tbuckley/cabot-search huggingface dataset:
Investigation of the mechanisms underlying the increased contraction of hypertrophied ventricular myocytes isolated from the spontaneously hypertensive rat
Authors: P. Brooksby, A. J Levi, J. V Jones
Journal: Cardiovascular Research (1993)

Objective: The aim was to investigate the cellular mechanisms responsible for the increased contraction of left ventricular myocytes isolated from the spontaneously hypertensive rat (SHR). Methods: Single myocytes were isolated enzymatically from the left ventricles of SHR, Wistar-Kyoto (WKY), and Wistar rats. WKY and Wistar myocytes were used as normotensive controls. Cytoplasmic calcium was measured with Fura-2 and contraction was measured optically. Membrane potential was measured with microelectrodes and cells were voltage clamped to measure the amplitude of L-type calcium current (iCa). Results: Under action potential conditions, SHR myocytes had a larger calcium transient and an increased sarcoplasmic reticular calcium content compared to normotensive myocytes. There was no detectable difference in the resting cytoplasmic calcium concentration between SHR and control myocytes. SHR myocytes also had a prolonged action potential compared to normotensive cells. However, when cells were voltage clamped and short pulses of 120 ms duration were applied (a similar duration of depolarisation to the action potential), the difference in the calcium transient or contraction between SHR and normotensive myocytes was abolished. SHR myocytes had an unchanged amplitude of ICa in comparison to control myocytes, and there was no detectable difference in the myofilament response to calcium between SHR and control myocytes. Conclusions: (1) Hypertrophied SHR myocytes stimulated with action potentials had an increased calcium transient compared to normotensive cells. The greater calcium transient in the SHR cells is likely to be a major factor responsible for their increased contraction. (2) SHR myocytes had a prolonged action potential in comparison to normotensive cells. (3) The amplitude of ICa and myofilament response to calcium were unchanged in SHR myocytes, suggesting that these factors do not play a role in the increased contraction of these cells. (4) Since the difference between SHR and control cells was abolished by voltage clamping the cells to prevent the difference of action potential, it is unlikely that an alteration of intrinsic mechanisms in SHR myocytes is responsible for their increased contraction. Rather, it suggests that the prolonged action potential of SHR myocytes plays a important role in causing their increased calcium transient and contraction. Our results indicate that the prolonged action potential in SHR cells results in an increased calcium content of the sarcoplasmic reticulum, which leads to a greater sarcoplasmic reticular calcium release upon stimulation and an increased contraction.
Nationwide Study of Cancer Risk Among Hip Replacement Patients in Sweden
Authors: L. B. Signorello, W. Ye, J. P. Fryzek, L. Lipworth, J. F. Fraumeni, W. J. Blot, J. K. McLaughlin, O. Nyren
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Orthopedic implants and their fixatives contain materials with carcinogenic potential. Whether these implants are linked to subsequent cancer development remains unknown, mainly because large-scale, long-term follow-up data are scarce. Methods: We conducted a nationwide cohort study in Sweden to examine cancer incidence among 116 727 patients who underwent hip replacement surgery during the period from 1965 through 1994. Through record linkage to the Swedish Cancer Register, we identified all incident cancers through 1995 in this population (693 954 person-years of observation). For each cancer type, the observed number of cases was divided by that expected in the general Swedish population to produce standardized incidence ratios (SIRs). Results: Relative to the general population, the cohort had no overall cancer excess (SIR = 1.01; 95% confidence interval [CI] = 0.99 to 1.03). However, we observed elevated SIRs for prostate cancer (SIR = 1.16; 95% CI = 1.11 to 1.22) and melanoma (SIR = 1.15; 95% CI = 1.01 to 1.30) and a reduction in stomach cancer risk (SIR = 0.83; 95% CI = 0.75 to 0.92). Long-term follow-up (≥15 years) revealed an excess of multiple myeloma (SIR = 1.86; 95% CI = 1.01 to 3.11) and a statistically nonsignificant increase in bladder cancer (SIR = 1.42; 95% CI = 0.98 to 1.99). There was no material increase in risk for bone or connective tissue cancer for either men or women in any follow-up period. Conclusions: In this, the largest study to date, hip implant patients had similar rates of most types of cancer to those in the general population. Although the excesses of melanoma, multiple myeloma, and prostate and bladder cancers may be due to chance, confounding, or detection bias and should be interpreted cautiously, they warrant further investigation because of the ever-increasing use of hip implants at younger ages.
Nontraditional Markers of Glycemia
Authors: Elizabeth Selvin, Lesley M.A. Francis, Christie M. Ballantyne, Ron C. Hoogeveen, Josef Coresh, Frederick L. Brancati, Michael W. Steffes
Journal: Diabetes Care (2011)

