tbuckley/cabot-search huggingface dataset:
Maximizing Ventricular Function With Multimodal Cell-Based Gene Therapy
Authors: Terrence M. Yau, Christopher Kim, Guangming Li, Yaoguang Zhang, Richard D. Weisel, Ren-Ke Li
Journal: Circulation (2005)

Angiogenesis is enhanced after transplantation of vascular endothelial growth factor (VEGF)-expressing cells into a myocardial scar. Insulin-like growth factor I (IGF-I) may induce hypertrophy and inhibit apoptosis. We evaluated the effect of cell-based IGF-I and VEGF multigene therapy on left ventricular (LV) function, cell survival, and apoptosis after bone marrow cell (BMC) transplantation.Female Lewis rats underwent left anterior descending ligation 3 weeks before transplantation with male donor BMC, BMC transfected with VEGF (BMC+VEGF), IGF-I (BMC+IGF-I), VEGF and IGF-I (BMC+VEGF+IGF-I), or medium without cells (control) (n=4 per group x 5 groups x 4 time points). Three days and 1, 2, and 4 weeks after transplantation, VEGF and IGF-I expression was quantitated by real-time polymerase chain reaction, cell survival by polymerase chain reaction for sry2, apoptosis by TUNEL staining, LV function by echocardiography and myosin heavy chain, and light chain and troponin I by Western blot. One week after transplantation, IGF-I expression in the scar and border zone was greatest in BMC+IGF-I and BMC+VEGF+IGF-I rats (P<0.05). VEGF expression in the scar and border zone was greatest in BMC+VEGF and BMC+VEGF+IGF-I hearts (P<0.05). Transplanted cell survival was lowest in BMC, intermediate in BMC+VEGF and BMC+IGF-I, and greatest in BMC+VEGF+IGF-I (P<0.05). Apoptotic indices were significantly reduced in BMC+VEGF+IGF-I, BMC+VEGF, and BMC+IGF-I (P<0.05). Two and 4 weeks after transplantation, LV ejection fraction was lowest in control, intermediate in BMC, BMC+VEGF, and BMC+IGF-I, and greatest in BMC+VEGF+IGF-I (P<0.05).Transplantation of VEGF- and IGF-I-expressing BMC reduced apoptosis, maximized transplanted cell survival, and enhanced LV function. Multimodal cell-based gene therapy may maximize the benefits of cell transplantation.
Plasma cell S1P1 expression determines secondary lymphoid organ retention versus bone marrow tropism
Authors: Kenji Kabashima, Nicole M. Haynes, Ying Xu, Stephen L. Nutt, Maria L. Allende, Richard L. Proia, Jason G. Cyster
Journal: The Journal of Experimental Medicine (2006)

After induction in secondary lymphoid organs, a subset of antibody-secreting cells (ASCs) homes to the bone marrow (BM) and contributes to long-term antibody production. The factors determining secondary lymphoid organ residence versus BM tropism have been unclear. Here we demonstrate that in mice treated with FTY720 or that lack sphingosine-1-phosphate (S1P) receptor-1 (S1P1) in B cells, IgG ASCs are induced and localize normally in secondary lymphoid organs but they are reduced in numbers in blood and BM. Many IgG ASCs home to BM on day 3 of the secondary response and day 3 splenic ASCs exhibit S1P responsiveness, whereas the cells remaining at day 5 are unable to respond. S1P1 mRNA abundance is higher in ASCs isolated from blood compared to spleen, whereas CXCR4 expression is lower. Blood ASCs also express higher amounts of Kruppel-like factor (KLF)2, a regulator of S1P1 gene expression. These findings establish an essential role for S1P1 in IgG plasma cell homing and they suggest that differential regulation of S1P1 expression in differentiating plasma cells may determine whether they remain in secondary lymphoid organs or home to BM.
THYMOCYTES FROM MICE IMMUNIZED AGAINST AN ALLOGRAFT RENDER BONE-MARROW CELLS SPECIFICALLY CYTOTOXIC
Authors: C. K. Grant, G. A. Currie, P. Alexander
Journal: The Journal of Experimental Medicine (1972)

