tbuckley/cabot-search huggingface dataset:
AN ANTIVIRAL SUBSTANCE FROM PENICILLIUM FUNICULOSUM
Authors: Richard E. Shope
Journal: The Journal of Experimental Medicine (1953)

Helenine exerts a therapeutic effect against Semliki Forest virus infections of mice. Cures, that is to say the survival of treated animals, were more frequently observed in Semliki Forest virus infections than they were in SK virus infections. It is believed that this difference in end-result probably represented only a quantitative difference in the therapeutic effect of helenine against these two viruses and not a qualitative difference in its mechanism of therapeutic action. The findings reported in this paper with regard to the treatment of Semliki Forest virus infections with helenine parallel very closely those described in an accompanying paper which deals with the action of helenine on SK. virus infections.
Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomised, placebo-controlled trial
Authors: Robert S Rosenson, Colin Hislop, Daniel McConnell, Michael Elliott, Yuri Stasiv, Nan Wang, David D Waters
Journal: The Lancet (2009)
Now wash your hands
Authors: Wendy Moore
Journal: BMJ (2007)

Pontius Pilate washed his hands of blame. Lady Macbeth feverishly tried to scrub away the “damned spot.” Yet healthcare professionals have remained imperviously resilient to the handwashing message.

Ever since the first tentative hints that a brief encounter with soap and water might be a good idea between examining patients, doctors have guffawed at the suggestion that their healing hands might actually spread disease. Charles White, the obstetrician who helped found Manchester Royal Infirmary, was possibly the first to mention the unmentionable. Observing the high death toll of mothers and babies in obstetrics practice, …
Fetal bile acid metabolism during infancy: Analysis of 1β-hydroxylated bile acids in urine, meconium and feces
Authors: Akihiko Kimura, Ryoichi Yamakawa, Kosuke Ushijima, Takuji Fujisawa, Norikazu Kuriya, Hirohisa Kato, Takahiro Inokuchi, Reijiro Mahara, Takao Kurosawa, Masahiko Tohma
Journal: Hepatology (1994)

Fetal bile acids (1 beta-hydroxylated, 6 alpha-hydroxylated and unsaturated bile acids), especially 1 beta, 3 alpha,7 alpha, 12 alpha-tetrahydroxy-5 beta-cholan-24-oic acid (CA-1 beta-ol), have been detected in urine and feces early in life. To investigate whether a fetal pathway of bile acid synthesis exists in infancy, we measured the concentrations of bile acids in the urine, meconium and feces from normal newborns and infants by means of gas chromatography-mass spectrometry. The mean ratio of total bile acids to creatinine in urine increased between birth and 7 days and then gradually decreased; however, the concentration of total bile acids in urine remained significantly higher than that in adult urine until 3 mo of age. The main urinary bile acid was CA-1 beta-ol, and substantial amounts of fetal bile acids were detected in urine until 3 mo of age. The ratio of cholic acid to chenodeoxycholic acid was abnormally low in meconium (mean, 0.44; range, 0.19 to 0.74), and hyocholic acid constituted 19.3% of total bile acids. The mean total bile acid content of feces decreased between birth and 7 days of age and thereafter increased. The mean percentage of fetal bile acids in feces decreased after birth, but substantial amounts were present in feces until 1 mo of age.(ABSTRACT TRUNCATED AT 250 WORDS)
Pituitary Adenylate Cyclase-Activating Polypeptide Is a Potent Inhibitor of the Growth of Light Chain-Secreting Human Multiple Myeloma Cells
Authors: Min Li, Shirley Cortez, Tomoya Nakamachi, Vecihi Batuman, Akira Arimura
Journal: Cancer Research (2006)

