tbuckley/cabot-search huggingface dataset:
GRP78 expression inhibits insulin and ER stress–induced SREBP-1c activation and reduces hepatic steatosis in mice
Authors: Hélène L. Kammoun, Hervé Chabanon, Isabelle Hainault, Serge Luquet, Christophe Magnan, Tatsuro Koike, Pascal Ferré, Fabienne Foufelle
Journal: Journal of Clinical Investigation (2009)

Hepatic steatosis is present in insulin-resistant obese rodents and is concomitant with active lipogenesis. Hepatic lipogenesis depends on the insulin-induced activation of the transcription factor SREBP-1c. Despite prevailing insulin resistance, SREBP-1c is activated in the livers of genetically and diet-induced obese rodents. Recent studies have reported the presence of an ER stress response in the livers of obese ob/ob mice. To assess whether ER stress promotes SREBP-1c activation and thus contributes to lipogenesis, we overexpressed the chaperone glucose-regulated protein 78 (GRP78) in the livers of ob/ob mice using an adenoviral vector. GRP78 overexpression reduced ER stress markers and inhibited SREBP-1c cleavage and the expression of SREBP-1c and SREBP-2 target genes. Furthermore, hepatic triglyceride and cholesterol contents were reduced, and insulin sensitivity improved, in GRP78-injected mice. These metabolic improvements were likely mediated by restoration of IRS-2 expression and tyrosine phosphorylation. Interestingly, GRP78 overexpression also inhibited insulin-induced SREBP-1c cleavage in cultured primary hepatocytes. These findings demonstrate that GRP78 inhibits both insulin-dependent and ER stress-dependent SREBP-1c proteolytic cleavage and explain the role of ER stress in hepatic steatosis in obese rodents.
Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ release in heart failure
Authors: Makoto Ono, Masafumi Yano, Akihiro Hino, Takeshi Suetomi, Xiaojuan Xu, Takehisa Susa, Hitoshi Uchinoumi, Hiroki Tateishi, Tetsuro Oda, Shinichi Okuda, Masahiro Doi, Shigeki Kobayashi, Takeshi Yamamoto, Noritaka Koseki, Hiroyuki Kyushiki, Noriaki Ikemoto, Masunori Matsuzaki
Journal: Cardiovascular Research (2010)

Calmodulin (CaM) is well known to modulate the channel function of the cardiac ryanodine receptor (RyR2). However, the possible role of CaM on the aberrant Ca2+ release in diseased hearts remains unclear. In this study, we investigated the state of RyR2-bound CaM and channel dysfunctions in pacing-induced failing hearts. The characteristics of CaM binding to RyR2 and the role of CaM on the aberrant Ca2+ release were assessed in normal and failing canine hearts. The affinity of CaM binding to RyR2 was lower in failing sarcoplasmic reticulum (SR) than in normal SR. Addition of FK506, which dissociates FKBP12.6 from RyR2, to normal SR reduced the CaM-binding affinity. Dantrolene restored a normal level of the CaM-binding affinity in either FK506-treated (normal) SR or failing SR, suggesting that the defective inter-domain interaction between the N-terminal domain and the central domain of RyR2 (the therapeutic target of dantrolene) is involved in the reduction of the CaM-binding affinity in failing hearts. In saponin-permeabilized cardiomyocytes, the frequency of spontaneous Ca2+ sparks was much more increased in failing cardiomyocytes than in normal cardiomyocytes, whereas the addition of a high concentration of CaM attenuated the aberrant increase of Ca2+ sparks. The defective inter-domain interaction between N-terminal and central domains within RyR2 reduces the binding affinity of CaM to RyR2, thereby causing the spontaneous Ca2+ release events in failing hearts. Correction of the defective CaM binding may be a new strategy to protect against the aberrant Ca2+ release in heart failure.
Elevated soluble CD4 levels in the cerebrospinal fluid in patients with adult T‐cell leukemia
Authors: Kimiharu Uozumi, Shuichi Hanada, Kenji Ishitsuka, Nobuhito Ohno, Maki Otsuka, Shigemi Shimotakahara, Katsushi Nakahara, Taketsugu Takeshita, Yoshiko Chyuman, Yasuo Kuwazuru, Torahiko Makino, Takeshi Saito, Kazuaki Ishibashi, Masahito Iwahashi, Atae Utsunomiya, Terukatsu Arima
Journal: American Journal of Hematology (1994)

