tbuckley/cabot-search huggingface dataset:
Adult Functional Outcomes of Common Childhood Psychiatric Problems
Authors: William E. Copeland, Dieter Wolke, Lilly Shanahan, E. Jane Costello
Journal: JAMA Psychiatry (2015)

Psychiatric problems are among the most common health problems of childhood.To test whether these health problems adversely affect adult functioning even if the problems themselves do not persist.Prospective, population-based study of 1420 participants from 11 predominantly rural counties of North Carolina who were assessed with structured interviews up to 6 times during childhood (9-16 years of age, for a total 6674 observations) for common psychiatric diagnoses and subthreshold psychiatric problems. The period for this study was from 1993 to 2010.A total of 1273 participants were assessed 3 times during young adulthood (19, 21, and 24-26 years of age, for a total of 3215 observations) for adverse outcomes related to health, the legal system, personal finances, and social functioning.Participants with a childhood disorder had 6 times higher odds (odds ratio [OR], 5.9 [95% CI, 3.6-9.7]) of at least 1 adverse adult outcome (ie, indicator) compared with those with no history of psychiatric problems and 9 times higher odds (OR, 8.7 [95% CI, 4.3-17.8]) of 2 or more such indicators (1 indicator: 59.5% vs 19.9% [P < .001]; ≥ 2 indicators: 34.2% vs 5.6% [P < .001]). These associations persisted after statistically controlling for childhood psychosocial hardships and adult psychiatric problems. Risk was not limited to those who received a diagnosis; participants with subthreshold psychiatric problems had 3 times higher odds (OR, 2.9 [95% CI, 1.8-4.8]) of adult adverse outcomes and 5 times higher odds (OR, 5.1 [95% CI, 2.4-10.7]) of 2 or more outcomes (1 indicator: 41.9% vs 19.9% [P < .001]; ≥ 2 indicators: 23.2% vs 5.6% [P < .001]). The best diagnostic predictor of adverse outcomes was cumulative childhood exposure to psychiatric disorders.Common, typically moderately impairing, childhood psychiatric problems are associated with a disrupted transition to adulthood even if the problems do not persist into adulthood and even if the problems are subthreshold. Such problems provide a potential target for public health efforts to ameliorate adult suffering and morbidity.
Prospective Multi-Institutional Study of Reverse Transcriptase Polymerase Chain Reaction for Molecular Staging of Melanoma
Authors: Charles R. Scoggins, Merrick I. Ross, Douglas S. Reintgen, R. Dirk Noyes, James S. Goydos, Peter D. Beitsch, Marshall M. Urist, Stephan Ariyan, B. Scott Davidson, Jeffrey J. Sussman, Michael J. Edwards, Robert C.G. Martin, Angela M. Lewis, Arnold J. Stromberg, Andrew J. Conrad, Lee Hagendoorn, Jeffrey Albrecht, Kelly M. McMasters
Journal: Journal of Clinical Oncology (2006)

To evaluate the prognostic significance of molecular staging using reverse transcriptase polymerase chain reaction (RT-PCR) in detecting occult melanoma cells in sentinel lymph nodes (SLNs) and circulating bloodstream.In this multicenter study, eligibility criteria included patient age 18 to 71 years, invasive melanoma > or = 1.0 mm Breslow thickness, and no clinical evidence of metastasis. SLN biopsy and wide excision of the primary tumor were performed. SLNs were examined by serial-section histopathology and S-100 immunohistochemistry. A portion of each SLN was frozen for RT-PCR. In addition, RT-PCR was performed on peripheral-blood mononuclear cells (PBMCs). RT-PCR analysis was performed using four markers: tyrosinase, MART1, MAGE3, and GP-100. Disease-free survival (DFS), distant-DFS (DDFS), and overall survival (OS) were analyzed.A total of 1,446 patients with histologically negative SLNs underwent RT-PCR analysis. At a median follow-up of 30 months, there was no difference in DFS, DDFS, or OS between the RT-PCR-positive (n = 620) and RT-PCR-negative (n = 826) patients. Analysis of PBMC from 820 patients revealed significant differences in DFS and DDFS, but not OS, for patients with detection of more than one RT-PCR marker in peripheral blood.In this large, prospective, multi-institutional study, RT-PCR analysis on SLNs and PBMCs provides no additional prognostic information beyond standard histopathologic analysis of SLNs. Detection of more than one marker in PBMC is associated with a worse prognosis. RT-PCR remains investigational and should not be used to direct adjuvant therapy at this time.
The life and death of Helicobacter pylori
Authors: D Scott, D Weeks, K Melchers, G Sachs
Journal: Gut (1998)

