tbuckley/cabot-search huggingface dataset:
P313Embryonic cardiomyocytes can orchestrate various cell protective mechanisms to survive metabolic stress
Authors: JD Drenckhahn, M Magarin, T Pohl, A Lill, S Donath, L Thierfelder
Journal: Cardiovascular Research (2014)

Whereas adult cardiomyocytes are highly susceptible to stress, cardiomyocytes in the prenatal heart appear to be rather resistant. To investigate how embryonic cardiomyocytes survive metabolic stress in vivo, we utilized tissue mosaicism for mitochondrial dysfunction in 13.5 dpc mouse hearts. The latter is based on inactivation of the X-linked gene encoding Holocytochrome c synthase (Hccs), which is essential for mitochondrial respiration. In heterozygous heart conditional Hccs knockout females (cHccs+/-) random X chromosomal inactivation results in a mosaic of healthy and Hccs deficient cells in the myocardium. Microarray RNA expression analyses identified genes involved in unfolded protein response (UPR) and programmed cell death as differentially expressed in cHccs+/- versus control embryonic hearts. Activation of the UPR localized to Hccs deficient cardiomyocytes but does not involve ER stress pathways, suggesting that it is caused by defective mitochondria. Consistently, various mitochondrial chaperones, such as HSP10 and HSP60, but not ER chaperones (e.g. GRP78) are induced in defective cells. Mitochondrial dysfunction often results in oxidative stress, and indeed we detected induction of SOD2 and reduced glutathione levels in cHccs+/- hearts. Interestingly, no increase in protein oxidation was observed, suggesting that antioxidative mechanisms in Hccs deficient cardiomyocytes prevent oxidative damage. Mitochondrial dysfunction and unrestricted UPR can induce cell death, and we indeed detected activation of upstream components of both intrinsic as well as extrinsic apoptosis in cHccs+/- hearts. Cell death is not executed, however, suggesting the activation of antiapoptotic mechanisms. Whereas most apoptosis inhibitors (i.e. Bcl-2, Bcl-x, c-FLIP, XIAP, survivin) were either unchanged or downregulated in Hccs deficient cardiomyocytes, ARC (apoptosis repressor with caspase recruitment domain) was induced. Given that ARC can inhibit both apoptotic pathways as well as necrosis and attenuates UPR, we generated cHccs+/- embryos on an ARC knockout background (cHccs+/-,ARC-/-). Surprisingly, the absence of ARC does not induce cell death in embryonic Hccs deficient cardiomyocytes, although no compensatory upregulation of other apoptosis inhibitors was observed. Also, induction of mitochondrial chaperones, antioxidative defense and UPR was not compromised in cHccs+/-,ARC-/- hearts. Taken together, our data demonstrate an impressive plasticity of embryonic cardiomyocytes to respond to metabolic stress, the loss of which might be involved in the high susceptibility of postnatal cardiomyocytes to cell death.
Response and survival in advanced breast cancer after two non-cross-resistant combinations.
Authors: C Brambilla, M De Lena, A Rossi, P Valagussa, G Bonadonna
Journal: BMJ (1976)

A prospective study with two cytotoxic combinations (cyclophosphamide, methotrexate, and fluorouracil (CMF), and adriamycin plus vincristine (AV)) was carried out in 110 patients with advanced breast cancer. There was no significant difference between the treatment groups in the response rate after primary treatment, the median duration of response, and the median survival. In both groups responders survived for longer than non-responders. Secondary treatment after crossover for progression or relapse resulted in response rates of 35% for AV and 20% for CMF. Toxicity was mainly represented by reversible haemosuppression. These results are comparable with those obtained with other multiple-drug regimens, and combination chemotherapy alone seems to have reached a plateau in its capacity to control disseminated breast cancer.
The Vitamin D Receptor and the Syndrome of Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets*
Authors: Peter J. Malloy, J. Wesley Pike, David Feldman
Journal: Endocrine Reviews (1999)

