tbuckley/cabot-search huggingface dataset:
New concepts of molecular communication among neurons
Authors: R. Key Dismukes
Journal: Behavioral and Brain Sciences (1979)

Abstract Recently a number of complex electrophysiological responses to neurotransmitters have been observed that cannot be described as simple excitation or inhibition. These responses are often characterized as modulatory, although there is no consensus on what defines modulation. Morphological studies reveal certain neurotransmitters stored in what might be release sites without synaptic contact. There is no direct evidence for nonsynaptic release from CNS sites, although such release does occur in the periphery and in invertebrates. Nonsynaptic release might provide a basis for diffuse one-cell-to-many communication, but it might also simply be a means of sending the transmitter to a broader area of a single neuron than occurs in typical synapses. Several kinds of macromolecules have been found to be transported in a retrograde direction – and in some cases transsynaptically. There have been suggestions that some neurons may release more than one type of transmitter. Particularly intriguing is the possibility of release of substances that modulate actions of a primary transmitter. Taken together this range of evidence suggests that neurons may use a variety of forms of molecular communication in addition to traditionally described synaptic transmission. Several authors have suggested modes of communication distinct from classical synaptic transmission and have classified released substances using terms such as neurohumor, neurohormone, neuroregulator, and modulator. These suggestions have the heuristic value of drawing together diverse kinds of data, but it remains to be established that the pieces fit together in that fashion – for example, that complex electrophysiological effects are associated with substances released nonsynaptically. In order to reduce confusion, a flexible, generic approach to nomenclature for substances released from neurons and for hypothetical modes of communication is recommended. Some behavioral implications of nonconventional transmission are considered.
Higher clearance of hepatitis C virus infection in females compared with males
Authors: I Bakr
Journal: Gut (2005)

According to the literature, 14-46% of subjects clear hepatitis C virus (HCV) from blood after infection. Controversy exists about sex differences in HCV clearance rates.We compared HCV clearance in males and females using data from a large population based study on HCV infection in Egypt. Definitions used in the paper were: cleared HCV infection (positive HCV antibody and negative HCV RNA test results) and chronic HCV infection (positive HCV antibody and positive HCV RNA test results). The study sample included 4720 village residents aged 18-65 years recruited through home based visits (n = 2425) or voluntary screening (n = 2295).Overall, HCV antibody prevalence was 910/4720 (19.3% (95% confidence interval 18.2-20.4)). Of those with HCV antibodies (n = 910), 61.5% had chronic HCV infection. Compared with males, females were more likely to have cleared the virus (44.6% v 33.7%, respectively; p = 0.001). Control for age, schistosomiasis history, iatrogenic exposures, and sexual exposure to HCV did not alter the positive association between female sex and viral clearance.This study provides strong evidence in favour of a higher HCV clearance rate in females compared with males.
Effect of cinnarizine on IgE antibody‐mediated experimental allergic reactions in guinea pigs
Authors: H. Nagai, H. Yamada, I. Yakuo, N. Inagaki, S. H. Choi, A. Koda, M. Daikoku
Journal: Allergy (1987)

The anti‐allergic activity and mechanism of cinnarizine was investigated in guinea pigs. Nifedipine, a calcium antagonist, and tranilast, a potent, orally active anti‐allergic agent, were used as comparative drugs. 1) Cinnarizine protected against fatal systemic anaphylactic shock in guinea pigs passively sensitized with IgE antibody. Cinnarizine reduced many of the features of severe respiratory disorders. Nifedipine and tranilast showed similar effects. 2) Cinnarizine and nifedipine inhibited the contractile response to antigen of sensitized tracheal smooth muscle when the challenge was carried out at low antigen concentrations. Tranilast showed a tendency to inhibit the antigen‐induced contraction of tracheal smooth muscle. 3) Cinnarizine and nifedipine inhibited Ca‐induced contraction in potassium‐depolarized tracheal smooth muscle, tranilast had no effect. 4) Cinnarizine showed antagonistic action to the contraction by histamine or leukotriene D 4 (LTD 4 ) of tracheal muscle. Nifedipine showed similar antagonistic action, although its potency is lower than cinnarizine. Tranilast showed slight antagonistic action to LTD 4 . 5) Antigen‐induced release of histamine and slow reacting substance of anaphylaxis (SRS‐A) from sensitized lung tissues was inhibited by nifedipine and tranilast but not by cinnarizine. 6) The release of histamine and SRS‐A from lung tissues by calcium ionophore A23187 was inhibited by nifedipine and tranilast but not by cinnarizine. These results suggest that the anti‐allergic action of cinnarizine is mainly due to the antagonistic action to allergic mediators and not by interfering with die release of mediators. Cinnarizine's mechanism seems to be related to its antagonistic action to Ca in smooth muscle, but not to the transport of Ca in releasing the anaphylactic chemical mediators in mast cells and other target cells.
Connexin43-dependent mechanism modulates renin secretion and hypertension
Authors: J.-A. Haefliger
Journal: Journal of Clinical Investigation (2006)

