tbuckley/cabot-search huggingface dataset:
Pharmacological Treatment of the Pathogenetic Defects in Type 2 Diabetes
Authors: Jeppe Gram, Jan Erik Henriksen, Ellen Grodum, Henning Juhl, Tony Bill Hansen, Christian Christiansen, Knud Yderstræde, Hans Gjessing, Henrik M. Hansen, Vibe Vestergaard, Jørgen Hangaard, Henning Beck-Nielsen
Journal: Diabetes Care (2010)

OBJECTIVE To determine the effect of treatment with insulin aspart compared with NPH insulin, together with metformin/placebo and rosiglitazone/placebo. The hypothesis was that combined correction of major pathogenetic defects in type 2 diabetes would result in optimal glycemic control. RESEARCH DESIGN AND METHODS This study was a 2-year investigator-driven randomized partly placebo-controlled multicenter trial in 371 patients with type 2 diabetes on at least oral antiglycemic treatment. Patients were assigned to one of eight treatment groups in a factorial design with insulin aspart at mealtimes versus NPH insulin once daily at bedtime, metformin twice daily versus placebo, and rosiglitazone twice daily versus placebo. The main outcome measurement was change in A1C. RESULTS A1C decreased more in patients treated with insulin aspart compared with NPH (−0.41 ± 0.10%, P &amp;lt; 0.001). Metformin decreased A1C compared with placebo (−0.60 ± 0.10%, P &amp;lt; 0.001), as did rosiglitazone (−0.55 ± 0.10%, P &amp;lt; 0.001). Triple therapy (rosiglitazone, metformin, and any insulin) resulted in a greater reduction in A1C than rosiglitazone plus insulin (−0.50 ± 0.14%, P &amp;lt; 0.001) and metformin plus insulin (−0.45 ± 0.14%, P &amp;lt; 0.001). Aspart was associated with a higher increase in body weight (1.6 ± 0.6 kg, P &amp;lt; 0.01) and higher incidence of mild daytime hypoglycemia (4.9 ± 7.5 vs. 1.7 ± 5.4 number/person/year, P &amp;lt; 0.001) compared with NPH. CONCLUSIONS Insulin treatment of postprandial hyperglycemia results in lower A1C than treatment of fasting hyperglycemia, at the expense of higher body weight and hypoglycemic episodes. However, insulin therapy has to be combined with treatment of both peripheral and liver insulin resistance to normalize blood glucose, and in this case, the insulin regimen is less important.
Cloning of phenotypically different human lymphocytes originating from a single stem cell.
Authors: M Hakoda, Y Hirai, H Shimba, Y Kusunoki, S Kyoizumi, Y Kodama, M Akiyama
Journal: The Journal of Experimental Medicine (1989)

By using hypoxanthine guanine phosphoribosyltransferase (hprt) gene alterations and chromosome aberrations as in vivo cellular markers, human T, NK, and B cells originating from a single stem cell have been successfully cloned from the peripheral blood of an atomic bomb survivor from Hiroshima. These mutant lymphocytes were selectively cloned, taking advantage of their resistance to a purine analogue, 6-thioguanine. The cloned lymphocytes possessed the same hprt gene alterations and the same chromosome aberration (20q-), but exhibited different surface or functional phenotypes and different rearrangements of TCR or Ig genes. The chromosome aberration patterns strongly suggested that the original stem cell initiated differentiation into each cell type after exposure to atomic bomb radiation. Since the person studied here was exposed to the bomb at 17 yr age, the results suggested that common stem cells exist in adults for at least T, NK, and B cells. The use of hprt gene alterations as specific cellular markers provides a novel method for identifying stem cells in the lymphocyte lineage and for studying lymphocyte differentiation in humans.
Clinicopathologic Features of Long-Term Survivors and Disease-Free Survivors After Resection of Hepatocellular Carcinoma: A Study of a Prospective Cohort
Authors: Ronnie Tung-Ping Poon, Irene Oi-Lin Ng, Sheung-Tat Fan, Edward Cheuk-Sin Lai, Chung-Mau Lo, Chi-Leung Liu, John Wong
Journal: Journal of Clinical Oncology (2001)

