tbuckley/cabot-search huggingface dataset:
A Missense Mutation in the Sodium Phosphate Co-transporter Slc34a1 Impairs Phosphate Homeostasis
Authors: Takayuki Iwaki, Mayra J. Sandoval-Cooper, Harriet S. Tenenhouse, Francis J. Castellino
Journal: Journal of the American Society of Nephrology (2008)

The sodium phosphate co-transporters Npt2a and Npt2c play important roles in the regulation of phosphate homeostasis. <i>Slc34a1</i>, the gene encoding Npt2a, resides downstream of the gene encoding coagulation factor XII (<i>f12</i>) and was inadvertently modified while generating <i>f12</i><sup>−/−</sup> mice. In this report, the renal consequences of this modification are described. The combined single allelic mutant <i>Slc34a1m</i> contains two point mutations in exon 13: A499V is located in intracellular loop 5, and V528M is located in transmembrane domain 11. In addition to the expected coagulopathy of the <i>f12</i><sup>−/−</sup> phenotype, mice homozygous for the double allelic modification (<i>f12</i><sup>−/−</sup><i>/slc34a1</i><sup>m/m</sup>) displayed hypophosphatemia, hypercalcemia, elevated levels of alkaline phosphatase, urolithiasis, and hydronephrosis. Strategic cross-breedings demonstrated that the kidney-related pathology was associated only with autosomal recessive transmission of the <i>slc34a1<sup>m</sup></i> gene and was not influenced by the simultaneous inactivation of <i>f12</i>. Npt2a[V528M] could be properly expressed in opossum kidney cells, but Npt2a[A499V] could not. These results suggest that a single amino acid substitution in Npt2a can lead to improper translocation of the protein to the cell membrane, disturbance of phosphate homeostasis, and renal calcification. Whether point mutations in the <i>SLC34A1</i> gene can lead to hypophosphatemia and nephrolithiasis in humans remains unknown.
Development and comorbidity of eczema, asthma and rhinitis to age 12 – data from the <scp>BAMSE</scp> birth cohort
Authors: N. Ballardini, I. Kull, T. Lind, E. Hallner, C. Almqvist, E. Östblom, E. Melén, G. Pershagen, G. Lilja, A. Bergström, M. Wickman
Journal: Allergy (2012)

Abstract Background Allergy‐related diseases are a public health issue, but knowledge on development and comorbidity among children is scarce. The aim was to study the development of eczema, asthma and rhinitis in relation to sex and parental allergy, in a population‐based cohort, during childhood. Methods At 1, 2, 4, 8 and 12 years, parental questionnaires were used to obtain data on allergy‐related diseases. Complete data for all five follow‐up occasions were available from 2916 children. Odds ratios for the risk of any allergy‐related disease in relation to heredity and sex were calculated using generalized estimating equations. Results At 12 years, 58% of the children had had eczema, asthma and/or rhinitis at some time. Disease turnover was high for all three diseases throughout the study. Comorbidity increased with age, and at 12 years, 7.5% of all the children were affected by at least two allergy‐related diseases. Parental allergy was associated with increased comorbidity and more persistent disease and increased the risk of having any allergy‐related disease (adjusted OR 1.76; 95% CI 1.57–1.97) up to 12 years. Male sex was associated with an increased risk throughout childhood. Boys and girls did not differ in disease persistence, and for comorbidity, the differences were minor. Conclusions Allergy‐related diseases may affect a majority of children. Eczema, asthma and rhinitis develop dynamically throughout childhood, and allergic comorbidity is common. These findings indicate that allergy‐related diseases should be neither seen nor studied as isolated entities.
Fibroblast growth factor 21 protects against acetaminophen-induced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1α-mediated antioxidant capacity in mice
Authors: Dewei Ye, Yudong Wang, Huating Li, Weiping Jia, Kwan Man, Chung Mau Lo, Yu Wang, Karen S.L. Lam, Aimin Xu
Journal: Hepatology (2014)

