tbuckley/cabot-search huggingface dataset:
Exercise Stress Test Amplifies Genotype-Phenotype Correlation in the LQT1 and LQT2 Forms of the Long-QT Syndrome
Authors: Kotoe Takenaka, Tomohiko Ai, Wataru Shimizu, Atsushi Kobori, Tomonori Ninomiya, Hideo Otani, Tomoyuki Kubota, Hiroshi Takaki, Shiro Kamakura, Minoru Horie
Journal: Circulation (2003)

Background— Experimental studies suggest that the interval between peak and end of T wave (Tpe) in transmural ECGs reflects transmural dispersion of repolarization (TDR), which is amplified by β-adrenergic stimulation in the LQT1 model. In 82 patients with genetically identified long-QT syndrome (LQTS) and 33 control subjects, we examined T-wave morphology and various parameters for repolarization in 12-lead ECGs including corrected QT (QTc; QT/R-R 1/2 ) and corrected Tpe (Tpec; Tpe/R-R 1/2 ) before and during exercise stress tests. Methods and Results— Under baseline conditions, LQT1 (n=51) showed 3 cardinal T-wave patterns (broad-based, normal-appearing, late-onset) and LQT2 (n=31) 3 patterns (broad-based, bifid with a small or large notch). The QTc and Tpec were 510±68 ms and 143±53 ms in LQT1 and 520±61 ms and 195±69 ms in LQT2, respectively, which were both significantly larger than those in control subjects (402±36 ms and 99±36 ms). Both QTc and Tpec were significantly prolonged during exercise in LQT1 (599±54 ms and 215±46 ms) with morphological change into a broad-based T-wave pattern. In contrast, exercise produced a prominent notch on the descending limb of the T wave, with no significant changes in the QTc and Tpec (502±82 ms and 163±86 ms: n=19) in LQT2. Conclusions— Tpe interval increases during exercise in LQT1 but not in LQT2, which may partially account for the finding that fatal cardiac events in LQT1 are more often associated with exercise.
THE OPTICAL ACTIVITY OF CEREBROSPINAL FLUID IN SUPPURATIVE MENINGITIS, AND ITS LACTIC ACID, SUGAR, AND CHLORIDE CONTENT
Authors: Sydney L. Wright, Elizabeth F. Herr, John R. Paul
Journal: Journal of Clinical Investigation (1930)

This study deals with the concentrations of lactate, chloride, and reducing substances, and with the optical activity of ultrafiltrates from 49 specimens of cerebrospinal fluid from 9 patients with menin- gitis.In 6 instances comparisons of the concentrations of lactate, chloride, and reducing substance in blood and spinal fluid are given.The change in concentration of lactate, and reducing substances, and in the optical activity in four specimens of cerebrospinal fluid during incubation at 370 for 1 or 2 days is reported.In an earlier study (1) we showed that the greatest part of the levoro- tatory substances detected in protein free ultralfiltrates from blood, consists of the salts of d-lactic acid present in the blood or formed in vitro as the result of the glycolysis of the sugar.In this study, when sufficient fluid was available, polarimetric observations were made to determine whether changes in the rotation observed are correlated with the lactates found in the cerebrospinal fluid in meningitis. LITERATURE Normal cerebrospinal fluidAn examination of the literature has revealed analyses for sugar or lactate in cerebrospinal fluid from individuals supposedly quite normal in 28 subjects by 5 observers.The results are shown in table 1.In addition to these there can be gathered from the literature data from various authors on patients in whom it was reasonably assumed by the authors that the disease from which the patient suffered would not be associated with abnormal values for the constituents of the cerebrospinal fluid under consideration.
Abstract 4142: The effects of SBHA on Notch 1 expression and platinum sensitivity in ovarian cancer cells
Authors: Stephen L. Rose, Muthusamy Kunnimalaiyaan, Jessica Drenzek, Nicole Seiler
Journal: Cancer Research (2010)

