tbuckley/cabot-search huggingface dataset:
Overexpression of Calmodulin in Pancreatic β Cells Induces Diabetic Nephropathy
Authors: Yukio Yuzawa, Ichiro Niki, Tomoki Kosugi, Shoichi Maruyama, Futoshi Yoshida, Motohiro Takeda, Yoshiaki Tagawa, Yukiko Kaneko, Toshihide Kimura, Noritoshi Kato, Jyunichiro Yamamoto, Waichi Sato, Takahiko Nakagawa, Seiichi Matsuo
Journal: Journal of the American Society of Nephrology (2008)

Recently, endothelial dysfunction induced by an uncoupling of vascular endothelial growth factor (VEGF) and nitric oxide has been implicated in the pathogenesis of diabetic nephropathy (DN). Investigating the pathogenesis of DN has been limited, however, because of the lack of animal models that mimic the human disease. In this report, pancreatic beta cell-specific calmodulin-overexpressing transgenic (CaMTg) mice, a potential new model of DN, are characterized with particular emphasis on VEGF and related molecules. CaMTg mice developed hyperglycemia at 3 wk and persistent proteinuria by 3 mo. Morphometric analysis showed considerable increases in the glomerular and mesangial areas with deposition of type IV collagen. Moreover, the pathologic hallmarks of human DN (mesangiolysis, Kimmelstiel-Wilson-like nodular lesions, exudative lesions, and hyalinosis of afferent and efferent arteries with neovascularization) were observed. In addition, increased VEGF expression was associated with an increased number of peritubular capillaries. Expression of endothelial nitric oxidase synthase was reduced and that of VEGF was markedly elevated in CaMTg mice kidney compared with nontransgenic mice. No differences in VEGF receptor-1 or VEGF receptor-2 expression were observed between CaMTg mice and nontransgenic kidneys. In summary, CaMTg mice develop most of the distinguishing lesions of human DN, and the elevated VEGF expression in the setting of diminished endothelial nitric oxide synthase expression may lead to endothelial proliferation and dysfunction. This model may prove useful in the study of the pathogenesis and treatment of DN.
Lung function after bilateral lower lobe lung volume reduction surgery for α1-antitrypsin emphysema
Authors: A.F. Gelb, R.J. McKenna, M Brenner, R Fischel, N Zamel
Journal: European Respiratory Journal (1999)

This study explores the mechanism(s) of airflow limitation following lung volume reduction surgery (LVRS) in patients with emphysema due to homozygous alpha1-antitrypsin (AT) deficiency. Bilateral targeted lower lobe stapled LVRS using video thoracoscopy was performed in six patients (five males) aged 61+/-9 yrs (mean+/-SD) with alpha1-AT emphysema. Two patients received only a 6-month follow-up. However, four patients, at 22, 24, 27 and 36 months post-LVRS, noted relief from dyspnoea and increased walk tolerance. At 27+/-6 months (mean+/-SD) post-LVRS, their forced expiratory volume in one second improved only from 30+/-2% of the predicted value (mean+/-SEM) before surgery to 33+/-1% pred after surgery. Yet, total lung capacity (TLC) decreased from 151+/-13 to 127+/-10% pred; diffusing capacity increased from 35+/-9 to 59+/-9% pred; and vital capacity increased from 68+/-10 to 88+/-5% pred. In three patients, static lung elastic recoil at TLC increased from 1.1+/-0.15 to 1.2+/-0.10 kPa. Using flow/pressure curves, the mechanism for expiratory airflow limitation pre-LVRS and the improvement noted post-LVRS could be primarily accounted for by the initial loss and subsequent increase in lung elastic recoil. Bilateral lung volume reduction surgery provides modest physiologic improvement for 2-3 yrs in patients with alpha1-antitrypsin emphysema due to increases in lung elastic recoil.
Cyclooxygenase inhibition: between the devil and the deep blue sea
Authors: C J Hawkey
Journal: Gut (2002)

