tbuckley/cabot-search huggingface dataset:
Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole
Authors: Amy Hauck Newman, Santosh Kulkarni
Journal: Medicinal Research Reviews (2002)

Abstract In an attempt to discover a cocaine‐abuse pharmacotherapeutic, extensive investigation has been directed toward elucidating the molecular mechanisms underlying the reinforcing effects of this psychostimulant drug. The results of these studies have been consistent with the inhibition of dopamine uptake, at the dopamine transporter (DAT), which results in a rapid and excessive accumulation of extracellular dopamine in the synapse as being the mechanism primarily responsible for the locomotor stimulant actions of cocaine. Nevertheless, investigation of the serotonin (SERT) and norepinephrine (NET) transporters, as well as other receptor systems, with which cocaine either directly or indirectly interacts, has suggested that the DAT is not solely responsible for the reinforcing effects of cocaine. In an attempt to further elucidate the roles of these systems in the reinforcing effects of cocaine, selective molecular probes, in the form of drug molecules, have been designed, synthesized, and characterized. Many of these compounds bind potently and selectively to the DAT, block dopamine reuptake, and are behaviorally cocaine‐like in animal models of psychostimulant abuse. However, there have been exceptions noted in several classes of dopamine uptake inhibitors that demonstrate behavioral profiles that are distinctive from cocaine. Structure–activity relationships between chemically diverse dopamine uptake inhibitors have suggested that different binding interactions, at the molecular level on the DAT, as well as divergent actions at the other monoamine transporters may be related to the differing pharmacological actions of these compounds, in vivo . These studies suggest that novel dopamine uptake inhibitors, which are structurally and pharmacologically distinct from cocaine, may be developed as potential cocaine‐abuse therapeutics. © 2002 Wiley Periodicals, Inc. Med Res Rev, 22, No. 5, 429–464, 2002; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/med.10014
Progressive Gray Matter Loss and Changes in Cognitive Functioning Associated With Exposure to Herpes Simplex Virus 1 in Schizophrenia: A Longitudinal Study
Authors: Konasale M. Prasad, Shaun M. Eack, Dhruman Goradia, Krishna M. Pancholi, Matcheri S. Keshavan, Robert H. Yolken, Vishwajit L. Nimgaonkar
Journal: American Journal of Psychiatry (2011)

Objective: Longitudinal changes in gray matter volume and cognitive performance were evaluated among individuals exposed to neurotropic herpes simplex virus subtype 1 (HSV1). There is a replicable association of HSV1 exposure with smaller prefrontal volumes and cognitive impairments in schizophrenia. Method: The authors concurrently examined the whole-brain longitudinal trajectory over 1 year of gray matter volumes and executive functioning measured with the Wisconsin Card Sorting Test among 26 first-episode antipsychotic-naive subjects with schizophrenia and 38 healthy subjects. Age, gender, socioeconomic status, and exposure to cytomegalovirus (another virus of the herpes family that was previously associated with cognitive impairments) were the covariates. Results: Significant gray matter loss in the posterior cingulate gyrus was noted among the HSV1-seropositive schizophrenia subjects over 1 year but not among other groups. Prefrontal gray matter volumes did not show longitudinal changes. Binomial mixed-effects models indicated that improvement over 1 year in Wisconsin Card Sorting Test categories completed and perseverative errors occurred in significantly fewer HSV1-seropositive schizophrenia subjects than in the HSV1-seronegative schizophrenia subjects or the healthy subjects regardless of serological status. Three-way interactions of diagnosis, HSV1 status, and time were significant for both categories completed and perseverative errors. An increase in perseverative errors over 1 year, but not the change in the number of categories completed, correlated with longitudinal volume loss of the posterior cingulate gyrus. Conclusions: These observations suggest that HSV1 exposure may be associated with longitudinal gray matter loss in the posterior cingulate gyrus and decline in executive functioning among subjects with schizophrenia.
Urea induces the heat shock response in human neuroblastoma cells.
Authors: A L Maddock, C Westenfelder
Journal: Journal of the American Society of Nephrology (1996)