Abstract Multiple myeloma represents a malignant proliferation of plasma cells in the bone marrow, which often overproduces immunoglobulin light chains. We have shown previously that pituitary adenylate cyclase-activating polypeptide (PACAP) markedly suppresses the release of proinflammatory cytokines from light chain-stimulated human renal proximal tubule epithelial cells and prevents the resulting tubule cell injury. In this study, we have shown that PACAP suppresses the proliferation of human κ and λ light chain-secreting multiple myeloma–derived cells. The addition of PACAP suppressed light chain-producing myeloma cell–stimulated interleukin 6 (IL-6) secretion by the bone marrow stromal cells (BMSCs). A specific antagonist to either the human PACAP-specific receptor or the vasoactive intestinal peptide receptor attenuated the suppressive effect of PACAP on IL-6 production in the adhesion of human multiple myeloma cells to BMSCs. The secretion of IL-6 by BMSCs was completely inhibited by 10−9 mol/L PACAP, which also attenuated the phosphorylation of both p42/44 and p38 mitogen-activated protein kinases (MAPK) as well as nuclear factor-κB (NF-κB) activation in response to the adhesion of multiple myeloma cells to BMSCs, whereas the inhibition of p42/44 MAPK signaling attenuated PACAP action. The signaling cascades involved in the inhibitory effect of PACAP on IL-6-mediated paracrine stimulation of light chain-secreting myeloma cell growth was mediated through the suppression of p38 MAPK as well as modulation of activation of transcription factor NF-κB. These findings suggest that PACAP may be a new antitumor agent that directly suppresses light chain-secreting myeloma cell growth and indirectly affects tumor cell growth by modifying the bone marrow milieu of the multiple myeloma. (Cancer Res 2006; 66(17): 8796-803)
Autophagy is not impaired in BALF alveolar macrophages in IPF: Preliminary results
Authors: Stella Sarantoulaki, George Margaritopoulos, Eliza Tsitoura, Konstantinos Karagiannis, Eleni Bibaki, Athol Wells, Nikos Siafakas, George Sourvinos, Katerina Antoniou
Journal: European Respiratory Journal (2014)

Introduction : Autophagy, derived from the Greek and meaning “self eating,” is a homeostatic mechanism which contributes to cellular homeostasis. The modulation of autophagy in alveolar macrophages (AM) has been explored in chronic obstructive pulmonary disease and  evidence of impaired autophagy was found. Although autophagy may protect against the development  of fibrosis, its role is still unknown in AM.   Aim  : With this background, we evaluated the autophagic activity in AM obtained form the bronchoalveolar lavage fluid (BALF) of patients with Idiopathic Pulmonary Fibrosis (IPF). Beclin-1 and p62, markers autophagic activity, have been evaluated and correlated with markers of disease severity (forced vital capacity: FVC, and diffusion capacity: DLco).   Patients and methods : We have prospectively studied 48 IPF patients and 16 controls. The expression of beclin-1 and p62 in AM has been evaluated with real-time PCR.   Results:  We found no differences in the m-RNA expression of the the two genes between the study groups. Although cigarette smoking influences autophagy in AM no differences were obseved in the levels of Beclin-1 and p62 in smokers compared to non-smokers. In addition, no correlation was observed with markers of disease severity.   Conclusion : We have studied, for the first time, AM isolated from BALF of IPF patients. Our preliminary results show that autophagy does not appear impaired, at the level of mRNA expression regarding beclin-1 and p62. Further study of autophagy gene expression is needed.
Impaired Decision Making in Suicide Attempters
Authors: Fabrice Jollant, Frank Bellivier, Marion Leboyer, Bernard Astruc, Stéphane Torres, Régis Verdier, Didier Castelnau, Alain Malafosse, Philippe Courtet
Journal: American Journal of Psychiatry (2005)

The understanding of suicidal behavior is incomplete. The stress-diathesis model suggests that a deficit in serotonergic projections to the orbitofrontal cortex is involved in susceptibility to suicidal behavior. The orbitofrontal cortex has been implicated in decision making, a cognitive function dealing with complex choices that may be under serotonergic modulation. In this preliminary study, the authors assessed decision making in suicide attempters.The authors used the Iowa Gambling Task to investigate patients with a history of violent (N=32) or nonviolent (N=37) suicidal behavior, patients suffering from affective disorders with no history of suicidal behavior (N=25), and healthy comparison subjects (N=82). Patients were assessed when they were not suffering from a current axis I disorder. The authors also assessed the correlation of Iowa Gambling Task performance with psychometric measures of impulsivity, hostility, anger, aggression, and emotional instability.Both groups of suicide attempters scored significantly lower than healthy comparison subjects, and violent suicide attempters performed significantly worse than affective comparison subjects. No significant differences were observed between the groups of suicide attempters or between the two comparison groups. The differences in performance could not be accounted for by age, intellectual ability, educational level, number of suicide attempts, age at first suicide attempt, history of axis I disorder, or medication use. Iowa Gambling Task performances were correlated positively with affective lability and with anger expression but not with impulsivity.Impaired decision making, possibly due to emotional dysfunction, may be a neuropsychological risk factor for suicidal behavior.
Electrical Potential Distribution Surrounding the Atria during Depolarization and Repolarization in the Dog
Authors: MADISON S. SPACH, TERRY D. KING, ROGER C. BARR, DAVID E. BOAZ, MARY N. MORROW, SCOTT HERMAN-GIDDENS
Journal: Circulation Research (1969)

