tbuckley/cabot-search huggingface dataset:
Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice
Authors: Stephan E. Lehnart, Marco Mongillo, Andrew Bellinger, Nicolas Lindegger, Bi-Xing Chen, William Hsueh, Steven Reiken, Anetta Wronska, Liam J. Drew, Chris W. Ward, W.J. Lederer, Robert S. Kass, Gregory Morley, Andrew R. Marks
Journal: Journal of Clinical Investigation (2008)

The Ca2+ release channel ryanodine receptor 2 (RyR2) is required for excitation-contraction coupling in the heart and is also present in the brain. Mutations in RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). CPVT-associated RyR2 mutations result in “leaky” RyR2 channels due to the decreased binding of the calstabin2 (FKBP12.6) subunit, which stabilizes the closed state of the channel. We found that mice heterozygous for the R2474S mutation in Ryr2 (Ryr2-R2474S mice) exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with a novel RyR2-specific compound (S107) that enhances the binding of calstabin2 to the mutant Ryr2-R2474S channel inhibited the channel leak and prevented cardiac arrhythmias and raised the seizure threshold. Thus, CPVT-associated mutant leaky Ryr2-R2474S channels in the brain can cause seizures in mice, independent of cardiac arrhythmias. Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exercise-induced sudden cardiac death.
Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis
Authors: John Victor Peter, Preeta John, Petra L Graham, John L Moran, Ige Abraham George, Andrew Bersten
Journal: BMJ (2008)

<b>Objective</b> To systematically review the efficacy of steroids in the prevention of acute respiratory distress syndrome (ARDS) in critically ill adults, and treatment for established ARDS. <b>Data sources</b> Search of randomised controlled trials (1966-April 2007) of PubMed, Cochrane central register of controlled trials, Cochrane database of systematic reviews, American College of Physicians Journal Club, health technology assessment database, and database of abstracts of reviews of effects. <b>Data extraction</b> Two investigators independently assessed trials for inclusion and extracted data into standardised forms; differences were resolved by consensus. <b>Data synthesis</b> Steroid efficacy was assessed through a Bayesian hierarchical model for comparing the odds of developing ARDS and mortality (both expressed as odds ratio with 95% credible interval) and duration of ventilator free days, assessed as mean difference. Bayesian outcome probabilities were calculated as the probability that the odds ratio would be ≥1 or the probability that the mean difference would be ≥0. Nine randomised trials using variable dose and duration of steroids were identified. Preventive steroids (four studies) were associated with a trend to increase both the odds of patients developing ARDS (odds ratio 1.55, 95% credible interval 0.58 to 4.05; P(odds ratio ≥1)=86.6%), and the risk of mortality in those who subsequently developed ARDS (three studies, odds ratio 1.52, 95% credible interval 0.30 to 5.94; P(odds ratio ≥1)=72.8%). Steroid administration after onset of ARDS (five studies) was associated with a trend towards reduction in mortality (odds ratio 0.62, 95% credible interval 0.23 to 1.26; P(odds ratio ≥1)=6.8%). Steroid therapy increased the number of ventilator free days compared with controls (three studies, mean difference 4.05 days, 95% credible interval 0.22 to 8.71; P(mean difference ≥0)=97.9%). Steroids were not associated with increase in risk of infection. <b>Conclusions</b> A definitive role of corticosteroids in the treatment of ARDS in adults is not established. A possibility of reduced mortality and increased ventilator free days with steroids started after the onset of ARDS was suggested. Preventive steroids possibly increase the incidence of ARDS in critically ill adults.
CONSEQUENCES OF METRAZOL SHOCK THERAPY
Authors: CHARLES F. READ
Journal: American Journal of Psychiatry (1940)

