tbuckley/cabot-search huggingface dataset:
CHARACTERISTICS OF POST-PARTUM MENTAL ILLNESS
Authors: JOHN J. MADDEN, JOSEPH A. LUHAN, WERNER TUTEUR, JOHN F. BIMMERLE
Journal: American Journal of Psychiatry (1958)

In our experience the most frequently encountered form of puerperal mental illness of sufficient gravity to require hospital care is the group of schizophrenic reactions. Many of these with a favorable outcome correspond to illnesses which were probably euphemistically and erroneously catalogued in much of the literature of the past three decades as toxic-exhaustive psychoses, and particularly non-toxic deliria. In their beginning, relatively benign postpartum schizophrenic reactions may be very difficult to distinguish from the hard core of process schizophrenia and of relapsing schizoaffective reactions. The residuum of deteriorating and relapsing schizophrenic illnesses in similar therapeutic environments is proportionately the same whether or not these first developed in the puerperium. These results imply that process schizophrenia and some schizoaffective reactions beginning after delivery are purely coincidental psychoses. The better outlook for those schizophrenic reactions which tend to be self-limited and are accelerated toward a favorable conclusion by early energetic therapy suggests that the stresses entailed in achieving motherhood and being confronted with its new responsibilities act as a precipitating factor in some women predisposed to develop personality disorganization. There seems to be an increasing incidence and recognition of serious, presumably functional mental disability of relatively favorable outcome arising in the puerperium which early in its course lacks the behavioral quality of schizophrenic reactions, is compatible with psychoneurotic depressive states, and is rapidly helped by short term intensive psychiatric treatment. In these cases the psychological stress of motherhood is a potent precipitating and partially causative factor. These reactions occur in certain women who react when loss of personality integrity is threatened with a fairly blatant display of psychoneurotic behavioral symptoms. About half of our patients who made a good long-term recovery from an initial postpartum mental illness subsequently had one or more children without recurrence. All those in our study classified as having a good outcome have remained well during an observation period averaging more than 7 years. We find that in a similar population in the same therapeutic milieu there is a somewhat better long-term outlook for recovery in puerperal as contrasted with similarly diagnosed mental reactions unassociated with childbearing.
Quantitative detection of multiple gene promoter hypermethylation in tumor tissue, serum, and cerebrospinal fluid predicts prognosis of malignant gliomas
Authors: B.-L. Liu, J.-X. Cheng, W. Zhang, X. Zhang, R. Wang, H. Lin, J.-L. Huo, H. Cheng
Journal: Neuro-Oncology (2010)

Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the malignant transformation in gliomas. We hypothesized that quantitative analysis of methylated genes will provide prognostic values in malignant glioma patients. We used an immunocapturing approach followed by real-time polymerase chain reaction analysis to detect altered patterns of promoter methylation in O-6-methylguanine-DNA methyltransferase (MGMT), p16INK4a, tissue inhibitor of metalloproteinase-3 (TIMP-3), and thrombospondin 1 (THBS1). The tumor tissue and paired serum as well as cerebrospinal fluid (CSF) from 66 patients with malignant gliomas were studied. Serum and CSF from 20 age-matched noncancer individuals were used as control. Promoter hypermethylation in MGMT, p16INK4a, TIMP-3, and THBS1 was detected at high frequencies in tumor tissue, serum, and CSF. None of the control serum or CSF showed aberrant methylation. Hypermethylation in serum and CSF DNA was all accompanied with methylation in the corresponding tumor tissues with 100% specificity. Highly elevated MGMT, p16INK4a, and THBS1 methylation levels in gliomas serum were the sole independent factors predicting inferior overall survival in this cohort. For progression-free survival, hypermethylation of MGMT and THBS1 in CSF were the independent prognostic factors. Multiple gene promoter hypermethylation analysis appears to be promising as a prognostic factor in glioma and as a mini-invasive tumor marker in serum and/or CSF DNA. Evaluation of these changes may help in selecting glioma patients for optimal adjuvant treatments and modifying chemotherapy.
Adjuvant Immunotherapy Is Dependent on Inducible Nitric Oxide Synthase
Authors: Daniel A. Kahn, D. Clay Archer, Daniel P. Gold, Carolyn J. Kelly
Journal: The Journal of Experimental Medicine (2001)