The potential distribution at the atrial surface during depolarization and repolarization was studied in intact dogs. A preparation was developed by implanting 30 to 40 miniature electrodes permanently on each atrium to record unipolar electrograms in the intact animal. Heart block was created to dissociate atrial and ventricular activity. The electrograms were recorded on magnetic tape and atrial isopotential heart maps produced with the use of a digital computer. The changing potential distribution during excitation indicated the early presence of multiple wave fronts which were related primarily to the crista terminalis, Bachmann's bundle, and a special bundle to the base of the right appendage. The interatrial septum provided a conducting bridge which had an important influence of global atrial excitation, depending on the site of impulse formation. Colliding excitation wave fronts were quite prominent. During terminal atrial excitation, repolarization maxima were present simultaneously with depolarization maxima. Repolarization was characterized by a changing potential distribution which followed the same general pattern as excitation spread; and, furthermore, the earliest areas of excitation were associated with a repolarization maximum and terminal areas of excitation were associated with repolarization minima.
Expression of cytokines and chemokine receptors in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis
Authors: M. Caproni, D. Torchia, E. Schincaglia, W. Volpi, A. Frezzolini, D. Schena, A. Marzano, P. Quaglino, C. De Simone, A. Parodi, E. Barletta, P. Fabbri
Journal: British Journal of Dermatology (2006)

Erythema multiforme (EM) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are caused by a dysregulation of cellular immunity.To evaluate further the potential role of certain cytokines and chemokine receptors in cutaneous lesions of patients affected by EM and SJS/TEN and to establish whether such diseases are polarized preferentially towards a T-helper (Th) 1 or Th2 pattern.Biopsy specimens from eight patients with EM, six with SJS/TEN and three healthy controls were stained for immunohistochemical examination using the alkaline phosphatase-antialkaline phosphatase method. The monoclonal antibodies used included those to tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-2, IL-5, IL-13, receptor 3 for C-C chemokines (CCR3), receptor 3 for C-x-C chemokines (CXCR3) and CXCR4.The SJS/TEN specimens showed significantly higher expression of all the cytokines and chemokine receptors (except CXCR3) tested than the EM specimens. Both lesional series showed significantly higher expression of all the receptors tested than the healthy control specimens, with the sole exception of a lower expression of CCR3 in EM specimens. Comparison between molecules associated with a Th1 or Th2 response revealed a predominance of Th1 response in EM and no significant imbalance between Th1 and Th2 in SJS/TEN.We have provided further evidence that TNF-alpha is strongly expressed in SJS/TEN lesions and therefore it may be involved in the epidermal necrosis featured in such diseases. IFN-gamma may play an important role both in EM and SJS/TEN. IL-2, IL-5 and IL-13 may contribute to the cutaneous immunoinflammation in these diseases. Chemokine receptors may be involved strongly in the recruitment of inflammatory cells in lesional skin. In our cases we found a sharp polarization towards a Th1 pattern in EM, while the SJS/TEN lesions showed a mixed Th1/Th2 pattern.
Major Cancer Regressions in Mesothelioma After Treatment with an Anti-Mesothelin Immunotoxin and Immune Suppression
Authors: Raffit Hassan, Andrew C. Miller, Elad Sharon, Anish Thomas, James C. Reynolds, Alexander Ling, Robert J. Kreitman, Markku M. Miettinen, Seth M. Steinberg, Daniel H. Fowler, Ira Pastan
Journal: Science Translational Medicine (2013)

In patients with advanced chemotherapy-refractory mesothelioma, treatment with the anti-mesothelin immunotoxin SS1P and immunosuppression with pentostatin and cyclophosphamide resulted in marked and durable tumor regressions.
The Evolutionarily Dynamic IFN-Inducible GTPase Proteins Play Conserved Immune Functions in Vertebrates and Cephalochordates
Authors: G. Li, J. Zhang, Y. Sun, H. Wang, Y. Wang
Journal: Molecular Biology and Evolution (2009)