To compare the associations of nontraditional (fructosamine, glycated albumin, 1,5-anhydroglucitol [1,5-AG]) and standard (fasting glucose, HbA(1c)) glycemic markers with common microvascular conditions associated with diabetes mellitus.We conducted a cross-sectional study of 1,600 participants (227 with a history of diabetes and 1,323 without) from the Atherosclerosis Risk in Communities (ARIC) Study, a community-based population. We conducted logistic regression analyses of the associations of diabetes-specific tertiles of fructosamine, glycated albumin, 1/(1,5-AG), fasting glucose, and HbA(1c) with prevalence of chronic kidney disease, albuminuria, and retinopathy after adjustment for demographic, clinical, and lifestyle variables.We observed significant positive trends in the associations of each marker with albuminuria and retinopathy, even after accounting for demographic, clinical, and lifestyle factors (all P trends <0.05). The associations with chronic kidney disease were similar in direction but were only significant for higher glycated albumin (P trend = 0.005), fructosamine (P trend = 0.003), and HbA(1c) (P trend = 0.005) values. After further adjustment for HbA(1c), glycated albumin and fructosamine remained significantly or borderline significantly associated with the microvascular outcomes.In cross-sectional analyses, two serum markers of glycemia-glycated albumin and fructosamine-are as, or more strongly, associated with microvascular conditions as HbA(1c). These markers may be useful in settings where whole blood is not available. Whether they might complement or outperform HbA(1c) in terms of long-term predictive value requires further investigation.
Antigen recognition by cloned cytotoxic T lymphocytes follows rules predicted by the altered-self hypothesis.
Authors: T R Hünig, M J Bevan
Journal: The Journal of Experimental Medicine (1982)

Radiation chimeras prepared by injecting H-2 heterozygous F1 stem cells into lethally irradiated parental hosts show a marked, but not absolute, preference for host-type H-2 antigens in the H-2-restricted cytotoxic T lymphocyte (CTL) response to minor histocompatibility (minor H) antigens. We have selected for the anti-minor HCTL that are restricted to the parental H-2 type absent from the chimeric host and found that in two out of eight cases, such CTL lysed target cells of either parental H-2 type. From one of these CTL populations that lysed H-2d and H-2k target cells expressing BALB minor H antigens, clones were derived and further analyzed. The results showed that: (a) lysis of both H-2d and H-2k target cells was H-2 restricted; (b) H-2d restriction mapped to Dd, and H-2k restriction mapped to Kk; (c) testing against various H-2d and H-2k strains of different and partially overlapping minor H backgrounds as well as against the appropriate F1 crosses revealed that in Dd- and Kk-restricted killing, different minor H antigens were recognized. In a second system, a CTL population was selected from normal (H-2d x H-2k)F1 mice that was specific for H-2d plus minor H antigens and for H-2k plus trinitrophenylated bovine serum albumin. We interpret these findings in terms of the altered-self hypothesis: The association of one H-2 antigen with one conventional antigen X may be recognized by the same T cell receptor specific for the complex formed by a different H-2 antigen in association with a second conventional antigen Y. The implications of these observations for the influence of self H-2 on the generation of the T cell receptor repertoire are discussed.
Water, acidosis, and experimental pyelonephritis
Authors: Vincent T. Andriole
Journal: Journal of Clinical Investigation (1970)

The effect of water restriction and ammonium chloride acidosis on the course of Escherichia coli pyelonephritis was determined in the nonobstructed kidney of the rat. To alter the chemical composition of the renal medulla, water intake was reduced in rats to one-half the normal daily intake. Water restriction increased the incidence of coliform pyelonephritis. Systemic acidosis, produced by giving a 300 mM solution of ammonium chloride, increased urinary osmolality to values comparable to water restriction and also predisposed to pyelonephritis. However, when rats were fed the same solution of ammonium chloride but were allowed access to tap water ad lib., urinary osmolality values were comparable to those observed in normal animals, and susceptibility to pyelonephritis was reduced or eliminated despite a degree of systemic acidosis similar to that observed in rats fed ammonium chloride solution without access to tap water. These results suggest that water diuresis may overcome the inactivation of complement produced by ammonium chloride acidosis and that renal medullary hypertonicity, produced by either water restriction or ammonium chloride acidosis, is a major determinant of this tissue's unique susceptibility to infection.
Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors
Authors: François Ghiringhelli, Lionel Apetoh, Antoine Tesniere, Laetitia Aymeric, Yuting Ma, Carla Ortiz, Karim Vermaelen, Theocharis Panaretakis, Grégoire Mignot, Evelyn Ullrich, Jean-Luc Perfettini, Frédéric Schlemmer, Ezgi Tasdemir, Martin Uhl, Pierre Génin, Ahmet Civas, Bernhard Ryffel, Jean Kanellopoulos, Jürg Tschopp, Fabrice André, Rosette Lidereau, Nicole M McLaughlin, Nicole M Haynes, Mark J Smyth, Guido Kroemer, Laurence Zitvogel
Journal: Nature Medicine (2009)
Fixed obstruction in severe asthma: not just a matter of time
Authors: M. Gaga
Journal: European Respiratory Journal (2004)