Thymocytes from C57BL mice immunized with the DBA/2 lymphoma L5178Y exert in vitro an immunologically specific cytotoxic action against the target cells in the presence of bone-marrow cells. Neither the nonimmune bone marrow nor the immune thymocytes are by themselves cytotoxic. The cells in the bone marrow which take part in the cytotoxic action adhere to glass and are sensitive to anti-macrophage serum. These bone-marrow cells can also be rendered specifically cytotoxic by exposure to the supernatant obtained from a culture of immune thymocytes with the specific target cells. The thymocytes before they are confronted with the specific target cells are very radiosensitive; however, on coming into contact with the target cells, an immunologically specific increase in RNA synthesis occurs and thereafter the thymocytes' capacity to render bone-marrow cells cytotoxic is relatively radioresistant. Two classes of immune lymphocytes occur in mice immunized with allogeneic cells, those that are capable of killing target cells directly and those that produce a factor capable of rendering macrophages (or monocytes) specifically cytotoxic. In the thymus of immune animals only the latter are found while both categories are present in the spleen and lymph nodes of immune animals.
Farr's Law Applied to AIDS Projections
Authors: Dennis J. Bregman
Journal: JAMA (1990)

Farr's Law of Epidemics, first promulgated in 1840 and resurrected by Brownlee in the early 1900s, states that epidemics tend to rise and fall in a roughly symmetrical pattern that can be approximated by a normal bell-shaped curve. We applied this simple law to the reported annual incidence of cases of acquired immunodeficiency syndrome in the United States from 1982 through 1987. The 6 years of incidence data closely fit a normal distribution that crests in late 1988 and then declines to a low point by the mid-1990s. The projected size of the epidemic falls in the range of 200 000 cases. A continuing incidence of endemic cases can be expected to emerge, but we believe it will occur at a low level.
Poor ventilatory response to mild hypoxia may inhibit acclimatization at moderate altitude in elderly patients after carotid surgery.
Authors: G Roeggla, M Roeggla, A Wagner, A N Laggner
Journal: British Journal of Sports Medicine (1995)

Peripheral chemoreceptors (carotid bodies) are the main sensing organs for hypoxaemia. During carotid surgery, the carotic body in the bifurcation of the common carotid artery is often involved and damaged or destroyed. Animals lose their ability to adapt to high altitude after experimental denervation of the carotid bodies. The objective of our study was to evaluate the ability of human patients to adapt to moderate altitude after single side carotid surgery. Blood gas analysis at rest at 171 m and after car and cable car transport to 1600 m before and after carotid surgery was performed. Mean(s.d.) paO2 decreased insignificantly from 74.8(3.56) at 171 m altitude to 71.6(2.07) at 1600 m (P = n.s.), means(s.d.) paCO2 decreased significantly from 36.2(2.86) to 31.4(2.7) mmHg (P < 0.05) before carotid surgery. Months after surgery, a significant drop in paO2 occurred after identical passive exposure to moderate altitude: mean(s.d.) paCO2 at 171 m 74.4(3.65) mmHg, at 1600 m 65.8(3.70) mmHg (P < 0.01), paCO2 did not change significantly. Mean(s.d.) paCO2 at 171 m: 36.0(2.35), at 1600 m 36.2(2.86) mmHg (P = n.s.). Although the sample investigated was small, after single side carotid surgery patients seem to lose their ability for satisfactory ventilatory response to acute exposure to moderate altitude. This is of possible alpine medical importance.
Ionic currents during hypoxia in voltage-clamped cat ventricular muscle.
Authors: A Vleugels, J Vereecke, E Carmeliet
Journal: Circulation Research (1980)

To explore the mechanisms underlying the shortening of the cardiac action potential in hypoxia, we studied the effect of hypoxia on the ionic currents in cat papillary and trabecular muscles using the single sucrose gap-voltage clamp technique. For potentials positive to -70 mV, hypoxia induces an increase in time-independent outward current. The changes in the tail current suggest that time-dependent outward current is not increased but, rather, reduced. Because the time course of ik remains unchanged, we concluded that the shortening of the action potential is not a result of a change in the time-dependent outward current. In the potential range of the plateau, the amplitude of the slow inward current is not affected by hpoxia. Its time constant of inactivation appears slightly decreased. The prolongation of the action potential by epinephrine during hypoxia is accompanied by an increase in the slow inward current. As a result of these studies, we conclude that the shortening of the cardiac action potential in the early stage of hypoxia results from an increase in K+ outward background current.
Long-Term Mental Health Effects of the Chernobyl Disaster: An Epidemiologic Survey in Two Former Soviet Regions
Authors: Johan M. Havenaar, Galina M. Rumyantzeva, Wim van den Brink, Nico W. Poelijoe, Jan van den Bout, Herman van Engeland, Maarten W.J. Koeter
Journal: American Journal of Psychiatry (1997)

