tbuckley/cabot-search huggingface dataset:
Suicides associated with the 2008-10 economic recession in England: time trend analysis
Authors: B. Barr, D. Taylor-Robinson, A. Scott-Samuel, M. McKee, D. Stuckler
Journal: BMJ (2012)

<b>Objective</b> To determine whether English regions worst affected by the economic recession in the United Kingdom in 2008-10 have had the greatest increases in suicides. <b>Design</b> Time trend analysis comparing the actual number of suicides with those that would be expected if pre-recession trends had continued. Multivariate regression models quantified the association between changes in unemployment (based on claimant data) and suicides (based on data from the National Clinical Health Outcomes Database). <b>Setting</b> 93 English regions, based on the Nomenclature of Territorial Units Statistics level 3 groupings of local authorities at county level and groups of unitary local authorities. <b>Participants</b> Men and women with a record of death from suicide or injury of undetermined cause in 2000-10. <b>Main outcome measure</b> Number of excess suicides during the economic recession (2008-10). <b>Results</b> Between 2008 and 2010, we found 846 (95% confidence interval 818 to 877) more suicides among men than would have been expected based on historical trends, and 155 (121 to 189) more suicides among women. Historically, short term yearly fluctuations in unemployment have been associated with annual changes in suicides among men but not among women. We estimated that each 10% increase in the number of unemployed men was significantly associated with a 1.4% (0.5% to 2.3%) increase in male suicides. These findings suggest that about two fifths of the recent increase in suicides among men (increase of 329 suicides, 126 to 532) during the 2008-10 recession can be attributed to rising unemployment. <b>Conclusion</b> The study provides evidence linking the recent increase in suicides in England with the financial crisis that began in 2008. English regions with the largest rises in unemployment have had the largest increases in suicides, particularly among men.
Back pain--what can we offer?
Authors: W A Mackey
Journal: BMJ (1979)

apparent fall in LAA concentration was simply due to the increasing proportion of granulo- cytes in the differential white blood cell count, and that a true fall in LAA concentration had not occurred.After the acute "stress" had subsided and the leucocytosis returned to normal, however, the LAA concentration and serum ascorbic acid concentration remained low, presumably because of tissue depletion of ascorbic acid.Both may remain low for up to 56 days.2We also found that tissue damage is pro- bably necessary to produce the long-term depletion of LAA and serum ascorbic acid concentrations since the acute changes in LAA only can be produced by tetracosactrin infusions in normal subjects.2
Rearrangement of λ Light Chain Genes in Mature B Cells In Vitro and In Vivo. Function of Reexpressed Recombination-activating Gene (<i>RAG</i>) Products
Authors: Masaki Hikida, Hitoshi Ohmori
Journal: The Journal of Experimental Medicine (1998)

V(D)J (V, variable; D, diversity; J, joining) combination of immunoglobulin (Ig) genes established in premature B cells has been thought to be conserved throughout differentiation at mature stages. However, germinal center (GC) B cells have been shown to reexpress recombination-activating gene (RAG)-1 and RAG-2 proteins in immunized mice. Here, we present several lines of evidence indicating that RAG proteins thus induced are functional as the V(D)J recombinase. DNA excision product reflecting Vλ1 to Jλ1 rearrangement was generated in parallel with the expression of RAG genes in mature mouse B cells that were activated in vitro with LPS and IL-4. Similar λ chain gene rearrangement was observed in the draining lymph node of immunized mice. Further, B cells that underwent λ gene rearrangement were shown by in situ PCR to be localized within GCs. Thus, secondary rearrangement of Ig genes (receptor editing) can occur in mature B cells.
Osmolality changes in nebulizer solutions
Authors: MH Schoni, R Kraemer
Journal: European Respiratory Journal (1989)