The ability of Helicobacter pylori to survive in the varying acidity of the stomach is considered to be linked to its ability to maintain a tolerable pH in its periplasmic space by acid dependent activation of internal urease activity. Whereas survival of H pylori can occur between a periplasmic pH of 4.0 to 8.0, growth can only occur between a periplasmic pH of 6.0 to 8.0. When urease activity is only able to elevate periplasmic pH to between 4.0 and 6.0, the organisms will survive but not divide. In the absence of division, antibiotics such as clarithromycin and amoxycillin are ineffective. Proton pump inhibitors, by elevating gastric pH, would increase the population of dividing organisms and hence synergise with these antibiotics.
Alpha-receptor stimulation by endogenous and exogenous norepinephrine and blockade by phentolamine in pial arteries of cats.
Authors: W Kuschinsky, M Wahl
Journal: Circulation Research (1975)

The question regarding the existence of an alpha-adrenergic component of pial arterial tone was investigated using a microapplication technique combined with the measurement of vascular diameter. Concentration-response curves for the alpha-receptor blocker, phentolamine, revealed no vascular reaction for a concentration range from 2.5 x 10(-11) to 2.5 x 10(-7) M. At higher concentrations (up to 1.3 x 10(-3) M) concentration-dependent dilations were observed. Constrictions of pial arteries induced by perivascular injection of 2.5 x 10(-6) M norepinephrine could be reduced by 38% and 73% when phentolamine was applied simultaneously in concentrations of 2.5 x 10(-7) and 2.5 x 10(-6) M, respectively, whereas constrictions due to 2.5 x 10(-4) M norepinephrine were not reduced by 2.5 x 10(-6) M phentolamine, indicating a competitive antagonism between norepinephrine and phentolamine for pial arteries. Stimulation of the cervical sympathetic chain (90 seconds, 10 v, 1.4 msec, 20 Hz) induced constrictions of pial arteries (mean 12%) which could be reduced by two-thirds during the simultaneous application of 2.5 x 10(-7) M phentolamine. Since the constriction induced by norepinephrine applied exogenously or released endogenously could be reduced by a concentration of phentolamine which had no vascular effect per se, we conclude that the resting tone of the pial arteries is not influenced by an alpha-adrenergic component under our experimental conditions. The dilations induced by high concentrations of phentolamine are believed to be nonspecific.
Brain-gut axis as an example of the bio-psycho-social model
Authors: I Wilhelmsen
Journal: Gut (2000)

In research we often apply hypothesis testing which assumes a linear, causal relationship between two or more factors. This is a valid way of testing fragments of a complicated chaos of known and unknown elements. However, I want us to reflect upon the thought that the answers we get are limited by the questions we ask. It is said that “If you have a hammer, the only thing you see are nails”. Western medical education and research has, for more than a century, been dominated by a dualistic view of human nature, and from the psychoanalytical tradition (based on Freud's work) we have learned to differentiate between biological (physical, organic, somatic) on one side and psychological (thoughts and emotions) on the other. This dualistic view, emphasising that psychological and biological are two entirely different aspects of human life, is mechanistic and reductionistic, and in today's world a non-scientific position to hold.1 In spite of many decades of research, there is no evidence that emotions can “pile up” somewhere in the body and that psychological conflicts, if unresolved, are converted to somatic symptoms or diseases. On the contrary, science is moving into a position of integration, and the cognitive science (such as neuroscience) has developed rapidly in recent years. You cannot experience an emotion or think a thought without biological correlates. Unresolved mental conflicts lead to activation of the central nervous system (CNS), and of the autonomic systems. Activation theories, such as the “cognitive activation theory of stress” states that the stress response is the same as activation—a general alarm system operating whenever the organism registers that there is a discrepancy between what is expected and what really exists.2 The brain-gut axis is a good example of a circular relationship between different factors, and illustrates that research on interrelationship …
Idiopathic pulmonary fibrosis (IPF) and gastroeosophageal disorders
Authors: Josipa Kokeza, Kornelija Mise, Zeljko Puljiz, Anteo Bradaric, Emilija Lozo, Josko Mise
Journal: European Respiratory Journal (2013)

