nearly 40% of pX-induced polyploid cells undergo apoptosis, whereas the surviving cells exhibit proliferation sensitive to p53. After 40 cell generations the pX-expressing polyploid cultures exhibit loss of p53 function and become growth factor- and anchorage-independent, indicative of oncogenic transformation. The pX-induced polyploid cultures in the course of 70 cell generations undergo progressively increasing DNA damage, propagate damaged DNA to daughter cells, and display increased expression of a cluster of proliferation genes shown to be elevated in human HCC, including HBV-HCC. One of these genes is the mitotic kinase Polo-like kinase 1 (Plk1). Oncogenic transformation is suppressed in the absence of pX expression, and significantly, by inhibition of Plk1. These results identify Plk1 as crucial in pX-mediated oncogenic transformation. Conclusion: Partial polyploidy induced by pX is not immediately associated with oncogenic transformation. Continued DNA damage for 40 cell generations is reproducibly associated with loss of p53 function, enhanced expression of Plk1, and oncogenic transformation. Because Plk1 expression is also elevated in HBV-HCC tumors, this in vitro cellular model simulates liver cancer progression and pathogenesis in chronic HBV patients. Inhibition of Plk1 activity suppresses pX-mediated oncogenic transformation, identifying Plk1 as a promising therapeutic target for HBV-mediated HCC. (HEPATOLOGY 2009.)
Fetal and Infant Growth Patterns and Kidney Function at School Age
Authors: Hanneke Bakker, Romy Gaillard, Oscar H. Franco, Albert Hofman, Albert J. van der Heijden, Eric A.P. Steegers, H. Rob Taal, Vincent W.V. Jaddoe
Journal: Journal of the American Society of Nephrology (2014)

Low birth weight is associated with ESRD. To identify specific growth patterns in early life that may be related to kidney function in later life, we examined the associations of longitudinally measured fetal and infant growth with kidney function in school-aged children. This study was embedded in a population-based prospective cohort study among 6482 children followed from fetal life onward. Fetal and childhood growth was measured during second and third trimesters of pregnancy, at birth, and at 6, 12, 24, 36, and 48 months postnatally. At the age of 6 years, we measured kidney volume by ultrasound. GFR was estimated using blood creatinine levels. Higher gestational age-adjusted birth weight was associated with higher combined kidney volume and higher eGFR (per 1 SD score increase in birth weight; 1.27 cm(3) [95% confidence interval, 0.61 to 1.93] and 0.78 ml/min per 1.73 m2 [95% CI, 0.16 to 1.39], respectively). Fetal weight, birth weight, and weight at 6 months were positively associated with childhood kidney volume, whereas higher second trimester fetal weight was positively associated with higher GFR (all P values<0.05). Fetal and childhood lengths were not consistently associated with kidney function. In this cohort, lower fetal and early infant weight growth is associated with smaller kidney volume in childhood, whereas only lower fetal weight growth is associated with lower kidney function in childhood, independent of childhood growth. Whether these associations lead to an increased risk of kidney disease needs to be studied further.
Psychiatric and psychological aspects of hysterectomy
Authors: S. Simkin
Journal: BMJ (1996)