Acetaminophen (APAP) overdose is a leading cause of drug-induced hepatotoxicity and acute liver failure worldwide, but its pathophysiology remains incompletely understood. Fibroblast growth factor 21 (FGF21) is a hepatocyte-secreted hormone with pleiotropic effects on glucose and lipid metabolism. This study aimed to investigate the pathophysiological role of FGF21 in APAP-induced hepatotoxicity in mice. In response to APAP overdose, both hepatic expression and circulating levels of FGF21 in mice were dramatically increased as early as 3 hours, prior to elevations of the liver injury markers alanine aminotransferase (ALT) and aspartate aminotransferase (AST). APAP overdose-induced liver damage and mortality in FGF21 knockout (KO) mice were markedly aggravated, which was accompanied by increased oxidative stress and impaired antioxidant capacities as compared to wild-type (WT) littermates. By contrast, replenishment of recombinant FGF21 largely reversed APAP-induced hepatic oxidative stress and liver injury in FGF21 KO mice. Mechanistically, FGF21 induced hepatic expression of peroxisome proliferator-activated receptor coactivator protein-1α (PGC-1α), thereby increasing the nuclear abundance of nuclear factor erythroid 2-related factor 2 (Nrf2) and subsequent up-regulation of several antioxidant genes. The beneficial effects of recombinant FGF21 on up-regulation of Nrf2 and antioxidant genes and alleviation of APAP-induced oxidative stress and liver injury were largely abolished by adenovirus-mediated knockdown of hepatic PGC-1α expression, whereas overexpression of PGC-1α was sufficient to counteract the increased susceptibility of FGF21 KO mice to APAP-induced hepatotoxicity. Conclusion : The marked elevation of FGF21 by APAP overdose may represent a compensatory mechanism to protect against the drug-induced hepatotoxicity, by enhancing PGC-1α/Nrf2-mediated antioxidant capacity in the liver. (Hepatology 2014;60:977–989)
Inflammatory Breast Cancer: The Disease, the Biology, the Treatment
Authors: Fredika M. Robertson, Melissa Bondy, Wei Yang, Hideko Yamauchi, Shannon Wiggins, Samira Kamrudin, Savitri Krishnamurthy, Huong Le-Petross, Luc Bidaut, Audrey N. Player, Sanford H. Barsky, Wendy A. Woodward, Thomas Buchholz, Anthony Lucci, Naoto Ueno, Massimo Cristofanilli
Journal: CA A Cancer Journal for Clinicians (2010)

Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 2.5% of all breast cancer cases. It is characterized by rapid progression, local and distant metastases, younger age of onset, and lower overall survival compared with other breast cancers. Historically, IBC is a lethal disease with less than a 5% survival rate beyond 5 years when treated with surgery or radiation therapy. Because of its rarity, IBC is often misdiagnosed as mastitis or generalized dermatitis. This review examines IBC's unique clinical presentation, pathology, epidemiology, imaging, and biology and details current multidisciplinary management of the disease, which comprises systemic therapy, surgery, and radiation therapy.
Screening, evaluation, and management of cancer‐related fatigue: Ready for implementation to practice?
Authors: Ann M. Berger, Sandra A. Mitchell, Paul B. Jacobsen, William F. Pirl
Journal: CA A Cancer Journal for Clinicians (2015)

Abstract Answer questions and earn CME/CNE Evidence regarding cancer‐related fatigue (fatigue) has accumulated sufficiently such that recommendations for screening, evaluation, and/or management have been released recently by 4 leading cancer organizations. These evidence‐based fatigue recommendations are available for clinicians, and some have patient versions; but barriers at the patient, clinician, and system levels hinder dissemination and implementation into practice. The underlying biologic mechanisms for this debilitating symptom have not been elucidated completely, hindering the development of mechanistically driven interventions. However, significant progress has been made toward methods for screening and comprehensively evaluating fatigue and other common symptoms using reliable and valid self‐report measures. Limited data exist to support the use of any pharmacologic agent; however, several nonpharmacologic interventions have been shown to be effective in reducing fatigue in adults. Never before have evidence‐based recommendations for fatigue management been disseminated by 4 premier cancer organizations (the National Comprehensive Cancer, the Oncology Nursing Society, the Canadian Partnership Against Cancer/Canadian Association of Psychosocial Oncology, and the American Society of Clinical Oncology). Clinicians may ask: Are we ready for implementation into practice? The reply: A variety of approaches to screening, evaluation, and management are ready for implementation. To reduce fatigue severity and distress and its impact on functioning, intensified collaborations and close partnerships between clinicians and researchers are needed, with an emphasis on system‐wide efforts to disseminate and implement these evidence‐based recommendations. CA Cancer J Clin 2015;65: 190–211. © 2015 American Cancer Society.
Effects of parathyroid hormone on plasma and urinary adenosine 3′,5′-monophosphate in man
Authors: Neil I. Kaminsky, Arthur E. Broadus, Joel G. Hardman, Douglas J. Jones, John H. Ball, Earl W. Sutherland, Grant W. Liddle
Journal: Journal of Clinical Investigation (1970)