Paradoxical effects (bronchoconstriction instead of bronchodilatation) have been reported after inhalation of beta2-mimetics in asthmatic children, and it has been suggested that this was due to osmolality and pH changes of the nebulizer solution. We tested commercially available nebulizer solutions and found osmolality changes after 5, 10 and 15 min of nebulization. Osmolality was measured in the nebulizer chamber and the airsteam of two types of jet nebulizers. When normal saline was nebulized chamber, from 282 +/- 7 mmol.kg-1 to 432 +/- 18 mmol.kg-1 resulted. Salbutamol ready made solution, and terbutaline respules were isotonic, whereas fenoterol, disodium cromogylcate (DSCG), beclomethasone dipropionate (BDP) and salbutamol (respirator solution 0.5%) were hypotonic (60-100 mmol.kg-1). When a mixture of sodium chloride (NaCl) and the drug solution (salbutamol, terbutaline, fenoterol) was nebulized for 10-15 min, the osmolality in the nebulizer cup increased to 420-500 mmol.kg-1. However, mixtures of the same beta 2-agonists with DSCG or with BDP remained hypo-osmolar. The same osmolality changes were present in the airstream. This study shows that after 10-15 min of nebulization osmotic changes occur in the nebulizer cup and airstream and that these changes differ according to the drug mixtures and the amount of the solution in the nebulizer chamber.
Peroxisome Proliferator–Activated Receptor α Activation Decreases Metastatic Potential of Melanoma Cells <i>In vitro</i> via Down-Regulation of Akt
Authors: Maja Grabacka, Przemyslaw M. Plonka, Krystyna Urbanska, Krzysztof Reiss
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Peroxisome proliferator-activated receptors (PPAR) regulate lipid and glucose metabolism but their anticancer properties have been recently studied as well. We previously reported the antimetastatic activity of the PPARα ligand, fenofibrate, against melanoma tumors in vivo. Here we investigated possible molecular mechanisms of fenofibrate anti metastatic action. Experimental Design: Monolayer cultures of mouse (B16F10) and human (SkMell88) melanoma cell lines, soft agar assay, and cell migration assay were used in this study. In addition, we analyzed PPARα expression and its transcriptional activity in response to fenotibrate by using Western blots and liciferase-based reporter system. Results: Fenofibrate inhibited migration of B16F10 and SkMel188 cells in Transwell chambers and colony formation in soft agar. These effects were reversed by PPAR inhibitor, GW9662. Western blot analysis revealed time-dependent down-regulation of Akt and extracellular signal–regulated kinase l/2 phosphorylation in fenofibrate-treated cells. A B16F10 cell line stably expressing constitutively active Akt mutant was resistant to fenofibrate. In contrast, Akt gene silencing with siRNA mimicked the fenofibrate action and reduced the migratory ability of B16F1O cells. In addition, fenofibrate strongly sensitized BI6FIO cells to the proapoptotic drug staurosporine, further supporting the possibility that fenofibrate-induced down-regulation of Akt function contributes to fenofibrate-mediated inhibition of metastatic potential in this experimental model. Conclusions: Our results show that the PPAR-dependent antimetastatic activity of fenofibrate involves down-regulation of Akt phosphorylation and suggest that supplementation with this drug may improve the effectiveness of melanoma chemotherapy.
Relationship between structure and correcting activity of bovine high molecular weight kininogen upon the clotting time of fitzgerald-trait plasma
Authors: AG Scicli, R Waldmann, JA Guimaraes, G Scicli, OA Carretero, H Kato, YN Han, S Iwanaga
Journal: The Journal of Experimental Medicine (1979)