This study aims to clarify the clinicopathologic features of long-term survivors and disease-free survivors after resection of hepatocellular carcinoma (HCC).The clinicopathologic features of 5-year survivors and disease-free survivors were elucidated in a cohort of 230 patients prospectively observed for > 5 years (64 to 192 months) after curative resection of HCC.The incidence of 5-year overall and disease-free survivors were 37% (85 of 230) and 20% (45 of 230), respectively. Clinicopathologic features associated with 5-year survivors included female sex (P =.024), preoperative serum albumin > or= 40 g/L (P =.033), AST < 50 u/L (P =.001), tumor < 5 cm (P =.001), solitary tumor (P =.035), encapsulated tumor (P =.021), no venous invasion (P =.001), no microsatellite nodule (P =.001), and early pathologic tumor-node-metastasis (pTNM) stage (I or II, P <.001). Features favoring 5-year disease-free survivors were preoperative serum AST < 50 u/L (P =.007), tumor < 5 cm (P =.005), encapsulated tumor (P =.007), no venous invasion (P <.001), no microsatellite nodule (P =.001), and early pTNM stage (I or II, P <.001). By multivariate analysis, pTNM stage was the only significant predictive factor for both overall and disease-free survival.This study shows that long-term disease-free survival > 5 years after resection of HCC can be achieved in patients with favorable tumor characteristics. Early pTNM stage was the most reliable predictor of both long-term overall and disease-free survivors.
Myoglobin: safeguard of myocardial oxygen supply during systolic compression?
Authors: A. Godecke
Journal: Cardiovascular Research (2010)

This editorial refers to ‘Significance of myoglobin as an oxygen store and oxygen transporter in the intermittently perfused human heart: a model study’ by V. Endeward et al. , pp. 22–29, this issue. 

Myoglobin (Mb) belongs to the family of vertebrate oxygen-binding haem proteins and is predominantly expressed in cardiac and red skeletal muscles that rely on aerobic metabolism to perform sustained work.1 Additional members of this protein family are of course haemoglobin, the red dye of blood, and the more recently discovered proteins neuroglobin and cytoglobin. Owing to the notoriously low solubility of oxygen in aqueous solutions, haem proteins such as haemoglobin and Mb substantially enhance the total oxygen content in blood and muscle, respectively, and therefore represent important oxygen stores. Mb is expressed at high concentrations in the heart (∼200 µM), and therefore Mb is thought to buffer short phases of ischaemia by release of oxygen when capillary oxygen supply is limited. Another function of Mb, termed ‘facilitated oxygen diffusion’, postulates that besides a flux of physically dissolved oxygen a flux of Mb-bound oxygen may exist.1 According to this model, oxygen is picked up by Mb at the plasma membrane and is transported to the mitochondria, where it is released and fed into the respiratory chain. In principle, both of these oxygen-related functions of Mb could be relevant because the oxygen partial pressure for half saturation of …
Freud and Aphasia: An Historical Analysis
Authors: OTTO M. MARX
Journal: American Journal of Psychiatry (1967)

Freud's monograph on aphasia has been acknowledged for its importance in the history of aphasia and its relevance for the development of psychoanalytic concepts. This author attributes to it a new significance as a final statement of late 19th-century neurology. Although Freud's own presentation on aphasia was limited by the absence of a neurophysiology upon which he could draw, he pointed out the illogicality of constructing an anatomical model on the basis of a psychological concept, thus identifying one of the major fallacies inherent in the principal psychophysical formulations of the time.
Expression, Up-Regulation, and Transport Activity of the Multidrug-Resistance Protein Abcg2 at the Mouse Blood-Brain Barrier
Authors: Salvatore Cisternino, Claire Mercier, Fanchon Bourasset, Françoise Roux, Jean-Michel Scherrmann
Journal: Cancer Research (2004)