Rodents immunized with complete Freund's adjuvant (CFA) are resistant to subsequent attempts to induce autoimmune disease, while animals immunized with incomplete Freund's adjuvant (IFA) remain susceptible. Mycobacterial extracts can stimulate inducible nitric oxide synthase (NOS2) gene transcription. Robust expression of NOS2 has been linked to suppression of T cell proliferation and alterations in immune responses. Our studies investigated the hypothesis that the immunoprotective effect of CFA before immunization requires functional NOS2. NOS2 gene expression is chronically elevated in lymph nodes and spleens of CFA-immunized mice. Maximal expression of NOS2 after CFA immunization requires the presence of functional type I tumor necrosis factor α receptor (TNFR1) and interferon γ. Groups of nontreated and CFA-preimmunized male C57BL/6J or C57BL/6NOS2−/− mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35–55 in CFA to induce experimental allergic encephalomyelitis (EAE). Wild-type C57BL/6J mice were protected from the development of symptoms of EAE, while the NOS2−/− mice failed to be protected. NOS2-dependent effects of CFA included an augmentation of the MOG-specific IgG1 response, a decrease in interleukin 6 production by MOG-reactive lymphocytes, and a marked decrease in mononuclear cell infiltrates in the central nervous system. These studies support the hypothesis that CFA immunization modulates immune responses through a nitric oxide–dependent mechanism.
Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs
Authors: Carolyn J. Foster, Dina M. Prosser, Jacqueline M. Agans, Ying Zhai, Michelle D. Smith, Jean E. Lachowicz, Fang L. Zhang, Eric Gustafson, Frederick J. Monsma, Maria T. Wiekowski, Susan J. Abbondanzo, Donald N. Cook, Marvin L. Bayne, Sergio A. Lira, Madhu S. Chintala
Journal: Journal of Clinical Investigation (2001)

ADP plays a critical role in modulating thrombosis and hemostasis. ADP initiates platelet aggregation by simultaneous activation of two G protein-coupled receptors, P2Y1 and P2Y12. Activation of P2Y1 activates phospholipase C and triggers shape change, while P2Y12 couples to Gi to reduce adenylyl cyclase activity. P2Y12 has been shown to be the target of the thienopyridine drugs, ticlopidine and clopidogrel. Recently, we cloned a human orphan receptor, SP1999, highly expressed in brain and platelets, which responded to ADP and had a pharmacological profile similar to that of P2Y12. To determine whether SP1999 is P2Y12, we generated SP1999-null mice. These mice appear normal, but they exhibit highly prolonged bleeding times, and their platelets aggregate poorly in responses to ADP and display a reduced sensitivity to thrombin and collagen. These platelets retain normal shape change and calcium flux in response to ADP but fail to inhibit adenylyl cyclase. In addition, oral clopidogrel does not inhibit aggregation responses to ADP in these mice. These results demonstrate that SP1999 is indeed the elusive receptor, P2Y12. Identification of the target receptor of the thienopyridine drugs affords us a better understanding of platelet function and provides tools that may lead to the discovery of more effective antithrombotic therapies.
Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial
Authors: Jean Jacques Grob, Mayur M Amonkar, Boguslawa Karaszewska, Jacob Schachter, Reinhard Dummer, Andrzej Mackiewicz, Daniil Stroyakovskiy, Kamil Drucis, Florent Grange, Vanna Chiarion-Sileni, Piotr Rutkowski, Mikhail Lichinitser, Evgeny Levchenko, Pascal Wolter, Axel Hauschild, Georgina V Long, Paul Nathan, Antoni Ribas, Keith Flaherty, Peng Sun, Jeffrey J Legos, Diane Opatt McDowell, Bijoyesh Mookerjee, Dirk Schadendorf, Caroline Robert
Journal: The Lancet Oncology (2015)
FGF21 is an endocrine signal of protein restriction
Authors: Thomas Laeger, Tara M. Henagan, Diana C. Albarado, Leanne M. Redman, George A. Bray, Robert C. Noland, Heike Münzberg, Susan M. Hutson, Thomas W. Gettys, Michael W. Schwartz, Christopher D. Morrison
Journal: Journal of Clinical Investigation (2014)