Bovine high molecular weight kininogen (bHMWK) partially corrects the activated plasma thromboplastin time (aPTT) of Fitzgerald trait plasma which is congenitally deficient in HMWK. The relationship between the structure and activity of HMWK was clarified by studying the effects of different fragments of bHMWK on the aPTT of Fitzgerald-trait plasma. The peptides studied were lys-bradykinin-free HMWK, bradykinin-fragment 1-2-free HMWK, heavy chain, fragment 1-2-light chain, and light chain. All fragments were tested in equimolar concentrations. Bradykinin-fragment 1-2-free HMWK, heavy chain, and light chain have little or no correcting activity upon Fitzgerald-trait plasma aPTr. Fragment 1-2 light chain has the same correcting activity as intact bHMWK, while that of lys-bradykinin-free HMWK appears to be higher. Both fragment 1-2 and fragment 2 inhibit the clotting time of normal human plasma. When compared on a molar basis, fragment 2 is a more active inhibitor than fragment 1-2. When the effects of bovine plasma kallikrein upon bHMWK and hHMWK were studied, it was found that it released kinins from both kininogens. However, while the correcting activity of bHMWK was completely destroyed after 60 min of incubation, that of hHMWK was fully retained. These data suggest that: (a) the active part of bHMWK is comprised of the fragment 1-2 light chain portion; (b) fragment 1-2 or fragment 2 is the binding site to negatively charged surfaces, while the light chain interacts with other components of the surface-mediated reactions; and (c) bovine plasma kallikrein releases kinins, but probably does not cause the release of fragment 1-2 from human HMWK.
Prevention of experimental colitis by parenteral administration of a pathogen-derived immunomodulatory molecule
Authors: H. Braat, P. McGuirk, F. J W Ten Kate, I. Huibregtse, P. J Dunne, D. W Hommes, S. J H Van Deventer, K. H G Mills
Journal: Gut (2006)

<b>Background:</b> Filamentous haemagglutinin (FHA) of <i>Bordetella pertussis</i> subverts host immune responses by inhibiting interleukin (IL)12 and enhancing IL10 production by macrophages and dendritic cells, and promoting the induction of regulatory T cells. <b>Hypothesis:</b> Injection of FHA would ameliorate disease in a T cell-dependent model of colitis via the induction of anti-inflammatory cytokines and regulatory T cells. <b>Methods:</b> Colitis was induced by injection of CD4CD45RB<sup>high</sup> naive T cells into severe combined immunodeficient (SCID) mice. Mice were treated with four subcutaneous injections of FHA or buffer alone. <b>Results:</b> Parenteral injection of FHA stimulated IL10 and/or transforming growth factor β production in local and mesenteric lymph nodes and Peyer's patches of mice 2–6 h after administration. Compared with phosphate-buffered saline-treated mice, FHA-treated SCID mice had significantly (p&lt;0.01) less weight loss, lower colon weight, less colon shrinkage and reduced inflammatory lesions. The therapeutic effect of FHA was associated with enhanced IL10 and reduced type 1 and type 2 T helper cytokine production by spleen cells. Finally, FHA also attenuated the symptoms of colitis in SCID mice transferred with CD4CD45RB<sup>high</sup> T cells from IL10-deficient mice. <b>Conclusions:</b> Our finding shows that FHA suppresses type 1 T helper and pro-inflammatory cytokines, and ameliorates disease activity in a chronic T cell-dependent model of colitis, an effect that was not dependent on IL10 production by T cells, but was associated with induction of anti-inflammatory cytokines in vivo. Having already been used as a pertussis vaccine component in children, FHA is a promising candidate for clinical testing in patients with Crohn's disease.
Longitudinal distribution of vascular resistance in the pulmonary arteries, capillaries, and veins
Authors: Jerome S. Brody, Edward J. Stemmler, Arthur B. DuBois
Journal: Journal of Clinical Investigation (1968)

A new method has been described for measuring the pressure and resistance to blood flow in the pulmonary arteries, capillaries, and veins. Studies were performed in dog isolated lung lobes perfused at constant flow with blood from a donor dog. Pulmonary artery and vein volume and total lobar blood volume were measured by the ether plethysmograph and dyedilution techniques. The longitudinal distribution of vascular resistance was determined by analyzing the decrease in perfusion pressure caused by a bolus of low viscosity liquid introduced into the vascular inflow of the lobe.
Corticotropin-Releasing Hormone in Humans*
Authors: DAVID N. ORTH
Journal: Endocrine Reviews (1992)

