tbuckley/cabot-search huggingface dataset:
Primary Pulmonary Hypertension
Authors: Stuart Rich
Journal: JAMA (1984)

PRIMARY pulmonary hypertension (PPH) is a term currently used to define the presence of pulmonary hypertension of unexplained etiology. Although the disease entity was recognized in the early 1900s, it was not until 1951 that Dresdale coined the term<i>primary pulmonary hypertension</i>, which is used today. The purpose of this update is to review the salient features of PPH and highlight some future directions. <h3>DIAGNOSIS</h3> To make the diagnosis of PPH, certain positive and negative clinical criteria must be met. It cannot be overemphasized that PPH is a diagnosis of exclusion and is only as reliable as the extent to which secondary causes of pulmonary hypertension have been ruled out. The most common secondary causes of pulmonary hypertension and the methods by which they can be diagnosed or excluded are listed in Table 1. The emphasis on making an accurate diagnosis is underscored because therapies for secondary forms of pulmonary
Changes in the prevalence of asthma in adults since 1966: the Busselton health study
Authors: A. L. James, M. W. Knuiman, M. L. Divitini, J. Hui, M. Hunter, L. J. Palmer, G. Maier, A. W. Musk
Journal: European Respiratory Journal (2009)

Asthma prevalence has increased worldwide; although less so in developed countries recently. This study assessed changes in the prevalence of asthma and related symptoms in the Busselton community since 1966. Cross-sectional respiratory health surveys of Busselton adults were conducted in 1966, 1969, 1972, 1975, 1981, 1990 and 2005–2007. Logistic regression models were used to estimate prevalence rates of asthma, respiratory symptoms, smoking, airway hyperresponsiveness (AHR) and atopy and to make comparisons in 2005–2007 and previous survey years. Asthma was defined as ever having doctor-diagnosed asthma (DDA). The prevalence of DDA was around 6% from 1966 to 1975, 8% in 1981 and rose to 19% in 2005–2007. From 1981 to 2005–2007, smoking prevalence declined and obesity and atopy increased but changes in these variables explained only a small part of the increase in DDA. Wheeze and cough/phlegm increased but AHR, breathlessness and doctor-diagnosed bronchitis remained relatively stable over the same period. These observations indicate that the increase in DDA is partly explained by increased symptoms and atopy. The lack of changes in AHR and doctor-diagnosed bronchitis suggests that factors such as diagnostic transfer and increased awareness of asthma have also contributed to the rise in prevalence of DDA.
Narrative Review: A Rational Approach to Starting Insulin Therapy
Authors: Arshag D. Mooradian, Marla Bernbaum, Stewart G. Albert
Journal: Annals of Internal Medicine (2006)