Interferon (IFN)-inducible GTPases currently include four families of proteins: myxovirus resistant proteins (Mxs), guanylate-binding proteins (GBPs), immunity-related GTPase proteins (IRGs), and very large inducible GTPase proteins (VLIGs). They are all under conserved regulation by IFNs in humans and mice and play a critical role in preventing microbial infections. However, differences between vertebrates are poorly characterized, and their evolutionary origins have not been studied in detail. In this study, we performed comparative genomic analysis of the four families in 18 representative animals that yielded several unexpected results. Firstly, we found that Mx, GBP, and IRG protein families arose before the divergence of chordate subphyla, but VLIG emerged solely in vertebrates. Secondly, IRG, GBP, and VLIG families have experienced a high rate of gene gain and loss during the evolution, with the GBP family being lost entirely in two pufferfish and VLIG family lost in primates and carnivores. Thirdly, the regulation of these genes by IFNs is highly conserved throughout vertebrates although the VLIG protein sequences in fish have lost the first 870 amino acid residues. Finally, amphioxus IFN-inducible GTPase genes are all highly expressed in immune-related organs such as gill, liver, and intestine and are upregulated after challenge with PolyI:C and pathogens, although no IFNs or their receptors were detected in the current amphioxus genome database. These results suggest that IFN-inducible GTPase genes play conserved immune functions both in vertebrates and in cephalochordates.
Screening for Diabetes and Pre-Diabetes With Proposed A1C-Based Diagnostic Criteria
Authors: Darin E. Olson, Mary K. Rhee, Kirsten Herrick, David C. Ziemer, Jennifer G. Twombly, Lawrence S. Phillips
Journal: Diabetes Care (2010)

OBJECTIVE An International Expert Committee (IEC) and the American Diabetes Association (ADA) proposed diagnostic criteria for diabetes and pre-diabetes based on A1C levels. We hypothesized that screening for diabetes and pre-diabetes with A1C measurements would differ from using oral glucose tolerance tests (OGTT). RESEARCH DESIGN AND METHODS We compared pre-diabetes, dysglycemia (diabetes or pre-diabetes), and diabetes identified by the proposed criteria (A1C ≥6.5% for diabetes and 6.0–6.4% [IEC] or 5.7–6.4% [ADA] for high risk/pre-diabetes) with standard OGTT diagnoses in three datasets. Non-Hispanic white or black adults without known diabetes who had A1C and 75-g OGTT measurements were included from the prospective Screening for Impaired Glucose Tolerance study (n = 1,581), and from the National Health and Nutrition Examination Survey (NHANES) III (n = 2014), and NHANES 2005–2006 (n = 1,111). RESULTS OGTTs revealed pre-diabetes in 35.8% and diabetes in 5.2% of combined study subjects. A1C provided receiver operating characteristic (ROC) curve areas for diabetes of 0.79–0.83, but ROC curve areas were ≤0.70 for dysglycemia or pre-diabetes. The proposed criteria missed 70% of individuals with diabetes, 71–84% with dysglycemia, and 82–94% with pre-diabetes. Compared with the IEC criteria, the ADA criteria for pre-diabetes resulted in fewer false-negative and more false-positive result. There were also racial differences, with false-positive results being more common in black subjects and false-negative results being more common in white subjects. With use of NHANES 2005–2006 data, ∼5.9 million non-Hispanic U.S. adults with unrecognized diabetes and 43–52 million with pre-diabetes would be missed by screening with A1C. CONCLUSIONS The proposed A1C diagnostic criteria are insensitive and racially discrepant for screening, missing most Americans with undiagnosed diabetes and pre-diabetes.
Pomalidomide (CC4047) Plus Low-Dose Dexamethasone As Therapy for Relapsed Multiple Myeloma
Authors: Martha Q. Lacy, Suzanne R. Hayman, Morie A. Gertz, Angela Dispenzieri, Francis Buadi, Shaji Kumar, Philip R. Greipp, John A. Lust, Stephen J. Russell, David Dingli, Robert A. Kyle, Rafael Fonseca, P. Leif Bergsagel, Vivek Roy, Joseph R. Mikhael, A. Keith Stewart, Kristina Laumann, Jacob B. Allred, Sumithra J. Mandrekar, S. Vincent Rajkumar
Journal: Journal of Clinical Oncology (2009)