Levels of the soluble form of the leukocyte surface antigen CD4 (sCD4) were measured by enzyme linked immunosorbent assay (ELISA) in the cerebrospinal fluid (CSF) of patients with adult T-cell leukemia (ATL) and other malignant and non-malignant diseases. All patients with ATL and meningeal infiltration had markedly elevated levels of sCD4 in the CSF (53.7 +/- 34.9 U/ml). ATL patients without CSF pleocytosis often had elevated levels of sCD4 (15.1 +/- 9.2 U/ml). Non-ATL patients with CSF pleocytosis had elevated levels of sCD4 (23.3 +/- 12.2 U/ml) and those without CSF pleocytosis also showed elevation of sCD4 levels (16.8 +/- 9.3 U/ml). However, the mean levels of sCD4 in CSF from these patients were significantly lower than ATL patients with meningeal infiltration. Soluble CD4 in the CSF from healthy volunteers were below the detectable limit. We conclude that meningeal infiltration of CD4(+) ATL cells is strongly associated with elevated sCD4 levels in CSF, and some part of sCD4 in CSF may be originated from the native cells in the CNS as a response of inflammatory stimulations. Therefore, measurement of sCD4 may be useful in the diagnosis of meningeal infiltration and/or meningeal irritation in patients with ATL.
EU pilot project promotes sharing of research data
Authors: R. Watson
Journal: BMJ (2014)

Background/Aim: Classical taxanes are routinely used in cancer therapy. In this study, mechanisms involved in death induction by the novel fluorine-containing taxane SB-T-12854 were investigated. Materials and Methods: We employed breast cancer SK-BR-3, MCF-7 and T47D cell lines to assess activation of individual caspases, changes in the expression of proteins of the Bcl-2 family, and the release of pro-apoptotic factors from mitochondria into the cytosol after SB-T-12854 treatment. Results: Caspase-2, -8, and -9 were activated in SK-BR-3 and MCF-7 cells. Only caspase-8 was activated in T47D cells. Caspase-7 and -6 were activated in all tested cells while caspase-3 was activated only in SK-BR-3 cells. Pro-apoptotic Bad protein seems to be important for cell death induction in all tested cells. Anti-apoptotic Bcl-2 and pro-apoptotic Bim, Bok, Bid and Bik seem to be also associated with cell death induction in some of the tested cells. The mitochondrial apoptotic pathway was significantly activated in association with the release of cytochrome c and Smac from mitochondria, but only in SK-BR-3 cells, not in MCF-7 and T47D cells. Conclusion: Cell death induced by SB-T-12854, in the tested breast cancer cells, differs regarding activation of caspases, changes in levels of pro-apoptotic and anti-apoptotic proteins of the Bcl-2 family and activation of the mitochondrial apoptotic pathway.
“Early” Class III Drugs for the Treatment of Atrial Fibrillation
Authors: Y. Blaauw, H. Gögelein, R.G. Tieleman, A. van Hunnik, U. Schotten, M.A. Allessie
Journal: Circulation (2004)