Abstract Objective: Despite advances in radical surgical debulking and intraperitoneal chemotherapy, ovarian cancer remains the most deadly gynecologic malignancy. The Notch signaling pathway plays an important role in cellular differentiation, proliferation, and apoptosis. We have previously found Notch 1 intracellular domain (NICD) to be highly expressed in the most platinum resistant ovarian cancer cell lines. Recent evidence has shown that histone deacetylase inhibitors (HDACi's) decrease platinum resistance in oral squamous cell cancers. In addition, the HDACi suberoyl bis-hydroxamic acid (SBHA) has been found to modify Notch 1 expression in other cancers. We hypothesized that SBHA would reduce ovarian cancer cell proliferation through inhibition of the Notch 1 signaling pathway and help sensitize ovarian cancer cells to platinum. Methods: Following treatment with SBHA, NICD expression in the ovarian carcinoma cell lines OVCAR3, SKOV3, and CaOV3 was analyzed by Western blot. The effects of SBHA and cisplatin on ovarian cancer cell growth were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) growth assay. Results: NICD expression by Western blot was consistently reduced in all 3 cell lines following treatment with SBHA. Dose-dependent growth inhibition of ovarian cancer cells was demonstrated with SBHA treatment. Furthermore, the addition of SBHA to cisplatin resulted in additional reduction of NICD and further growth suppression in SKOV3, the most platinum resistant cell line tested. Conclusions: SBHA treatment of ovarian cancer cells led to decreased NICD expression and dose dependent growth reduction in ovarian cancer cells. In addition, we found that SBHA in combination with platinum further reduced NICD expression and growth in SKOV3 cells. These findings provide a compelling argument for further study into the role that Notch 1 signaling may be playing in platinum resistance and ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4142.
Identification of a single nucleotide change in the hypoxanthine-guanine phosphoribosyltransferase gene (HPRTYale) responsible for Lesch-Nyhan syndrome.
Authors: S Fujimori, B L Davidson, W N Kelley, T D Palella
Journal: Journal of Clinical Investigation (1989)

Complete deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) causes the Lesch-Nyhan syndrome. Previous characterization of a mutant form of HPRT, HPRTYale, from a subject with the Lesch-Nyhan syndrome revealed normal mRNA and protein concentrations, no residual catalytic activity, and cathodal migration upon PAGE. We have cloned and sequenced HPRTYale cDNA. The nucleotide sequence of full-length HPRTYale cDNA revealed a single nucleotide substitution compared with normal HPRT cDNA: G----C at nucleotide position 211. This transversion predicts substitution of arginine for glycine at amino acid position 71, explaining the cathodal migration of HPRTYale. Chou-Fasman secondary structure analysis predicts a change in the probability of beta-turn formation in the region containing the mutation. Inclusion of the bulky arginine side chain in place of glycine probably disrupts protein folding as well. Cloning mutant forms of cDNA allows identification of specific mutations, provides insight into mutational mechanisms, and facilitates structure-function analysis of mutant proteins.
Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus.
Authors: R A DeFronzo, R Gunnarsson, O Björkman, M Olsson, J Wahren
Journal: Journal of Clinical Investigation (1985)

The mechanism(s) and site(s) of the insulin resistance were examined in nine normal-weight noninsulin-dependent diabetic (NIDD) subjects. The euglycemic insulin clamp technique (insulin concentration approximately 100 microU/ml) was employed in combination with hepatic and femoral venous catheterization and measurement of endogenous glucose production using infusion of tritiated glucose. Total body glucose metabolism in the NIDD subjects (4.37 +/- 0.45 mg/kg per min) was 38% (P less than 0.01) lower than in controls (7.04 +/- 0.63 mg/kg per min). Quantitatively, the most important site of the insulin resistance was found to be in peripheral tissues. Leg glucose uptake in the diabetic group was reduced by 45% as compared with that in controls (6.0 +/- 0.2 vs. 11.0 +/- 0.1 mg/kg leg wt per min; P less than 0.01). A strong positive correlation was observed between leg and total body glucose uptake (r = 0.70, P less than 0.001). Assuming that muscle is the primary leg tissue responsible for glucose uptake, it could be estimated that 90 and 87% of the infused glucose was disposed of by peripheral tissues in the control and NIDD subjects, respectively. Net splanchnic glucose balance during insulin stimulation was slightly more positive in the control than in the diabetic subjects (0.31 +/- 0.10 vs. 0.05 +/- 0.19 mg/kg per min; P less than 0.07). The difference (0.26 mg/kg per min) in net splanchnic glucose balance in NIDD represented only 10% of the reduction (2.67 mg/kg per min) in total body glucose uptake in the NIDD group and thus contributed very little to the insulin resistance. The results emphasize the importance of the peripheral tissues in the disposal of infused glucose and indicate that muscle is the most important site of the insulin resistance in NIDD.
Comment on Kulkarni et al. Maternal Lipids Are as Important as Glucose for Fetal Growth: Findings From the Pune Maternal Nutrition Study. Diabetes Care 2013;36:2706–2713
Authors: Jaya Prakash Sahoo, Sadishkumar Kamalanathan, Subarna Mitra, Prasanta Kumar Nayak, Ashok Kumar Das
Journal: Diabetes Care (2014)

We read with great interest the article by Kulkarni et al. (1), which shows maternal fasting glucose, total cholesterol, and triglyceride but not HDL cholesterol to be associated with neonatal birth size. These findings, however, are not consistent with many other related studies, including one from India (2–4).