Uremic encephalopathy is a complication of renal failure that reflects stresses exerted by as yet poorly defined uremic toxins. All cells respond to stresses by undergoing the "heat shock" response. Although urea kinetics and creatinine concentration are routinely used to assess dialysis adequacy, the roles of urea and creatinine as uremic toxins remain controversial. To investigate their potential roles in uremic encephalopathy, cultured human neuroblastoma cells (SK-N-SH) were exposed to 0.5 to 14 mg/dL creatinine, or to 20 to 200 mg/dL urea, or to mannitol, NaCl, or glycerol at equivalent osmolalities for 30 min to 48 h, and the induction of Hsp72 (heat shock) protein was used as a marker of cell stress. Although creatinine failed to elicit a heat shock response, urea in clinically relevant concentrations (40 to 200 mg/dL) induced it at 30 min. The response peaked at 10 h and returned to zero by 48 h. Cells exposed to equivalent osmolalities of mannitol, NaCl, or glycerol failed to exhibit this response. Protein extracts from cells exposed to urea showed significant carbamylation that increased as a function of time. These results demonstrate: (1) that urea is neurotoxic in vitro and that creatinine is not: (2) that the insult urea causes is not simply the result of hypertonicity; but rather (3) that urea, via breakdown to cyanate and ammonium ions, may cause cell stress because of its ability to cause carbamylation of cellular proteins. The cells attenuation of the heat shock response after 10 h of exposure to urea suggests that they can adapt to the presence of urea or carbamylation. This may explain, in part, why the same degree of azotemia causes fewer neurological symptoms in patients with chronic as opposed to acute renal failure.
Malignant and benign ganglioglioma: A pathological and molecular study1
Authors: Ajay Pandita, Anandh Balasubramaniam, Richard Perrin, Patrick Shannon, Abhijit Guha
Journal: Neuro-Oncology (2007)

Gangliogliomas are generally benign tumors, composed of transformed neuronal and glial elements, with rare malignant progression of the glial component. The current study of a rare case of a woman harboring a ganglioglioma with areas of malignant transformation addresses two fundamental questions: (1) Are the ganglioglioma and its malignant component clonal in origin? (2) What are the genetic alterations associated with the initiation and subsequent malignant progression of ganglioglioma? By using the human androgen receptor gene (HUMARA) assay, we found the ganglioglioma and the malignant component to be clonal in origin, suggestive of initial transformation of a single neuroglial precursor cell with subsequent malignant progression. Conventional and array comparative genomic hybridization (approximately 2.5-Mb resolution) analyses found chromosomal losses to be predominant in the benign areas of the ganglioglioma, with gains more prevalent in the malignant component. Regions of chromosomal loss, postulated to harbor genes involved in the initiation of ganglioglioma, included 1p35-36, 2p16-15, 3q13.1-13.3, 3q24-25.3, 6p21.3-21.2, 6q24-25.2, 9p12, Xp11.3-11.22, and Xq22.1-22.3. Direct analysis demonstrated loss of p19 expression and p53 mutation in the malignant areas, highly suggestive of these alterations being involved in the malignant progression of the ganglioglioma. Additional chromosomal alterations specific to the malignancy involved gains on 1p35-34.2, 2q24.1-32.3, 3q13.1-13.3, 6q13-16.2, 7q11.2-31.3, 8q21.1-23, 11q12-31, and 12q13.2-21.3. This molecular-pathological study has provided insight into the pathogenesis of gangliogliomas and associated rare malignant progression. Deciphering the specific genes residing in these chromosomal regions may further our understanding of not only these rare tumors but also the more common gliomas.
Innate Immune Recognition
Authors: Charles A. Janeway, Ruslan Medzhitov
Journal: Annual Review of Immunology (2002)

The innate immune system is a universal and ancient form of host defense against infection. Innate immune recognition relies on a limited number of germline-encoded receptors. These receptors evolved to recognize conserved products of microbial metabolism produced by microbial pathogens, but not by the host. Recognition of these molecular structures allows the immune system to distinguish infectious nonself from noninfectious self. Toll-like receptors play a major role in pathogen recognition and initiation of inflammatory and immune responses. Stimulation of Toll-like receptors by microbial products leads to the activation of signaling pathways that result in the induction of antimicrobial genes and inflammatory cytokines. In addition, stimulation of Toll-like receptors triggers dendritic cell maturation and results in the induction of costimulatory molecules and increased antigen-presenting capacity. Thus, microbial recognition by Toll-like receptors helps to direct adaptive immune responses to antigens derived from microbial pathogens.
Age-related macular degeneration and its effect on quality of life
Authors: Alexander Silvester
Journal: Journal of the Royal Society of Medicine (2009)

I was interested to read the review article on age-related macular degeneration (AMD) by Tariq Ayoub and Nishal Patel.1 While the article discussed in great detail the pathogenesis, diagnosis and management of AMD, the authors failed to mention the effect of all this on a patient's quality of life, thus supporting the findings of Stein et al.2 that clinicians undervalue or are not well aware of the broad impact of AMD on health-related quality of life.