Currently available antiarrhythmic drugs are only moderately effective against atrial fibrillation (AF) and may cause ventricular proarrhythmia. AVE0118 is a blocker of atrium-specific early K+ currents (I(Kur)/I(to)).Effects of intravenous AVE0118 and dofetilide on atrial effective refractory period (AERP) and inducibility of AF were measured before and after 48-hours of AF-induced electrical remodeling in the goat. During persistent AF (53+/-19 days), the cardioversion efficacy and effects on atrial wavelength of AVE0118, dofetilide, and ibutilide were evaluated. QT durations were measured during atrial pacing and persistent AF. After 48 hours of AF, the effect of dofetilide on AERP was reduced, and induction of AF was not prevented. In contrast, the class III action of AVE0118 was enhanced, and AF inducibility decreased from 100% to 32% (P<0.001). At 1, 3, and 10 mg x kg(-1) x h(-1), AVE0118 terminated persistent AF in 1 of 8, 3 of 8, and 5 of 8 goats, respectively. Dofetilide and ibutilide terminated AF in 1 of 5 and 2 of 7 goats. AVE0118 0.5, 1.5, and 5 mg/kg prolonged the AERP during AF and increased the fibrillation wavelength from 6.7+/-0.6 to 8.5+/-0.5, 9.7+/-0.5, and 11.2+/-0.9 cm (P<0.01). Whereas dofetilide and ibutilide prolonged QT duration, AVE0118 had no appreciable effect.AVE0118 markedly prolongs the AERP during AF without affecting QT duration. Cardioversion of AF was due to an approximately 2-fold increase in fibrillation wavelength. Atrium-selective class III drugs like AVE0118 may be a promising new option for safe and effective cardioversion of AF.
Abstract 4981: NADPH oxidase is a novel target of delphinidin to inhibits UVB-induced MMP-1 expression in human dermal fibroblasts
Authors: Tae-Gyu Lim
Journal: Cancer Research (2012)

Abstract Ultraviolet (UV) induced ROS production is considered a major cause of photoaging via abnormal expression of matrix metalloproteinase (MMP)-1 and NADPH oxidase (NOX) is a key enzyme of endogenous ROS production. Here, we investigated the anti-photoaging effect of delphidin, a major anthocyanin found in berry, beans, and red wine, and its molecular target in UVB-induced MMP-1 expression using primary cultured human dermal fibroblast. Delphinidin inhibited UVB-induced MMP-1 expression in human dermal fibroblasts. UVB-induced MKK4-JNK1/2, MKK3/6-p38, and MEK-ERK1/2 phosphorylation were suppressed by delphinidin. In addition, quantification of ROS stained with the 2′,7′-dichlorofluorescein diacetate (DCF-DA) dye showed that delphinidin significantly inhibited UVB-induced ROS production. Delphinidin significantly inhibited UVB-induced NOX activity. Interestingly, the inhibitory effect of delphinidin on UVB-induced NOX activity was stronger than apocynin, a pharmaceutical NOX inhibitor. Fractioned cell analysis results using a western blot assay showed that delphinidin strongly suppressed UVB-induced P47phox, a NOX subunit, translocation from the cytosol to the membrane. Delphinidin produced similar effects with apocynin on UVB-induced MMP-1 expression. Pull down assays showed that delphinidin directly bound to P47phox. Collectively, our results suggest that NOX is a potential target of delphinidin in the suppression of UVB-induced MMP-1 expression in human dermal fibroblasts. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4981. doi:1538-7445.AM2012-4981
LABORATORY EXAMINATIONS IN DIABETES AND IN GASTRIC DISORDERS
Authors: E. H. Boyer
Journal: JAMA (1933)

<h3>To the Editor:</h3> —In the editorial comment on serum amylase (The Journal, March 11) appears the following: "Chemical examination of the blood... has displaced the older chemical examination of the urine in several directions, such as for the study of the diabetic state." Such a statement is not in accord with the facts. When studying the diabetic state the physician is primarily concerned with the metabolism of carbohydrate and the ability of the patient to utilize the carbohydrate ingested. Blood sugar estimations are of occasional importance in determining the existence of the diabetic state; i. e., in differentiating true diabetes from nondiabetic glycosuria. Occasionally the renal threshold for dextrose is so high that glycosuria does not occur in the diabetic state, so that blood sugar determinations afford the best means of ascertaining the individual's carbohydrate metabolism. But after the diagnosis of diabetes has been established and the renal threshold value
Continuing Incapacity Despite "Medical Recovery"
Authors: Milton H. Miller
Journal: JAMA (1961)

The physician not infrequently encounters patients who have achieved good medical or surgical recovery but fail to return to a life of useful activity. Such patients show a continuing incapacity despite "medical recovery." This is especially likely to occur after illnesses that immobilize the patient and make him dependent upon others for his care. His relation to the physician and the physician's understanding and interest strongly influence the results. The histories of 2 male patients aged 44 and 37 years illustrate these principles. It is recommended that discharge planning begin at the time of the physician's first interview with the patient and that measures to keep the patient alert, stimulated, and self-confident be considered, especially if treatment involves long periods of immobilization.
Smoking cessation services for young people
Authors: G. M Grimshaw, A. Stanton
Journal: BMJ (2008)