Kulkarni et al. probably attribute the absence of the relationship …
Clinical Manifestations of Systemic Lupus Erythematosus
Authors: Edmund L. Dubois, Denny L. Tuffanelli
Journal: JAMA (1964)

Diagnosis of systemic lupus erythematosus (SLE) was confirmed by the presence of lupus erythematosus cells in 75.7% of the patients, findings of skin biopsies in 6.0% and of renal biopsies in 1.2%, and by the clinical picture alone in 17.1%. Negroes comprised 34% of the subjects. Spontaneous remissions occurred in 35% of the patients. Proven familial SLE occurred in 2%. Myalgia was present in 48.2%. No history of cutaneous involvement at any time was found in 28%. Classic skin lesions of chronic discoid lupus at the onset of their illness were present in 10.8%. Urinary abnormalities were noted in only 46.1%. Uremia caused 34% of the 135 deaths and progressive central nervous system involvement caused 18.4%. The prognosis has markedly improved. The mean duration is now 94.8 months for the entire series versus 38.5 months in an untreated control group.
Is PlGF a plaque growth factor?
Authors: J. Sainz, M. Sata
Journal: Cardiovascular Research (2010)

This editorial refers to 'Short-term delivery of anti-PlGF antibody delays progression of atherosclerotic plaques to vulnerable lesions' by C. Roncal et al., pp.29 -36, this issue.The placental growth factor (PlGF) is a cysteine-knot protein, highly homologous to the vascular endothelial growth factor (VEGF). 1 Initially described in placenta, 2 it was subsequently demonstrated to be expressed in other tissues, including the lung and heart. 3Circulating levels of PlGF are normally undetectable.However, increased PlGF levels have been described under several pathological conditions, including cancer, cutaneous wounds, bone fractures, sicklecell disease, and atherosclerosis. 4In humans, the PlGF gene encodes four different isoforms (PlGF-1, -2, -3, and -4) 5 that are generated by alternative splicing and differ in their binding affinities and secretion properties.In mice, PlGF-2 is the only isoform of PlGF. 6oncal et al. 7 report the efficacy of short-term anti-PlGF treatment in preventing atherosclerosis development by using a neutralizing anti-PlGF monoclonal antibody (aPlGF mAb) at early stages of the disease.Administration of the aPlGF mAb for 5-10 weeks was sufficient to reduce lesion size and inflammation in the less severe murine atherosclerosis models.The antibody used in this study (clone PL5D11D4) specifically recognizes murine PlGF-2 and inhibits its binding to the VEGF receptor-1 (VEGFR-1/Flt-1) and to one of its semaphorin co-receptors, namely neuropilin-1 (NRP-1).The importance of PlGF-2 in the pathogenesis of atherosclerosis was formerly brought to light by Khurana et al., 8 who reported that (i) perivascular transfer of PlGF-2 in hypercholesterolaemic rabbits resulted in enhanced neointima formation and macrophage accumulation, and (ii) early atherosclerotic lesions of ApoE2/2PlGF2/2 mice were smaller and had less macrophage accumulation than ApoE2/2 PlGFþ/þ mice.In the present work, 7 the authors first show increased expression of PlGF and its receptor Flt-1 in ApoE2/2 mice.PlGF was mainly located at the shoulders of atherosclerotic plaques.Then, several murine models of mild and aggressive atherosclerosis were used to assess the potential range of efficacy of short-term aPlGF mAb treatment.These models include: (i) ApoE2/2 mice fed a normal chow (mild ApoE2/2), which induces mild atherosclerosis development; (ii) ApoE2/2 mice that were put on a hypercholesterolaemic diet for 10 or 20 weeks (HC 10 or HC 20 ApoE2/2), which triggers enhanced
Krüppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation
Authors: Yumiko Oishi, Ichiro Manabe, Kazuyuki Tobe, Kensuke Tsushima, Takayuki Shindo, Katsuhito Fujiu, Go Nishimura, Koji Maemura, Toshimasa Yamauchi, Naoto Kubota, Ryo Suzuki, Toshio Kitamura, Shizuo Akira, Takashi Kadowaki, Ryozo Nagai
Journal: Cell Metabolism (2005)
Recent experience with heart transplantation.
Authors: T A English, D K Cooper, R Cory-Pearce
Journal: BMJ (1980)