In fact, there is significant evidence that AMD reduces quality of life3 and that in severe forms of the disease this is comparable to a patient with end-stage prostate cancer.4 Furthermore, measures of quality of life, e.g. MacDQoL,5 can be (and have been) used as outcome measures to determine the effectiveness of various interventions, including many mentioned in the review article.
Steroid treatment causes deterioration of myocardial function in the -sarcoglycan-deficient mouse model for dilated cardiomyopathy
Authors: R. Bauer, G.A. MacGowan, A. Blain, K. Bushby, V. Straub
Journal: Cardiovascular Research (2008)

As oral corticosteroids have a beneficial effect on muscle strength in Duchenne muscular dystrophy, it has been suggested that they may also be a useful treatment in the pathologically related sarcoglycanopathies. The delta-sarcoglycan-deficient mouse (Sgcd-null) is a model for both limb girdle muscular dystrophy 2F (LGMD2F) and dilated cardiomyopathy.To study the effect of oral corticosteroids on cardiac function, we treated 8-week-old Sgcd-null mice with prednisolone (1.5 mg/kg body weight/day orally) for 8 weeks. In vivo cardiac function was assessed by pressure-volume loops using a conductance catheter. We found a well-compensated cardiomyopathy at baseline in Sgcd-null mice with decreased myocardial contractility, increased preload, and decreased afterload, maintaining a high cardiac output. Cardiac haemodynamics, surprisingly, did not improve in prednisolone-treated mice, but instead deteriorated with evidence of ventricular stiffening. On histology, after steroid treatment there was increased myocardial cell damage and increased myocardial fibrosis.Prednisolone led to a decompensation of cardiac haemodynamics in Sgcd-null mice and induced additional cardiac damage. On the basis of these findings, although mouse models may not completely replicate the human situation for LGMD2F, we conclude that careful cardiac monitoring is clearly indicated in patients on long-term corticosteroids.
Increased factor VIII-related antigen in necrobiosis lipoidica and widespread granuloma annulare without associated diabetes
Authors: B.B.J. MAJEWSKI, M.S. KOH, S. BARTER, E.L. RHODES
Journal: British Journal of Dermatology (1982)

Journal Article Increased factor VIII‐related antigen in necrobiosis lipoidica and widespread granuloma annulare without associated diabetes Get access B.B.J. MAJEWSKI, B.B.J. MAJEWSKI Department of Dermatology, St Helier Hospital, Carshalton, Surrey Search for other works by this author on: Oxford Academic Google Scholar M.S. KOH, M.S. KOH Department of Dermatology, St Helier Hospital, Carshalton, Surrey Search for other works by this author on: Oxford Academic Google Scholar S. BARTER, S. BARTER Department of Dermatology, St Helier Hospital, Carshalton, Surrey Search for other works by this author on: Oxford Academic Google Scholar E.L. RHODES E.L. RHODES Department of Dermatology, St Helier Hospital, Carshalton, Surrey Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 107, Issue 6, 1 December 1982, Pages 641–645, https://doi.org/10.1111/j.1365-2133.1982.tb00521.x Published: 01 December 1982 Article history Accepted: 20 April 1982 Published: 01 December 1982
Impaired Insulin Sensitivity as Indexed by the HOMA Score Is Associated With Deficits in Verbal Fluency and Temporal Lobe Gray Matter Volume in the Elderly
Authors: Christian Benedict, Samantha J. Brooks, Joel Kullberg, Jonathan Burgos, Matthew J. Kempton, Richard Nordenskjöld, Ruta Nylander, Lena Kilander, Suzanne Craft, Elna-Marie Larsson, Lars Johansson, Håkan Ahlström, Lars Lind, Helgi B. Schiöth
Journal: Diabetes Care (2012)