Background: The emergence of multiple insulin products has provided new opportunities to achieve diabetes control. However, the number of options has raised concerns about the optimal choices of products. Purpose: To briefly review the pharmacologic characteristics of currently available insulin products and to suggest an initial insulin regimen based on common blood glucose profiles among patients with diabetes. Data Sources: Relevant manuscripts were identified through a MEDLINE search (1996 to 25 February 2006) of the English-language literature. The key phrase used was therapeutic use of insulin. The literature search was limited to core clinical journals that have accessible full texts. Study Selection: Clinical trials and authoritative reviews published between 1996 and February 2006 were selected. A total of 420 manuscripts was reviewed. Data Extraction: The authors independently reviewed the relevant available literature. This literature, along with the authors' clinical experience, was used to construct practical suggestions. Data Synthesis: Several new insulin and insulin analogue preparations are now available for clinical use. Used as prandial insulin (for example, insulin lispro, insulin aspart, or insulin glulisine) and basal insulin (for example, insulin glargine or insulin detemir), the analogues simulate physiologic insulin profiles more closely than the older conventional insulins. There is currently no strong rationale favoring glargine, neutral protamine Hagedorn insulin, insulin detemir, or fixed-ratio insulin preparations as the preferred agent for initiating insulin therapy. Limitations: This was a retrospective review of previously published manuscripts chosen at the authors' discretion. Conclusions: The advent of recombinant DNA technology made it possible to overcome limitations in the time-action profiles of conventional insulins. Insulin therapy must be individualized. Nevertheless, certain subgroups of patients with diabetes can be differentiated from each other according to the pattern of blood glucose changes during the day. On the basis of the blood glucose profile, the authors suggest an initial insulin regimen that can be used to evaluate individual responsiveness and plan a long-term regimen.
Bcl-2 Protein in 518A2 Melanoma Cells <i>In vivo</i> and <i>In vitro</i>
Authors: Luba Benimetskaya, Kanyalakshmi Ayyanar, Noah Kornblum, Daniela Castanotto, John Rossi, Sijian Wu, Johnathan Lai, Bob D. Brown, Natalia Popova, Paul Miller, Harilyn McMicken, Yin Chen, C.A. Stein
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Bcl-2 is an apoptotic protein that is highly expressed in advanced melanoma. Several strategies have been employed to target the expression of this protein, including G3139, an 18-mer phosphorothioate oligodeoxyribonucleotide targeted to the initiation region of the Bcl-2 mRNA. This compound has recently completed phase III global clinical evaluation, but the function of Bcl-2 as a target in melanoma has not been completely clarified. To help resolve this question, we have permanently and stably down-regulated Bcl-2 protein and mRNA expression in 518A2 cells by two different technologies and evaluated the resulting clones both in vitro and in vivo. Experimental Design: 518A2 melanoma cells were transfected with plasmids engineered to produce either a single-stranded antisense oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA or a short hairpin RNA also targeted to the Bcl-2 mRNA. In vitro growth, the apoptotic response to G3139, and the G3139-induced release of cytochrome c from isolated mitochondria were evaluated. Cells were then xenografted into severe combined immunodeficient mice and tumor growth was measured. Results: In vitro, down-regulation of Bcl-2 expression by either method produced no change either in the rate of growth or in sensitivity to standard cytotoxic chemotherapeutic agents. Likewise, the induction of apoptosis by G3139 was entirely Bcl-2 independent. In addition, the G3139-induced release from isolated mitochondria was also relatively independent of Bcl-2 expression. However, when xenografted into severe combined immunodeficient mice, cells with silenced Bcl-2, using either technology, either failed to grow at all or grew to tumors of low volume and then completely regressed. In contrast, control cells with “normal” levels of Bcl-2 protein expression expanded to be large, necrotic tumors. Conclusions: The presence of Bcl-2 protein profoundly affects the ability of 518A2 melanoma cells to grow as human tumor xenografts in severe combined immunodeficient mice. The in vivo role of Bcl-2 in melanoma cells thus differs significantly from its in vitro role, and these experiments further suggest that Bcl-2 may be an important therapeutic target even in tumors that do not contain the t14:18 translocation.
Evolution of epicardial R wave voltage following experimental coronary artery occlusion: effects of hyaluronidase
Authors: L. G T RIBEIRO, L D. HILLIS, P. R MAROKO
Journal: Cardiovascular Research (1981)

The goals of this investigation were: 1) to examine the pattern of evolution of epicardial R wave voltage during the 24 h after experimental coronary artery occlusion; and 2) to determine whether hyaluronidase, an agent shown previously to reduce myocardial ischaemic injury, alters this evolution. Coronary artery occlusion was performed in 36 dogs. In the control dogs, the average R wave voltage (R) recorded over the ischaemic myocardium increased by 7.6 ± 0.8 mV (P <0.001) from before to 15 min after coronary artery occlusion, then gradually returned to baseline over the ensuing 4 h. Subsequently, R wave voltage continued to fall, and 24 h after occlusion, R was 17.8 ± 1.8 mV (P <0.001) less than before occlusion. In the hyaluronidase-treated dogs (500 NF units·kg−1), R recorded over the ischaemic myocardium increased similarly to the controls before hyaluronidase administration. However, in contrast to the control dogs, the administration of hyaluronidase 20 min after occlusion caused R to return to baseline over the ensuing 40 min and 24 h after occlusion, the treated animals lost significantly less R wave voltage than the controls (P <0.001).
Micro<scp>RNA</scp>‐155 modulates P2R signaling and Th2 priming of dendritic cells during allergic airway inflammation in mice
Authors: A. Zech, C. K. Ayata, F. Pankratz, A. Meyer, K. Baudiß, S. Cicko, G. G. Yegutkin, S. Grundmann, M. Idzko
Journal: Allergy (2015)

