tbuckley/cabot-search huggingface dataset:
Risks of Psychiatric Disorders and Suicide Attempts in Children and Adolescents With Type 1 Diabetes: A Population-Based Cohort Study
Authors: Agnieszka Butwicka, Louise Frisén, Catarina Almqvist, Björn Zethelius, Paul Lichtenstein
Journal: Diabetes Care (2015)

To assess the risk of psychiatric disorders and suicide attempts in children with type 1 diabetes and their healthy siblings.We performed a population-based case-cohort study of individuals born in Sweden between 1973 and 2009. Children with type 1 diabetes (n = 17,122) and their healthy siblings (n = 18,847) were identified and followed until their 18th birthday. Their risk of psychiatric disorders was compared with that of matched control subjects.The risk of psychiatric morbidity in children with type 1 diabetes compared with the general population was tripled within 6 months after the onset of diabetes (hazard ratio [HR] 3.0 [95% CI 2.7-3.4]) and doubled within the total observation period (HR 2.1 [95% CI 2.0-2.2]). An increased risk was noted in suicide attempts (HR 1.7 [95% CI 1.4-2.0]) and in most categories of psychiatric disorders. The risk of psychiatric disorders in probands declined from HR 2.7 (95% CI 2.2-3.3) for those in the cohort born 1973-1986 to 1.9 (95% CI 1.8-2.0) in those born 1997-2009. The risk for any psychiatric disorders among siblings of patients with type 1 diabetes was estimated to be HR 1.1 (95% CI 1.0-1.1), and there was no increased risk in any of the specific category of disorders.Children with type 1 diabetes are at high risk of psychiatric disorders, which seems to be a consequence of the disease rather than due to a common familial etiology. The results support recommendations on comprehensive mental health surveillance in children with type 1 diabetes, especially in recently diagnosed children.
Somatostatin inhibits gastric acid secretion after gastric mucosal prostaglandin synthesis inhibition by indomethacin in man.
Authors: M H Mogard, V Maxwell, T Kovacs, G Van Deventer, J D Elashoff, T Yamada, G L Kauffman, J H Walsh
Journal: Gut (1985)

The inhibitory effect of indomethacin, 200 + 200 mg administered per os over 24 hours, on the prostaglandin E2 generative capacity of gastric mucosal tissue was determined in healthy male volunteers. The effect of prostaglandin synthesis inhibition on somatostatin induced suppression of food-stimulated acid secretion was tested. Peptone meal stimulated acid secretion was quantified in five healthy volunteers by intragastric titration with and without indomethacin pretreatment. Somatostatin doses of 200, 400, and 800 pmol/kg/h each significantly inhibited the peptone stimulated acid output. Indomethacin treatment, resulting in 90% inhibition of prostaglandin E2 synthesis, did not affect glucose- or peptone-stimulated acid output or modify the inhibitory action of somatostatin. Clinically, acid inhibition by somatostatin has been used to treat bleeding peptic ulcers. Ulcer haemorrhage may be preceded by an excessive use of drugs that inhibit prostaglandin synthesis such as aspirin or other non-steroidal anti-inflammatory agents. Recent observations in the rat indicate that prostaglandins mediate the inhibitory action of somatostatin on gastric acid secretion. The present results suggest that prostaglandins are not required for inhibition of gastric acid secretion by somatostatin in man.
Regulation of Vascular Connexin43 Gene Expression by Mechanical Loads
Authors: Douglas B. Cowan, Stephen J. Lye, B. Lowell Langille
Journal: Circulation Research (1998)