Impaired insulin sensitivity is linked to cognitive deficits and reduced brain size. However, it is not yet known whether insulin sensitivity involves regional changes in gray matter volume. Against this background, we examined the association between insulin sensitivity, cognitive performance, and regional gray matter volume in 285 cognitively healthy elderly men and women aged 75 years from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.Insulin sensitivity was calculated from fasting serum insulin and plasma glucose determinations using the homeostasis model assessment of insulin resistance (HOMA-IR) method. Cognitive performance was examined by a categorical verbal fluency. Participants also underwent a magnetic resonance imaging (MRI) brain scan. Multivariate analysis using linear regression was conducted, controlling for potential confounders (sex, education, serum LDL cholesterol, mean arterial blood pressure, and abdominal visceral fat volume).The HOMA-IR was negatively correlated with verbal fluency performance, brain size, and temporal lobe gray matter volume in regions known to be involved in speech production (Brodmann areas 21 and 22, respectively). No such effects were observed when examining diabetic (n = 55) and cognitively impaired (n = 27) elderly subjects as separate analyses.These cross-sectional findings suggest that both pharmacologic and lifestyle interventions improving insulin signaling may promote brain health in late life but must be confirmed in patient studies.
Exercise training improves cardiac function in infarcted rabbits: involvement of autophagic function and fatty acid utilization
Authors: Ching‐Yi Chen, Hsiu‐Ching Hsu, Bai‐Chin Lee, Hung‐Ju Lin, Ying‐Hsien Chen, Hui‐Chun Huang, Yi‐Lwun Ho, Ming‐Fong Chen
Journal: European Journal of Heart Failure (2010)
Origin and Expansion of Haplogroup H, the Dominant Human Mitochondrial DNA Lineage in West Eurasia: The Near Eastern and Caucasian Perspective
Authors: U Roostalu, I Kutuev, E-L Loogväli, E Metspalu, K Tambets, M Reidla, EK Khusnutdinova, E Usanga, T Kivisild, R Villems
Journal: Molecular Biology and Evolution (2006)

More than a third of the European pool of human mitochondrial DNA (mtDNA) is fragmented into a number of subclades of haplogroup (hg) H, the most frequent hg throughout western Eurasia. Although there has been considerable recent progress in studying mitochondrial genome variation in Europe at the complete sequence resolution, little data of comparable resolution is so far available for regions like the Caucasus and the Near and Middle East—areas where most of European genetic lineages, including hg H, have likely emerged. This gap in our knowledge causes a serious hindrance for progress in understanding the demographic prehistory of Europe and western Eurasia in general. Here we describe the phylogeography of hg H in the populations of the Near East and the Caucasus. We have analyzed 545 samples of hg H at high resolution, including 15 novel complete mtDNA sequences. As in Europe, most of the present-day Near Eastern–Caucasus area variants of hg H started to expand after the last glacial maximum (LGM) and presumably before the Holocene. Yet importantly, several hg H subclades in Near East and Southern Caucasus region coalesce to the pre-LGM period. Furthermore, irrespective of their common origin, significant differences between the distribution of hg H sub-hgs in Europe and in the Near East and South Caucasus imply limited post-LGM maternal gene flow between these regions. In a contrast, the North Caucasus mitochondrial gene pool has received an influx of hg H variants, arriving from the Ponto-Caspian/East European area.
Variants in Iron Metabolism Genes Predict Higher Blood Lead Levels in Young Children
Authors: Marianne R. Hopkins, Adrienne S. Ettinger, Mauricio Hernández-Avila, Joel Schwartz, Martha María Téllez-Rojo, Héctor Lamadrid-Figueroa, David Bellinger, Howard Hu, Robert O. Wright
Journal: Environmental Health Perspectives (2008)

Given the association between iron deficiency and lead absorption, we hypothesized that variants in iron metabolism genes would predict higher blood lead levels in young children.We examined the association between common missense variants in the hemochromatosis (HFE) and transferrin (TF) genes and blood lead levels in 422 Mexican children.Archived umbilical cord blood samples were genotyped for HFE (H63D and C282Y) and TF (P570S) variants. Blood lead was measured at 24, 30, 36, 42, and 48 months of age. A total of 341 subjects had at least one follow-up blood lead level available and data available on covariates of interest for inclusion in the longitudinal analyses. We used random-effects models to examine the associations between genotype (HFE, TF, and combined HFE + TF) and repeated measures of blood lead, adjusting for maternal blood lead at delivery and child's concurrent anemia status.Of 422 children genotyped, 17.7, 3.3, and 18.9% carried the HFE H63D, HFE C282Y, and TF P570S variants, respectively. One percent of children carried both the HFE C282Y and TF P570S variants, and 3% of children carried both the HFE H63D and TF P570S variants. On average, carriers of either the HFE (beta = 0.11, p = 0.04) or TF (beta = 0.10, p = 0.08) variant had blood lead levels that were 11% and 10% higher, respectively, than wild-type subjects. In models examining the dose effect, subjects carrying both variants (beta = 0.41, p = 0.006) had blood lead 50% higher than wild-type subjects and a significantly higher odds of having a blood lead level > 10 microg/dL (odds ratio = 18.3; 95% confidence interval, 1.9-177.1).Iron metabolism gene variants modify lead metabolism such that HFE variants are associated with increased blood lead levels in young children. The joint presence of variant alleles in the HFE and TF genes showed the greatest effect, suggesting a gene-by-gene-by-environment interaction.
Hemodynamic mechanisms of antianginal action of calcium channel blocker nisoldipine in dynamic exercise-induced angina.
Authors: M Yokota, T Miyahara, M Iwase, M Watanabe, T Matsunami, S Kamihara, M Koide, H Saito, J Takeuchi
Journal: Circulation (1990)