Dendritic cells (DCs) are the professional antigen-presenting cells (APCs) in the lung. They are known to be key players in the induction and maintenance of allergic asthma by cross-linking innate and adaptive immune responses. MicroRNAs (miRNAs) are known to influence cell fate and function by translational suppression or induction of messenger RNA (mRNA) degradation. miR-155 has been shown to be a crucial regulator of the immune system. However, its function in the pathogenesis of allergic airway inflammation (AAI) is not completely elucidated yet.Wild type (WT) and miR-155-deficient (miR-155(-/-) ) mice were used in ovalbumin (OVA) and house dust mite (HDM) models of AAI. Adoptive transfer of sensitized DCs to the lungs, migration, and T-cell priming assays were used to investigate the functional relevance of miR-155 in DCs.miR-155(-/-) mice showed reduced eosinophilic airway inflammation compared to WT mice in both models of AAI. Furthermore, miR-155(-/-) DCs showed limited Th2 priming capacity and failed to induce airway inflammation in allergen-exposed WT mice. miR-155 deficiency on DCs was also associated with impaired purinergic receptor signaling, as miR-155(-/-) DCs showed reduced chemotaxis and IL-1beta secretion upon stimulation with ATP, probably due to direct targeting of ectonucleoside triphosphate diphosphohydrolases (ENTPD) by miR-155.miR-155 deficiency alleviates AAI by diminishing Th2 priming capacity and ATP-/P2R-induced activation of DCs in mice, suggesting this miRNA as a potential therapeutic target of AAI.
Mutations of the Light Meromyosin Domain of the β-Myosin Heavy Chain Rod in Hypertrophic Cardiomyopathy
Authors: Edward Blair, Charles Redwood, Marisa de Jesus Oliveira, J.C. Moolman-Smook, Paul Brink, V.A. Corfield, Ingegerd Östman-Smith, Hugh Watkins
Journal: Circulation Research (2002)

Familial hypertrophic cardiomyopathy (HCM) is caused by mutations in 9 sarcomeric protein genes. The most commonly affected is beta-myosin heavy chain (MYH7), where missense mutations cluster in the head and neck regions and directly affect motor function. Comparable mutations have not been described in the light meromyosin (LMM) region of the myosin rod, nor would these be expected to directly affect motor function. We studied 82 probands with HCM in whom no mutations had been found in MYH7 exons encoding the head and neck regions of myosin nor in the other frequently implicated disease genes. Primers were designed to amplify exons 24 to 40 of MYH7. These amplimers were subjected to temperature modulated heteroduplex analysis by denaturing high-performance liquid chromatography. An Ala1379Thr missense mutation in exon 30 segregated with disease in three families and was not present in 200 normal chromosomes. The mutation occurred on two haplotypes, indicating that it was not a polymorphism linked with another disease-causing mutation. The position of this residue within the LMM region of myosin suggests that it may be important for thick filament assembly or for accessory protein binding. A further missense mutation in exon 37, Ser1776Gly, segregated with disease in a single family and was absent from 400 population-matched control chromosomes. Because the Ser1776 residue occupies a core position in the myosin rod at which the substitution of glycine is extremely energetically unfavorable, it is likely to disrupt the coiled-coil structure. We conclude that mutation of the LMM can cause HCM and that such mutations may act through novel mechanisms of disease pathogenesis involving myosin filament assembly or interaction with thick filament binding proteins.
Programming of Adiposity in Offspring of Mothers With Type 1 Diabetes at Age 7 Years
Authors: Robert S. Lindsay, Scott M. Nelson, James D. Walker, Stephen A. Greene, Gillian Milne, Naveed Sattar, Donald W. Pearson
Journal: Diabetes Care (2010)

The goals of this study were to examine the influence of maternal type 1 diabetes during pregnancy on offspring adiposity and glucose tolerance at age 7 years and to assess whether metabolic factors at birth (neonatal leptin and insulin) predict adverse outcomes.We examined 100 offspring of mothers with type 1 diabetes (OT1DM) and 45 offspring of control mothers. Mothers had previously been recruited during pregnancy, and, where possible, birth weight, umbilical cord insulin, and leptin were measured. Children were classed as overweight and obese using age-specific reference ranges.OT1DM had similar height (control, 1.25 +/- 0. 06 m; OT1DM, 1.24 +/- 0.06 m; P = 0.81) but were heavier (control, 25.5 +/- 3.8 kg; OT1DM, 27.1 +/- 5.7 kg; P = 0.048) and had an increased BMI (control, 16.4 kg/m(2); OT1DM, 17.4 +/- 2.6 kg/m(2), P = 0.005). Waist circumference (control, 56.0 +/- 3.7 cm; OT1DM, 58 +/- 6.8 cm; P = 0.02) and sum of skinfolds were increased (control, 37.5 +/- 17.0 mm [n = 42]; OT1DM, 46.1 +/- 24.2 mm [n = 91]; P = 0.02), and there was a marked increase in the prevalence of overweight and obese children (OT1DM, 22% overweight and 12% obese; control, 0% overweight and 7% obese; chi(2) P = 0.001). Glucose tolerance was not different compared with that in control subjects. BMI at age 7 years correlated with cord leptin (OT1DM, r = 0.25; n = 61, P = 0.047), weakly with adjusted birth weight (r = 0.19; P = 0.06) and hematocrit (r = 0.25; n = 50, P = 0.07), but not cord insulin (OT1DM, r = -0.08; P = 0.54).OT1DM are at increased risk of overweight and obesity in childhood. This risk appears to relate, in part, to fetal leptin and hematocrit but not insulin.
Psychosocial Treatments for Schizophrenia
Authors: Kim T. Mueser, Frances Deavers, David L. Penn, Jeffrey E. Cassisi
Journal: Annual Review of Clinical Psychology (2013)