OBJECTIVE: This study assessed the long-term mental health effects of the nuclear accident at Chernobyl. METHOD: Two population samples (N=3,044), one from the Gomel region, close to the accident site, and one from Tver, 500 miles away, were studied 6 years after the event with the use of a variety of self-report questionnaires and a standardized psychiatric interview. RESULTS: The prevalence of psychological distress and DSM-III-R psychiatric disorders was exceptionally high in both regions. Scores on the self-report scales were consistently higher in the exposed region; however, a higher risk of DSM-III-R psychiatric disorders could be demonstrated only among women with children under 18 years of age in the exposed region. CONCLUSIONS: A substantial long-term mental health effect of the Chernobyl incident was demonstrated, mainly at a subclinical level. (Am J Psychiatry 1997; 154:1605–1607)
CCR5 Deletion Protects Against Inflammation-Associated Mortality in Dialysis Patients
Authors: Friso L.H. Muntinghe, Marion Verduijn, Mike W. Zuurman, Diana C. Grootendorst, Juan Jesus Carrero, Abdul Rashid Qureshi, Karin Luttropp, Louise Nordfors, Bengt Lindholm, Vincent Brandenburg, Martin Schalling, Peter Stenvinkel, Elisabeth W. Boeschoten, Raymond T. Krediet, Gerjan Navis, Friedo W. Dekker
Journal: Journal of the American Society of Nephrology (2009)

The CC-chemokine receptor 5 (CCR5) is a receptor for various proinflammatory chemokines, and a deletion variant of the CCR5 gene (CCR5Δ32) leads to deficiency of the receptor. We hypothesized that CCR5Δ32 modulates inflammation-driven mortality in patients with ESRD. We studied the interaction between CCR5 genotype and levels of high-sensitivity C-reactive protein (hsCRP) in 603 incident dialysis patients from the multicenter, prospective NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort. CCR5 genotype and hsCRP levels were both available for 413 patients. During 5 yr of follow-up, 170 patients died; 87 from cardiovascular causes. Compared with the reference group of patients who had the wild-type CCR5 genotype and hsCRP ≤ 10 mg/L (<i>n</i> = 225), those carrying the deletion allele with hsCRP ≤ 10 mg/L (<i>n</i> = 55) had similar mortality, and those carrying the wild-type genotype with hsCRP &gt; 10 mg/L (<i>n</i> = 108) had an increased risk for mortality (HR: 1.82; 95% CI: 1.29 to 2.58). However, those carrying the deletion allele with hsCRP &gt; 10 mg/L (<i>n</i> = 25) had a mortality rate similar to the reference group; this seemingly protective effect of the CCR5 deletion was even more pronounced for cardiovascular mortality. We replicated these findings in an independent Swedish cohort of 302 ESRD patients. In conclusion, the CCR5Δ32 polymorphism attenuates the adverse effects of inflammation on overall and cardiovascular mortality in ESRD.
Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
Authors: Thomas W. Kensler, Nobunao Wakabayashi, Shyam Biswal
Journal: The Annual Review of Pharmacology and Toxicology (2006)

Keap1-Nrf2-ARE signaling plays a significant role in protecting cells from endogenous and exogenous stresses. The development of Nrf2 knockout mice has provided key insights into the toxicological importance of this pathway. These mice are more sensitive to the hepatic, pulmonary, ovarian, and neurotoxic consequences of acute exposures to environmental agents and drugs, inflammatory stresses, as well as chronic exposures to cigarette smoke and other carcinogens. Under quiescent conditions, the transcription factor Nrf2 interacts with the actin-anchored protein Keap1, largely localized in the cytoplasm. This quenching interaction maintains low basal expression of Nrf2-regulated genes. However, upon recognition of chemical signals imparted by oxidative and electrophilic molecules, Nrf2 is released from Keap1, escapes proteasomal degradation, translocates to the nucleus, and transactivates the expression of several dozen cytoprotective genes that enhance cell survival. This review highlights the key elements in this adaptive response to protection against acute and chronic cell injury provoked by environmental stresses.
Elevated expression of transforming growth factor-beta and proteoglycan production in experimental glomerulonephritis. Possible role in expansion of the mesangial extracellular matrix.
Authors: S Okuda, L R Languino, E Ruoslahti, W A Border
Journal: Journal of Clinical Investigation (1990)