I. The Syndrome of Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets (HVDRR) A. Historical B. Clinical features of HVDRR C. Pathophysiology D. Alopecia E. 1,25-Dihydroxyvitamin D [1,25-(OH)2D] action and HVDRR II. Vitamin D Physiology A. Metabolism B. 1α-Hydroxylase deficiency III. 1,25-Dihydroxyvitamin D Action Mediated by the Vitamin D receptor (VDR) A. Historical aspects of VDR structure and function B. The domain structure of the VDR C. The regulation of gene expression by the VDR IV. Cellular Basis of HVDRR A. Studies in cultured skin fibroblasts B. Studies in other cells V. The VDR Gene and the Molecular Basis of HVDRR A. The VDR chromosomal gene B. The VDR gene promoter C. Polymorphisms of the VDR gene VI. HVDRR Mutations Causing the Ligand-Binding Positive Phenotype A. Initial description of DNA-binding domain (DBD) mutations B. Characterization of additional DBD mutations C. Structural analysis of DBD mutations VII. HVDRR Mutations Causing the Ligand-Binding Negative Phenotype A. Initial descr...
Threshold Levels of ABL Tyrosine Kinase Inhibitors Retained in Chronic Myeloid Leukemia Cells Determine Their Commitment to Apoptosis
Authors: Thomas O'Hare, Christopher A. Eide, Anupriya Agarwal, Lauren T. Adrian, Matthew S. Zabriskie, Ryan J. MacKenzie, Dorian H. LaTocha, Kara J. Johnson, Huihong You, Jenny Luo, Steven M. Riddle, Bryan D. Marks, Kurt W. Vogel, Dennis R. Koop, John Apgar, Jeffrey W. Tyner, Michael W. Deininger, Brian J. Druker
Journal: Cancer Research (2013)

Abstract The imatinib paradigm in chronic myelogenous leukemia (CML) established continuous BCR-ABL inhibition as a design principle for ABL tyrosine kinase inhibitors (TKI). However, clinical responses seen in patients treated with the ABL TKI dasatinib despite its much shorter plasma half-life and the apparent rapid restoration of BCR-ABL signaling activity following once-daily dosing suggested acute, potent inhibition of kinase activity may be sufficient to irrevocably commit CML cells to apoptosis. To determine the specific requirements for ABL TKI-induced CML cell death for a panel of clinically important ABL TKIs (imatinib, nilotinib, dasatinib, ponatinib, and DCC-2036), we interrogated response of CML cell lines and primary CML cells following acute drug exposure using intracellular fluorescence-activated cell sorting and immunoblot analyses of BCR-ABL signaling, apoptosis measurements, liquid chromatography/tandem mass spectrometry of intracellular drug levels, and biochemical TKI dissociation studies. Importantly, significant intracellular TKI stores were detected following drug washout, levels of which tracked with onset of apoptosis and incomplete return of BCR-ABL signaling, particularly pSTAT5, to baseline. Among TKIs tested, ponatinib showed the most robust capacity for apoptotic commitment showing sustained suppression of BCR-ABL signaling even at low intracellular levels following extensive washout, consistent with high-affinity binding and slow dissociation from ABL kinase. Together, our findings suggest commitment of CML cells to apoptosis requires protracted incomplete restoration of BCR-ABL signaling mediated by intracellular retention of TKIs above a quantifiable threshold. These studies refine our understanding of apoptotic commitment in CML cells and highlight parameters important to design of therapeutic kinase inhibitors for CML and other malignancies. Cancer Res; 73(11); 3356–70. ©2013 AACR.
Children in deprived areas at most risk of road injuries
Authors: O. Mashta
Journal: BMJ (2009)

Child pedestrians from the most deprived areas in Great Britain are four times more likely to be killed or injured on the roads than those from wealthier districts, a report by a cross party group of MPs said.

Death rates among child pedestrians in Great Britain are worse than in France, the Netherlands, Japan, Austria, Australia, and Belgium, in terms of the number killed as a proportion of the population, says the report by the House of Commons Public Accounts Committee.

There were 121 pedestrian casualties younger than 17 years old per 100 000 population in the most deprived areas of England, compared with 32 …
The effect of intracoronary injection of contrast medium upon coronary blood flow.
Authors: M Bassan, W Ganz, H S Marcus, H J Swan
Journal: Circulation (1975)