Abstract —Vascular tissues respond to changes in the mechanical forces imposed on them with changes in vasomotor tone in the short term and with structural remodeling in the long term. Since these responses involve intercellular communication, we have investigated regulation of the gap junction proteins, connexin26 (Cx26), connexin37 (Cx37), connexin40 (Cx40), and connexin43 (Cx43), by mechanical loads. Results were compared with parallel experiments on c- fos and GAPDH. Twenty percent stretch of cultured vascular smooth muscle cells caused a 3-fold increase in Cx43 mRNA levels by 2 hours. Cx26 was expressed at low levels but failed to respond to stretch, and Cx37 and Cx40 were not detected. c- fos mRNA levels increased after 30 minutes of stretch, whereas GAPDH mRNA did not change. Protein levels of Cx43 increased by 4 hours and remained elevated for 16 hours. Nuclear run-on experiments confirmed that Cx43 and c- fos were transcriptionally regulated by stretch. New protein synthesis was not a requirement for the stretch-induced rise in Cx43 expression, since mRNA levels were unaffected by treatment with cycloheximide. To examine transcriptional control of Cx43, stretched and unstretched vascular smooth muscle cells were transfected with a variety of promoter-reporter gene constructs. Cx43 sequences extending from within exon 1 (+162) to −1686 in the 5′-flanking region were coupled to the chloramphenicol acetyl transferase reporter gene. Deletions from the 5′ end of these sequences differentially regulated reporter gene expression and indicated multiple potential regulatory sites. In particular, a putative activator protein-1 site at the −42 to −48 region was required for basal reporter activity. None of the promoter constructs revealed stretch sensitivity, indicating that the site of transcriptional control by stretch lies outside the −1686 to +162 region. Finally, Cx43 mRNA levels were assessed in cultured endothelial cells subjected to laminar shear stress of 15 dynes/cm 2 . Cx43 mRNA levels increased by ≈4-fold at 1 hour and remained elevated for the duration of shear force. In conclusion, both mechanical strain and fluid shear stress caused increased expression of the gap junction protein Cx43.
Cardiac Malformations in the Rat Induced by Maternal Hypercapnia with Hypoxia
Authors: OLGA M. HARING
Journal: Circulation Research (1966)

Forty-seven pregnant rats were exposed for 24 hours to a gas mixture of 6% carbon dioxide, 10% oxygen and 84% nitrogen on different days during gestation. The earliest exposure was on the fifth day after observed copulation, the latest on the sixteenth. The hearts of 370 newborn test rats were studied in serial sections and compared with those from 111 newborn control rats. The over-all incidence of cardiac malformations was 28.1% in the experimental animals and 4.5 % in the controls. In the test groups, severe structural anomalies resulted from exposures as early as the fifth day of gestation. The results of the present and of previous experiments suggest that maternal hypercapnia in the presence of normal and low oxygen tensions is markedly teratogenic for the cardiovascular system in the rat.
The phylogenetic origin of the bifunctional tyrosine-pathway protein in the enteric lineage of bacteria.
Authors: S Ahmad, R A Jensen
Journal: Molecular Biology and Evolution (1988)

Because bifunctional enzymes are distinctive and highly conserved products of relatively infrequent gene-fusion events, they are particularly useful markers to identify clusters of organisms at different hierarchical levels of a phylogenetic tree. Within the subdivision of gram-negative bacteria known as superfamily B, there are two distinctive types of tyrosine-pathway dehydrogenases: (1) a broad-specificity dehydrogenase (recently termed cyclohexadienyl dehydrogenase [CDH]) that can utilize either prephenate or L-arogenate as alternative substrates and (2) a bifunctional CDH that also posseses chorismate mutase activity. (T-proteins). The bifunctional T-protein, thought to be encoded by fused ancestral genes for chorismate mutase and CDH, was found to be present in enteric bacteria (Escherichia, Shigella, Salmonella, Citrobacter, Klebsiella, Erwinia, Serratia, Morganella, Cedecea, Kluyvera, Hafnia, Edwardsiella, Yersinia, and Proteus) and in Aeromonas and Alteromonas. Outside of the latter "enteric lineage," the T-protein is absent in other major superfamily-B genera, such as Pseudomonas (rRNA homology group I), Xanthomonas, Acinetobacter, and Oceanospirillum. Hence, the T-protein must have evolved after the divergence of the enteric and Oceanospirillum lineages. 3-Deoxy-D-arabino-heptulosonate 7-phosphate synthase-phe, an early-pathway isozyme sensitive to feedback inhibition by L-phenylalanine, has been found in each member of the enteric lineage examined. The absence of both the T-protein and DAHP synthase-phe elsewhere in superfamily B indicates the emergence of these character states at approximately the same evolutionary time.
Mannose-binding lectin enhances Toll-like receptors 2 and 6 signaling from the phagosome
Authors: W.K. Eddie Ip, Kazue Takahashi, Kathryn J. Moore, Lynda M. Stuart, R. Alan B. Ezekowitz
Journal: The Journal of Experimental Medicine (2008)