The major factors contributing to the recommencement of clinical heart transplantation in the United Kingdom last year were the steadily improving results from Stanford University, the clarification of the diagnosis of brain death, and advances in preserving donor hearts. Twelve men aged 16 to 52 years received heart transplants at Papworth Hospital from January 1979 to July 1980. Six had cardiomyopathies and six ischaemic heart disease. The donors were aged 16 to 35 (mean 21) years. A combination of road and air transport was used to transport the heart to Papworth in seven cases. The total donor heart ischaemic time ranged from 108 to 171 minutes (mean 151), and early graft function was satisfactory in all cases. Postoperative management was directed towards preventing rejection and infection. Equine antihuman thymocyte globulin, prednisolone, and azathioprine were used for immunosuppression. Endomyocardial biopsy was performed every 10 to 14 days during the early postoperative period. There were three deaths: one at 17 days from brain damage and two at 59 and 76 days from rejection. Of the remaining nine patients six left hospital and three returned to work. The number of patients who might benefit from heart transplantation is large, but the cost is high. The cost would fall if an effective non-toxic immunosuppressive agent were developed. Meanwhile, a careful evaluation of the benefits of heart transplantation should continue.
Autophagy in axonal degeneration in glaucomatous optic neuropathy
Authors: Yasunari Munemasa, Yasushi Kitaoka
Journal: Progress in Retinal and Eye Research (2015)

The role of autophagy in retinal ganglion cell (RGC) death is still controversial. Several studies focused on RGC body death, although the axonal degeneration pathway in the optic nerve has not been well documented in spite of evidence that the mechanisms of degeneration of neuronal cell bodies and their axons differ. Axonal degeneration of RGCs is a hallmark of glaucoma, and a pattern of localized retinal nerve fiber layer defects in glaucoma patients indicates that axonal degeneration may precede RGC body death in this condition. As models of preceding axonal degeneration, both the tumor necrosis factor (TNF) injection model and hypertensive glaucoma model may be useful in understanding the mechanism of axonal degeneration of RGCs, and the concept of axonal protection can be an attractive approach to the prevention of neurodegenerative optic nerve disease. Since mitochondria play crucial roles in glaucomatous optic neuropathy and can themselves serve as a part of the autophagosome, it seems that mitochondrial function may alter autophagy machinery. Like other neurodegenerative diseases, optic nerve degeneration may exhibit autophagic flux impairment resulting from elevated intraocular pressure, TNF, traumatic injury, ischemia, oxidative stress, and aging. As a model of aging, we used senescence-accelerated mice to provide new insights. In this review, we attempt to describe the relationship between autophagy and recently reported noteworthy factors including Nmnat, ROCK, and SIRT1 in the degeneration of RGCs and their axons and propose possible mechanisms of axonal protection via modulation of autophagy machinery.
Some Clinical and Physiologic Effects of Mitral Commissurotomy
Authors: JOHN A. WOOD, JAMES K. ALEXANDER, CHARLES W. FRANK, JOHN R. WEST, DICKINSON W. RICHARDS
Journal: Circulation (1956)

Eighteen patients, selected for mitral commissurotomy on the basis of appreciable hemodynamic abnormalities as well as physical disability have been studied prior to and following surgery. The results suggest that well compensated patients with mitral stenosis, normal sinus rhythm and pulmonary hypertension are likely to benefit from operation. Patients with atrial fibrillation, good compensation and moderate pulmonary hypertension may benefit from mitral commissurotomy. In patients with atrial fibrillation, marked pulmonary hypertension and congestive heart failure, operation is hazardous and the likelihood of benefit is small. The importance of myocardial function in the production of these results is discussed.
Tumorigenic Conversion of Primary Human Esophageal Epithelial Cells Using Oncogene Combinations in the Absence of Exogenous Ras
Authors: Seok-Hyun Kim, Hiroshi Nakagawa, Arunasalam Navaraj, Yoshio Naomoto, Andres J.P. Klein-Szanto, Anil K. Rustgi, Wafik S. El-Deiry
Journal: Cancer Research (2006)