The changes in coronary blood flow in response to intracoronary injection of 3 ml of 76% Renografin were studied in 47 patients using the thermodilution technique for continuous measurement of coronary sinus blood flow. Within seconds after left coronary injection, an increase in coronary sinus flow began which peaked at an average of 53% above control in 5-10 seconds. There was a corresponding decrease in coronary resistance. Flow returned to control level in almost all patients within one minute of injection. Twenty-four of 35 patients had no change in coronary sinus flow in response to right coronary injection. This can be explained by the fact that most of the venous flow from the right coronary artery returns in such a way that it cannot be measured by the coronary sinus catheter. Of the eleven patients who did show an increase, seven had angiographically documented right to left collaterals, suggesting that the increase in flow was the result of vasodilatation of the left coronary bed by contrast arriving via the right to left collaterals. The percent changes in flow and resistance in response to left coronary injection were isgnificantly greater in the 13 normals than in the 34 with obstructive disease of the left coronary artery (P lessthan 0.01). Flow rose 70 plus or minus 27% (mean plus or minus standard deviation) in the normals versus 46 plus or minus 25% in the patients with coronary artery disease, while resistance fell 44 plus or minus 9% versus 33 plus or minus 11%. The differences, however, were not sufficient for these changes to be of value in the assessment of the degree of impairment of the coronary arterial bed in the individual patient.
Mutations in the SIX1/2 Pathway and the DROSHA/DGCR8 miRNA Microprocessor Complex Underlie High-Risk Blastemal Type Wilms Tumors
Authors: Jenny Wegert, Naveed Ishaque, Romina Vardapour, Christina Geörg, Zuguang Gu, Matthias Bieg, Barbara Ziegler, Sabrina Bausenwein, Nasenien Nourkami, Nicole Ludwig, Andreas Keller, Clemens Grimm, Susanne Kneitz, Richard D. Williams, Tas Chagtai, Kathy Pritchard-Jones, Peter van Sluis, Richard Volckmann, Jan Koster, Rogier Versteeg, Tomas Acha, Maureen J. O’Sullivan, Peter K. Bode, Felix Niggli, Godelieve A. Tytgat, Harm van Tinteren, Marry M. van den Heuvel-Eibrink, Eckart Meese, Christian Vokuhl, Ivo Leuschner, Norbert Graf, Roland Eils, Stefan M. Pfister, Marcel Kool, Manfred Gessler
Journal: Cancer Cell (2015)
Enhanced Efficacy of the CDNF/MANF Family by Combined Intranigral Overexpression in the 6-OHDA Rat Model of Parkinson's Disease
Authors: Óscar Cordero-Llana, Benjamin C Houghton, Federica Rinaldi, Hannah Taylor, Rafael J Yáñez-Muñoz, James B Uney, Liang-Fong Wong, Maeve A Caldwell
Journal: Molecular Therapy (2014)

Cerebral Dopamine Neurotrophic Factor (CDNF) and Mesencephalic Astrocyte-derived Neurotrophic factor (MANF) are members of a recently discovered family of neurotrophic factors (NTFs). Here, we used intranigral or intrastriatal lentiviral vector-mediated expression to evaluate their efficacy at protecting dopaminergic function in the 6-OHDA model of Parkinson's disease (PD). In contrast to the well-studied Glial-Derived Neurotrophic Factor (GDNF), no beneficial effects were demonstrated by striatal overexpression of either protein. Interestingly, nigral overexpression of CDNF decreased amphetamine-induced rotations and increased tyroxine hydroxylase (TH) striatal fiber density but had no effect on numbers of TH(+) cells in the SN. Nigral MANF overexpression had no effect on amphetamine-induced rotations or TH striatal fiber density but resulted in a significant preservation of TH(+) cells. Combined nigral overexpression of both factors led to a robust reduction in amphetamine-induced rotations, greater increase in striatal TH-fiber density and significant protection of TH(+) cells in the SN. We conclude that nigral CDNF and MANF delivery is more efficacious than striatal delivery. This is also the first study to demonstrate that combined NTF can have synergistic effects that result in enhanced neuroprotection, suggesting that multiple NTF delivery may be more efficacious for the treatment of PD than the single NTF approaches attempted so far.
Myocardial acidosis associated with CO2 production during cardiac arrest and resuscitation.
Authors: M von Planta, M H Weil, R J Gazmuri, J Bisera, E C Rackow
Journal: Circulation (1989)