Enhanced fibroblast growth factor 21 (FGF21) production and circulation has been linked to the metabolic adaptation to starvation. Here, we demonstrated that hepatic FGF21 expression is induced by dietary protein restriction, but not energy restriction. Circulating FGF21 was increased 10-fold in mice and rats fed a low-protein (LP) diet. In these animals, liver Fgf21 expression was increased within 24 hours of reduced protein intake. In humans, circulating FGF21 levels increased dramatically following 28 days on a LP diet. LP-induced increases in FGF21 were associated with increased phosphorylation of eukaryotic initiation factor 2α (eIF2α) in the liver, and both baseline and LP-induced serum FGF21 levels were reduced in mice lacking the eIF2α kinase general control nonderepressible 2 (GCN2). Finally, while protein restriction altered food intake, energy expenditure, and body weight gain in WT mice, FGF21-deficient animals did not exhibit these changes in response to a LP diet. These and other data demonstrate that reduced protein intake underlies the increase in circulating FGF21 in response to starvation and a ketogenic diet and that FGF21 is required for behavioral and metabolic responses to protein restriction. FGF21 therefore represents an endocrine signal of protein restriction, which acts to coordinate metabolism and growth during periods of reduced protein intake.
Production of oxidants in alveolar macrophages and blood leukocytes
Authors: TS Haugen, OH Skjonsberg, H Kahler, T Lyberg
Journal: European Respiratory Journal (1999)

Increased production of oxidants subsequent to phagocyte stimulation has been associated with tissue damage in lung inflammatory disorders. The overall oxidative burden of the lung may vary with inflammatory cell composition. Flow cytometry using three different dyes, dihydroethidium (DHE), dichlorofluorescein diacetate (DCFH-DA) and dihydrorhodamine 123 (DHR), all compounds that by interaction with oxidants are transformed to fluorescent products, was used to examine the production of intracellular oxidants in alveolar macrophages (AMs), including size-defined subpopulations, monocytes (Ms) and polymorphonuclear neutrophils (PMNs) during in vitro incubation in the presence or absence of phorbol myristate acetate (PMA). PMA stimulation led to slightly increased (two-fold) (p<0.05) DHE-induced fluorescence in AMs, whereas it was greatly increased in Ms and PMNs (13-fold and 113-fold, respectively). The levels of DCFH-DA- and DHR-induced fluorescence were significantly (p<0.05) increased (four-fold and 110-fold, respectively) by PMA stimulation of PMNs, but not of AMs and Ms. Significant differences (p<0.05) in the levels of DHE- and DCFH-DA-induced fluorescence in small and large AMs were also demonstrated. The results show that the potential to increase the generation of various oxidants upon stimulation was: PMNs> Ms>AMs, suggesting that the total oxidative burden of the lungs is dependent on the type of inflammatory cells present, as well as on their state of activation.
Utility of adjuvant systemic therapy in melanoma
Authors: A.M.M. Eggermont, A. Testori, J. Marsden, P. Hersey, I. Quirt, T. Petrella, H. Gogas, R.M. MacKie, A. Hauschild
Journal: Annals of Oncology (2009)

The lack of effective drugs in stage IV melanoma has impacted the effectiveness of adjuvant therapies in stage II/III disease. To date, chemotherapy, immunostimulants and vaccines have been used with minimal success. Interferon (IFN) has shown an effect on relapse-free survival (RFS) in several clinical trials; however, without a clinically significant effect on overall survival (OS). A recently conducted meta-analysis demonstrated prolongation of disease-free survival (DFS) in 7% and OS benefit in 3% of IFN-treated patients when compared with observation-only patients. There were no clear differences for the dose and duration of treatment observed. Observation is still an appropriate control arm in adjuvant clinical trials. Regional differences exist in Europe in the adjuvant use of IFN. In Northwest Europe, IFN is infrequently prescribed. In Central and Mediterranean Europe, dermatologists commonly prescribe low-dose IFN therapy for AJCC stage II and III disease. High-dose IFN regimens are not commonly used. The population of patients that may benefit from IFN needs to be further characterised, potentially by finding biomarkers that can predict response. Such studies are ongoing.
CD43, but not P-Selectin Glycoprotein Ligand-1, Functions as an E-Selectin Counter-Receptor in Human Pre-B–Cell Leukemia NALL-1
Authors: Chizu Nonomura, Jiro Kikuchi, Nobutaka Kiyokawa, Hidenori Ozaki, Kanae Mitsunaga, Hidenobu Ando, Akiko Kanamori, Reiji Kannagi, Junichiro Fujimoto, Kazuo Muroi, Yusuke Furukawa, Mitsuru Nakamura
Journal: Cancer Research (2008)