Fear conditioning has been ascribed to presynaptic mechanisms, particularly presynaptic facilitation of transmission at thalamo- and cortico-amygdala synapses. Here, by labeling surface receptors with biotin or using membrane fractionation approaches, we report that fear conditioning resulted in an increase in surface expression of GluR1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in the amygdala, whereas total GluR1 mRNA and protein levels were unchanged. The control group that received conditioned stimulus (CS) and unconditioned stimulus in an unpaired fashion did not present any increase, indicating that GluR1 increase was specific to the learning component of the task. Conditioning-induced increase in surface expression of GluR1 depended on the activation of <i>N</i>-methyl-d-aspartate receptors and protein kinases and required the synthesis of new proteins. CS-alone trials applied 24 h before training attenuated fear-potentiated startle and prevented conditioning-induced increase in surface expression of GluR1. Increase in GluR1 was also observed in the amygdala slices after delivery of tetanic stimulation that elicited long-term potentiation of synaptic transmission. Proteasome inhibitor increased surface expression of GluR1 in a time- and dose-dependent manner. Furthermore, pretraining administration of proteasome inhibitor into the amygdala facilitated the fear-potentiated startle. These results suggest that long-term memory formation is correlated with the change in synaptic expression of GluR1, and trafficking of GluR1 to the synaptic sites contributes at least in part to the expression of fear memory.
European evidence based consensus on the diagnosis and management of Crohn's disease: special situations
Authors: R Caprilli
Journal: Gut (2006)

This third section of the European Crohn's and Colitis Organisation (ECCO) Consensus on the management of Crohn's disease concerns postoperative recurrence, fistulating disease, paediatrics, pregnancy, psychosomatics, extraintestinal manifestations, and alternative therapy. The first section on definitions and diagnosis reports on the aims and methods of the consensus, as well as sections on diagnosis, pathology, and classification of Crohn's disease. The second section on current management addresses treatment of active disease, maintenance of medically induced remission, and surgery of Crohn's disease.
Role of Dicer and Drosha for Endothelial MicroRNA Expression and Angiogenesis
Authors: Angelika Kuehbacher, Carmen Urbich, Andreas M. Zeiher, Stefanie Dimmeler
Journal: Circulation Research (2007)

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by binding to the cellular transcript leading to translational repression or degradation of the target mRNA. Dicer and Drosha are the miRNA processing enzymes that are required for the maturation of miRNAs. Here, we investigated the role of Dicer and Drosha for angiogenesis. Endothelial cells were transfected with siRNA against Dicer and Drosha to inhibit miRNA biogenesis. Genetic silencing of Dicer and Drosha significantly reduced capillary sprouting of endothelial cells and tube forming activity. Migration of endothelial cells was significantly decreased in Dicer siRNA–transfected cells, whereas Drosha siRNA had no effect. Silencing of Dicer but not of Drosha reduced angiogenesis in vivo. Next, we attempted to identify miRNAs expressed in endothelial cells. A screening analysis of 168 human miRNAs using real-time PCR revealed that members of the let-7 family, mir-21, mir-126, mir-221, and mir-222 are highly expressed in endothelial cells. Dicer and Drosha siRNA reduced lef-7f and mir-27b expression. Inhibitors against let-7f and mir-27b also reduced sprout formation indicating that let-7f and mir-27b promote angiogenesis by targeting antiangiogenic genes. In silico analysis of predicted targets for let-7 cluster identified the endogenous angiogenesis inhibitor thrombospondin-1. Indeed, Dicer and Drosha siRNA significantly increased the expression of thrombospondin-1. Taken together, transient reduction of the miRNA-regulating enzyme Dicer impairs angiogenesis in vitro and in vivo, whereas Drosha siRNA induced a minor antiangiogenic effect in vitro and was not effective in vivo. The let-7 family and mir-27b appear to be attractive targets for modulating angiogenesis.
TWO YEARS CLINICAL OUTCOMES AFTER LARGE CORONARY STENT (4.0MM) PLACEMENT: COMPARISION OF BARE-METAL STENT VERSUS DRUG-ELUTING STENT
Authors: Chang-Wook Nam, Yun-Kyeong Cho, Seung-Ho Hur, Kwon-Bae Kim, Hyun-Tae Kim, Young-Jo Kim, Jong-Seon Park, Sang-Hee Lee, Geu-Ru Hong, Ung Kim, Sang-Hoon Seol, Tae-Hyun Yang, Doo-Il Kim, William F Fearon, None Keimyung University Dongsan Hospital, Daegu, South Korea
Journal: Journal of the American College of Cardiology (2010)
Allogeneic Mesenchymal Precursor Cells in Type 2 Diabetes: A Randomized, Placebo-Controlled, Dose-Escalation Safety and Tolerability Pilot Study
Authors: Jay S. Skyler, Vivian A. Fonseca, Karen R. Segal, Julio Rosenstock
Journal: Diabetes Care (2015)