Abstract The breast cancer resistance protein (BCRP/ABCG2) is, like P-glycoprotein (P-gp), a member of the ABC family of drug transporters. These proteins actively transport various anticancer drugs from cells, causing multidrug resistance. The physiological expression of P-gp/ABCB1 at the blood-brain barrier (BBB) effectively restricts the brain uptake of many antitumor drugs by mediating their active efflux from the brain to the blood vessel lumen. However, little is known about the function of Abcg2 at the BBB in vivo. We used in situ brain perfusion to measure the uptake of two known Abcg2 substrates, prazosin and mitoxantrone, and the nonsubstrate vinblastine by the brains of wild-type and P-gp-deficient mutant mdr1a(−/−) mice with or without the P-gp/Abcg2 inhibitor GF120918 or the P-gp inhibitor PSC833. P-gp had no effect on the brain transport of prazosin and mitoxantrone at the mouse BBB, but wild-type and P-gp-deficient mouse brains perfused with GF120918 or a high concentration of prazosin showed carrier-mediated effluxes of prazosin and mitoxantrone from the brain that did not involve P-gp. In contrast, the brain uptake of vinblastine was restricted only by P-gp and not by Abcg2 at the BBB. The amounts of abcg2 mRNA in cortex homogenates and capillary-enriched fractions of wild-type and mdr1a(−/−) mouse brains were measured by real-time quantitative reverse transcription-PCR. There was ∼700-times more abcg2 mRNA in brain microvessels than in the cortex of the wild-type mice, confirming that Abcg2 plays an important role at the BBB. There was also ∼3 times more abcg2 mRNA in the microvessels from P-gp-deficient mutant mouse brains than in the microvessels of wild-type mouse brains. These findings confirm that Abcg2 is a physiological transporter at the BBB that restricts the permeability of the brain to its substrates in vivo. Lastly, the defective P-gp in the mutant mdr1a(−/−) mice was associated with increased abcg2 mRNA at the BBB and a greater export of prazosin and mitoxantrone from the brain, as measured in the P-gp-deficient mice versus the wild-type mice.
USP8 Is a Novel Target for Overcoming Gefitinib Resistance in Lung Cancer
Authors: Sanguine Byun, Sung-Young Lee, Jihoon Lee, Chul-Ho Jeong, Lee Farrand, Semi Lim, Kanamata Reddy, Ji Young Kim, Mee-Hyun Lee, Hyong Joo Lee, Ann M. Bode, Ki Won Lee, Zigang Dong
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Common treatment modalities for non–small cell lung cancer (NSCLC) involve the EGF receptor-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib. However, the vast majority of treated patients acquire resistance to EGFR-TKIs, due, in large part, to secondary mutations in EGFR or amplification of the MET gene. Our purpose was to test ubiquitin-specific peptidase 8 (USP8) as a potential therapeutic target for gefitinib-resistant and -sensitive non–small cell lung cancer (NSCLC). Experimental Design: Testing the effect of knockdown of USP8 and use of a synthetic USP8 inhibitor to selectively kill gefitinib-resistant (or -sensitive) NSCLCs with little effect on normal cells in cell culture and a xenograft mouse model. Results: Knockdown of ubiquitin-specific peptidase 8 (USP8) selectively kills gefitinib-resistant NSCLCs while having little toxicity toward normal cells. Genetic silencing of USP8 led to the downregulation of several receptor tyrosine kinases (RTK) including EGFR, ERBB2, ERBB3, and MET. We also determined that a synthetic USP8 inhibitor markedly decreased the viability of gefitinib-resistant and -sensitive NSCLC cells by decreasing RTK expression while having no effect on normal cells. Moreover, treatment with a USP8 inhibitor led to significant reductions in tumor size in a mouse xenograft model using gefitinib-resistant and -sensitive NSCLC cells. Conclusions: Our results show for the first time that the inhibition of USP8 activity or reduction in USP8 expression can selectively kill NSCLC cells. We propose USP8 as a potential therapeutic target for gefitinib-resistant and -sensitive NSCLC cells. Clin Cancer Res; 19(14); 3894–904. ©2013 AACR.
ATROPINE TOXICITY IN THE TREATMENT OF MENTAL DISEASE
Authors: GORDON R. FORRER
Journal: American Journal of Psychiatry (1951)