Innate immunity is the first-line defense against pathogens and relies on phagocytes, soluble components, and cell-surface and cytosolic pattern recognition receptors. Despite using hard-wired receptors and signaling pathways, the innate immune response demonstrates surprising specificity to different pathogens. We determined how combinatorial use of innate immune defense mechanisms defines the response. We describe a novel cooperation between a soluble component of the innate immune system, the mannose-binding lectin, and Toll-like receptor 2 that both specifies and amplifies the host response to Staphylococcus aureus. Furthermore, we demonstrate that this cooperation occurs within the phagosome, emphasizing the importance of engulfment in providing the appropriate cellular environment to facilitate the synergy between these defense pathways.
Analysis of 2,440 human exomes highlights the evolution and functional impact of rare coding variation
Authors: Joshua Akey
Journal: Genome biology (2011)

Deep exome resequencing is a powerful approach for delineating patterns of protein-coding variation among genes, pathways, individuals and populations.We analyzed exome data from 2,440 individuals of European and African ancestry as part of the National Heart, Lung, and Blood Institute's Exome Project, the aim of which is to discover novel genes and mechanisms that contribute to heart, lung and blood disorders.Each exome was sequenced to a mean coverage of 116×, allowing detailed inferences about the population genomic patterns of both common variation and rare coding variation.We identifi ed more than 500,000 single nucleotide variations, the majority of which were novel and rare (76% of variants had a minor allele frequency of less than 0.1%), refl ecting the recent dramatic increase in the size of the human population.The unprecedented magnitude of this dataset allowed us to rigorously characterize the large variation in nucleotide diversity among genes (ranging from 0 to 1.32%), as well as the role of positive and purifying selection in shaping patterns of proteincoding variation and the diff erential signatures of population structure from rare and common variation.This dataset provides a framework for personal genomics and is an important resource that will allow inferences of broad importance to human evolution and health.
Lysophosphatidic acid receptor inhibition as a new multipronged treatment for rheumatoid arthritis
Authors: Beatriz Orosa, Samuel García, Paula Martínez, Antonio González, Juan J Gómez-Reino, Carmen Conde
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To investigate the effect of lysophosphatidic acid (LPA) receptor inhibition in a mouse model of autoantibody-mediated arthritis. <h3>Methods</h3> Arthritis was induced in C57BL/6 mice by K/BxN serum transfer. Arthritic mice were treated with the LPA receptor antagonist, Ki16425 and arthritis severity was assessed clinically and histologically. Expression of inflammatory mediators in joints was identified by a mouse cytokine array and validated by western blot and real-time PCR assays. Effects of treatment with LPA receptor antagonist or with small interfering RNA on bone metabolism were assessed by in vitro assays of osteoclastogenesis, bone resorption, osteoblasts differentiation and bone mineralisation. <h3>Results</h3> Mice treated with the LPA receptor antagonist Ki16425 showed attenuated arthritis characterised by reduction of synovial inflammation, cartilage damage and, more markedly, bone erosion. We detected increased apoptosis, reduction of inflammatory mediators and of bone remodelling proteins in arthritic joints from mice treated with Ki16425. In addition, we demonstrated that inhibition or suppression of LPA<sub>1</sub> receptor reduces osteoclast differentiation and bone resorption and, on the contrary, it promotes differentiation of osteoblasts and bone mineralisation. <h3>Conclusions</h3> Pharmacological inhibition of LPA<sub>1</sub> receptor in the K/BxN serum-transfer arthritis model led to reduction of severity of arthritis involving multiple mechanisms, increased apoptosis, reduced inflammatory mediators and proteins involved in bone remodelling, that show LPA<sub>1</sub> as a very promising target in rheumatoid arthritis treatment.
Biochemical changes associated with the use of haemodilution with 5% dextrose in water and mannitol for open-heart surgery
Authors: I. W. P. Obel, P. Marchand, L. Du Plessis
Journal: Thorax (1967)