Introduction: IPF is a disease of unknown etiology, frequent in person older than 65 years. It relates with gastroesophageal (GE) reflux disease.  Goal: to examine GE system of people with newfound IPF before including the therapy (corticosteroids, bronchodilators) for lungs9 problems which could seriously harm the GE system. And to determine the pH value in the lungs.  Methods: at any newfound IPF (by the principles of ATS/ ERS) gastroscopy and determination of the pH value in the respiratory system during the bronchoscopy were done.  Results: 32 patients were examined, 22 men, 10 women, X = 64.66±11.12 year.  Results of pulmonary function tests showed: FVC%: 86.64± 22.62, FEV1%:90.85± 18.34, DLco%:59.56± 14.33, Kco%:58.92± 20.07, pO2 kPa: 9.46± 1.98, pCO2 kPa: 4.42±0.87.  Gastroscopy showed these findings: GE reflux (1- 3 stage) in 30 pts (93.75%), hiatal hernia in 21 pts, hypersecretion in 22 pts, Helicobacter pylori infection in 25 and ulcer in 11 pts. Combination of these findings were present in 84.3% of the pts. Acidity in the bronchi was X= 5.26±0.46 (5.0-6.5). Value of pH in the lungs with bacterial infections: X = 7.88±0.33.  Conclusion: changes in the GE system were found in almost every patient, 75% (24/32) had symptoms, others had silent GE reflux. High percentage of H. pylori was found (78%). The values of pH in the bronchi/ lungs were extremely low (5-6.5). H. pylori was not found in the biopsy specimen of the lungs. The question is could long lasting GE reflux cause IPF?
Immunomodulatory Drug CC-5013 or CC-4047 and Rituximab Enhance Antitumor Activity in a Severe Combined Immunodeficient Mouse Lymphoma Model
Authors: Francisco J. Hernandez-Ilizaliturri, Nishitha Reddy, Beata Holkova, Edris Ottman, Myron S. Czuczman
Journal: Clinical Cancer Research (2005)

Abstract New thalidomide derivatives CC-5013 and CC-4047 (immunomodulatory drugs, IMiD) are up to 10,000 times more potent than Thalidomide. The biological effects of IMiDs are presumed to be mediated by (a) activation of some components of the innate [natural killer (NK) cells] or adoptive immune system (T cells), (b) modification of cytokine microenvironment in the tumor bed, or by (c) inhibition of angiogenesis. In this article, we tested an innovative combination strategy involving rituximab and IMiDs in aggressive lymphoma cell lines and human lymphoma xenografts. Treatment of non-Hodgkin's lymphoma cells with CC-5013 resulted in a 40% to 70% growth inhibition when compared with controls (P &amp;lt; 0.05). Exposure of lymphoma cells to CC-4047 resulted in a lesser degree of growth inhibition. Induction of apoptosis was shown in 10% to 26% of lymphoma cells 24 hours following exposure to either IMiD. In vivo studies in severe combined immunodeficient mice showed synergistic activity between CC-4047 (and to a lesser degree, CC-5013) plus rituximab. Animals treated with the CC-4047/rituximab combination had a median survival of 74 days (P = 0.0012) compared with 58 days (P = 0.167) in CC-5013/rituximab-treated animals compared with 45 days in rituximab monotherapy–treated animals. The synergistic effect between IMiDs and rituximab in our mouse model was attributed to NK cell expansion. The enhancement of rituximab activity by IMiDs was abrogated by in vivo depletion of NK cells. Augmenting NK cell function by CC-4047 or CC-5013 exposure may increase the antitumor effects of rituximab against B-cell lymphomas and warrants further exploration in the context of a clinical trial.
Voodoo Poisoning in Buffalo, NY
Authors: J. Robin Saphir
Journal: JAMA (1967)

