tbuckley/cabot-search huggingface dataset:
Pivotal role of tyrosine phosphatase SHP-1 in AT2 receptor-mediated apoptosis in rat fetal vascular smooth muscle cell
Authors: T Cui
Journal: Cardiovascular Research (2001)

Objective: To examine the possible crosstalk and the roles of angiotensin (Ang) II type 1 (AT1) and type 2 (AT2) receptors in the control of apoptosis in fetal vascular smooth muscle cells (VSMCs). Methods: Fetal VSMCs were prepared from rat fetal aorta at embryonic day 20. Expression of Ang II receptors was measured by a radioligand binding assay. Apoptotic changes were assessed by caspase 3 activity and chromatin dye staining. Regulation of extracellular signal-regulated kinase (ERK) activity via Ang II receptors was analysed by determinating phosphorylated ERK with Western blot. Ang II receptor-mediated activation of tyrosine phosphatase SHP-1 was assessed by protein tyrosine phosphatase assay. Results: The expression of AT1 and AT2 receptors was approximately 70%: 30% per cell. Serum depletion induced apoptosis in fetal VSMCs and selective AT1 receptor stimulation attenuated the apoptotic changes, whereas selective AT2 receptor activation enhanced apoptosis. Ang II increased ERK phosphorylation, which was inhibited by addition of the AT1 receptor-specific antagonist CV11974, but enhanced by addition of the AT2 receptor-specific antagonist PD123319, suggesting that activation of AT2 receptor attenuated the AT1 receptor-mediated ERK phosphorylation. Moreover, we demonstrated that AT2 receptor stimulation activated SHP-1 in fetal VSMCs, whereas AT1 receptor stimulation did not. Transient transfection of a dominant-negative SHP-1 mutant into rat fetal VSMCs resulted in a significant decrease of the AT2 receptor-mediated inhibition of ERK phosphorylation and attenuated the proapoptotic effect of AT2 receptor. Conclusion: These results indicate that a crosstalk between AT1 and AT2 receptors regulates the survival of fetal VSMCs and substantiate SHP-1 as a key molecule in AT2 receptor signaling.
Mechanisms Underlying the Formation and Dynamics of Subcellular Calcium Alternans in the Intact Rat Heart
Authors: Gary L. Aistrup, Yohannes Shiferaw, Sunil Kapur, Alan H. Kadish, J. Andrew Wasserstrom
Journal: Circulation Research (2009)

Optical mapping of intact cardiac tissue reveals that, in some cases, intracellular calcium (Ca) release can alternate from one beat to the next in a large-small-large sequence, also referred to as Ca transient (CaT) alternans. CaT alternans can also become spatially phase-mismatched within a single cell, when one part of the cell alternates in a large-small-large sequence, whereas a different part alternates in a small-large-small sequence, a phenomenon known as subcellular discordant alternans. The mechanisms for the formation and spatiotemporal evolution of these phase-mismatched patterns are not known. We used confocal Ca imaging to measure CaT alternans at the sarcomeric level within individual myocytes in the intact rat heart. After a sudden change in cycle length (CL), 2 distinct spatial patterns of CaT alternans emerge. CaTs can form spatially phase-mismatched alternans patterns after the first few beats following the change in CL. The phase mismatch persists for many beats, after which it gradually becomes phase matched via the movement of nodes, which are junctures between phase-mismatched cell regions. In other examples, phase-matched alternans gradually become phase-mismatched, via the formation and movement of nodes. In these examples, we observed large beat-to-beat variations in the cell activation times, despite constant CL pacing. Using computer simulations, we explored the underlying mechanisms for these dynamical phenomena. Our results show how heterogeneity at the sarcomeric level, in conjunction with the dynamics of Ca cycling and membrane voltage, can lead to complex spatiotemporal phenomena within myocytes of the intact heart.
A NEW METHOD OF SHORTENING THE ROUND LIGAMENTS INTRAPERITONEALLY FOR RETROVERSION.
Authors: HENRY T. BYFORD
Journal: JAMA (1903)