Have only modest effects, but respect and encouragement may help

In the United Kingdom, around 12% of teenagers are regular smokers and in parts of the world more than 35% of young people smoke.1 Evidence suggests that preventive measures have limited success in stemming the progress from early experimentation to addiction and on to long term regular smoking in adulthood.2

The white paper, Smoking Kills , noted that people who start smoking at an early age are more likely than other smokers to smoke for a long period of time and more likely to die prematurely from a smoking related disease. Yet studies have shown that young people who smoke repeatedly attempt to quit,3 and around 70% of young smokers express a desire to quit shortly after taking up the habit.4 The primary aim of smoking cessation services is to help young people to quit before smoking becomes addictive, heavy, and ingrained. In the light of this, we need to know what works for young people who have …
Potential importance of the sexual transmission of non-A, non-B hepatitis Alter MJ, Coleman PJ, Alexander WJ, Kramer E, Miller JK, Mandel E, Hadler SC, et al. Importance of heterosexual activity in the transmission of hepatitis B and non-A, non-B hepatitis. JAMA 1989;262:1201–1205
Authors: R Perillo
Journal: Hepatology (1991)
Patient-Physician Communication: Respect for Culture, Religion, and Autonomy
Authors: Stella Fitzgibbons
Journal: JAMA (1996)

<h3>To the Editor.</h3> —Drs Carrese and Rhodes<sup>1</sup>offer us a detailed exposition of the Navajo view that bad outcomes can be avoided by not speaking or even thinking of them, a view refuted by the Navajos' own rate of morbidity and death from treatable and preventable diseases. The physicians find it "ethically troublesome" to discuss advance directives with hospitalized Navajos, a group who have already broken with that view by consenting to hospitalization. It is time for a reality check when contributors to<i>JAMA</i>start asking physicians to avoid discussions of sickness, injury, and death, the very reasons our profession exists. Are we to withhold the facts about possible operative complications from Navajos faced with surgery? Or prescribe antibiotics without mentioning the infection they are supposed to treat? Respecting our patients' views is both noble and necessary. But refusing to give them the facts about their condition and possible
TCF-1 and LEF-1 act upstream of Th-POK to promote the CD4+ T cell fate and interact with Runx3 to silence Cd4 in CD8+ T cells
Authors: Farrah C Steinke, Shuyang Yu, Xinyuan Zhou, Bing He, Wenjing Yang, Bo Zhou, Hiroshi Kawamoto, Jun Zhu, Kai Tan, Hai-Hui Xue
Journal: Nature Immunology (2014)
Missed Opportunities in Embryonic Stem-Cell Research
Authors: George Q. Daley
Journal: New England Journal of Medicine (2004)

Three years have passed since August 9, 2001, when President George W. Bush drew a line in the sand: he announced that research on human embryonic stem cells created before that date would be supported by federal dollars; research on lines created later would not. The President's policy has severely curtailed opportunities for U.S. scientists to study the cell lines that have since been established, many of which have unique attributes or represent invaluable models of human disease.Some 128 new human embryonic stem-cell lines have been produced worldwide since the President's announcement.1 Douglas Melton et al. of Harvard University . . .
598 Functional genetic polymorphisms of microsomal triglyceride transfer protein and manganase-SOD in nonalcoholic steatohepatitis and primary biliary cirrhosis
Authors: T. Saibara, C. Namikawa, S.P. Zhang, Y. Nozaki, N. Yoshihisa, M. Ono, N. Akisawa, S. Iwasaki, S. Onishi, M. Hiroi, H. Enzan
Journal: Journal of Hepatology (2004)
STUDIES ON THE SITE OF ANTIBODY FORMATION IN RABBITS FOLLOWING INTRACUTANEOUS INJECTIONS OF PNEUMOCOCCUS OR OF STREPTOCOCCUS VACCINE
Authors: Paul F. deGara, D. Murray Angevine
Journal: The Journal of Experimental Medicine (1943)