The effect of repeated administrations of 32 mgms. of atropine sulfate to 183 unselected mentally ill patients has been studied. There was one death in this series. One hundred and fifty-four of these cases have been statistically analysed. Five to six months following the termination of therapy the following was found: Sixteen percent of all patients were on convalescent status, markedly improved. Sixty percent of all neurotic patients were on convalescent status, markedly improved. Twenty percent of all catatonic schizophrenic patients were on convalescent status, markedly improved. Twenty-three percent of all manic-depressive patients, manic phase, were on convalescent status markedly improved. Eleven percent of all paranoid schizophrenic patients were on convalescent status, improved. It is apparent that toxic doses of atropine sulfate are necessary to be therapeutically effective. Further investigation into pharmacotoxic therapy with other drug agents appears to be a promising field for research.
Children's mortality increased after hospital introduced computerised ordering system
Authors: Janice Hopkins Tanne
Journal: BMJ (2006)

We report a case of a male infant who presented with congenital anomalies and was found to have a de novo deletion in the terminal region of the long arm of chromosome 9. He died at the age of 17 weeks of cardiorespiratory failure owing to RSV positive bronchiolitis. A review of previously published reports documented one previous report of a patient with a deletion of (9)(q34.3) and multiple congenital anomalies. Comparison with the previously reported case suggests that the phenotype observed constitutes a clinically recognisable pattern of malformations.
Quantifying tracheobronchial tree dimensions: methods, limitations and emerging techniques
Authors: J. P. Williamson, A. L. James, M. J. Phillips, D. D. Sampson, D. R. Hillman, P. R. Eastwood
Journal: European Respiratory Journal (2009)

The ability to measure airway dimensions is important for clinicians, interventional bronchoscopists and researchers in order to accurately quantify structural abnormalities and track their changes over time or in response to treatment. Most quantitative airway measurements are based on X-ray computed tomography and, more recently, on multidetector computed tomography. Quantitative bronchoscopic techniques have also been developed, although these are less widely employed. Emerging techniques, including magnetic resonance imaging, endoscopic optical coherence tomography, endobronchial ultrasound and confocal endomicroscopy, provide new research tools with potential clinical applications. An understanding of issues related to the acquisition, processing and analysis of images, and how such issues impact on imaging the tracheobronchial tree, is essential in order to assess measurement accuracy and to make effective use of the newer methods. This article contributes to this understanding by providing a comprehensive review of current and emerging techniques for quantifying airway dimensions.
Diet in the management of Crohn's disease.
Authors: A J Levi
Journal: Gut (1985)

Leading articleDiet in the management of Crohn's diseaseThere is an ebb and flow in the tides of medical opinion concerning the treatment of diseases of unknown aetiology, especially those with a prolonged or variable course.The role of diet in the management of Crohn's disease illustrates this well.Burrill B Crohn in his notable description of the disease that commonly bears his name in this country (but not in the United States), stated in 1932 that 'medical treatment is purely palliative and supportive.In general, the proper approach to complete care is by surgical resection of the diseased segment'.Sir Arthur Hurst said in 1937: 'the only satisfactory treatment is operative '. 2 In the following decades, however, greater emphasis was placed on dietary management.Almy in Cecil and Loeb (1959) recommends 'a high calorie and protein diet, low in seasoning and cold fluids.Roughage should be reduced'.3Avery Jones suggests that 'the inflammation of Crohn's disease . . .responds well to a period of rest and good food . . .A low residue diet is important if the bowel is narrowed'."Donaldson puts it more pithily: 'although many patients and a few physicians pay compulsive attention to diet there is no evidence that what the patient eats in any way affects the symptoms, or course of Crohn's disease with one noteable exceptionthose patients with narrowing of the gut lumen . . .should avoid all foods that contain cellulose'.5 Paradoxically the new 1500 page
Different Phylogenomic Approaches to Resolve the Evolutionary Relationships among Model Fish Species
Authors: E. Negrisolo, H. Kuhl, C. Forcato, N. Vitulo, R. Reinhardt, T. Patarnello, L. Bargelloni
Journal: Molecular Biology and Evolution (2010)