Abstract B-cell precursor acute lymphoblastic leukemia (BCP-ALL/B-precursor ALL) is characterized by a high rate of tissue infiltration. The mechanism of BCP-ALL cell extravasation is not fully understood. In the present study, we have investigated the major carrier of carbohydrate selectin ligands in the BCP-ALL cell line NALL-1 and its possible role in the extravascular infiltration of the leukemic cells. B-precursor ALL cell lines and clinical samples from patients with BCP-ALL essentially exhibited positive flow cytometric reactivity with E-selectin, and the reactivity was significantly diminished by O-sialoglycoprotein endopeptidase treatment in NALL-1 cells. B-precursor ALL cell lines adhered well to E-selectin but only very weakly to P-selectin with low-shear-force cell adhesion assay. Although BCP-ALL cell lines did not express the well-known core protein P-selectin glycoprotein ligand-1 (PSGL-1), a major proportion of the carbohydrate selectin ligand was carried by a sialomucin, CD43, in NALL-1 cells. Most clinical samples from patients with BCP-ALL exhibited a PSGL-1neg/low/CD43high phenotype. NALL-1 cells rolled well on E-selectin, but knockdown of CD43 on NALL-1 cells resulted in reduced rolling activity on E-selectin. In addition, the CD43 knockdown NALL-1 cells showed decreased tissue engraftment compared with the control cells when introduced into γ-irradiated immunodeficient mice. These results strongly suggest that CD43 but not PSGL-1 plays an important role in the extravascular infiltration of NALL-1 cells and that the degree of tissue engraftment of B-precursor ALL cells may be controlled by manipulating CD43 expression. [Cancer Res 2008;68(3):790–9]
Decreased Selenium-Binding Protein 1 in Esophageal Adenocarcinoma Results from Posttranscriptional and Epigenetic Regulation and Affects Chemosensitivity
Authors: Amy L. Silvers, Lin Lin, Adam J. Bass, Guoan Chen, Zhuwen Wang, Dafydd G. Thomas, Jules Lin, Thomas J. Giordano, Mark B. Orringer, David G. Beer, Andrew C. Chang
Journal: Clinical Cancer Research (2010)

The chemopreventive effects of selenium have been extensively examined, but its role in cancer development or as a chemotherapeutic agent has only recently been explored. Because selenium-binding protein 1 (SELENBP1, SBP1, hSP56) has been shown to bind selenium covalently and selenium deficiency has been associated with esophageal adenocarcinoma (EAC), we examined its role in EAC development and its potential effect on chemosensitivity in the presence of selenium.SELENBP1 expression level and copy number variation were determined by oligonucleotide microarrays, real-time reverse transcription-PCR, tissue microarrays, immunoblotting, and single-nucleotide polymorphism arrays. Bisulfite sequencing and sequence analysis of reverse transcription-PCR-amplified products explored epigenetic and posttranscriptional regulation of SELENBP1 expression, respectively. WST-1 cell proliferation assays, senescence-associated beta-galactosidase staining, immunoblotting, and flow cytometry were done to evaluate the biological significance of SELENBP1 overexpression in selenium-supplemented EAC cells.SELENBP1 expression decreased significantly in Barrett's esophagus to adenocarcinoma progression. Both epigenetic and posttranscriptional mechanisms seemed to modulate SELENBP1 expression. Stable overexpression of SELENBP1 in methylseleninic acid-supplemented Flo-1 cells resulted in enhanced apoptosis, increased cellular senescence, and enhanced cisplatin cytotoxicity. Although inorganic sodium selenite similarly enhanced cisplatin cytotoxicity, these two forms of selenium elicited different cellular responses.SELENBP1 expression may be an important predictor of response to chemoprevention or chemosensitization with certain forms of selenium in esophageal tissues. AACR.
How to read a paper: Papers that report drug trials
Authors: T. Greenhalgh
Journal: BMJ (1997)