Previous studies from our institution demonstrated significant hypercarbic acidosis in the mixed venous (pulmonary artery) blood in animals and human patients during cardiac arrest and cardiopulmonary resuscitation (CPR). In the present study, the acid-base state of the myocardium during cardiac arrest was investigated. Cardiac arrest was electrically induced in 11 pentobarbital-anesthetized and mechanically ventilated domestic pigs. Precordial compression was begun 3 minutes after onset of ventricular fibrillation and continued for 8 minutes. During CPR, there was rapid onset of profound myocardial acidosis with an increase in intramyocardial [H+] from 54 +/- 5 to 146 +/- 20 nmol/l (7.27 +/- 0.04 to 6.88 +/- 0.20 pH units). Great cardiac vein PCO2 increased from 57 +/- 2 to 158 +/- 12 mm Hg. Profound hypercarbic acidosis in great cardiac vein blood was associated with myocardial lactate production to levels of 8.1 +/- 0.7 mmol/l. Only moderate decreases in cardiac vein bicarbonate concentrations from 31 +/- 1 to 23 +/- 1 mmol/l were observed. These acid-base changes were almost completely reversed over an interval of 60 minutes after the animals were successfully resuscitated by DC countershock. The PCO2 in cardiac vein blood was significantly greater than that of mixed venous blood, demonstrating disproportionate myocardial production of CO2 during CPR. Accordingly, it is CO2 production during ischemia that is implicated as the predominant mechanism accounting for myocardial [H+] increases during cardiac arrest. Important clinical implications for buffer therapy during CPR and, in particular, treatment with bicarbonate emerge from these observations.
Indication-Specific Pricing for Cancer Drugs
Authors: Peter B. Bach
Journal: JAMA (2014)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Frequent detection of hepatitis A viral RNA in serum during the early convalescent phase of acute hepatitis A
Authors: K Fujiwara
Journal: Hepatology (1997)

The diagnosis of type A hepatitis is performed mainly by immunoglobulin M (IgM) anti-hepatitis A antibody assay, but it has not been established whether there is a correlation between changes in viremia and the clinical course of type A hepatitis. We examined hepatitis A virus (HAV) RNA in the sera from type A and non-A, non-B, non-C acute hepatitis and analyzed the relation of HAV viremia with alanine aminotransferase (ALT) and IgM-HA levels. Two hundred sera from 38 patients with type A acute hepatitis and 20 patients with non-A, non-B, non-C acute hepatitis were examined for the presence of HAV RNA. HAV RNA was detected by nested reverse transcription-polymerase chain reaction (RT-PCR) with primers located at the 5′ non-translated region of HAV. HAV RNA was detected in 35 of 38 (92%) type A hepatitis patients and in 60 of 156 (38%) serum samples. In contrast, it was detected in none of 44 serum specimens from 20 non-A, non-B, non-C acute hepatitis patients. In type A hepatitis, the mean ALT level in HAV RNA positive specimens was 1,481 ± 2,042 (range, 20-10,370) IU/L and that in HAV RNA negative specimens 186 ± 330 (range, 8-1,698). The positivity of HAV RNA was correlated with the level of transaminase at the time of sample collection. The mean duration from the onset of symptoms to disappearance of HAV RNA was 18 ± 14 days. The mean titer of IgM-HA in HAV RNA positive cases was 5.0 ± 1.4, in negative cases 5.7 ± 1.1, with no statistical difference. Our results indicate that HAV RNA in serum is detectable in the majority of type A hepatitis cases in their early convalescent phase by nested RT-PCR.
Baroreflex control of renal sympathetic nerve activity is potentiated at early phase of two-kidney, one-clip Goldblatt hypertension in conscious rabbits.
Authors: H Kumagai, H Suzuki, M Ryuzaki, S Matsukawa, T Saruta
Journal: Circulation Research (1990)

Conscious normotensive and two-kidney, one-clip Goldblatt hypertensive rabbits were studied to determine the sensitivity of the arterial baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate. The relations of the mean arterial pressure-RSNA and mean arterial pressure-heart rate were examined over a wide range of blood pressures produced by infusions of phenylephrine and nitroglycerin. The maximum slope obtained by logistic function analysis was considered to represent the baroreflex sensitivity. In the early hypertensive group (n = 8; mean arterial pressure +/- SEM, 88 +/- 2 mm Hg) on day 5 after renal clip application, the maximum slope of the mean arterial pressure-RSNA relation was -11.3 +/- 1.2, which was significantly greater than that of the sham normotensive group (-6.9 +/- 0.3, p less than 0.05). The maximum slope (-4.3 +/- 0.2) of the mean arterial pressure-RSNA relation in the late hypertensive group (n = 8; mean arterial pressure, 96 +/- 3 mm Hg) on day 21 after renal clipping was significantly smaller than that of another sham group (-7.2 +/- 0.2, p less than 0.05). In contrast to these changes in the baroreflex control of RSNA, the control of heart rate was attenuated according to the magnitude of mean arterial pressure. To elucidate the mechanisms underlying the potentiated baroreflex, the effects of endogenous neuropeptides were investigated. First, plasma concentrations of angiotensin II and arginine vasopressin that are known to affect the baroreflex were determined. Plasma concentrations of vasopressin (3.1 +/- 0.6 pg/ml) as well as of angiotensin II (34 +/- 7 pg/ml) were increased in the early hypertensive group, and the plasma vasopressin returned to a similar level to the sham group in the late hypertensive group (1.3 +/- 0.4 pg/ml). Second, to study endogenous effects of these neuropeptides on the baroreflex, the maximum slopes of the baroreflex curves during infusions of antagonists for the peptides were determined in the early hypertensive group. The maximum slope of mean arterial pressure-RSNA during intravertebral arterial [Sar1, Ala8]-angiotensin II (-16.4 +/- 1.5) was significantly greater (p less than 0.05), whereas the maximum slope during intravertebral arterial infusion of d(CH2)5Tyr(Me)arginine vasopressin (-4.7 +/- 0.5) was significantly smaller (p less than 0.05) than that during vehicle infusion (-11.3 +/- 1.2).(ABSTRACT TRUNCATED AT 400 WORDS)
Use of a conical spacer device in severe asthma
Authors: S J Williams
Journal: BMJ (1984)