A new era in the treatment of retroversion of the uterus began with the introduction of Alexander's operation. Women had been until then worried with pessaries to hold the uterus in place, and with douches to keep the pessaries clean, yet without being cured. Abdominal suspension has occupied the attention of the profession considerably in the meantime, but it has not proven a satisfactory remedy, and is being used less than formerly. Intraperitoneal shortening of the round ligaments has become an acceptable substitute in cases in which it is found necessary or advisable to open the peritoneal cavity, for in such cases the ligaments are accessible without making the additional inguinal incision, and thus with less trauma. W. Gill Wylie made a backward fold or loop in the ligament and sewed together the edges of the fold, and thus obtained a fair degree of success in holding the uterus in place. A. Palmer Dudley folds the ligament anteriorly
Editorial: Progress in the treatment of colorectal cancer
Authors: G. M. Mavligit
Journal: JAMA (1976)

Colorectal cancer is a major public health problem. Unfortunately, treatment results have not improved much over the past two decades, in spite of surgery and rediotherapy. The most effective single, chemotherapeutic agent for carcinoma of the large bowel<sup>1</sup>has been fluorouracil, first used in clinical trials in 1958 by Curreri and associates.<sup>2</sup>Partial remissions have occurred in 20% to 30% of patients with metastatic disease in whom fluorouracil has been used. Further progress may result from prompt and more aggressive approaches that combine therapeutic modalities. One such approach is adjuvant systemic therapy (chemotherapy or immunotherapy or both) immediately following surgery with or without radiotherapy in the early stages of the disease. This is especially true in patients with Dukes stage C lesions, where the likelihood of surgical failure is approximately 70% to 75%, due to the presence of foci of micrometastases at adjacent or distant organs at the
Membrane-associated PGE synthase-1 (mPGES-1) is coexpressed with both COX-1 and COX-2 in the kidney
Authors: André Schneider, Yahua Zhang, Mingzhi Zhang, Wendell J. Lu, Reena Rao, Xuefeng Fan, Reyadh Redha, Linda Davis, Richard M. Breyer, Raymond Harris, Youfei Guan, Matthew D. Breyer
Journal: Kidney International (2004)
Drug-Induced Thrombocytopenia
Authors: James N. George
Journal: Annals of Internal Medicine (1998)

Purpose: To determine the strength of clinical evidence for individual drugs as a cause of thrombocytopenia. Data Sources: All English-language reports on drug-induced thrombocytopenia. Study Selection: Articles describing thrombocytopenia caused by heparin were excluded from review. Of the 581 articles reviewed, 20 were excluded because they contained no patient case reports. The remaining 561 articles reported on 774 patients. Data Extraction: Two of the authors used a priori criteria to independently review each patient case report. Two hundred fifty-nine patient case reports were excluded from further review because of lack of evaluable data, platelet count of 100 000 cells/µL or more, use of cytotoxic or nontherapeutic agents, occurrence of drug-induced systemic disease, or occurrence of disease in children. For the remaining 515 patient case reports, a level of evidence for the drug as the cause of thrombocytopenia was assigned. Data on bleeding complications and clinical course were recorded. Data Synthesis: The evidence supported a definite or probable causal role for the drug in 247 patient case reports (48%). Among the 98 drugs described in these reports, quinidine was mentioned in 38 case reports, gold in 11, and trimethoprim-sulfamethoxazole in 10. Of the 247 patients described in the case reports, 23 (9%) had major bleeding and 2 (0.8%) died of bleeding. Conclusions: Many reports of drug-induced thrombocytopenia do not provide evidence supporting a definite or probable causal relation between the disease and the drug. Future patient case reports should incorporate standard criteria to clearly establish the etiologic role of the drug.
Abstract 2256: p53 gene expression is epigenetically regulated during replicative senescence in keratinocytes
Authors: Reuben H. Kim, Mo K. Kang, Terresa Kim, Paul Yang, Christine Hong, Ki-Hyuk Shin, No-Hee Park
Journal: Cancer Research (2014)