Because of a highly suggestive history and characteristic clinical manifestations, poisoning (possibly carbon tetrachloride) was diagnosed in a 24-year-old Voodoo worshipper. The poison was apparently included in a medicinal potion prepared by a Voodoo priestess. The evidence for the above, while circumstantial, appears medically sound. The episode occurred in the urban North among the American Negroes. It is yet another occult way for the unsuspecting—patient and physician—to be led astray.
Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation
Authors: Debyani Chakravarty, Elmer Santos, Mabel Ryder, Jeffrey A. Knauf, Xiao-Hui Liao, Brian L. West, Gideon Bollag, Richard Kolesnick, Tin Htwe Thin, Neal Rosen, Pat Zanzonico, Steven M. Larson, Samuel Refetoff, Ronald Ghossein, James A. Fagin
Journal: Journal of Clinical Investigation (2011)

Advanced human thyroid cancers, particularly those that are refractory to treatment with radioiodine (RAI), have a high prevalence of BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutations. However, the degree to which these cancers are dependent on BRAF expression is still unclear. To address this question, we generated mice expressing one of the most commonly detected BRAF mutations in human papillary thyroid carcinomas (BRAF(V600E)) in thyroid follicular cells in a doxycycline-inducible (dox-inducible) manner. Upon dox induction of BRAF(V600E), the mice developed highly penetrant and poorly differentiated thyroid tumors. Discontinuation of dox extinguished BRAF(V600E) expression and reestablished thyroid follicular architecture and normal thyroid histology. Switching on BRAF(V600E) rapidly induced hypothyroidism and virtually abolished thyroid-specific gene expression and RAI incorporation, all of which were restored to near basal levels upon discontinuation of dox. Treatment of mice with these cancers with small molecule inhibitors of either MEK or mutant BRAF reduced their proliferative index and partially restored thyroid-specific gene expression. Strikingly, treatment with the MAPK pathway inhibitors rendered the tumor cells susceptible to a therapeutic dose of RAI. Our data show that thyroid tumors carrying BRAF(V600E) mutations are exquisitely dependent on the oncoprotein for viability and that genetic or pharmacological inhibition of its expression or activity is associated with tumor regression and restoration of RAI uptake in vivo in mice. These findings have potentially significant clinical ramifications.
Statins inhibit oxidized-LDL-mediated LOX-1 expression, uptake of oxidized-LDL and reduction in PKB phosphorylation
Authors: D Li
Journal: Cardiovascular Research (2001)

Objectives: LOX-1, a lectin-like receptor on endothelial cells, facilitates the uptake of oxidized-LDL. Expression of LOX-1 is involved in the pathobiological effects of oxidized-LDL in endothelial cells, including apoptosis, suppression of cNOS activity and cell adhesion. Recent studies show that intracellular signal protein kinase B (PKB) is involved in the regulation of cNOS. Further, HMG CoA reductase inhibitors (statins) may affect LOX-1 expression. In this study, we examined the modulation of LOX-1 expression and PKB activity in response to oxidized-LDL by two different statins (simvastatin and atorvastatin). Methods and results: Cultured human coronary artery endothelial cells (HCAECs) were used in this study. Oxidized-LDL (40 μg/ml) was found to upregulate the expression of LOX-1 (mRNA and protein), enhance [125I]-ox-LDL uptake and to reduce the phosphorylation of PKB (p-PKB). Two different statins, simvastatin and atorvastatin (each 1 and 10 μM), upregulated the activity of PKB and decreased LOX-1 expression and [125I]-ox-LDL uptake. A high concentration of statins (10 μM) gave a more potent effect than the low concentration (1 μM). The effects of the two different statins were similar. Conclusions: These observations show that statins decrease LOX-1 expression, a novel oxidized-LDL endothelial receptor, and uptake of oxidized-LDL in HCAECs. The effect of statins on LOX-1 expression is associated with an increase in PKB activity in HCAECs.
The TP53 Colorectal Cancer International Collaborative Study on the Prognostic and Predictive Significance of <i>p53</i> Mutation: Influence of Tumor Site, Type of Mutation, and Adjuvant Treatment
Authors: Antonio Russo, Viviana Bazan, Barry Iacopetta, David Kerr, Thierry Soussi, Nicola Gebbia
Journal: Journal of Clinical Oncology (2005)