can produce syndromes clinically indistinguish- able from schizophrenia, although septal lesions seem to be associated with a psychosis particularly characterised by perceptual distortions, depersonalisation, anxiety, and de- pression (paper in preparation).Since this region is of critical importance in the integra- tion of sensory information at a sophisticated level, it is perhaps not surprising that increased neuronal activity-as is likely during benzodiazepine withdrawal-should result in hal- lucinations and illusions.The benzodiazepine withdrawal syndrome may constitute not only an important topic for research in its own right but also a useful model for further investigating the nature of functional psychoses.
Indoor Tanning–Related Injuries Treated in a National Sample of US Hospital Emergency Departments
Authors: Gery P. Guy, Meg Watson, Tadesse Haileyesus, Joseph L. Annest
Journal: JAMA Internal Medicine (2014)

Indoor tanning exposes users to intense UV radiation, which is a known carcinogen.1 However, little is known about the more immediate adverse outcomes of indoor tanning. To our knowledge, this study provides the first national estimates of indoor tanning–related injuries treated in US hospital emergency departments (EDs).
Drug resistance in Mycobacterium tuberculosis: a survey over 25 years in Blackburn.
Authors: L P Ormerod, J M Harrison, P A Wright
Journal: Thorax (1986)

Over the past 25 years the incidence of tuberculosis in Blackburn has changed from one that was below the national average to one which is consistently in the 10 highest local authority areas in England and Wales. A survey of primary and acquired drug resistance over the same period included 974 ethnic white patients and 538 of Indian subcontinent ethnic origin. Primary drug resistance in the white population has fallen consistently from 1965 onwards and is now zero. Only one case of acquired resistance has occurred in the last five years. Primary resistance in the immigrant community has been 11-15% from 1965 onwards, and five cases of acquired resistance have occurred since 1970. The pattern of drug resistance over this period supports the view that there is no evidence of cross infection between the native white and immigrant ethnic groups.
Hypersensitivity reaction and acute immune-mediated thrombocytopenia from oxaliplatin: two case reports and a review of the literature
Authors: Marnelli A Bautista, W Tait Stevens, Chien-Shing Chen, Brian R Curtis, Richard H Aster, Chung-Tsen Hsueh
Journal: Journal of Hematology & Oncology (2010)

Abstract Background Oxaliplatin is a platinum compound used in the treatment of gastrointestinal malignancies, including colorectal cancer. The incidence of hypersensitivity reaction in patients receiving oxaliplatin is approximately 15%, with severe reaction (grade 3 and 4) occurring in 2% of patients. Case presentation We report two patients with metastatic colorectal cancer who developed de novo hypersensitivity reaction and acute thrombocytopenia after oxaliplatin infusion. Both patients had oxaliplatin treatment several years before and exhibited hypersensitivity on the third dose of oxaliplatin in recent treatment. Oxaliplatin was discontinued when clinical reaction was identified. Both patients were confirmed to have strong oxaliplatin-induced IgG platelet-reactive antibodies. Both patients' thrombocytopenia resolved within two weeks after discontinuation of oxaliplatin. One patient had disease stabilization lasting for three months without chemotherapy. Both patients subsequently received other chemotherapeutic agents without evidence of hypersensitivity reaction or immune-mediated thrombocytopenia. Conclusion We recommend vigilant monitoring of complete blood count and signs and symptoms of bleeding after the occurrence of oxaliplatin-induced hypersensitivity to avoid serious complications of immune-mediated thrombocytopenia.