HARRIS' 1948 hypothesis (1) that anterior pituitary function is regulated by hypothalamic factors released into and carried by the hypothalamic-hypophysial portal blood to the adenohypophysis was not lost upon clinical investigators. Soon thereafter G. W. Liddle, for example, referred to this regulatory influence of the central nervous system as the “pituitary driving mechanism” (2), recognizing that such a mechanism was essential for explaining the diurnal rhythm in pituitary-adrenal axis function and its response to stress. According to this concept, the pituitary driving mechanism was the variable force against which cortisol exerted its negative feedback inhibitory action on ACTH secretion. Long before CRH [ovine CRH (oCRH) mol wt = 4671; human CRH (hCRH) mol wt = 4758] was isolated, characterized, and synthesized (3), vasopressin [either arginine vasopressin (AVP) or lysine vasopressin (LVP)] was known to cause release of ACTH from the pituitary gland and, as a consequence, to increase adrenal cortisol production. Although vasopressin saw limited investigative and diagnostic use, its acceptance as the major physiological mediator of the pituitary driving mechanism was limited because of its known vasopressor and antidiuretic activities, the observation that patients with isolated diabetes insipidus generally had normal pituitary-adrenal function, and the suspicion that the ACTH released in response to vasopressin administration was nonspecific, resulting from the stress of the unpleasant side effects of pharmacological doses of the peptide. Consequently, the discovery of CRH offered a potential explanation for many unsolved clinical questions, and the availability of pure synthetic CRH provided a research and diagnostic tool whose potential was quickly exploited by many clinical investigators.
Children and Violence: The World of the Defenseless
Authors: Carl C. Bell
Journal: JAMA (2009)

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Insulin Receptor Substrate Regulation of Phosphoinositide 3-Kinase
Authors: Heather E. Metz, A. McGarry Houghton
Journal: Clinical Cancer Research (2010)

Insulin receptor substrates (IRS) serve as downstream messengers from activated cell surface receptors to numerous signaling pathway cascades. One of these pathways, phosphoinositide 3-kinase (PI3K), frequently displays aberrant function in the setting of cancer. IRS proteins are capable of both regulating and activating PI3K, depending on the cell of origin. As such, both prohost and protumor functions have been described for IRS proteins in human cancers. IRS proteins may eventually serve as biomarkers of PI3K activity, and serve a much-needed role as a guide to using targeted pathway therapy. Additionally, IRS-1 could be indirectly targeted in lung cancer, by inhibiting neutrophil elastase, which functions to degrade IRS-1 in lung tumor cells, thereby generating PI3K hyperactivity.
Clinical and polygraphic evolution of sleep-related breathing disorders in adolescents
Authors: A. Sánchez-Armengol, A. Ruiz-García, C. Carmona-Bernal, G. Botebol-Benhamou, E. García-Díaz, J. Polo-Padillo, J. L. López-Campos, F. Capote
Journal: European Respiratory Journal (2008)

It has been suggested that sleep-related breathing disorders (SRBD) involve a continuum that develops over the course of life. If modifiable factors could be identified, the progression of SRBD could perhaps be addressed early in life. Although some studies have looked at the evolution of SRBD in pre-pubertal children, very few studies obtained data in adolescents. Anthropometric, clinical and polygraphic variables were collected during a 4-yr follow-up study among 148 normal adolescents after initial cross-sectional analysis. From a total of 267 adolescents studied at baseline (mean± sd age 14.3±2.1 yrs), 148 (55.4%) were followed up for 4 yrs. During follow-up, there were no significant changes in snoring and polygraphic parameters. However, a tendency toward weight gain with centrally distributed fat was observed. Habitual snorers had a significantly higher body mass index and more centrally distributed fat than nonsnorers. Males had a higher snoring prevalence and a higher number of respiratory events than females. Snoring at baseline, male sex and poor academic performance were significant predictors of snoring at follow-up. Snoring tends to persist during adolescence and male sex acts as a risk factor. A relationship between snoring and academic performance was observed. These findings may have implications for long-term management of sleep-related breathing disorders.
<i>VHL</i> Gene Mutations and Their Effects on Hypoxia Inducible Factor HIFα: Identification of Potential Driver and Passenger Mutations
Authors: Markus P. Rechsteiner, Adriana von Teichman, Anna Nowicka, Tullio Sulser, Peter Schraml, Holger Moch
Journal: Cancer Research (2011)