To investigate the mechanism of antianginal action of the calcium channel blocker nisoldipine and to determine the reproducibility of the clinical and hemodynamic events induced by supine leg exercise, 30 patients with stable effort angina pectoris were studied. They were divided into two groups; one group of 19 patients received a single 10-mg dose of nisoldipine orally, and the other group of 11 patients received a single dose of placebo orally. Chest pain was induced in all of 30 patients during the control exercise test. After nisoldipine administration, chest pain was not induced in 13 of 19 patients and was of lessened severity in five patients with the same work load as those performing control exercise. ST segment at peak exercise showed less severe depression after nisoldipine. Systemic vascular resistance was reduced by 38% (p less than 0.001) at rest and 22% (p less than 0.001) at peak exercise, and coronary vascular resistance was reduced by 31% (p less than 0.01) at rest and 18% (p less than 0.01) at peak exercise. Pulmonary artery wedge pressure fell from 6 +/- 1 to 3 +/- 1 mm Hg (p less than 0.001) at rest and from 28 +/- 3 to 11 +/- 2 mm Hg (p less than 0.001) at peak exercise. Coronary sinus flow at rest and myocardial oxygen uptake both at rest and during exercise was not modified by nisoldipine. However, coronary sinus flow at peak exercise increased significantly from 219 +/- 24 to 249 +/- 31 ml/min (p less than 0.01) after nisoldipine, and myocardial oxygen uptake was not significantly changed despite decreased coronary vascular resistance. The clinical and hemodynamic events induced by the exercise during invasive studies (except pulmonary artery wedge pressure at rest) were reproducible after placebo administration. Our data demonstrate that increased coronary blood flow could be the major mechanism of the antianginal action of nisoldipine in supine leg exercise-induced angina.
Failure Pattern and Factors Predictive of Local Failure in Rhabdomyosarcoma: A Report of Group III Patients on the Third Intergroup Rhabdomyosarcoma Study
Authors: Moody D. Wharam, Jane Meza, James Anderson, John C. Breneman, Sarah S. Donaldson, Thomas J. Fitzgerald, Jeff Michalski, Lisa A. Teot, Eugene S. Wiener, William H. Meyer
Journal: Journal of Clinical Oncology (2004)

To analyze patterns of failure and factors predictive of local treatment failure in children enrolled on the third Intergroup Rhabdomyosarcoma Study who had either biopsy only or subtotal resection of their primary tumor, had no distant metastases, and received radiation therapy for local control.Treatment failure was categorized as local, regional nodal, or distant metastatic. The 5-year cumulative risk of failure was estimated for each category and factors predictive of local failure risk were determined using the Cox model and binary recursive partitioning.The estimated 5-year cumulative incidence rates by failure category were: total local (with or without concurrent regional or distant failure), 19%; total regional nodal, 2%; total distant, 11%; and death from toxicity or unknown recurrence type, 4%. Lymph node involvement at diagnosis was the single factor most predictive of increased total local failure risk (5-year cumulative incidence 32%) compared with children with negative nodes or unknown node status (16%). No significant effect on local failure risk was observed by total radiotherapy dose over the prescribed range of 41.4 Gy to 50.4 Gy. For all patients (N = 405), the estimated 5-year failure-free survival and overall survival were, respectively, 70% and 78%.Local failure after radiotherapy for group III rhabdomyosarcoma patients is the predominant type of relapse. Involved lymph nodes at diagnosis predict a higher risk of local and distant treatment failure compared with patients whose lymph nodes are negative.