Serum IgM testing is needed in all cases of suspected measles EDiTOR,-We agree with Laura Ryall and colleagues that testing for virus specific IgM, in either a saliva specimen or a serum sample, is the appropriate initial method for diagnosing measles.'The main advantage of IgM testing, given the current epidemiology of measles in England and Wales, is its high specificity.Currently measles infections are rare, and less than 1% of notified cases have been confirmed by IgM assay of saliva in the past six months.2In this context, even a test that was 99% specific would be expected to have a positive predictive value of around 50%: for every 1000 suspected cases tested there will be about 10 false positive and 10 true positive results.Since 1995, therefore, the Public Health Laboratory Service Communicable Disease Surveillance Centre has requested additional tests on all cases of labora- tory confirmed measles reported in England and Wales.The reporting doctor or laboratory has been asked to refer a serum specimen for IgM assay, either to a local laboratory or to the Public Health Laboratory Service Enteric and Respiratory Virus Laboratory.Table 1-Cases of measles reported to Comtnuni- cable Disease Surveillance Centre by method of diagnosis Serum measles IgM result Initial method of No No No (%) diagnosis reported tested positive Single high IgG in CFT 46 31 13 (42) Fourfold rise in IgG in CFT 12 8 3 (38) Salivary IgM test 38 12 8 (67) Serum IgM test* 11 8 5 (75) Total 107 59 29 (49) CFT = complement fixation test.Reports of cases that were positive on IgM testing by ELISA and were retested with an IgM antibody capture radio- immunoassay.
Palindromic rheumatism: different genetic background implies a distinct disease entity
Authors: S-K Kim, H-S Lee, K W Lee, S-C Bae, J-B Jun
Journal: Annals of the Rheumatic Diseases (2006)

obtained using genotype relative risk and affected familybased control tests (table 1).Moreover, our results showed the same distribution of SLAMF1 alleles and genotypes between Tunisian patients and controls (p.0.05).Three different haplotypes (CCC, CCA, ACC) were identified at the SLAMF1 gene, with a frequency .5% in the French and Tunisian populations.Neither a significant disequilibrium of transmission to patients with rheumatoid arthritis nor a significant difference in distribution of these haplotypes between Tunisian patients with rheumatoid arthritis and controls was found.Our study is the first report to examine the potential role of the SLAMF1 gene in the susceptibility to rheumatoid arthritis in both the French and Tunisian populations, which indicates that SLAMF1 polymorphisms do not contribute to susceptibility to rheumatoid arthritis in the studied populations.Our study should be replicated in other populations to confirm our preliminary results.Genotypes are available at http:// www.GenHotel.com.
David M. Grennen "Rheumatology"
Authors: M. F. T. Read
Journal: British Journal of Sports Medicine (1984)

This book is written for medical students and MRCP examination candidates.It is well laid out with heavy type headings for each subsection and a reasonable index that makes revising for examination much easier.One of the strengths, for the student, of this little book of 225 pages, is the tables that list differential diagnoses and the diagnostic indices, for this is the way the student gleans many last minute facts, but an index of these would have been helpful.There is plenty of detail of laboratory tests and their rationale: diagrammatic and photographic illustrations are generally clear but more precise indication to the medical student of what to look for would have been helpful, even when used, some arrows are hard to see.Small facts like the upside down knee X-ray and wrong figure reference (myelography) should easily be corrected in later editions.Overall a well presented precis that still deals in detail with rheumatic disease including the numerous exotica that appear in this subject.What a shame that manipulation, which in its own right has spawned an industry, should summarily be dismissed and there are one or two treatment modalities that are not even mentioned in this area, but I expect that reflects the needs of examination rather than the requirements of the patients.At the price it is good value and well recommended.
Defining Clinical Phenotypes of Juvenile Mania
Authors: Ellen Leibenluft, Dennis S. Charney, Kenneth E. Towbin, Robinder K. Bhangoo, Daniel S. Pine
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: The authors suggest criteria for a range of narrow to broad phenotypes of bipolar disorder in children, differentiated according to the characteristics of the manic or hypomanic episodes, and present methods for validation of the criteria. METHOD: Relevant literature describing bipolar disorder in both children and adults was reviewed critically, and the input of experts was sought. RESULTS: Areas of controversy include whether the diagnosis of bipolar disorder should require clearly demarcated affective episodes and, if so, of what duration, and whether specific hallmark symptoms of mania should be required for the diagnosis. The authors suggest a phenotypic system of juvenile mania consisting of a narrow phenotype, two intermediate phenotypes, and a broad phenotype. The narrow phenotype is exhibited by patients who meet the full DSM-IV diagnostic criteria for hypomania or mania, including the duration criterion, and also have hallmark symptoms of elevated mood or grandiosity. The intermediate phenotypes include 1) hypomania or mania not otherwise specified, in which the patient has clear episodes and hallmark symptoms, but the episodes are between 1 and 3 days in duration, and 2) irritable hypomania or mania, in which the patient has demarcated episodes with irritable, but not elevated, mood. The broad phenotype is exhibited by patients who have a chronic, nonepisodic illness that does not include the hallmark symptoms of mania but shares with the narrower phenotypes the symptoms of severe irritability and hyperarousal. CONCLUSIONS: The presence of distinct episodes and hallmark symptoms can be used to differentiate clinical phenotypes of juvenile mania. The utility and validity of this system can be tested in subsequent research.
Retinoid protection against x-ray-induced chromatid damage in human peripheral blood lymphocytes.
Authors: K K Sanford, R Parshad, F M Price, R E Tarone, K H Kraemer
Journal: Journal of Clinical Investigation (1992)