Abstract Cancer is one of the most prevalent age-associated diseases in elderly populations and is largely attributed to accumulation of genetic mutations secondary to the loss of tumor suppressive functions. p53 is a potent tumor suppressor that is implicated in organismal aging in vivo and replicative senescence in vitro; however, its transcriptional regulation during replicative senescence in cells remain unclear. The current study was undertaken to examine the epigenetic regulation of p53 transcription during replicative senescence in normal human keratinocytes. Normal human oral keratinocytes (NHOKs) undergoing senescence upon serial subcultures exhibited a decrease in p53 gene expression. Methylation status of two CpG islands in the p53 promoter was evaluated by treating with 5-aza-CdR, a demethylating agent, and by using bisulfite methylation sequencing analysis. Status of histone modification was evaluated using Chromatin Immunoprecipitation (ChIP) assay with anti-H3K27me3, a repressive mark, and anti-H3Ac, an active mark at the 5 different sites of the p53 promoter regions. In the presence of 5-aza-CdR, there was no increase in p53 expression in senescent NHOK at both mRNA and protein level. Bisulfite-sequencing analysis revealed no methylation changes at the CpG islands in the p53 promoters from young and senescent NHOK. However, during replicative senescence in NHOK, there were notable enrichment of anti-H3K27me3 occupancy and significant decrease in anti-H3Ac occupancy in the p53 promoter regions, indicating that chromatin at the p53 locus undergo compaction during replicative senescence. Our study demonstrates that the diminution of p53 during replicative senescence is epigenetically regulated in human keratinocytes. Citation Format: Reuben H. Kim, Mo K. Kang, Terresa Kim, Paul Yang, Christine Hong, Ki-Hyuk Shin, No-Hee Park. p53 gene expression is epigenetically regulated during replicative senescence in keratinocytes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2256. doi:10.1158/1538-7445.AM2014-2256
Hip fractures up to date.
Authors: J Dinley
Journal: BMJ (1977)

concerning the use of hydrochloric acid for the correction of severe metabolic alkalosis perpetuates a small but significant error originally contained within one of the references.'The author states that 150 ml of 1-M HCI in one litre of sterile water yields 300 mmol of H+ and Cl per litre.By definition a 1-M solution of any preparation contains 1000 mmol of solute.Therefore 150 ml of the 1-M HCl solution will contain 150 mmol of H+ and Cl-.When the 150-ml aliquot is added to the sterile water the molarity of the final solution is 015 M, not 0 3 M as would be calculated using the 300 mmol figure.Such miscalculations may be critical when one is attempting rapidly to correct severe metabolic alkalosis.Furthermore, while the author, as well as others,' 2confirms the safety of dilute solutions of HCl (0 1-0 2 M), several reports2 '1 indicate that HCl in 0 3 M concen- trations or greater may precipitate acute haemolysis of red blood cells.Thus great care should be directed toward ordering and pre- paring intravenous hydrochloric acid solutions for reasons both of efficacy and of safety.
SPECT Imaging with TI-201 and Ga-67 in Myocardial Sarcoidosis
Authors: CHINORI KURATA, KAZUYUKI SAKATA, TAKAHISA TAGUCHI, YOSHIHIRO FUKUMOTO, HARUO MIYATA, SHIGEYUKI AOSHIMA, NOBORU YAMAZAKI
Journal: Clinical Nuclear Medicine (1990)

Two patients with myocardial sarcoidosis are presented, both of whom underwent SPECT imaging with TI-201 and Ga-67. The first had Ga-67 myocardial uptake with a TI-201 defect, which disappeared with corticosteroid therapy. The second had multiple TI-201 defects without Ga-67 uptake, which persisted despite corticosteroid therapy. Therefore, the combination of TI-201 and Ga-67 imaging may be useful for recognizing myocardial sarcoidosis and for predicting the response to corticosteroid therapy.
Damage of the pharyngeal mucosa and hyperresponsiveness of airway in sinusitis☆☆☆★★★
Authors: Giovanni Rolla, Paola Colagrande, Ermanno Scappaticci, Flavia Bottomicca, Mauro Magnano, Luisa Brussino, Luca Dutto, Caterina Bucca
Journal: Journal of Allergy and Clinical Immunology (1997)
Clinical, immunological, and genetic heterogeneity of diabetes in an Italian population-based cohort of lean newly diagnosed patients aged 30-54 years. Piedmont Study Group for Diabetes Epidemiology.
Authors: G Bruno, A De Salvia, R Arcari, M Borra, N Grosso, Q Carta, M Trovati, M Veglio, G Pagano
Journal: Diabetes Care (1999)