Abstract Mutations of the von Hippel-Lindau (VHL) gene are frequent in clear cell renal cell carcinomas (ccRCC). Nonsense and frameshift mutations abrogate the function of the VHL protein (pVHL), whereas missense mutations can have different effects. To identify those missense mutations with functional consequences, we sequenced VHL in 256 sporadic ccRCC and identified 187 different VHL mutations of which 65 were missense mutations. Location and destabilizing effects of VHL missense mutations were determined in silico. The majority of the thermodynamically destabilizing missense mutations were located in exon 1 in the core of pVHL, whereas protein surface mutations in exon 3 affected the interaction domains of elongin B and C. Their impact on pVHL's functionality was further investigated in vitro by stably reintroducing VHL missense mutations into a VHL null cell line and by monitoring the green fluorescent protein (GFP) signals after the transfection of a hypoxia inducible factor (HIF)α-GFP expression vector. pVHL's functionality ranged from no effect to complete HIF stabilization. Interestingly, Asn78Ser, Asp121Tyr, and Val130Phe selectively influenced HIF1α and HIF2α degradation. In summary, we obtained three different groups of missense mutations: one with severe destabilization of pVHL; a second without destabilizing effects on pVHL but relevance for the interaction with HIFα, elongin B, and elongin C; and a third with pVHL functions comparable with wild type. We therefore conclude that the specific impact of missense mutations may help to distinguish between driver and passenger mutations and may explain responses of ccRCC patients to HIF-targeted therapies. Cancer Res; 71(16); 5500–11. ©2011 AACR.
Studies on hyperkalemic periodic paralysis. Evidence of changes in plasma Na and Cl and induction of paralysis by adrenal glucocorticoids
Authors: David H. P. Streeten, Theodore G. Dalakos, Herbert Fellerman
Journal: Journal of Clinical Investigation (1971)

In a 19 yr old male with familial hyperkalemic periodic paralysis, paralysis was consistently induced by the administration of potassium chloride, corticotropin-gel, and a variety of glucocorticoids (dexamethasone, 6-methylprednisolone, triamcinolone) but not by mineralocorticoids (D-aldosterone, deoxycorticosterone) or by adrenocorticotropin (ACTH)-gel plus metyrapone. Induced attacks were virtually identical with spontaneous attacks, being associated, after a latent period of a few hours, with a rise in plasma K(+) and HCO(3) (-) and a simultaneous fall in plasma Na(+) and Cl(-) concentrations to an extent implying exchange of 1 K(+) with 2 Na(+) and 2 Cl(-) between extracellular and intracellular fluid. ACTH-induced paralysis was preceded by rising serum inorganic P, and associated with increased plasma glucose, blood lactate, and serum creatine phosphokinase concentrations. In normal subjects ACTH, cortisol, and triamcinolone administration failed to change plasma electrolytes or strength, while ingestion of KCl produced no weakness and smaller changes in plasma K and Na than in the patient.Since the patient and normal subjects showed the same changes in renal excretion of K after the administration of cortisol and KCl, it seems likely that paralysis in the patient resulted from abnormally slow uptake (and/or excessive loss) of K by the muscle cells, possibly caused by an abnormal "ion-exchange pump." Normal adrenocortical function and absence of a peak in plasma 11-hydroxycorticoid (11-OHCS) concentration preceding spontaneous paralysis, indicated that spontaneous paralysis did not result from changes in cortisol secretion. Similar hyperkalemic paralysis was precipitated by ACTH-gel in a brother and first cousin of the propositus. Administration of acetazolamide and fludrocortisone reduced the rise in plasma K concentration and prevented the weakness which otherwise invariably followed KCl administration to the patient. He and two close relatives have been completely protected from severe attacks of paralysis in the past 14 months by treatment with these two medications.