Many advantages are gained from the use of haemodilution in open-heart surgery. There is a lessened post-operative morbidity from bleeding, renal failure, and serum hepatitis. However, dilution with 5% dextrose in water is associated with a greater metabolic acidosis and a higher incidence of serious dysrhythmias than is pure blood. In order to elucidate the causes of these complications, 26 patients were studied using different degrees of haemodilution. The metabolic acidosis appeared to be mainly due to the dilution of blood buffer. Changes in electrolyte balance were more marked with greater dilution. The effects on serum sodium and chlorides were transient. The serum potassium level fell markedly during the post-operative phase and was associated with dysrhythmias. We believe that variation in potassium concentration is due to redistribution of potassium between the intracellular and extracellular phase as well as to an increased urinary excretion of potassium. The acidosis and hypokalaemia can be rapidly corrected by the administration of sodium bicarbonate and potassium. The changes in acid-base metabolism and electrolyte balance can possibly be prevented by suitably modifying the priming fluid.
Epidermal ornithine decarboxylase activity and thymidine incorporation following treatment with ultraviolet A combined with topical 8-methoxy-psoralen or anthracene in the hairless mouse
Authors: RICHARD W. GANGE
Journal: British Journal of Dermatology (1981)

Journal Article Epidermal ornithine decarboxylase activity and thymidine incorporation following treatment with ultraviolet A combined with topical 8‐methoxy‐psoralen or anthracene in the hairless mouse Get access RICHARD W. GANGE RICHARD W. GANGE Division of Dermatology, University of California, San Diego School of Medicine, San Diego, California, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 105, Issue 3, 1 September 1981, Pages 247–255, https://doi.org/10.1111/j.1365-2133.1981.tb01282.x Published: 01 September 1981 Article history Accepted: 19 January 1981 Published: 01 September 1981
Early Morphologic Alterations in Mouse Skin After Topical Application of 3-Methylcholanthrene and Its Metabolites2
Authors: Kurt Bürki, Edward Bresnick
Journal: JNCI Journal of the National Cancer Institute (1975)

The effects of topical administration of 3-methylcholanthrene (MCA) or its metabolites on BALB/cKi mice were reported on inflammatory skin reactions, the alterations in epidermal thickness, the number of nucleated cells, pyknotic nuclei and/or nuclear fragments, and mitotic figures in the interfollicular epidermis (IFE). In the two-stage carcinogenesis system, MCA, the powerful complete carcinogen, induced an ordered sequence of cell changes strikingly similar to those caused by tumor-promoting agents such as the phorbol esters. These changes were absent after application of the "K-region" oxide of MCA. Other MCA metabolites also failed to induce notable inflammation, epidermal hyperplasia, and/or hypertrophy. Several MCA derivatives, however, caused a thinning of IFE paralleled by an increase in the relative number of pyknotic nuclei and a decrease in the total number of epithelial cells. The inhibitor of polycyclic hydrocarbon metabolism alpha-naphthoflavone did not prevent MCA-mediated skin reactions but, under suitable conditions, apparently potentiated the hyperplastic effects of MCA. The findings indicate that important events in the promotion phase of MCA-mediated skin carcinogenesis might be associated with the parent compound rather than with one of its metabolites.
The origin and differentiation of the heteromorphic sex chromosomes Z, W, X, and Y in the frog Rana rugosa, inferred from the sequences of a sex-linked gene, ADP/ATP translocase
Authors: I. Miura, H. Ohtani, M. Nakamura, Y. Ichikawa, K. Saitoh
Journal: Molecular Biology and Evolution (1998)

Sex chromosomes of the Japanese frog Rana rugosa are heteromorphic in the male (XX/XY) or in the female (ZZ/ZW) in two geographic forms, whereas they are still homomorphic in both sexes in two other forms (Hiroshima and Isehara types). To make clear the origin and differentiation mechanisms of the heteromorphic sex chromosomes, we isolated a sex-linked gene, ADP/ATP translocase, and constructed a phylogenetic tree of the genes derived from the sex chromosomes. The tree shows that the Hiroshima gene diverges first, and the rest form two clusters: one includes the Y and Z genes and the other includes the X, W, and Isehara genes. The Hiroshima gene shares more sequence similarity with the Y and Z genes than with the X, W, and Isehara genes. This suggests that the Y and Z sex chromosomes originate from the Hiroshima type, whereas the X and W chromosomes originate from the Isehara-type sex chromosome. Thus, we infer that hybridization between two ancestral forms, with the Hiroshima-type sex chromosome in one and the Isehara-type sex chromosome in the other, was the primary event causing differentiation of the heteromorphic sex chromosomes.
Formation of Primary Cilia in the Renal Epithelium Is Regulated by the von Hippel-Lindau Tumor Suppressor Protein
Authors: Miguel A. Esteban, Sarah K. Harten, Maxine G. Tran, Patrick H. Maxwell
Journal: Journal of the American Society of Nephrology (2006)