To assess the safety, tolerability, and feasibility of adult allogeneic bone marrow-derived mesenchymal precursor cells (MPCs) in type 2 diabetes inadequately controlled with metformin either alone or with one additional oral antidiabetic agent.The study was a dose-escalating randomized placebo-controlled trial assessing one intravenous (IV) infusion of MPCs (rexlemestrocel-L; Mesoblast Inc.) 0.3 × 10(6)/kg (n = 15), 1.0 × 10(6)/kg (n = 15), or 2.0 × 10(6)/kg (n = 15) or placebo (n = 16). Study duration was 12 weeks.Subjects (21 women, 40 men) with a mean ± SD baseline HbA1c 8.3 ± 1.0% (67 ± 10.9 mmol/mol), BMI 33.5 ± 5.5 kg/m(2), and diabetes duration 10.1 ± 6.0 years were enrolled at 18 U.S. sites. No acute adverse events (AEs) were associated with infusion. No serious AEs, serious hypoglycemia AEs, or discontinuations due to AEs over 12 weeks were found. No subjects developed donor-specific anti-HLA antibodies or became sensitized. The safety profile was comparable among treatment groups. Compared with placebo, a single IV infusion of rexlemestrocel-L reduced HbA1c at all time points after week 1. The adjusted least squares mean ± SE dose-related differences in HbA1c from placebo in the rexlemestrocel-L groups ranged from -0.1 ± 0.2% (-1.1 ± 2.2 mmol/mol) to -0.4 ± 0.2% (4.4 ± 2.2 mmol/mol) at 8 weeks and from 0.0 ± 0.25% to -0.3 ± 0.25% (-3.3 ± -2.7 mmol/mol) at 12 weeks (P < 0.05 for 2.0 × 10(6)/kg dose at 8 weeks). The clinical target HbA1c <7% (53 mmol/mol) was achieved by 33% (5 of 15) of the subjects who received the 2.0 × 10(6)/kg dose vs. 0% of those who received placebo (P < 0.05).This short-term study demonstrates the safety and feasibility of up to 246 million MPCs in subjects with type 2 diabetes.
A Standardized Triglyceride and Carbohydrate Challenge
Authors: Anastasia C. Thanopoulou, Basil G. Karamanos, Demetra P. Roussi
Journal: Diabetes Care (2004)

We read with interest the article by Mohanlal and Holman (1) on the oral triglyceride tolerance test, showing that the test meal they propose is palatable, acceptable to subjects, and provides reproducible evaluation of postchallenge triglyceride profiles.

Although there is a tendency to consider postprandial hypertriglyceridemia as an independent risk factor for cardiovascular disease, no test meal for its evaluation has been universally accepted or normal ranges for postprandial triglycerides have been identified. Moreover, a clear distinction should be made between postprandial, which is the daily situation, …
MYC regulates the unfolded protein response and glucose and glutamine uptake in endocrine resistant breast cancer
Authors: Ayesha N Shajahan-Haq, Katherine L Cook, Jessica L Schwartz-Roberts, Ahreej E Eltayeb, Diane M Demas, Anni M Warri, Caroline O B Facey, Leena A Hilakivi-Clarke, Robert Clarke
Journal: Molecular Cancer (2014)