The effects of parathyroid hormone (PTH) on plasma and urinary adenosine 3',5'-monophosphate (cyclic AMP) levels were studied in normal subjects. Under basal conditions normal adults have plasma concentrations of cyclic AMP ranging from 10 to 25 nmoles/liter and excrete from 1.5 to 5 mumoles of cyclic AMP per g of urinary creatinine. About one-half to two-thirds of the cyclic AMP excreted in the urine is derived from the plasma by glomerular filtration, and the remainder is produced by the kidney. Renal production of cyclic AMP is partly under the control of PTH. It can be suppressed by infusions of calcium and stimulated by infusions of the calcium chelating agent, EDTA. Infusions of PTH in doses up to 10 mU/kg per min were associated with dose-related increases both in urinary cyclic AMP and phosphate. Infusions of PTH in doses ranging from 20 to 80 mU/kg per min did not lead to any further increase in phosphaturia but did lead to further marked increases in urinary cyclic AMP. A modest increase in plasma cyclic AMP was noted when PTH was infused at 40 mU/kg per min. Anephric patients failed to show appreciable increases in plasma cyclic AMP in response to large doses of PTH but did show expected increases in response to glucagon. Surgical removal of parathyroid adenomas from nine patients with primary hyperparathyroidism was invariably followed by a decrease in urinary cyclic AMP, PTH, in large doses, and calcium infusion produced up to 2-fold increases in the other known naturally occurring cyclic nucleotide, guanosine 3',5'-monophosphate (cyclic GMP).
Immunological mechanisms in pleural disease
Authors: V.B. Antony
Journal: European Respiratory Journal (2003)

The pleural membrane consisting of pleural mesothelial cells and its underlying connective tissue layers play a critical role in immunological responses in both local and systemic diseases. The pleura, because of its intimate proximity to the lung, is positioned to respond to inflammatory changes in the lung parenchyma. Importantly, several systemic diseases have a predilection for expression on the pleural surface. Immunological responses in the pleura include the development of pleural permeability and pleural effusion formation as well as the development of pleural fibrosis and scarring. Under either circumstance, the normal functioning of the pleura is impaired and has multiple consequences leading to increased morbidity and even mortality for the patient. During infections in the pleural space, the pleural mesothelium responds by actively recruiting inflammatory phagocytic cells and allowing the movement of proteins from the vascular compartment into the pleural space. The release of chemokines by the pleural mesothelium allows for directed migration of phagocytic cells from the basilar surface of the pleura towards the apical surface. In malignant disease, the pleura may be the site of primary tumours such as mesothelioma and also the site for malignant metastatic deposits. Certain cancers such as cancers of the breast, ovary, lung, and stomach have a predilection for the pleural mesothelium. The process whereby malignant cells attach to the pleural mesothelium and develop autocrine mechanisms for survival in the pleural space are elucidated in this review. The pleura functions not only as a mechanical barrier, but also as an immunologically and metabolically responsive membrane that is involved in maintaining a dynamic homeostasis in the pleural space.
NOTES ON WAR SURGERY
Authors: A. M. Forbes
Journal: BMJ (1916)

6W WAR SURGERY.[t M TiCz BaOuD 369 was possible, each time with success.In no case was the wound dressed in less than forty-eight hours.In only one case did sterilization of the track of the projectile as far the dura mater fail; in this case the sepsis was mild, and was limited to tlle track, the flap uniting by first intention.There was one death, from meningitis and cerebral abscess, one week after operation; outside the cranial cavity there was no sepsis in this 6ase.In only one patient was there any suggestion of a hernia cerebri.This was in a case with most extensive injury, a large lacerated scalp wound, with marked comminution and depression of skull and extensive laceration and discharge of brain substance.There was also considerable intracranial haemorrllage with pressure symptoms and paralysis of the left arm and face.A large clot was removed at tle time of the operation, and subsequently a small protrusion of brain occurred.The protrusion gradually diminislhed and the face and arm steadily improved.No untoward synmptom developed.
Effect of bile acid perfusion on colonic motor function in patients with the irritable colon syndrome.
Authors: I Taylor, P Basu, P Hammond, C Darby, M Flynn
Journal: Gut (1980)