To investigate the function of Cx43 during hypertension, we studied the mouse line Cx43KI32 (KI32), in which the coding region of Cx32 replaces that of Cx43. Within the kidneys of homozygous KI32 mice, Cx32 was expressed in cortical and medullary tubules, as well as in some extra- and intraglomerular vessels, i.e., at sites where Cx32 and Cx43 are found in WT mice. Under such conditions, renin expression was much reduced compared with that observed in the kidneys of WT and heterozygous KI32 littermates. After exposure to a high-salt diet, all mice retained a normal blood pressure. However, whereas the levels of renin were significantly reduced in the kidneys of WT and heterozygous KI32 mice, reaching levels comparable to those observed in homozygous littermates, they were not further affected in the latter animals. Four weeks after the clipping of a renal artery (the 2-kidney, 1-clip [2K1C] model), 2K1C WT and heterozygous mice showed an increase in blood pressure and in the circulating levels of renin, whereas 2K1C homozygous littermates remained normotensive and showed unchanged plasma renin activity. Hypertensive, but not normotensive, mice also developed cardiac hypertrophy. The data indicate that replacement of Cx43 by Cx32 is associated with decreased expression and secretion of renin, thus preventing the renin-dependent hypertension that is normally induced in the 2K1C model.
Pulmonary abnormalities in obligate heterozygotes for cystic fibrosis.
Authors: P B Davis, K Vargo
Journal: Thorax (1987)

Parents of children with cystic fibrosis have been reported to have a high prevalence of increased airway reactivity, but these studies were done in a select young, healthy, symptomless population. In the present study respiratory symptoms were examined in 315 unselected parents of children with cystic fibrosis and 162 parents of children with congenital heart disease (controls). The cardinal symptom of airway reactivity, wheezing, was somewhat more prevalent in cystic fibrosis parents than in controls, but for most subgroups this increased prevalence did not reach statistical significance. Among those who had never smoked, 38% of obligate heterozygotes for cystic fibrosis but only 25% of the controls reported wheezing (p less than 0.05). The cystic fibrosis parents who had never smoked but reported wheezing had lower FEV1 and FEF25-75, expressed as a percentage of the predicted value, than control parents; and an appreciable portion of the variance in pulmonary function was contributed by the interaction of heterozygosity for cystic fibrosis with wheezing. For cystic fibrosis parents, but not controls, the complaint of wheezing significantly contributed to the prediction of pulmonary function (FEV1 and FEF25-75). In addition, parents of children with cystic fibrosis reported having lung disease before the age of 16 more than twice as frequently as control parents. Other respiratory complaints, including dyspnoea, cough, bronchitis, and hay fever, were as common in controls as in cystic fibrosis heterozygotes. These data are consistent with the hypothesis that heterozygosity for cystic fibrosis is associated with increased airway reactivity and its symptoms, and that the cystic fibrosis heterozygotes who manifest airway reactivity and its symptoms may be at risk for poor pulmonary function.
The pattern of cytokine expression determines the degree of mucosal damage
Authors: A J Leon, E Gomez, J A Garrote, E Arranz
Journal: Gut (2007)

after exclusion of more common aetiologies for the presenting complaints.The investigation in these patients should proceed with an EEG.Treatment typically begins with anticonvulsant drugs; oxcarbazepine is an effective anticonvulsant in this syndrome.
Prophylaxis for Thromboembolism in Hospitalized Medical Patients
Authors: Charles W. Francis
Journal: New England Journal of Medicine (2007)