1. The antibody response of rabbits following intracutaneous injections of pneumococcus or of streptococcus vaccines showed three phases. (a) Within 5 to 12 days following a single injection of pneumococcus or of streptococcus vaccine, high antibody titres were detected in extracts from the site of the injection into the skin, the spleen, the bone marrow, and the liver. Occasionally, antibodies were also found in the draining lymph nodes. During this first phase, the titre of the circulating antibodies was low or negative. (b) During the next phase, when the interval between antigen injection and antibody titrations was prolonged from 2 to 4 weeks, the titres of the blood and of the organs showed only slight differences. High titres were observed during this period in extracts from the injected parts of the skin. (c) After a still longer interval during a third phase of antibody response, the serum titre decreased more rapidly than the titre of the extracts from spleen, bone marrow, and injected skin. 2. Similar results were obtained in rabbits following repeated intracutaneous injections of the vaccines. In these rabbits, however, antibodies usually were not detected during the first phase in extracts from the site of the injection into the skin. The repeated injections of the antigen had perhaps neutralized locally formed antibodies and interfered with their detection until an excess of antibodies was produced. No antibodies were found in the lymph nodes of the rabbits that had received repeated injections of vaccines. 3. The antibody titre of the kidney, anterior wall of the stomach, and non-injected parts of the skin was negative or very low. 4. The demonstration of antibodies in extracts from the site of the injection of antigen into the skin and their presence in lymph nodes before they are demonstrable in the blood shows that they are formed at the local site of inflammation. At the same time antibodies are formed in organs that fix antigen, namely in spleen, liver, and bone marrow.
Gene-Environment Interactions and Depression
Authors: Christian Schwahn
Journal: JAMA (2009)

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Steroids in Nephrotic Syndrome
Authors: Hans Erik Rugstad
Journal: JAMA (1962)

<h3>To the Editor:—</h3> I have just read Heymann's and Hunter's article "Importance of Early Treatment of the Nephrotic Syndrome (<i>JAMA</i><b>175</b>:563 [Feb. 18] 1961). I should like to comment on the article. Recovery from the nephrotic syndrome in children is more likely to take place when the disease has lasted for a short time. When the nephrotic syndrome has persisted for a long time there is little probability of recovery. As far as I can see, the authors have missed this important point. They have found a statistically significant difference in prognosis between the group of children starting steroid treatment within the first 3 months after onset of the disease and the group starting treatment any time thereafter. I am not surprised that they find a statistically significant difference between these 2 groups but I am surprised that the authors claim it to be the result of early steroid
Tc-99m HMPAO Brain Scintigraphy in Children With Partial Epilepsy
Authors: LUCIANO FEGGI, PAOLS SCARPA, FERDINANDO CALZOLARI
Journal: Clinical Nuclear Medicine (1995)

The aim of this article is to verify if SPECT is useful for better classification and therapy of pediatric partial epilepsy when clinical findings, electroencephalogram (EEG), and neuroimaging are inconclusive. Twenty patients, who ranged in age from 9 months to 17 years, were studied qualitatively and semiquantitatively by Tc-99m HMPAO SPECT during the interictal phase. SPECT demonstrated areas of reduced cerebral perfusion in all patients. In four patients, SPECT agreed with the clinical and electroencephalographic data. In eight patients with generalized anomalies on EEG, SPECT showed focal hypoperfusion in accord with the clinical findings. In four patients, SPECT agreed only with the EEG findings. In the remaining four patients, SPECT findings, inconsistent with clinical and EEG data, did not improve the diagnostic accuracy. Semiquantitative analysis does not modify the scintigraphic information. SPECT was particularly useful in borderline cases. The identification of localized hypoperfusion areas in patients with generalized seizures, either primary or secondary, but with focal EEG abnormalities, confirms the possibility of seizures of focal origin. In pediatric patients with partial epilepsy, SPECT is able to detect changes in cerebral blood flow which probably correspond to the epileptogenic foci. It can influence the prognosis and the therapy when the results of EEG and neuroradiologic examinations are nonspecific or negative.