Glomerular accumulation of extracellular matrix is a prominent feature of progressive glomerulonephritis. Previously, we have shown that transforming growth factor-beta (TGF-beta) is unique among growth factors in regulating the production of the proteoglycans biglycan and decorin by glomerular mesangial cells in vitro. We now provide evidence of an elevated expression of TGF-beta, proteoglycans, and fibronectin in glomerulonephritis induced in rats by injection of anti-thymocyte serum (ATS). Glomeruli were cultured from rat kidneys at 1, 4, 7, 14, and 28 d after ATS administration. Increased proteoglycan synthesis was detected beginning on day 4, which peaked at a 4,900% increase compared with control on day 7, and returned toward control levels by day 28. The increased proteoglycan synthesis by cultured nephritic glomeruli, as well as that of fibronectin, were greatly reduced by addition of antiserum raised against a synthetic peptide from TGF-beta. Conditioned media from ATS glomerular cultures, when added to normal cultured mesangial cells, induced elevated proteoglycan synthesis that also peaked on day 7 and that mimicked the response to added exogenous TGF-beta. The stimulatory activity of the conditioned media was blocked by addition of TGF-beta antiserum. Prior addition of the immunizing peptide to the antiserum abolished the blocking effect. The main induced proteoglycans were identified as biglycan and decorin by immunoprecipitation with antiserum made against synthetic peptides from the proteoglycan core proteins. Glomerular histology showed mesangial matrix expansion in a time course that roughly paralleled both the elevated proteoglycan synthesis by the ATS glomeruli and the ability of the conditioned media from these glomeruli to induce proteoglycan synthesis. At the same time there was an increased expression of TGF-beta mRNA and TGF-beta protein in the glomeruli. These results suggest a central role for TGF-beta in the accumulation of pathological extracellular matrix in glomerulonephritis.
Symptoms, emergency admissions and place of death in patients with pleural malignancy
Authors: Fiona Christie, Maanasa Polubothu, Fiona Thomson, Kevin G. Blyth
Journal: European Respiratory Journal (2012)

Pleural malignancy is often associated with a poor prognosis, but qualitative outcomes are rarely published. We describe the journey of these patients, focusing on symptoms, admissions and place of death.  Methods  In August 2011 we reviewed case-notes and electronic records of 157 patients with pleural cytology sent during 2009. In 73 patients diagnosed with pleural malignancy we recorded: performance status (PS), nature of diagnosis (tissue or clinical), pleurodesis, emergency admissions, symptomatic effusion at death and place of death.  Results  71/73 patients (97%) had died by data collection. Important clinical data included:  The mean (SD) number of admissions and days spent as inpatient were 3 (1.7) and 26 (23), respectively. 21/73 (29%) underwent pleurodesis (13 at VATS), 22/71 (31%) had symptomatic effusion at death, 11/71 (15%) had an intercostal drain inserted in the week preceding death.  33/73 (45%) spent >30% of their remaining time in hospital. 49/71 (69%) died in an acute hospital ward, 1/71 (1%) died in a regional oncology centre, 13/71 (18%) died at home and 6/71 (8%) died in a hospice.  Conclusion  Patients with pleural malignancy spend a significant proportion of their remaining time in hospital. The majority in our audit died in acute hospital units, often with symptomatic pleural effusion. Few died at home or in specialist palliative care facilities.
Statins and micronutrients: unanswered questions
Authors: R J Walden
Journal: Journal of the Royal Society of Medicine (2005)

Dr McNaught is right to point out examples of racism in the NHS (December 2004 JRSM 1 ).But what to do about it?Maybe we can learn some lessons from the past.Today there is an over-representation of black people in the mental health system but in the 1960s Irish people were over-represented. 2 Psychiatrists thought that the prevalence of schizophrenia was high in people from the west of Ireland and invented a new syndrome 'western seaboard psychosis'. 3 Anthropologists descended on the unsuspecting immigrants to ask them if their Catholic faith caused their minds to unbalance and psychiatrists followed to dole out antipsychotics.But then some proper research was done and it showed no excess of schizophrenia in Irish immigrants. 4 The methods of case collection in the early studies were poor and cross-cultural comparisons were not properly thought through. 3 Today Irish people are no more likely to be diagnosed with schizophrenia than anyone else.How did this happen?I would love to say that it was because of the new research or because of government initiatives.The research helped a bit but the main cures for anti-Irish discrimination were that the new immigrants were richer, better educated, better informed and more questioning.They would not be fobbed off with a misdiagnosis.An increasing understanding and appreciation of Irish culture also helped reduce anti-Irish discrimination generally.The most effective cure of all was time.A cynic would add that, nowadays, people have a new batch of immigrants (such as asylum seekers) to discriminate against.So we need fewer new policy drives and more changes of heart.These will only come from changes in society.Blaming individuals or even the NHS will not help.
-3 polyunsaturated fatty acid supplementation for the treatment of heart failure: mechanisms and clinical potential
Authors: M. K. Duda, K. M. O'Shea, W. C. Stanley
Journal: Cardiovascular Research (2009)