Non-steroidal anti-inflammatory drugs (NSAIDs) account for more reports of drug related toxicity than any other class of drugs. Their most widely recognised adverse effects are on the gastrointestinal tract. They cause acute erosions and chronic ulcers that result in hospitalisation and death because of ulcer bleeding and perforation. Between them, aspirin and non-aspirin NSAIDs may account for more than half of all episodes of ulcer bleeding and perforation.
Dysfunction of TGF-β signaling in Alzheimer’s disease
Authors: Pritam Das, Todd Golde
Journal: Journal of Clinical Investigation (2006)

Accumulation of beta-amyloid peptide (Abeta) in the brain is believed to trigger a complex and poorly understood pathologic reaction that results in the development of Alzheimer's disease (AD). Despite intensive study, there is no consensus as to how Abeta accumulation causes neurodegeneration in AD. In this issue of the JCI, Tesseur et al. report that the expression of TGF-beta type II receptor (TbetaRII) by neurons is reduced very early in the course of AD and that reduced TGF-beta signaling increased Abeta deposition and neurodegeneration in a mouse model of AD (see the related article beginning on page 3060). Intriguingly, reduced TGF-beta signaling in neuroblastoma cells resulted in neuritic dystrophy and increased levels of secreted Abeta. Collectively, these data suggest that dysfunction of the TGF-beta/TbetaRII signaling axis in the AD brain may accelerate Abeta deposition and neurodegeneration.
Axis I Psychiatric Comorbidity and Its Relationship to Historical Illness Variables in 288 Patients With Bipolar Disorder
Authors: S L McElroy, L L Altshuler, T Suppes, P E Keck, M A Frye, K D Denicoff, W A Nolen, R W Kupka, G S Leverich, J R Rochussen, A J Rush, R M Post
Journal: American Journal of Psychiatry (2001)

Bipolar disorder often co-occurs with other axis I disorders, but little is known about the relationships between the clinical features of bipolar illness and these comorbid conditions. Therefore, the authors assessed comorbid lifetime and current axis I disorders in 288 patients with bipolar disorder and the relationships of these comorbid disorders to selected demographic and historical illness variables.They evaluated 288 outpatients with bipolar I or II disorder, using structured diagnostic interviews and clinician-administered and self-rated questionnaires to determine the diagnosis of bipolar disorder, comorbid axis I disorder diagnoses, and demographic and historical illness characteristics.One hundred eighty-seven (65%) of the patients with bipolar disorder also met DSM-IV criteria for at least one comorbid lifetime axis I disorder. More patients had comorbid anxiety disorders (N=78, 42%) and substance use disorders (N=78, 42%) than had eating disorders (N=9, 5%). There were no differences in comorbidity between patients with bipolar I and bipolar II disorder. Both lifetime axis I comorbidity and current axis I comorbidity were associated with earlier age at onset of affective symptoms and syndromal bipolar disorder. Current axis I comorbidity was associated with a history of development of both cycle acceleration and more severe episodes over time.Patients with bipolar disorder often have comorbid anxiety, substance use, and, to a lesser extent, eating disorders. Moreover, axis I comorbidity, especially current comorbidity, may be associated with an earlier age at onset and worsening course of bipolar illness. Further research into the prognostic and treatment response implications of axis I comorbidity in bipolar disorder is important and is in progress.
Endothelin-1 stimulates human colonic myofibroblast contraction and migration
Authors: L E Kernochan
Journal: Gut (2002)