Oral administration of isotretinoin (13-cis retinoic acid) was shown previously (Kraemer, K. H., J. J. DiGiovanna, A. N. Moshell, R. E. Tarone, and G. L. Peck. 1988. N. Engl. J. Med. 318:1633-1637) to reduce the frequency of skin cancers in xeroderma pigmentosum (XP) patients. The mechanism of protection was unclear. In the present study, x-ray-induced chromatid damage in PHA-stimulated blood lymphocytes from five XP patients receiving isotretinoin was approximately half that in blood samples from the same patients before or subsequent to treatment. The x-ray-induced chromatid damage in blood lymphocytes from a normal control was reduced significantly by cocultivation with blood or plasma from an XP patient receiving isotretinoin or by addition of 10(-6) M isotretinoin to cultures 1 h before x-irradiation. A similar reduction in x-ray-induced chromatid damage was reported previously by adding to the culture medium, mannitol, a scavenger of the free hydroxyl radical, or catalase, which decomposes hydrogen peroxide; both of these products are generated during ionizing radiation. The present observations suggest that isotretinoin acts as a scavenger of such radiation products, thereby providing protection against x-ray-induced chromatid damage.
Treating Diabetes and Obesity with an FGF21-Mimetic Antibody Activating the βKlotho/FGFR1c Receptor Complex
Authors: Ian N. Foltz, Sylvia Hu, Chadwick King, Xinle Wu, Chaofeng Yang, Wei Wang, Jennifer Weiszmann, Jennitte Stevens, Jiyun Sunny Chen, Noi Nuanmanee, Jamila Gupte, Renee Komorowski, Laura Sekirov, Todd Hager, Taruna Arora, Hongfei Ge, Helene Baribault, Fen Wang, Jackie Sheng, Margaret Karow, Minghan Wang, Yongde Luo, Wallace McKeehan, Zhulun Wang, Murielle M. Véniant, Yang Li
Journal: Science Translational Medicine (2012)

A monoclonal antibody mimic of FGF21 exerts beneficial metabolic effects in obese monkeys.
Comparison of Epi-LASIK and Off-Flap Epi-LASIK for the Treatment of Low and Moderate Myopia
Authors: Maria I. Kalyvianaki, George D. Kymionis, George A. Kounis, Sophia I. Panagopoulou, Michael A. Grentzelos, Ioannis G. Pallikaris
Journal: Ophthalmology (2008)
Chromosome Instability in Patients With Medullary Carcinoma of the Thyroid
Authors: T. C. Hsu
Journal: JAMA (1981)

Chromosome analysis in the cultured peripheral blood lymphocytes of multiple endocrine adenomatosis (MEA-II) patients and their siblings demonstrated a preponderance of higher frequency of metaphases with chromosome and chromatid type abnormalities (average, 11.0%) as compared to controls (average, 3.8%). Our preliminary data suggest that MEA-II patients exhibit some degree of chromosome instability. (<i>JAMA</i>1981;246:2046-2048)