A 62-year-old man is admitted with fever, cough, and dyspnea. He is weak, appears to be dehydrated, and has purulent sputum. His temperature is 39.2°C, respirations 22, and blood pressure 128/69 mm Hg. There are crackles over the left lower lung field, and chest radiography shows a density in the left lower lobe that is consistent with pneumonia. Should thromboprophylaxis be provided? If so, in what form?
Meta-analysis of MTHFR 677C→ T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?
Authors: Sarah J Lewis, Shah Ebrahim, George Davey Smith
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objectives</b> To investigate the association between the MTHFR 677C→ T polymorphism and coronary heart disease, assessing small study bias and heterogeneity between studies. <b>Data sources</b> Medline and Embase citation searches between January 2001 and August 2004; no language restrictions. <b>Study selection</b> Case-control and prospective studies of association between MTHFR 677C→ T variant and myocardial infarction, coronary artery occlusion, or both; 80 studies were included. <b>Data extraction</b> Data on genotype frequency and mean homocysteine concentrations by genotype were extracted. Odds ratios were calculated for TT genotype versus CC genotype. Heterogeneity was explored, with stratification by geographical region of the study samples, and meta-regression by difference in mean serum homocysteine concentrations (CC minus TT genotypes) was carried out. <b>Results</b> 26 000 cases and 31 183 controls were included. An overall random effects odds ratio of 1.14 (95% confidence intervals 1.05 to 1.24) was found for TT versus CC genotype. There was strong evidence of heterogeneity (P &lt; 0.001, <i>I<sup>2</sup></i> = 38.4%), which largely disappeared after stratification by geographical region. Odds ratios in Europe, Australia, and North America attenuated towards the null, unlike those in the Middle East and Asia. <b>Conclusions</b> No strong evidence exists to support an association of the MTHFR 677 C→T polymorphism and coronary heart disease in Europe, North America, or Australia. Geographical variability may be due to higher folate intake in North America and Europe or to publication bias. The conclusion drawn from previous meta-analyses that folic acid, through lowering homocysteine, has a role in prevention of cardiovascular disease is in some doubt.
Attention to Threats and Combat-Related Posttraumatic Stress Symptoms
Authors: Ilan Wald, Kathryn A. Degnan, Elena Gorodetsky, Dennis S. Charney, Nathan A. Fox, Eyal Fruchter, David Goldman, Gad Lubin, Daniel S. Pine, Yair Bar-Haim
Journal: JAMA Psychiatry (2013)