A study was performed to determine the effect of bile acid perfusion on motility in the sigmoid colon of patients with the irritable colon syndrome compared with normal subjects. Deoxycholic acid (15 mM) statistically significantly increased motility in normal subjects (control 25.0 +/- 6.4%, perfusion 71.4 +/- 7.2%, P &lt; 0.05) but neither chenodeoxycholic acid nor cholic acid had any apparent effect. In patients with the irritable colon syndrome, however, deoxycholic acid at 5 mM concentration (control 29.8 +/- 4.2%, during perfusion 57.4 +/- 6.5%, P &lt; 0.05) as well as at 15 mM concentration (control 19.4 +/- 5.7+, perfusion 57.8 +/- 9.6%, P &lt; 0.05) statistically significantly increased rectosigmoid motility. Patients with the irritable colon syndrome had a high resting 0.033-0.066 Hz (2-4 c/m) electrical activity, whereas in normal subjects 0.1-0.15 Hz (6-9 c/m) activity was greater. However, there was no statistically significant alteration in either electrical rhythm during the period of bile acid perfusion. In conclusion, additional evidence is presented to suggest that deoxycholic acid is the only bile acid likely to be implicated in the motor disorder of the irritable colon syndrome.
Phylogenetic detection of numerous gene duplications shared by animals, fungi and plants
Authors: Xiaofan Zhou, Zhenguo Lin, Hong Ma
Journal: Genome biology (2010)

Abstract Background Gene duplication is considered a major driving force for evolution of genetic novelty, thereby facilitating functional divergence and organismal diversity, including the process of speciation. Animals, fungi and plants are major eukaryotic kingdoms and the divergences between them are some of the most significant evolutionary events. Although gene duplications in each lineage have been studied extensively in various contexts, the extent of gene duplication prior to the split of plants and animals/fungi is not clear. Results Here, we have studied gene duplications in early eukaryotes by phylogenetic relative dating. We have reconstructed gene families (with one or more orthogroups) with members from both animals/fungi and plants by using two different clustering strategies. Extensive phylogenetic analyses of the gene families show that, among nearly 2,600 orthogroups identified, at least 300 of them still retain duplication that occurred before the divergence of the three kingdoms. We further found evidence that such duplications were also detected in some highly divergent protists, suggesting that these duplication events occurred in the ancestors of most major extant eukaryotic groups. Conclusions Our phylogenetic analyses show that numerous gene duplications happened at the early stage of eukaryotic evolution, probably before the separation of known major eukaryotic lineages. We discuss the implication of our results in the contexts of different models of eukaryotic phylogeny. One possible explanation for the large number of gene duplication events is one or more large-scale duplications, possibly whole genome or segmental duplication(s), which provides a genomic basis for the successful radiation of early eukaryotes.
A Nested Case–Control Study on Treatment-related Risk Factors for Early Relapse of Tuberculosis
Authors: Kwok C. Chang, Chi C. Leung, Wing W. Yew, Suzanne C. Ho, Cheuk M. Tam
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

This nested case–control study aimed at evaluating treatment-related risk factors of relapse of tuberculosis under a service program of directly observed treatment. Out of 12,183 patients with pulmonary tuberculosis who completed treatment within 1 year, 113 relapsed within 30 months after commencement of therapy. The overall 30-month relapse rate was 0.9% (95% confidence interval [CI] 0.8–1.1%). On matching 113 cases with 226 control subjects in a conditional logistic model, thrice-weekly treatment increased the risk of relapse in comparison with daily treatment (odds ratio 3.92, 95% CI 1.78–8.63), whereas prolonging both intensive phase and overall treatment by 50% or more protected against relapse (odds ratio 0.24, 95% CI 0.08–0.70). When pretreatment culture was positive and cavitation was absent, the 30-month relapse rate for standard thrice-weekly regimen was 1.1% (95% CI 0.6–2.0%). The corresponding rates in the presence of cavitation were 7.8% (95% CI 4.0–14.6%) for standard thrice-weekly regimen; 3.3% (95% CI 1.9–5.5%) for standard daily regimen; 0.5% (95% CI 0.1–2.6%) for extended thrice-weekly regimen; and 0.4% (95% CI 0.1–0.9%) for extended daily regimen. Further studies are required to reduce the risk of relapse under program settings.
New Evidence of Association Between COMT Gene and Prefrontal Neurocognitive Function in Healthy Individuals From Sibling Pairs Discordant for Psychosis
Authors: Araceli Rosa, Víctor Peralta, Manuel J. Cuesta, Amalia Zarzuela, Fermín Serrano, Alfredo Martínez-Larrea, Lourdes Fañanás
Journal: American Journal of Psychiatry (2004)