If you prescribe drugs, the pharmaceutical industry is interested in you and is investing a staggering sum of money trying to influence you. The most effective way of changing the prescribing habits of a clinician is through personal representatives (known in Britain as "drug reps" and in North America as "detailers"), who travel round with a briefcase full of "evidence" in support of their wares.1 Pharmaceutical "reps" do not tell nearly as many lies as they used to (drug marketing has become an altogether more sophisticated science), but they have been known to cultivate a shocking ignorance of basic epidemiology and clinical trial design when it suits them.2 It often helps their case, for example, to present the results of uncontrolled trials and express them in terms of before and after differences in a particular outcome measure.3 The recent correspondence in the Lancet and BMJ on placebo effects should remind you why uncontrolled before and after studies are the stuff of teenage magazines, not hard science.4 5 6 7 8 9 10 11 12 Sackett and colleagues have argued that before giving a drug to a patient the doctor should: #### Summary points Pharmaceutical "reps" are now much more informative than they used to be, but they may show ignorance of basic epidemiology and clinical trial design The value of a drug should be expressed in terms of safety, tolerability, efficacy, and price The efficacy of a drug should ideally be measured in terms of clinical end points that are relevant to patients; if surrogate end points are used they should be valid Promotional literature of low scientific validity (such as uncontrolled before and after trials) should not be allowed to influence practice
Lipid and Carbohydrate Metabolism of Myocardium During the Biphasic Inotropic Response to Epinephrine
Authors: TIMOTHY J. REGAN, CHRISTOS B. MOSCHOS, PATRICK H. LEHAN, HENRY A. OLDEWURTEL, HARPER K. HELLEMS
Journal: Circulation Research (1966)

The metabolic response of the left ventricle to a 90 min regional infusion of 1-epinephrine (5 µg/min) was assessed in the intact anesthetized dog for 3 hr. The first hour was characterized by a rise in stroke output at constant filling pressure. Subsequently, contractility fell and there was release of K and PO 4 ions as well as SGOT from the myocardium that was attributed to tissue injury. The myocardial RQ rose for the first hour, presumably due to glycogenolysis, since carbohydrate extraction from blood was unaltered. Production of lactate by the myocardium during the RQ rise occurred without ischemia, since blood flow (Kr 85 method) and O 2 uptake rose 10%. The proportionately greater increase in contractility was not consistent with "O 2 wasting" as a basis for the injury. After 1 hr the RQ fell to levels consistent with predominant lipid utilization. However, FFA extraction declined and the oxidation, extraction and incorporation of palmitate-l-C 14 into tissue lipid were diminished during hormone exhibition. Plasma triglyceride uptake, insignificant in controls, was enhanced during the 3 hr without a rise in arterial concentration. Oxidation of this lipid was insufficient to prevent a threefold triglyceride increment in the myocardium. The authors discuss a possible relationship of these metabolic alterations to the pathophysiologic response induced by epinephrine.
Impaired Development of CD4+ CD25+ Regulatory T Cells in the Absence of STAT1
Authors: Takeaki Nishibori, Yoshinari Tanabe, Leon Su, Michael David
Journal: The Journal of Experimental Medicine (2003)

Type I and II interferons (IFNs) exert opposing effects on the progression of multiple sclerosis, even though both IFNs use the signal transducer and activator of transcription 1 (STAT1) as a signaling mediator. Here we report that STAT1-deficient mice expressing a transgenic T cell receptor against myelin basic protein spontaneously develop experimental autoimmune encephalomyelitis with dramatically increased frequency. The heightened susceptibility to this autoimmune disease appears to be triggered by a reduced number as well as a functional impairment of the CD4+ CD25+ regulatory T cells in STAT1-deficient animals. Adoptive transfer of wild-type regulatory T cells into STAT1-deficient hosts is sufficient to prevent the development of autoimmune disease. These results demonstrate an essential role of STAT1 in the maintenance of immunological self-tolerance.
Two factors that may underpin outstanding outcomes after ACL rehabilitation
Authors: H Grindem, M A Risberg, I Eitzen
Journal: British Journal of Sports Medicine (2015)

Because ACL reconstruction does not automatically lead to successful outcomes and return to play,1 ,2 active rehabilitation is a realistic option that is being adopted by an increasing number of patients.3 In the Delaware-Oslo ACL Cohort Study, we found no differences in 2-year knee function, sports participation or new knee injuries between patients treated with ACL reconstruction followed by progressive preoperative and postoperative active rehabilitation, and patients treated with active rehabilitation alone.4 In our 2015 paper, we found that 86–94% of our ACL reconstruction and active rehabilitation group reported 2-year Knee injury and Osteoarthritis Outcome Score (KOOS) within …