The current state of the literature regarding psychosocial treatments for schizophrenia is reviewed within the frameworks of the recovery model of mental health and the expanded stress-vulnerability model. Interventions targeting specific domains of functioning, age groups, stages of illness, and human service system gaps are classified as evidence-based practices or promising practices according to the extent to which their efficacy is currently supported by meta-analyses and individual randomized controlled trials (RCTs). Evidence-based practices include assertive community treatment (ACT), cognitive behavior therapy (CBT) for psychosis, cognitive remediation, family psychoeducation, illness self-management training, social skills training, and supported employment. Promising practices include cognitive adaptive therapy, CBT for posttraumatic stress disorder, first-episode psychosis intervention, healthy lifestyle interventions, integrated treatment for co-occurring disorders, interventions targeting older individuals, peer support services, physical disease management, prodromal stage intervention, social cognition training, supported education, and supported housing. Implications and future directions are discussed.
RS rearrangement frequency as a marker of receptor editing in lupus and type 1 diabetes
Authors: Anil K. Panigrahi, Noah G. Goodman, Robert A. Eisenberg, Michael R. Rickels, Ali Naji, Eline T. Luning Prak
Journal: The Journal of Experimental Medicine (2008)

Continued antibody gene rearrangement, termed receptor editing, is an important mechanism of central B cell tolerance that may be defective in some autoimmune individuals. We describe a quantitative assay for recombining sequence (RS) rearrangement that we use to estimate levels of antibody light chain receptor editing in various B cell populations. RS rearrangement is a recombination of a noncoding gene segment in the κ antibody light chain locus. RS rearrangement levels are highest in the most highly edited B cells, and are inappropriately low in autoimmune mouse models of systemic lupus erythematosus (SLE) and type 1 diabetes (T1D), including those without overt disease. Low RS rearrangement levels are also observed in human subjects with SLE or T1D.
Lineage-Specific Patterns of Functional Diversification in the - and -Globin Gene Families of Tetrapod Vertebrates
Authors: F. G. Hoffmann, J. F. Storz, T. A. Gorr, J. C. Opazo
Journal: Molecular Biology and Evolution (2010)

The alpha- and beta-globin gene families of jawed vertebrates have diversified with respect to both gene function and the developmental timing of gene expression. Phylogenetic reconstructions of globin gene family evolution have provided suggestive evidence that the developmental regulation of hemoglobin synthesis has evolved independently in multiple vertebrate lineages. For example, the embryonic beta-like globin genes of birds and placental mammals are not 1:1 orthologs. Despite the similarity in developmental expression profiles, the genes are independently derived from lineage-specific duplications of a beta-globin pro-ortholog. This suggests the possibility that other vertebrate taxa may also possess distinct repertoires of globin genes that were produced by repeated rounds of lineage-specific gene duplication and divergence. Until recently, investigations into this possibility have been hindered by the dearth of genomic sequence data from nonmammalian vertebrates. Here, we report new insights into globin gene family evolution that were provided by a phylogenetic analysis of vertebrate globins combined with a comparative genomic analysis of three key sauropsid taxa: a squamate reptile (anole lizard, Anolis carolinensis), a passeriform bird (zebra finch, Taeniopygia guttata), and a galliform bird (chicken, Gallus gallus). The main objectives of this study were 1) to characterize evolutionary changes in the size and membership composition of the alpha- and beta-globin gene families of tetrapod vertebrates and 2) to test whether functional diversification of the globin gene clusters occurred independently in different tetrapod lineages. Results of our comparative genomic analysis revealed several intriguing patterns of gene turnover in the globin gene clusters of different taxa. Lineage-specific differences in gene content were especially pronounced in the beta-globin gene family, as phylogenetic reconstructions revealed that amphibians, lepidosaurs (as represented by anole lizard), archosaurs (as represented by zebra finch and chicken), and mammals each possess a distinct independently derived repertoire of beta-like globin genes. In contrast to the ancient functional diversification of the alpha-globin gene cluster in the stem lineage of tetrapods, the physiological division of labor between early- and late-expressed genes in the beta-globin gene cluster appears to have evolved independently in several tetrapod lineages.
Reduction of Renal Superoxide Dismutase in Progressive Diabetic Nephropathy
Authors: Hiroki Fujita, Hiromi Fujishima, Shinsuke Chida, Keiko Takahashi, Zhonghua Qi, Yukiko Kanetsuna, Matthew D. Breyer, Raymond C. Harris, Yuichiro Yamada, Takamune Takahashi
Journal: Journal of the American Society of Nephrology (2009)