Using a sample of sibling pairs discordant for psychosis, the authors attempted to replicate the findings of previous studies suggesting that the functional genetic polymorphism Val158Met in the catechol O-methyltransferase (COMT) gene influences prefrontal cognitive function and increases the risk for schizophrenia.Eighty-nine sibling pairs discordant for psychosis were genotyped for this polymorphism and were assessed with the Wisconsin Card Sorting Test, a measure of prefrontal function. Additionally, the preferential transmission of alleles for this polymorphism was analyzed in a sample of 89 nuclear families in order to examine the genetic association.In the healthy siblings, a linear relationship was seen in which performance on the Wisconsin Card Sorting Test was associated in an allele dosage fashion with COMT genotype (i.e., fewer perseverative errors with higher number of methionine alleles). However, this association was not observed in patients. Furthermore, no evidence of genetic association with psychosis was detected.These results seem to confirm the role of COMT genotype in the modulation of executive functions related to frontal lobe function in healthy individuals but not in schizophrenia patients.
Autoantibodies associated with lupus induced by diverse drugs target a similar epitope in the (H2A-H2B)-DNA complex.
Authors: R L Rubin, S A Bell, R W Burlingame
Journal: Journal of Clinical Investigation (1992)

IgG reactivity with the (H2A-H2B)-DNA complex, a subunit of the nucleosome, has been detected in many patients with lupus induced by procainamide and quinidine, but the similarity among the epitopes targeted by these antibodies in this heterogeneous patient group as well as the prevalence of this specificity in lupus induced by other drugs is unknown. Studies with histone-DNA complexes formed by sequential addition on a solid phase demonstrated that complexes containing single histones had negligible antigenicity, indicating that DNA stabilizes a protein epitope in the H2A-H2B dimer or that the complete epitope is generated by a surface feature involving H2A-H2B and DNA. F(ab')2 isolated from a patient with procainamide-induced lupus blocked greater than 90% of the anti-[(H2A-H2B)-DNA] reactivity in six of six sera from patients with lupus induced by procainamide, four of four quinidine-induced patients and in sera from patients with lupus induced by acebutolol, penicillamine, and isoniazid, but not methyldopa or auto-antibodies to the component macromolecules. Fab fragments purified from the IgG of two quinidine-induced lupus patients and patients with isoniazid- and procainamide-induced lupus retained 39% +/- 8% of their original IgG reactivity compared to 34 +/- 28% of the original anti-tetanus toxoid activity of Fab fragments in two of the same sera and two normal sera. These results indicate that anti-[(H2A-H2B)-DNA] does not require divalent antigen-antibody complexes for stability, and that the complete epitope is created by the monomeric, trimolecular histone-DNA complex. We conclude that despite their pharmacologic and chemical heterogeneity, many lupus-inducing drugs elicit near identical autoantibodies.
Treatment with TNF blockers and mortality risk in patients with rheumatoid arthritis
Authors: L. T H Jacobsson, C. Turesson, J.-A. Nilsson, I. F Petersson, E. Lindqvist, T. Saxne, P. Geborek
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objective:</b> To assess mortality in patients with rheumatoid arthritis (RA) treated with tumour necrosis factor (TNF) inhibitors, compared with a standard RA population. <b>Methods:</b> Patients were recruited from a regional register, which includes over 90% of patients with RA treated with TNF blockers in the area in 1999 or later, and a local community-based cohort of patients with RA, established in 1997. Of a total of 1430 patients in the combined cohort &lt;80 years old, 921 received treatment with TNF inhibitors during the study period. The total cohort was linked with the national register for cause of death. Overall mortality in those treated versus those not treated with TNF blockers was estimated using standardised mortality ratios and time-dependent Cox proportional hazards. <b>Results:</b> There were 188 deaths per 7077 person-years at risk in the total cohort. Controlling for age, sex, disability and baseline comorbidity, the adjusted HR for death was 0.65 (95% CI 0.46 to 0.93) in those treated with anti-TNF versus those not treated. The effect was significant in women (HR = 0.52, 95% CI 0.33 to 0.82) but not in men (HR = 0.95, 95% CI 0.52 to 1.71). <b>Conclusion:</b> After adjusting for disease severity, treatment with TNF inhibitors was found to be associated with a reduced mortality in women but not men with RA. These findings are compatible with a critical role for inflammation in RA-associated premature mortality.