Background: Although the contractile, migratory, and proliferative responses of subepithelial myofibroblasts to injury have been postulated to be important events in intestinal wound healing, contractile force generation and migration by these cells has not been investigated previously, and the signals that regulate proliferation by these cells are poorly understood. Aims: The primary aim of this study was to test the hypothesis that the inflammatory mediator endothelin-1 modulates contraction, migration, and proliferation of intestinal myofibroblasts. We also sought to examine the signal transduction pathways which might underlie these putative effects. Methods: Contraction, migration, proliferation, cytosolic [Ca<sup>2+</sup>], and myosin phosphorylation were measured in human colonic subepithelial myofibroblasts in the absence and presence of endothelin receptor agonists and antagonists. Results: Endothelin-1, but not interleukin 1α, interleukin 6, interleukin 8, interleukin 10, or tumour necrosis factor α, induced a rapid and robust generation of contractile force, which was associated with an increase in cytosolic [Ca<sup>2+</sup>] and myosin phosphorylation. Inhibition of rho associated kinase reduced endothelin-1 stimulated myosin phosphorylation and contractile force development. Endothelin-1 stimulated migration with a dose-response relationship similar to that observed for contraction. Endothelin A and B receptors mediated contraction while migration was mediated predominantly through endothelin B receptors. Platelet derived growth factor and serum, but not endothelin-1, induced proliferation. Conclusions: Endothelin-1 stimulates colonic subepithelial myofibroblast contraction and migration via endothelin receptor mediated myosin phosphorylation. These results support an important role for subepithelial myofibroblasts in the injury response of the gut and consequently intestinal wound repair.
Genetic <i>Ace2</i> Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the <i>ApoE</i> Knockout Mouse
Authors: Merlin C. Thomas, Raelene J. Pickering, Despina Tsorotes, Audrey Koitka, Karen Sheehy, Stella Bernardi, Barbara Toffoli, Thu-Phuc Nguyen-Huu, Geoffrey A. Head, Yi Fu, Jaye Chin-Dusting, Mark E. Cooper, Chris Tikellis
Journal: Circulation Research (2010)

Rationale: Angiotensin-converting enzyme (ACE)2 opposes the actions of angiotensin (Ang) II by degrading it to Ang 1-7. Objective: Given the important role of Ang II/Ang 1-7 in atherogenesis, we investigated the impact of ACE2 deficiency on the development of atherosclerosis. Methods and Results: C57Bl6 , Ace2 knockout (KO), apolipoprotein E ( ApoE ) KO and ApoE/Ace2 double KO mice were followed until 30 weeks of age. Plaque accumulation was increased in ApoE/Ace2 double KO mice when compared to ApoE KO mice. This was associated with increased expression of adhesion molecules and inflammatory cytokines, including interleukin-6, monocyte chemoattractant protein-1, and vascular cell adhesion molecule-1, and an early increase in white cell adhesion across the whole aortae on dynamic flow assay. In the absence of a proatherosclerotic ( ApoE KO ) genotype, ACE2 deficiency was also associated with increased expression of these markers, suggesting that these differences were not an epiphenomenon. ACE inhibition prevented increases of these markers and atherogenesis in ApoE/ACE2 double KO mice. Bone marrow macrophages isolated from Ace2 KO mice showed increased proinflammatory responsiveness to lipopolysaccharide and Ang II when compared to macrophages isolated from C57Bl6 mice. Endothelial cells isolated from Ace2 KO mice also showed increased basal activation and elevated inflammatory responsiveness to TNF-α. Similarly, selective inhibition of ACE2 with MLN-4760 also resulted in a proinflammatory phenotype with a physiological response similar to that observed with exogenous Ang II (10 −7 mol/L). Conclusions: Genetic Ace2 deficiency is associated with upregulation of putative mediators of atherogenesis and enhances responsiveness to proinflammatory stimuli. In atherosclerosis-prone ApoE KO mice, these changes potentially contribute to increased plaque accumulation. These findings emphasize the potential utility of ACE2 repletion as a strategy to reduce atherosclerosis.
Unexpected Dynamic Gene Family Evolution in Algal Actins
Authors: Min Wu, Josep M. Comeron, Hwan Su Yoon, Debashish Bhattacharya
Journal: Molecular Biology and Evolution (2008)