Combat places soldiers at risk for posttraumatic stress disorder (PTSD). The excessive rates of PTSD and other adjustment disorders in soldiers returning home make it imperative to identify risk and resilience factors that could be targeted by novel therapeutic treatments.To investigate the interplay among attention to threat, combat exposure, and other risk factors for PTSD symptoms in soldiers deployed to combat.Longitudinal prospective study of Israeli Defense Force infantry soldiers carried out in 2008 through 2010. Repeated measurements during a 1-year period included baseline and predeployment data collected in training camps and deployment data collected in the combat theater.Infantry soldiers (1085 men; mean age, 18.8 years).Postcombat PTSD symptoms. RESULTS Soldiers developed threat vigilance during combat deployment, particularly when they were exposed to high-intensity combat, as indicated by faster response times to targets appearing at the location of threat relative to neutral stimuli (P < .001). Threat-related attention bias also interacted with combat exposure to predict risk for PTSD (P < .05). Bias toward threat at recruitment (P < .001) and bias away from threat just before deployment (P < .05) predicted postcombat PTSD symptoms. Moreover, these threat-related attention associations with PTSD were moderated by genetic and environmental factors, including serotonin transporter (5-HTTLPR) genotype.Combat exposure interacts with threat-related attention to place soldiers at risk for PTSD, and interactions with other risk factors account for considerable variance in PTSD vulnerability. Understanding these associations informs research on novel attention bias modification techniques and prevention of PTSD.
Clinical and functional characterisation of a novel TNFRSF1A c.605T&gt;A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment
Authors: S Stojanov, C Dejaco, P Lohse, K Huss, C Duftner, B H Belohradsky, M Herold, M Schirmer
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> To study the clinical outcome, treatment response, T-cell subsets and functional consequences of a novel tumour necrosis factor (TNF) receptor type 1 (TNFRSF1A) mutation affecting the receptor cleavage site. <h3>Methods:</h3> Patients with symptoms suggestive of tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and 22 healthy controls (HC) were screened for mutations in the <i>TNFRSF1A</i> gene. Soluble TNFRSF1A and inflammatory cytokines were measured by ELISAs. TNFRSF1A shedding was examined by stimulation of peripheral blood mononuclear cells (PBMCs) with phorbol 12-myristate 13-acetate followed by flow cytometric analysis (FACS). Apoptosis of PBMCs was studied by stimulation with TNFα in the presence of cycloheximide and annexin V staining. T cell phenotypes were monitored by FACS. <h3>Results:</h3> <i>TNFRSF1A</i> sequencing disclosed a novel V173D/p.Val202Asp substitution encoded by exon 6 in one family, the c.194–14G&gt;A splice variant in another and the R92Q/p.Arg121Gln substitution in two families. Cardiovascular complications (lethal heart attack and peripheral arterial thrombosis) developed in two V173D patients. Subsequent etanercept treatment of the V173D carriers was highly effective over an 18-month follow-up period. Serum TNFRSF1A levels did not differ between TRAPS patients and HC, while TNFRSF1A cleavage from monocytes was significantly reduced in V173D and R92Q patients. TNFα-induced apoptosis of PBMCs and T-cell senescence were comparable between V173D patients and HC. <h3>Conclusions:</h3> The TNFRSF1A V173D cleavage site mutation may be associated with an increased risk for cardiovascular complications and shows a strong response to etanercept. T-cell senescence does not seem to have a pathogenetic role in affected patients.
Persistent Left Superior Vena Cava Demonstrated With Multislice Spiral Computed Tomography
Authors: Thomas C. Gerber, Ronald S. Kuzo
Journal: Circulation (2002)

A 64-year-old man with atypical angina presented for partic- ipation in a clinical trial of minimally invasive coronary angiography with use of contrast-enhanced, retrospectively gated multislice spiral computed tomography (Figure).Two of the 12 coronary segments defined by the American Heart Association could not be assessed because of dense calcification; the remaining segments were free of significant obstructions.A persistent left superior vena cava (PLSVC) connected to the coronary sinus was noted incidentally.There were no associated cardiac malformations.A PLSVC connected to the coronary sinus is the most common anomaly of systemic venous return.This anomaly usually requires no treatment unless it is associated with other cardiac malformations.However, it can create problems with procedures that require access to the right ventricle or pulmonary artery or with new therapeutic techniques that make use of the cardiac veins overlying the left ventricle, such as left ventricular pacing or percutaneous in situ coronary venous arterialization.
Molecular Pathways: Regulation and Therapeutic Implications of Multidrug Resistance
Authors: Kevin G. Chen, Branimir I. Sikic
Journal: Clinical Cancer Research (2012)

Abstract Multidrug transporters constitute major mechanisms of MDR in human cancers. The ABCB1 (MDR1) gene encodes a well-characterized transmembrane transporter, termed P-glycoprotein (P-gp), which is expressed in many normal human tissues and cancers. P-gp plays a major role in the distribution and excretion of drugs and is involved in intrinsic and acquired drug resistance of cancers. The regulation of ABCB1 expression is complex and has not been well studied in a clinical setting. In this review, we elucidate molecular signaling and epigenetic interactions that govern ABCB1 expression and the development of MDR in cancer. We focus on acquired expression of ABCB1 that is associated with genomic instability of cancer cells, including mutational events that alter chromatin structures, gene rearrangements, and mutations in tumor suppressor proteins (e.g., mutant p53), which guard the integrity of genome. In addition, epigenetic modifications of the ABCB1 proximal and far upstream promoters by either demethylation of DNA or acetylation of histone H3 play a pivotal role in inducing ABCB1 expression. We describe a molecular network that coordinates genetic and epigenetic events leading to the activation of ABCB1. These mechanistic insights provide additional translational targets and potential strategies to deal with clinical MDR. Clin Cancer Res; 18(7); 1863–9. ©2012 AACR.
Enhanced collagen synthesis in cultured skin fibroblasts from insulin-dependent diabetic patients with nephropathy.
Authors: R Trevisan, J Yip, L Sarika, L K Li, G Viberti
Journal: Journal of the American Society of Nephrology (1997)