OBJECTIVE: In lean diabetic patients, the presentation of the disease does not allow one to easily distinguish between type 1 and type 2. Aims of this study were to describe clinical, immunological, and genetic features of lean newly diagnosed diabetic patients. RESEARCH DESIGN AND METHODS: A population-based cohort of 130 lean (BMI &amp;lt; 25 kg/m2) newly diagnosed patients, aged 30-54 years, was identified among residents of the province of Turin. Islet cell antibodies (ICAs), anti-GAD, fasting and glucagon-stimulated C-peptide values, and HLA DQA1-DQB1 susceptibility genotypes were assessed within 2 months of the diagnosis. RESULTS: A total of 45 (34.6%) and 29 (22.3%) patients were, respectively, ICA+ and anti-GAD+, with 15 (11.5%) having both antibodies. In 59 patients, ICAs and/or anti-GAD antibodies were detected, giving a high prevalence of autoimmunity (45.4%, 95% Cl 36.8-54.0); relative to patients without markers (n = 71), they were younger (40.8 +/- 7.5 vs. 45.0 +/- 6.5 years, P &amp;lt; 0.001) and showed lower values of fasting C-peptide (0.56 +/- 0.33 vs. 0.79 +/- 0.41 nmol/l, P &amp;lt; 0.001) and stimulated C-peptide (1.03 +/- 0.56 vs. 1.42 +/- 0.69 nmol/l, P &amp;lt; 0.001). The lowest stimulated C-peptide values were found in patients with both ICA and anti-GAD antibodies. Frequencies of adult-onset type 1 and type 2 diabetes were, respectively, 49.2 and 50.8%. Clinical and genetic features were not useful in the classification of patients. CONCLUSIONS: Almost 50% of lean young and middle-aged patients were ICA+ and/or anti-GAD+, suggesting a high prevalence of a slowly evolving form of type 1 diabetes. The evaluation at diagnosis of both beta-cell secretory capacity and markers of autoimmunity is recommended to provide a pathogenetic classification of the disease.
Where Does Insulin Resistance Start?
Authors: Uberto Pagotto
Journal: Diabetes Care (2009)

During the last two decades, many studies have focused on the pivotal role of the hypothalamus in the control of energy metabolism (1). Hypothalamic nuclei, particularly the arcuate and the ventromedial, receive numerous peripheral inputs from adipokines (leptin, adiponectin, and resistin) and free fatty acids. These signals of “nutrient abundance” lead to the activation of multiple hypothalamic pathways that overlap and generate a plethora of central and peripheral responses (2). In this context, the central neuronal signals generated by insulin have been the most extensively studied (3).

The pivotal experiment performed by Woods et al. (4) in the late 1970s showed that intracerebral infusion of insulin in baboons reduced food intake and body weight and paved the way for intense scientific investigation over subsequent years by highlighting the key role of insulin at the central nervous system (CNS) level. Insulin receptors (5) and components of the insulin signaling pathway (6) are widely distributed in the brain. Insulin interacts with its binding sites by crossing the blood-brain barrier through a receptor-mediated and saturable transport mechanism (7), although it has been hypothesized that insulin is also synthesized in the brain (7).

Considerable evidence has been generated to indicate that insulin can modulate the expression of neuropeptides involved in the regulation of food intake within the CNS (8) and also can influence glucoregulation via CNS connections that regulate hepatic glucose production (9), glycogen synthesis in the skeletal muscle (10), and fat metabolism in adipocytes (11). By activating its receptors, insulin directly suppresses prepro-NPY mRNA transcription in the arcuate nucleus, leading to a reduction in NPY and a decrease in food intake (12), whereas intracerebroventricular delivery of insulin increases the expression of pro-opiomelanocortin (POMC) (13) (Fig. 1). This hypothalamic mode of insulin action resembles the well-known effect of leptin, suggesting that these …
Biological effects of short-term, high-concentration exposure to methyl isocyanate. IV. Influence on the oxygen-binding properties of guinea pig blood.
Authors: L A Maginniss, J M Szewczak, C M Troup
Journal: Environmental Health Perspectives (1987)