Actin is a conserved cytoskeletal protein that is well studied in model organisms although much less is known about actin molecular evolution in taxonomically diverse algae. Here, we analyzed 107 novel partial algal actin sequences and report some unexpected results. First, monophyletic actin gene families in multiple, phylogenetically distantly related algal taxa contain two distinct clades of sequences. One of these clades contains highly conserved sequences, whereas the second has multiple members with a significantly elevated substitution rate. This rate difference is associated with an excess of synonymous substitutions, strongly suggesting that both isoforms are active. These results paint a novel picture of actin gene evolution in algae showing it to be a remarkably dynamic system with duplication, homogenization, and potential functional diversification occurring independently in distantly related lineages.
Two Orphan Seven-Transmembrane Segment Receptors Which Are Expressed in CD4-positive Cells Support Simian Immunodeficiency Virus Infection
Authors: Michael Farzan, Hyeryun Choe, Kathleen Martin, Luisa Marcon, Wolfgang Hofmann, Gunilla Karlsson, Ying Sun, Peter Barrett, Nathalie Marchand, Nancy Sullivan, Norma Gerard, Craig Gerard, Joseph Sodroski
Journal: The Journal of Experimental Medicine (1997)

Clinical isolates of primate immunodeficiency viruses, including human immunodeficiency virus type 1 (HIV-1), enter target cells by sequential binding to CD4 and the chemokine receptor CCR5, a member of the seven-transmembrane receptor family. HIV-1 variants which use additional chemokine receptors are present in the central nervous system or emerge during the course of infection. Simian immunodeficiency viruses (SIV) have been shown to use CCR5 as a coreceptor, but no other receptors for these viruses have been identified. Here we show that two orphan seven-transmembrane segment receptors, gpr1 and gpr15, serve as coreceptors for SIV, and are expressed in human alveolar macrophages. The more efficient of these, gpr15, is also expressed in human CD4+ T lymphocytes and activated rhesus macaque peripheral blood mononuclear cells. The gpr15 and gpr1 proteins lack several hallmarks of chemokine receptors, but share with CCR5 an amino-terminal motif rich in tyrosine residues. These results underscore the potential diversity of seven-transmembrane segment receptors used as entry cofactors by primate immunodeficiency viruses, and may contribute to an understanding of viral variation and pathogenesis.
Expanding whole exome resequencing into non-human primates
Authors: Eric J Vallender
Journal: Genome biology (2011)

Complete exome resequencing has the power to greatly expand our understanding of non-human primate genomes. This includes both a better appreciation of the variation that exists in non-human primate model species, but also an improved annotation of their genomes. By developing an understanding of the variation between individuals, non-human primate models of human disease can be better developed. This effort is hindered largely by the lack of comprehensive information on specific non-human primate genetic variation and the costs of generating these data. If the tools that have been developed in humans for complete exome resequencing can be applied to closely related non-human primate species, then these difficulties can be circumvented.Using a human whole exome enrichment technique, chimpanzee and rhesus macaque samples were captured alongside a human sample and sequenced using standard next-generation methodologies. The results from the three species were then compared for efficacy. The chimpanzee sample showed similar coverage levels and distributions following exome capture based on the human genome as the human sample. The rhesus macaque sample showed significant coverage in protein-coding sequence but significantly less in untranslated regions. Both chimpanzee and rhesus macaque showed significant numbers of frameshift mutations compared to self-genomes and suggest a need for further annotation.Current whole exome resequencing technologies can successfully be used to identify coding-region variation in non-human primates extending into old world monkeys. In addition to identifying variation, whole exome resequencing can aid in better annotation of non-human primate genomes.
Effects of combined estrogen and progestin administration on plasma lipoprotein metabolism in postmenopausal women.
Authors: B M Wolfe, M W Huff
Journal: Journal of Clinical Investigation (1989)