Growing evidence points to defects in the primary cilium as a critical mechanism underlying renal cyst development. Inactivation of the VHL gene is responsible for the autosomal dominant condition von Hippel-Lindau (VHL) disease and is implicated in most sporadic clear cell renal carcinomas. Manifestations of VHL disease include cysts in several organs, particularly in the kidney. Here it is shown that VHL inactivation is associated with abrogation of the primary cilium in renal cysts of patients with VHL disease and in VHL-defective cell lines. Complementation of VHL-defective clear cell renal carcinoma cell lines with wild-type VHL restored primary cilia. Moreover, it is shown that the effects of VHL on the primary cilium are mediated substantially via hypoxia-inducible factor. The effect of VHL status on the primary cilium provides a potential mechanism for renal cyst development in VHL disease and may help in the understanding of how VHL acts as a tumor suppressor.
Confirmation That a Specific Haplotype of the Dopamine Transporter Gene Is Associated With Combined-Type ADHD
Authors: Philip Asherson
Journal: American Journal of Psychiatry (2007)

Objective: The primary purpose of this study was to confirm the association of a specific haplotype of the dopamine transporter gene and attention deficit hyperactivity disorder (ADHD), which could be one source of the heterogeneity seen across published studies. Method: The authors previously reported the association of ADHD with a subgroup of chromosomes containing specific alleles of two variable-number tandem repeat polymorphisms within the 3′ untranslated region and intron 8 of the dopamine transporter gene. They now report on this association in a sample of ADHD combined-type probands. Results: The original observations were confirmed, with an overall odds ratio of 1.4 across samples. Conclusions: These data challenge results of meta-analyses suggesting that dopamine transporter variation does not have an effect on the risk for ADHD, and they indicate that further investigation of functional variation in the gene is required.
Accrual Experience of National Cancer Institute Cooperative Group Phase III Trials Activated From 2000 to 2007
Authors: Edward L. Korn, Boris Freidlin, Margaret Mooney, Jeffrey S. Abrams
Journal: Journal of Clinical Oncology (2010)

Recent reports have suggested that 40% or more of National Cancer Institute (NCI) -sponsored Cooperative Group phase III trials failed to achieve their accrual goals. We examine in detail the accrual experience of the Cooperative Group phase III trials.
Factors related to radiological damage in 61 Spaniards with early rheumatoid arthritis
Authors: P Richi
Journal: Annals of the Rheumatic Diseases (2002)

Objective: To determine whether the presence of radiographic erosions at disease onset in patients with early rheumatoid arthritis (RA) is associated with clinical, serological, or genetic factors of poor outcome and whether patients with erosions only in the feet have a different pattern of presentation. Methods: Sixty one patients with early RA (&lt;6 months of evolution) were studied. Clinical evaluation and serological, radiological, and genetic studies were performed at disease onset and after one year. Results: Forty one (67%) patients showed erosions in their hands or in their feet, or in both. Subjects with erosive RA had a higher number of swollen joints (SJN; 9 (SD 6) <i>v</i> 6 (3), p=0.008), and rheumatoid factor (RF) positivity was more common (80% <i>v</i> 50%, p&lt;0.02) than those without erosions. Seven (17%) of the 41 patients in the group with erosions had erosions only in their feet. This group had a longer duration of morning stiffness (120 (60) <i>v</i> 72 (52) min, p&lt;0.005), better patient9s global assessment of general health (34 (22) <i>v</i> 57 (25), p&lt; 0.05), and lower erythrocyte sedimentation rate (32 (22) <i>v</i> 60 (30) mm/1st h, p &lt;0.05) than the rest of the subjects with erosions, and none of them was in remission after one year. Remission after one year was related to a lack of cortical damage at onset and RF negativity. Conclusions: Radiological damage at disease onset is associated with a worse clinical presentation and RF positivity, which are markers of poor outcome. There is a subgroup of patients, with erosions only in their feet, whose clinical presentation is less aggressive. To identify these cases of early erosive RA, radiographs of the feet should be obtained routinely.