Whole blood oxygen equilibrium curves (O2 ECs), blood buffer lines, and several hematologic properties were determined for adult guinea pigs exposed to 700 ppm methyl isocyanate (MIC) for 15 min. MIC inhalation effected a significant reduction of blood O2 affinity; the half-saturation pressure (P50) at 38 degrees C increased from the control (untreated) level of 22.8 +/- 0.1 mm Hg to values ranging from 28.5 to 43.7 mm Hg for experimental animals. MIC exposure had no apparent influence on O2 EC shape or CO2 Bohr effect. Erythrocyte volume, [metHb], O2 binding capacity, and combined red cell organic phosphate concentration (DPG + ATP) were not affected by MIC treatment. However, experimental animals experienced a severe metabolic acid-base disturbance; blood lactate concentration ranged from 8.6 to 24.0 mmole/L. Results indicate that lactic acidosis was solely responsible for increased blood P50 of MIC-treated animals. No direct effects of MIC on hemoglobin function were observed. Reduced Hb-O2 affinity, in conjunction with severe hypoxemia, compromised the guinea pigs' capacity for pulmonary O2 loading; at PaO2 of 30 mm Hg, Hb-O2 saturation (S) decreased from 66% S for controls to 42% S for MIC-treated animals.
240 Inhibition of cjun and FADD protects hepatocytes against azathioprine-induced necrosis
Authors: B JONES, W WU, M TAPNER, G FARRELL
Journal: Hepatology (2003)

Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal-recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Three types of PFIC have been identified and associated with mutations in hepatocellular transport-system genes involved in bile formation. PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may arise later in infancy, in childhood or even during young adulthood. The main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and in ABCB11 encoding bile salt export pump (BSEP) protein, respectively. Defects in ABCB4, encoding multidrug resistance 3 protein (MDR3), impair biliary phospholipid secretion, resulting in PFIC3. Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests to exclude other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates for whom genotyping could be proposed to confirm the diagnosis. Antenatal diagnosis may be proposed for affected families in which a mutation has been identified. Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 and PFIC2 patients, biliary diversion may also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of liver tumors, especially in PFIC2 patients, should be offered from the first year of life. Hepatocyte transplantation, gene therapy and specific targeted pharmacotherapy may represent alternative treatments in the future.
Reevaluation of Oxidative Phosphorylation in Cardiac Mitochondria from Normal Animals and Animals in Heart Failure
Authors: GEORGE E. LINDENMAYER, LOUIS A. SORDAHL, ARNOLD SCHWARTZ
Journal: Circulation Research (1968)

For an adequate evaluation of mitochondria from diseased hearts, basic characteristics of isolation, storage, media, ultrastructure and type of assay were first determined using mitochondria from normal animals. A proteinase procedure yielded mitochondria from small laboratory animals, with low respiratory control and marked permeability changes. The isolation medium yielding the most stable mitochondria with the highest respiratory control contained 0.18M KCl, 10mM EDTA, and 0.5% to 1% bovine serum albumin at pH 7.2. Heart failure in guinea pigs and rabbits was produced by varying degrees of stenosis of the ascending aorta. An aberration in respiratory control was found in mitochondria from hearts in severe failure. The quantitative differences between normal and experimental respiratory control values were greatest when the highest possible normal respiratory control levels were obtained. The difference between mitochondria prepared by a proteinase method from control and failing hearts was minimal. No changes in oxidative phosphorylation were noted in mitochondria from hearts arrested by nitrogen, suggesting that acute hypoxia does not irreversibly damage energy-liberating reactions. It is concluded that severe heart failure is characterized by defects in mitochondrial oxidative phosphorylation, and that techniques of isolation or assay or both are probably not causing the abnormalities.
Trimethoprim-sulphamethoxazole in enteric fevers.
Authors: S Bassily, Z Farid, J S Lehman, K Sorensen
Journal: BMJ (1971)

Clinical improvement was rapid in all 13 patients with enteric fever and one with Brucella abortus infection treated with trimethoprim-sulphamethoxazole. There were no side-effects of the treatment and it was found easy to administer to toxic and delirious patients.
TREATMENT-RESISTANT BLOOD PRESSURE AMONG PATIENTS WITH CORONARY ARTERY DISEASE &amp;ndash; CAUSE FOR CONCERN: NEW DATA FROM THE EXTENDED FOLLOW-UP OF THE INTERNATIONAL VERAPAMAIL SR-TRANDOLAPRIL STUDY (INVEST)
Authors: Rhonda M. Cooper-DeHoff, Yan Gong, Eileen Handberg, Franz Messerli, George Bakris, Ali Ahmed, Anthony Bavry, Carl Pepine
Journal: Journal of the American College of Cardiology (2012)