Thalidomide and lenalidomide are immunomodulatory drugs (IMiDs) that produce high remission rates in the treatment of multiple myeloma. Pomalidomide is a new IMiD with high in vitro potency. We report, to our knowledge, the first phase II trial of pomalidomide administered in combination with low-dose dexamethasone for the treatment of relapsed or refractory multiple myeloma.Pomalidomide was administered orally at a dose of 2 mg daily on days 1 through 28 of a 28-day cycle. Dexamethasone 40 mg daily was administered orally on days 1, 8, 15, and 22 of each cycle. Responses were recorded using the criteria of the International Myeloma Working Group.Sixty patients were enrolled. Thirty-eight patients (63%) achieved confirmed response including complete response in three patients (5%), very good partial response in 17 patients (28%), and partial response in 18 patients (30%). Responses were seen in 40% of lenalidomide-refractory patients, 37% of thalidomide-refractory patients, and 60% of bortezomib-refractory patients. Responses were seen in 74% of patients with high-risk cytogenetic or molecular markers. Toxicity consisted primarily of myelosuppression. Grade 3 or 4 hematologic toxicity consisted of anemia (5%), thrombocytopenia (3%), and neutropenia (32%). One patient (1.6%) had a thromboembolic event. The median progression-free survival time was 11.6 months and was not significantly different in patients with high-risk disease compared with patients with standard-risk disease.The combination of pomalidomide and low-dose dexamethasone is extremely active in the treatment of relapsed multiple myeloma, including high response rates in patients refractory to other novel agents.
Analysis of the structural correlates for antibody polyreactivity by multiple reassortments of chimeric human immunoglobulin heavy and light chain V segments.
Authors: Y Ichiyoshi, P Casali
Journal: The Journal of Experimental Medicine (1994)

Polyreactive antibodies (Abs) constitute a major proportion of the early Ab repertoire and are an important component of the natural defense mechanisms against infections. They are primarily immunoglobulin M (IgM) and bind a variety of structurally dissimilar self and exogenous antigens (Ags) with moderate affinity. We analyzed the contribution of Ig polyvalency and of heavy (H) and light (L) chain variable (V) regions to polyreactivity in recombinatorial experiments involving the VH-diversity(D)-JH and V kappa-J kappa gene segments of a human polyreactive IgM, monoclonal antibody 55 (mAb55), and those of a human monoreactive anti-insulin IgG, mAb13, in an in vitro C gamma l and C kappa human expression system. These mAbs are virtually identical in their VH and V kappa gene segment sequences. First, we expressed the VH-D-JH and V kappa-J kappa genes of the IgM mAb55 as V segments of an IgG molecule. The bivalent recombinant IgG Ab bound multiple Ags with an efficiency only slightly lower than that of the original decavalent IgM mAb55, suggesting that class switch to IgG does not affect the Ig polyreactivity. Second, we coexpressed the mAb55-derived H or kappa chain with the mAb13-derived kappa or H chain, respectively. The hybrid IgG Ab bearing the mAb55-derived H chain V segment paired with the mAb13-derived kappa V segment, but not that bearing the mAb13-derived H chain V segment paired with the mAb55-derived kappa V segment, bound multiple Ags, suggesting that the Ig H chain plays a major role in the Ig polyreactivity. Third, we shuffled the framework 1 (FR1)-FR3 and complementarity determining region 3 (CDR3) regions of the H and kappa chain V segments of the mAB55-derived IgG molecule with the corresponding regions of the monoreactive IgG mAb13. The mAb55-derived IgG molecule lost polyreactivity when the H chain CDR3, but not the FR1-FR3 region, was replaced by the corresponding region of mAb13, suggesting that within the H chain, the CDR3 provides the major structural correlate for multiple Ag-binding. This was formally proved by the multiple Ag-binding of the originally monoreactive mAb13-derived IgG molecule grafted with the mAb55-derived H chain CDR3. The polyreactivity of this chimeric IgG was maximized by grafting of the mAb55-derived kappa chain FR1-FR3, but not that of the kappa chain CDR3.(ABSTRACT TRUNCATED AT 400 WORDS)