Heart failure (HF) is a complex clinical syndrome with multiple aetiologies. Current treatment options can slow the progression to HF, but overall the prognosis remains poor. Clinical studies suggest that high dietary intake of the ω-3 polyunsaturated fatty acids (ω-3PUFA) found in fish oils (eicosapentaenoic and docosahexaenoic acids) may lower the incidence of HF, and that supplementation with pharmacological doses prolongs event-free survival in patients with established HF. The mechanisms for these potential benefits are complex and not well defined. It is well established that fish oil supplementation lowers plasma triglyceride levels, and more recent work demonstrates anti-inflammatory effects, including reduced circulating levels of inflammatory cytokines and arachidonic acid-derived eicosanoids, and elevated plasma adiponectin. In animal studies, fish oil favourably alters cardiac mitochondrial function. All of these effects may work to prevent the development and progression of HF. The ω-3PUFA found in plant sources, α-linolenic acid, may also be protective in HF; however, the evidence is not as compelling as for fish oil. This review summarizes the evidence related to use of ω-3PUFA supplementation as a potential treatment for HF and discusses possible mechanisms of action. In general, there is growing evidence that supplementation with ω-3PUFA positively impacts established pathophysiological targets in HF and has potential therapeutic utility for HF patients.
Pathogenic Fungi Regulate Immunity by Inducing Neutrophilic Myeloid-Derived Suppressor Cells
Authors: Nikolaus Rieber, Anurag Singh, Hasan Öz, Melanie Carevic, Maria Bouzani, Jorge Amich, Michael Ost, Zhiyong Ye, Marlene Ballbach, Iris Schäfer, Markus Mezger, Sascha N. Klimosch, Alexander N.R. Weber, Rupert Handgretinger, Sven Krappmann, Johannes Liese, Maik Engeholm, Rebecca Schüle, Helmut Rainer Salih, Laszlo Marodi, Carsten Speckmann, Bodo Grimbacher, Jürgen Ruland, Gordon D. Brown, Andreas Beilhack, Juergen Loeffler, Dominik Hartl
Journal: Cell Host & Microbe (2015)

Despite continuous contact with fungi, immunocompetent individuals rarely develop pro-inflammatory antifungal immune responses. The underlying tolerogenic mechanisms are incompletely understood. Using both mouse models and human patients, we show that infection with the human pathogenic fungi Aspergillus fumigatus and Candida albicans induces a distinct subset of neutrophilic myeloid-derived suppressor cells (MDSCs), which functionally suppress T and NK cell responses. Mechanistically, pathogenic fungi induce neutrophilic MDSCs through the pattern recognition receptor Dectin-1 and its downstream adaptor protein CARD9. Fungal MDSC induction is further dependent on pathways downstream of Dectin-1 signaling, notably reactive oxygen species (ROS) generation as well as caspase-8 activity and interleukin-1 (IL-1) production. Additionally, exogenous IL-1β induces MDSCs to comparable levels observed during C. albicans infection. Adoptive transfer and survival experiments show that MDSCs are protective during invasive C. albicans infection, but not A. fumigatus infection. These studies define an innate immune mechanism by which pathogenic fungi regulate host defense.
Suppression of 7,12-Dimethylbenz[&lt;italic&gt;a&lt;/italic&gt;]anthracene-Induced Chromosome Aberrations in Rat Bone Marrow Cells After Treatment With Sudan III and Related Azo Dyes&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Y Ito, S Maeda, T Fujihara, N Ueda, T Sugiyama
Journal: JNCI Journal of the National Cancer Institute (1982)

Noninbred Long-Evans rats fed Sudan III at 24 hours before they were given an injection of 7,12-dimethylbenz[a]anthracene (DMBA) displayed prominently suppressed DMBA-induced chromosome aberrations (CA) in their bone marrow cells. Rats fed Sudan III simultaneously with the DMBA injection showed no suppressed CA effect. The suppressive effect of Sudan III on DMBA-induced CA paralleled the dose rate of Sudan III when given in the range between 1 and 10 mg Sudan III/kg body weight; higher doses produced no additional suppression. The capacity of various Sudan III-related chemicals to prevent DMBA-induced CA paralleled their capacity to prevent DMBA-induced adrenal apoplexy and mammary cancer. Among the azo dyes investigated, Sudan III was most efficient in protecting against DMBA-induced CA. Polychlorinated biphenyl and phenobarbital, inducers of drug-metabolizing enzymes, also suppressed DMBA-induced CA.