Treatment of postmenopausal women with low doses of estradiol-17 beta (1 mg/d) and dl-norgestrel (0.075 [corrected] mg/d) significantly reduced fasting serum levels of low density lipoprotein (LDL) cholesterol and lowered very low density lipoprotein (VLDL) triglycerides in four of five subjects. To explain these results, the kinetics of VLDL and LDL apolipoprotein (apo) B turnover were studied by injecting autologous 125I-labeled VLDL and 131I-labeled LDL into subjects before discontinuing long-term (4-yr) treatment with the estradiol-17 beta and dl-norgestrel and again 7 wk after stopping treatment. The 24% mean decrease in VLDL apo B pool size during treatment was associated with a significant increase in VLDL apo B fractional catabolic rate (15 +/- 1 vs. 11 +/- 1 pools/d), whereas production rate was similar to control (24 +/- 3 vs. 21 +/- 2 mg/kg per d). There was a significant 25% mean decrease in LDL apo B pool size (27 +/- 2 vs. 36 +/- 3 mg/kg) due to a significant decrease in total (8.3 +/- 0.3 vs. 11 +/- 1 mg/kg per d) and independent (3.3 +/- 0.5 vs. 6.6 +/- 0.8 mg/kg per d, P less than 0.05) LDL apo B production. Estradiol-17 beta together with dl-norgestrel lowered plasma VLDL by enhancing their clearance and LDL by reducing their production.
SUSTAINED HYPERTENSION FOLLOWING THE ADMINISTRATION OF DESOXYCORTICOSTERONE ACETATE
Authors: Sydney M. Friedman, Constance L. Friedman, Miyoshi Nakashima
Journal: The Journal of Experimental Medicine (1951)

DCA was administered in two separate experiments to rats in amounts sufficient to cause marked elevation of the blood pressure. It was then abruptly withdrawn. Following this treatment, observations of blood pressure, blood urea nitrogen, plasma potassium, and plasma volume were carried out for over a year. Approximately one-third of the animals so treated developed a sustained, permanent hypertension after treatment had been stopped. This sustained hypertension is not due to any anatomical fault in the kidney and in that sense is not primarily renal in origin. An hypothesis to explain the findings is presented.
Severe intestinal involvement in Wegener's granulomatosis.
Authors: S J Haworth, C D Pusey
Journal: Gut (1984)

A case of Wegener's granulomatosis is described, in which the presentation was blood stained mucus diarrhoea. Severe ileal, caecal, and rectal involvement improved rapidly after treatment with cyclophosphamide, azathioprine, and prednisolone. Although intestinal disease is an uncommon feature of Wegener's granulomatosis, both in our own experience (four of 45 cases) and in the literature, this diagnosis should be considered in view of the response to appropriate therapy.
Pediatric Intracerebral Hemorrhage
Authors: Lauren A. Beslow, Nicholas S. Abend, Melissa C. Gindville, Rachel A. Bastian, Daniel J. Licht, Sabrina E. Smith, Argye E. Hillis, Rebecca N. Ichord, Lori C. Jordan
Journal: JAMA Neurology (2013)