Excessive production and deposition of extracellular matrix proteins are characteristic features of diabetic nephropathy. This study tests the hypothesis that cells from diabetic patients who develop nephropathy have a disturbance in collagen metabolism compared with cells from diabetic patients without complications. Kinetics of overall collagen metabolism and total protein synthesis were examined in serially passaged, subconfluent, quiescent skin fibroblasts cultured in either normal (5 mM) or high (25 mM) glucose concentrations from 14 insulin-dependent diabetic (IDDM) patients with nephropathy; 14 IDDM patients without nephropathy matched for age, diabetes duration, and body mass index; and 14 healthy subjects. Fibroblasts were incubated in the presence of 2 microCi/ml [3H]proline, and after labeling the incorporation of [3H]proline into total protein, collagen (collagenase-sensitive material), and noncollagen proteins (collagenase-resistant material) was determined at different time points. Collagen degradation was determined in pulse-chase experiments by following the residual collagen-bound radioactivity after incubation for 8 h with 10 microCi/ml [3H]proline. In high glucose concentrations (25 mM), overall collagen synthesis (measured as [3H]proline incorporation into extracellular and intracellular collagenase-sensitive material) was significantly greater in the patients with nephropathy (mean +/- SEM after a 24-h labeling period: 7189 +/- 671 dpm/10(6) cells) than in the patients without (4341 +/- 267 dpm/10(6) cells; P < 0.01) or healthy control subjects (3836 +/- 234 dpm/10(6) cells; P < 0.01). No significant differences were observed in noncollagen protein production or in collagen degradation rates among the three groups of subjects. In the presence of normal glucose concentrations (5 mM), collagen synthesis was lower in all groups studied, but the differences between IDDM patients with nephropathy and those without remained unaltered. These results suggest that long-term cultured fibroblasts derived from diabetic patients with nephropathy exhibit an abnormality in collagen metabolism. Cells from long-standing diabetic patients without nephropathy have normal collagen metabolism. The increased collagen synthesis is likely to be intrinsic to those diabetic patients susceptible to nephropathy and may play an important role in the sclerotic processes that occur in the kidneys, arteries, and heart.
Identification of a Putative Tumor Suppressor Gene <i>Rap1GAP</i> in Pancreatic Cancer
Authors: Lizhi Zhang, Li Chenwei, Redah Mahmood, Kenneth van Golen, Joel Greenson, Gangyong Li, Nisha J. D'Silva, Xiangquan Li, Charles F. Burant, Craig D. Logsdon, Diane M. Simeone
Journal: Cancer Research (2006)

Abstract Human chromosome 1p35-p36 has long been suspected to harbor a tumor suppressor gene in pancreatic cancer and other tumors. We found that expression of rap1GAP, a gene located in this chromosomal region, is significantly down-regulated in pancreatic cancer. Only a small percentage of preneoplastic pancreatic intraductal neoplasia lesions lost rap1GAP expression, whereas loss of rap1GAP expression occurred in 60% of invasive pancreatic cancers, suggesting that rap1GAP contributes to pancreatic cancer progression. In vitro and in vivo studies showed that loss of rap1GAP promotes pancreatic cancer growth, survival, and invasion, and may function through modulation of integrin activity. Furthermore, we showed a high frequency of loss of heterozygosity of rap1GAP in pancreatic cancer. Collectively, our data identify rap1GAP as a putative tumor suppressor gene in pancreatic cancer. (Cancer Res 2006; 66(2): 898-906)