Comparative genomics holds the promise to magnify the information obtained from individual genome sequencing projects, revealing common features conserved across genomes and identifying lineage-specific characteristics. To implement such a comparative approach, a robust phylogenetic framework is required to accurately reconstruct evolution at the genome level. Among vertebrate taxa, teleosts represent the second best characterized group, with high-quality draft genome sequences for five model species (Danio rerio, Gasterosteus aculeatus, Oryzias latipes, Takifugu rubripes, and Tetraodon nigroviridis), and several others are in the finishing lane. However, the relationships among the acanthomorph teleost model fishes remain an unresolved taxonomic issue. Here, a genomic region spanning over 1.2 million base pairs was sequenced in the teleost fish Dicentrarchus labrax. Together with genomic data available for the above fish models, the new sequence was used to identify unique orthologous genomic regions shared across all target taxa. Different strategies were applied to produce robust multiple gene and genomic alignments spanning from 11,802 to 186,474 amino acid/nucleotide positions. Ten data sets were analyzed according to Bayesian inference, maximum likelihood, maximum parsimony, and neighbor joining methods. Extensive analyses were performed to explore the influence of several factors (e.g., alignment methodology, substitution model, data set partitions, and long-branch attraction) on the tree topology. Although a general consensus was observed for a closer relationship between G. aculeatus (Gasterosteidae) and Di. labrax (Moronidae) with the atherinomorph O. latipes (Beloniformes) sister taxon of this clade, with the tetraodontiform group Ta. rubripes and Te. nigroviridis (Tetraodontiformes) representing a more distantly related taxon among acanthomorph model fish species, conflicting results were obtained between data sets and methods, especially with respect to the choice of alignment methodology applied to noncoding parts of the genomic region under study. This may limit the use of intergenic/noncoding sequences in phylogenomics until more robust alignment algorithms are developed.
Impaired pulmonary function and the risk of tuberculosis: a population-based cohort study
Authors: M. Inghammar, C-G. Löfdahl, N. Winqvist, B. Ljungberg, A. Egesten, G. Engström
Journal: European Respiratory Journal (2011)

To the Editors:

It is well known that pulmonary tuberculosis (TB) can cause lung impairment leading to chronic obstructive pulmonary disease (COPD) 1, but less is known to what extent impaired lung function increases the risk of TB. A case–control study from the UK found patients with emphysema to have a three-fold increased risk of TB, adjusted for smoking and the use of corticosteroids 2. A cohort study from Denmark found moderate-to-severe COPD to be associated with a two- to three-fold increased risk of hospitalisation with TB 3. We have previously shown that patients hospitalised with COPD have a three-fold increased risk of active TB compared with population controls 4. In the present study, we examine the risk of active TB in relation to lung function in a cohort who underwent spirometry in 1974–1992.

Between 1974 and 1992, 22,444 males and 10,902 females, born 1921–1949, participated in a health screening programme, the Malmo Preventive Project. Complete birth cohorts, born in pre-specified years, from the city of Malmo were invited; the overall participation proportion was ∼70% 5. The screening included physical examination, spirometry, blood samples and assessment of lifestyle factors by means of a self-administered questionnaire. Some questions varied between the cohorts. We excluded 4,413 individuals because of missing spirometry data; 26 individuals were excluded because of missing data on either body mass index (BMI), smoking or immigration status, leaving a total of 28,907 individuals in final analysis (21,174 males and 7,733 females).

BMI as was calculated as mass/height2 (in kg·m−2). Individuals were regarded as having diabetes mellitus if they answered positively to the question “Do you have diabetes mellitus?” or their fasting blood glucose level was ≥6.1 mmol·L−1.

Around 96% of the cohort (n = 27,789) answered questions on alcohol. Individuals …