Seizures are believed to be common presenting symptoms in neonates and children with spontaneous intracerebral hemorrhage (ICH). However, few data are available on the epidemiology of acute symptomatic seizures or the risk for later epilepsy.To define the incidence of and explore risk factors for seizures and epilepsy in children with spontaneous ICH. Our a priori hypotheses were that younger age at presentation, cortical involvement of ICH, acute symptomatic seizures after presentation, ICH due to vascular malformation, and elevated intracranial pressure requiring urgent intervention would predict remote symptomatic seizures and epilepsy.Prospective cohort study conducted between March 1, 2007, and January 1, 2012.Three tertiary care pediatric hospitals.Seventy-three pediatric subjects with spontaneous ICH including 20 perinatal (≥37 weeks' gestation to 28 days) and 53 childhood subjects (>28 days to <18 years at presentation).Acute symptomatic seizures (clinically evident and electrographic-only seizures within 7 days), remote symptomatic seizures, and epilepsy.Acute symptomatic seizures occurred in 35 subjects (48%). Acute symptomatic seizures as a presenting symptom of ICH occurred in 12 perinatal (60%) and 19 childhood (36%) subjects (P = .07). Acute symptomatic seizures after presentation occurred in 7 children. Electrographic-only seizures were present in 9 of 32 subjects (28%) with continuous electroencephalogram monitoring. One-year and 2-year remote symptomatic seizure-free survival rates were 82% (95% CI, 68-90) and 67% (95% CI, 46-82), respectively. One-year and 2-year epilepsy-free survival rates were 96% (95% CI, 83-99) and 87% (95% CI, 65-95), respectively. Elevated intracranial pressure requiring acute intervention was a risk factor for seizures after presentation (P = .01; Fisher exact test), remote symptomatic seizures, and epilepsy (P = .03, and P = .04, respectively; log-rank test).Presenting seizures are common in perinatal and childhood ICH. Continuous electroencephalography may detect electrographic seizures in some subjects. Single remote symptomatic seizures occur in many, and development of epilepsy is estimated to occur in 13% of patients at 2 years. Elevated intracranial pressure requiring acute intervention is a risk factor for acute seizures after presentation, remote symptomatic seizures, and epilepsy.
Comparison of Exercise Performance in Patients With Chronic Severe Heart Failure Versus Left Ventricular Assist Devices
Authors: Donna Mancini, Rochelle Goldsmith, Howard Levin, Ainat Beniaminovitz, Eric Rose, Katharine Catanese, Margaret Flannery, Mehmet Oz
Journal: Circulation (1998)

Background —Left ventricular assist devices (LVADs) are frequently used as a bridge to cardiac transplantation and may be useful as long-term therapy. The purpose of this study was to compare the exercise performance of LVAD patients with that of ambulatory heart failure patients. Methods and Results —Exercise testing with hemodynamic and respiratory gas measurements was performed in 65 congestive heart failure (CHF) patients (age 53±10 years) and 20 LVAD patients (age 49±8 years). Peak V̇ o 2 was significantly higher in the LVAD than the CHF patients (CHF, 12±3; LVAD, 15.9±3.8 mL · kg −1 · min −1 ; P &lt;0.001), as was the V̇ o 2 at the anaerobic threshold (CHF, 8.1±2.1; LVAD, 12.2±2.9 mL · kg −1 · min −1 ; P &lt;0.001). At rest, mean arterial blood pressure (CHF, 87±11; LVAD, 94±9 mm Hg) and cardiac output (CHF, 4±1; LVAD, 4.9±0.9 L/min) were increased, whereas mean pulmonary artery pressure (CHF, 28±11; LVAD, 18±4 mm Hg) and pulmonary artery wedge pressure (CHF, 16±10; LVAD 5±3 mm Hg) were reduced (all P &lt;0.01). At peak exercise, heart rate (CHF,125±24; LVAD, 148±24 bpm), blood pressure (CHF, 87±14; LVAD,96±12 mm Hg), and cardiac output (CHF, 7.6±2.2; LVAD, 11.2±2.6 L/min) were higher (all P &lt;0.01), whereas mean pulmonary artery pressure (CHF, 48±12; LVAD, 30±5 mm Hg) and mean pulmonary capillary wedge pressure (CHF, 31±11; LVAD, 14±6 mm Hg) were lower in the LVAD group (both P &lt;0.001). In the LVAD patients, Fick cardiac output was higher than LVAD flow sensor value measurements (Fick, 11.6±2.5; LVAD, 8.1±1.2 L/min; P &lt;0.001). Conclusions —Hemodynamic measurements at rest and during exercise are significantly improved in patients with devices compared with those in ambulatory heart failure patients awaiting cardiac transplantation. Similarly, the exercise capacity of device patients is better than that of transplant candidates and in the majority of patients is similar to that of patients with mild CHF.