About 70% of all breast cancers are estrogen receptor alpha positive (ER+) and are treated with antiestrogens. However, 50% of ER + tumors develop resistance to these drugs (endocrine resistance). In endocrine resistant cells, an adaptive pathway called the unfolded protein response (UPR) is elevated that allows cells to tolerate stress more efficiently than in sensitive cells. While the precise mechanism remains unclear, the UPR can trigger both pro-survival and pro-death outcomes that depend on the nature and magnitude of the stress. In this study, we identified MYC, an oncoprotein that is upregulated in endocrine resistant breast cancer, as a regulator of the UPR in glucose-deprived conditions. ER+ human breast cancer cell lines (LCC1, LCC1, LY2 and LCC9) and rat mammary tumors were used to confirm upregulation of MYC in endocrine resistance. To evaluate functional relevance of proteins, siRNA-mediated inhibition or small molecule inhibitors were used. Cell density/number was evaluated with crystal violet assay; cell cycle and apoptosis were measured by flow cytometry. Relative quantification of glutamine metabolites were determined by mass spectrometry. Signaling molecules of the UPR, apoptosis or autophagy pathways were investigated by western blotting. Increased MYC function in resistant cells correlated with increased dependency on glutamine and glucose for survival. Inhibition of MYC reduced cell growth and uptake of both glucose and glutamine in resistant cells. Interestingly, in glucose-deprived conditions, glutamine induced apoptosis and necrosis, arrested autophagy, and triggered the unfolded protein response (UPR) though GRP78-IRE1α with two possible outcomes: (i) inhibition of cell growth by JNK activation in most cells and, (ii) promotion of cell growth by spliced XBP1 in the minority of cells. These disparate effects are regulated, at different signaling junctions, by MYC more robustly in resistant cells. Endocrine resistant cells overexpress MYC and are better adapted to withstand periods of glucose deprivation and can use glutamine in the short term to maintain adequate metabolism to support cell survival. Our findings reveal a unique role for MYC in regulating cell fate through the UPR, and suggest that targeting glutamine metabolism may be a novel strategy in endocrine resistant breast cancer.
Regression of Human T-cell Leukemia Virus Type I (HTLV-I)-Associated Lymphomas in a Rat Model: Peptide-Induced T-Cell Immunity
Authors: S. Hanabuchi, T. Ohashi, Y. Koya, H. Kato, A. Hasegawa, F. Takemura, T. Masuda, M. Kannagi
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Human T-cell leukemia virus type I (HTLV-I) is etiologically linked to adult T-cell leukemia (ATL). The disease has a high mortality rate and is resistant to chemotherapy; therefore, immunologic approaches to treatment could be of interest. We have previously shown that athymic rats inoculated with a syngeneic (i.e., with the same genetic background) HTLV-I-infected T-cell line (FPM1-V1AX) develop ATL-like disease and that the transfer of T cells from normal syngeneic rats immunized with FPM1-V1AX cells prevents disease development. In this study, we further characterized the host antitumor immunity to explore the possibility of peptide-based vaccination against the ATL-like disease. Methods: Immune T cells from rats immunized with FPM1-V1AX cells were analyzed for their phenotypes and cytotoxic properties. The epitope recognized by the T cells was analyzed by fine mapping. To evaluate the antitumor effects of a peptide-based vaccine, normal rats were immunized with synthetic oligopeptides corresponding to the epitope, the T cells were transferred to athymic rats inoculated with HTLV-I infected cells, and tumor size was monitored. Results: Both CD4+ and CD8+ T-cell populations from rats immunized with FPM1-V1AX cells inhibited the growth of FPM1-V1AX cell-induced lymphomas in vivo. Long-term culture of splenic T cells from the immunized rats repeatedly resulted in establishment of CD8+ HTLV-I-specific cytotoxic T lymphocyte (CTL) lines restricted to the rat major histocompatibility complex class I molecule, RT1.Al . The cytotoxicity of these lines was directed against the HTLV-I regulatory protein Tax and, specifically, against the epitope, amino acids 180–188 (GAFLTNVPY). Adoptive transfer of the Tax 180–188-specific CTL line or freshly prepared T cells from rats vaccinated with the Tax 180–188 oligopeptide prevented the development of FPM1-V1AX-cell induced lymphomas in athymic rats in comparison with control groups (two rats in each group). Conclusions: This study indicated a potential therapeutic effect of peptide-based vaccination against HTLV-I-induced lymphoproliferative disease.
Dharam Pal Singh Anhal
Authors: Rohit Anhal
Journal: BMJ (2004)

Former general practitioner Luton (b 1937; q Delhi 1961), d 26 August 2004.​2004.




Figure 1




Dharam Pal Singh Anhal, known as DP to his friends, came to the United Kingdom in 1962, and worked in east London and at Hillingdon Hospital before entering general practice in Luton in 1965. He built up several practices, with a total of 9000 patients between them. He leaves a wife and three children.