Abstract To investigate pathways of human esophageal squamous cell transformation, we generated esophageal tumor cells using human telomerase– and SV40-immortalized primary esophageal epithelial cells (EPC2) by overexpression of selected combinations of oncogenes. H-Ras, c-Myc, or Akt, but not epidermal growth factor receptor (EGFR), induced transformed colonies in soft agar. By contrast, bioluminescence imaging of genetically altered immortalized esophageal cells revealed that Akt, EGFR, or H-Ras, but not c-Myc, resulted in tumor formation in immunodeficient mice. H-Ras-driven tumors showed highly tumorigenic phenotypes with 2.6 ± 0.6 days for doubling, whereas Akt and EGFR tumors doubled every 9.5 ± 1.6 and 6.1 ± 1.2 days, respectively. H-Ras-driven tumors expressed the hypoxia-inducible factor target Glut1, whereas Akt- or EGFR-driven tumors had evidence of angiogenesis and no detectable Glut1 expression. Proliferation rates among these tumors were similar, but there was reduced apoptosis in the more aggressive H-Ras-driven tumors that also developed aneuploidy and multiple centrosomes. c-Myc overexpression did not result in tumorigenic conversion but introduction of Bcl-XL into c-Myc-expressing cells generated tumors. Although cytokeratin expression was typical of squamous carcinoma, gene expression profiling was done to compare the four different types of engineered tumors with human esophageal squamous cell carcinomas and adenocarcinomas. Interestingly, c-Myc plus Bcl-XL transformants mimicked squamous carcinomas, whereas H-Ras-, EGFR-, and Akt-driven tumors were similar to adenocarcinomas in their molecular profiles. These genetically engineered models may provide new platforms for understanding human esophagus cancer and may assist in the evaluation of new therapies. (Cancer Res 2006; 66(21): 10415-24)
High Basal Nuclear Levels of Nrf2 in Acute Myeloid Leukemia Reduces Sensitivity to Proteasome Inhibitors
Authors: Stuart A. Rushworth, Kristian M. Bowles, David J. MacEwan
Journal: Cancer Research (2011)

Proteasome inhibitors such as bortezomib exhibit clinical efficacy in multiple myeloma, but studies in acute myeloid leukemia (AML) have been disappointing to date. The apparent failure in AML likely reflects a lack of biological understanding that might clarify applications of proteosome inhibitors in this disease. Here we show that AML cells are considerably less sensitive than control noncancerous cells to bortezomib-induced cytotoxicity, permitting most bortezomib-treated AML cells to survive treatment. We traced reduced bortezomib sensitivity to increased basal levels of nuclear Nrf2, a transcription factor that stimulates protective antioxidant enzymes. Bortezomib stimulates cytotoxicity through accumulation of reactive oxygen species (ROS) but elevated basal levels of nuclear Nrf2 present in AML cells reduced ROS levels, permitting AML cells to survive drug treatment. We further found that the Nrf2 transcriptional repressor Bach1 is rapidly inactivated by bortezomib, allowing rapid induction of Nrf2-regulated cytoprotective and detoxification genes that protect AML cells from bortezomib-induced apoptosis. By contrast, nonmalignant control cells lacked constitutive activation of Nrf2, such that bortezomib-mediated inactivation of Bach1 led to a delay in induction of Nrf2-regulated genes, effectively preventing the manifestation of apoptotic protection that is seen in AML cells. Together, our findings argue that AML might be rendered sensitive to proteasome inhibitors by cotreatment with either an Nrf2-inhibitory or Bach1-inhibitory treatment, rationalizing a targeted therapy against AML.
Pioneer Microbiologists of America
Authors: John H. Raach
Journal: JAMA (1961)

Students of the history of American public health problems or of America's contribution to the development of microbiology will find this book a mine of nuggets. It offers biographical sketches with limited bibliographies of apparently all the leaders in the field of microbiology and contagious disease. The reader is introduced to the subject by a short historical survey of the various epidemics that plagued mankind until the "miasmic" concept of disease gave way to rationality aided by the development of bacteriology. The author emphasizes our debt to our European colleagues in the development of scientific concepts and progress. We receive the impression that man's fight against disease is an arena in which national interests are nonexistent. Many of the men who worked, struggled, and even died from the diseases they were studying have been forgotten, except, perhaps, locally. They were men, however, who tackled the problem of these epidemic diseases