Superoxide excess plays a central role in tissue damage that results from diabetes, but the mechanisms of superoxide overproduction in diabetic nephropathy (DN) are incompletely understood. In the present study, we investigated the enzyme superoxide dismutase (SOD), a major defender against superoxide, in the kidneys during the development of murine DN. We assessed SOD activity and the expression of SOD isoforms in the kidneys of two diabetic mouse models (C57BL/6-Akita and KK/Ta-Akita) that exhibit comparable levels of hyperglycemia but different susceptibility to DN. We observed down-regulation of cytosolic CuZn-SOD (SOD1) and extracellular CuZn-SOD (SOD3), but not mitochondrial Mn-SOD (SOD2), in the kidney of KK/Ta-Akita mice which exhibit progressive DN. In contrast, we did not detect a change in renal SOD expression in DN-resistant C57BL/6-Akita mice. Consistent with these findings, there was a significant reduction in total SOD activity in the kidney of KK/Ta-Akita mice compared with C57BL/6-Akita mice. Finally, treatment of KK/Ta-Akita mice with a SOD mimetic, tempol, ameliorated the nephropathic changes in KK/Ta-Akita mice without altering the level of hyperglycemia. Collectively, these results indicate that down-regulation of renal SOD1 and SOD3 may play a key role in the pathogenesis of DN.
Phosphorylation of Galectin-3 Contributes to Malignant Transformation of Human Epithelial Cells via Modulation of Unique Sets of Genes
Authors: Nachman Mazurek, Yun Jie Sun, Janet E. Price, Latha Ramdas, Wendy Schober, Pratima Nangia-Makker, James C. Byrd, Avraham Raz, Robert S. Bresalier
Journal: Cancer Research (2005)

Abstract Galectin-3 is a multifunctional β-galactoside-binding protein implicated in apoptosis, malignant transformation, and tumor progression. The mechanisms by which galectin-3 contributes to malignant progression are not fully understood. In this study, we found that the introduction of wild-type galectin-3 into nontumorigenic, galectin-3-null BT549 human breast epithelial cells conferred tumorigenicity and metastatic potential in nude mice, and that galectin-3 expressed by the cells was phosphorylated. In contrast, BT549 cells expressing galectin-3 incapable of being phosphorylated (Ser6→Glu Ser6→Ala) were nontumorigenic. A microarray analysis of 10,000 human genes, comparing BT549 transfectants expressing wild-type and those expressing phosphomutant galectin-3, identified 188 genes that were differentially expressed (&amp;gt;2.5-fold). Genes affected by introduction of wild-type phosphorylated but not phosphomutant galectin-3 included those involved in oxidative stress, a novel noncaspase lysosomal apoptotic pathway, cell cycle regulation, transcriptional activation, cytoskeleton remodeling, cell adhesion, and tumor invasion. The reliability of the microarray data was validated by real-time reverse transcription-PCR (RT-PCR) and by Western blot analysis, and clinical relevance was evaluated by real-time RT-PCR screening of a panel of matched pairs of breast tumors. Differentially regulated genes in breast cancers that are also predicted to be associated with phospho-galectin-3 in transformed BT549 cells include C-type lectin 2, insulin-like growth factor-binding protein 5, cathepsins L2, and cyclin D1. These data show the functional diversity of galectin-3 and suggest that phosphorylation of the protein is necessary for regulation (directly or indirectly) of unique sets of genes that play a role in malignant transformation.