The aims of the TP53 Colorectal Cancer (CRC) International Collaborative Study were to evaluate the possible associations between specific TP53 mutations and tumor site, and to evaluate the prognostic and predictive significance of these mutations in different site, stage, and treatment subgroups.A total of 3,583 CRC patients from 25 different research groups in 17 countries were recruited to the study. Patients were divided into three groups according to site of the primary tumor. TP53 mutational analyses spanned exons 4 to 8.TP53 mutations were found in 34% of the proximal colon tumors and in 45% of the distal colon and rectal tumors. They were associated with lymphatic invasion in proximal tumors. In distal colon tumors, deletions causing loss of amino acids were associated with worse survival. In proximal colon tumors, mutations in exon 5 showed a trend toward statistical significance (P < .05) when overall survival was considered. Dukes' C tumors with wild-type TP53 and those with mutated TP53 (proximal tumors) showed significantly better prognosis when treated with adjuvant chemotherapy.Analysis of TP53 mutations from a large cohort of CRC patients has identified tumor site, type of mutation, and adjuvant treatment as important factors in determining the prognostic significance of this genetic alteration.
Antigen-specific, MHC nonrestricted T helper cell-induced B cell activation.
Authors: S M Friedman, J A Jover, E K Chartash, M K Crow
Journal: The Journal of Experimental Medicine (1986)

We used a cloned, TNP-specific, MHC-restricted, human Th cell line, E-11, and an assay of cognate Th-B cell interaction, BLAST-2 antigen expression on the B cell surface, to investigate the functional nature of the Th cell antigen receptor. We observed that E-11 induces BLAST-2 expression by resting B cells in a hapten-dependent, hapten-specific, but MHC nonrestricted manner. The implication of these results for the Th cell receptor are discussed.
What is new about Rio?
Authors: Rogerio Souza, Steven M. Kawut
Journal: European Respiratory Journal (2015)

This issue of the European Respiratory Journal includes the results of three different studies of riociguat, a soluble guanylate cyclase stimulator, for the treatment of pulmonary hypertension [1–3]. As the first drug in a novel class for the treatment of pulmonary hypertension, riociguat has raised hopes of an expanded drug armamentarium against the still incurable diseases of pulmonary arterial hypertension (PAH) and surgically inaccessible (or persistent post-operative) chronic thromboembolic pulmonary hypertension (CTEPH). Two of these studies are long-term extension studies from pivotal phase III trials: CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1) [4] and PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1) [5]. The third study (PATENT PLUS) studied the safety and efficacy of the combination of riociguat and the phosphodiesterase (PDE)-5 inhibitor, sildenafil. Long -term use of riociguat in PAH and inoperable CTEPH provides important information on the safety of this new drug <http://ow.ly/K0lxr>
Glycoprotein (gp) 96 expression: induced during differentiation of intestinal macrophages but impaired in Crohn's disease
Authors: K Schreiter
Journal: Gut (2005)

<b>Background:</b> The glycoprotein (gp) 96 links the adaptive with the innate immune system. It is a chaperone with a binding domain for peptides generated by proteasomal degradation. During cellular stress, peptide loaded gp96 can be released and presented to T cells by antigen presenting cells (APCs). <b>Methods:</b> mRNAs from in vitro differentiated macrophages (iv mac) and normal intestinal macrophages (IMACs) were compared by subtractive hybridisation and Affymetrix GeneChip analysis. Differentiation induced expression of gp96 was investigated in the multicellular spheroid (MCS) model<i>.</i> In vivo gp96 protein expression was detected by double labelling immunohistochemistry of human colon and in the CD4<sup>+</sup> CD62L<sup>+</sup> T cell transfer mouse model. <b>Results:</b> Five of 76 clones obtained by subtractive hybridisation revealed &gt;99% sequence homology to gp96. Affymetrix GeneChip analysis confirmed induction of gp96 in IMACs. Gp96 mRNA was detected in IMACs from normal and intestinal bowel disease mucosa. Induction of gp96 protein was observed after seven days in the MCS model of IMAC differentiation. Immunohistochemistry confirmed the presence of gp96 protein in IMACs in normal mucosa as well as in mucosa from patients with ulcerative colitis and diverticulitis. In mucosa from Crohn’s disease (CD) patients, gp96 protein was not detectable. In the CD4<sup>+</sup> CD62L<sup>+</sup> T cell transfer mouse model, gp96 was verifiable in non-activated IMACs. <b>Conclusion:</b> Gp96 is induced during differentiation of normal IMACs but is not detected in IMACs in CD mucosa. As gp96 has been described as having a role in tolerance induction, this may be relevant for loss of tolerance against luminal bacteria found in CD patients.