Some 320 schizophrenic patients—so diagnosed to the best of our ability—were surveyed physically, neurologically and psychiatrically at least twelve months after the completion of their treatment, in order to establish in so far as possible just what are the risks involved in metrazol shock-therapy. Fifty-one patients in all were thought to show present damage, some of which "damage" might very possibly have occurred without the intervention of this treatment. The evident damages suffered were for the most part confined to three large groups. Vertebral fractures were numerous in the past, possibly 20-30 per cent. However, 50 patients checked after their treatment in 1940 show no fractures. Our inquiry indicates that thus far at least, spinal compression fractures, though highly undesirable, have not proved to be serious complications. Pulmonary tuberculosis developed in 25 patients, 8 per cent of all those treated, as contrasted with a 3.0 per cent incidence in non- metrazol-treated schizophrenics during the same period. Myocardial damage and a tendency to hypertension occurred in a relatively small number of patients. Defects of memory were not obvious enough to be reported upon. Clinical evidences of damage to the central nervous system were suggestive but questionable. Elsewhere in the literature we have presented histological evidence of brain damage in experimental animals and in human subjects following the use of metrazol. To the best of our knowledge, no intracranial accidents occurred. The percentage of mental improvements obtained, including those in out-patients reported upon by social workers, was less than that claimed for "spontaneous" remissions. However, more than 43 per cent of those with a psychosis duration of less than 3 years had improved greatly, whereas in the group of longer duration only 13.2 per cent improved. Many patients showed improvement by psychological tests who apparently had not improved in adjustment to their life-situation as a whole. We realize that many of the findings discussed in this report represent conclusions rather than facts, and that upon the whole trends are indicated rather than exact data. As a result of this investigation, the Elgin staff feels justified in the use of metrazol convulsive shock-therapy—principally in the frankly affective disorders—after careful consideration in each case of possible resultant damage as related to the possibility of improvement.
Oscillation-Free Ballistocardiography
Authors: IRWIN HOFFMAN, MILTON KISSIN, MYRON M. SCHWARZSCHILD
Journal: Circulation (1956)

Body motion resulting from cardiac forces may be recorded as displacement, velocity or acceleration by a variety of methods. None of these is identical with the cardiac force curve because of distortion due to body oscillations. Schwarzschild devised an electronic mixer that combines displacement, velocity, and acceleration in any proportion desired. This device permits recording ballistocardiograms that are free of oscillations due to body resonance. Validity of the technic was established by the identity of strain gage records of forces applied to a log phantom with simultaneous records obtained with the method presented.
Induction of potent TRAIL-mediated tumoricidal activity by hFLEX/Furin/TRAIL recombinant DNA construct
Authors: Xiaofeng Wu, Kam M. Hui
Journal: Molecular Therapy (2004)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to exert selectively cytotoxic activity against many tumor cells but not normal cells. On the other hand, the ligand for the receptor tyrosine kinase Fms-like tyrosine kinase 3 (Flt3L) is a growth factor for hematopoietic progenitors and is a potent stimulating factor for dendritic and NK cells. Previously, we have demonstrated that it is possible to inhibit the outgrowth of primary tumors by the administration of an hFlex (the extracellular domain of the Flt3L) and TRAIL (amino acid residues 95-281) secreted fusion protein. Here, we report that by the insertion of a linker sequence encoding the cleavage site for the Golgi-expressed endoprotease furin between the DNA sequences encoding hFlex and TRAIL, the tumoricidal activity of the cleaved TRAIL protein generated was greatly enhanced in comparison to the hFlex/TRAIL fusion protein. Furthermore, we demonstrate that intratumoral injection of the hFlex/furin/TRAIL DNA, in conjunction with cationic liposomes, significantly suppressed the outgrowth of the human CNE-2 nasopharyngeal tumor xenografts in SCID mice. In situ histological examinations confirmed the expression of TRAIL in the treated tumor nodules and the induction of apoptosis was also evidenced by the presence of numerous pyknotic nuclei.
Angiotensin-converting enzyme and angiotensin II receptor 1 polymorphism in coronary disease and malignant ventricular arrhythmias
Authors: A Anvari
Journal: Cardiovascular Research (1999)

Objectives: It has been reported that patients carrying the angiotensin-converting enzyme (ACE) deletion DD genotype with the angiotensin II type 1 (AT1) C allele are at increased risk for myocardial infarction. The frequency distribution of the ACE and AT1 receptor gene polymorphism and their possible relation regarding malignant ventricular arrhythmias in patients with coronary artery disease (CAD) and left ventricular dysfunction was determined. Methods: The ACE I/D and AT1 A/C polymorphisms (using polymerase chain reaction) in 100 Caucasian patients suffering from CAD with a history of malignant ventricular arrhythmias treated with an implantable cardioverter defibrillator (ICD group) was compared to 127 age-matched Caucasian patients with CAD and no history of malignant ventricular arrhythmias (control group). All patients had reduced left ventricular ejection fraction of <40% and were comparable regarding sex distribution, body mass index, ACE-inhibitor treatment, lipid status and duration of CAD. Results: The prevalence of DD/CC in the ICD group was significantly higher (19% versus 10%, p<0.0001). The risk for malignant ventricular arrhythmias was associated with the combination of ACE D and AT1 C alleles (odds-ratio: 2.4, 95% confidence interval 1.41 to 3.94, p<0.001). The distribution of ACE and AT1 genotypes was not different between the two group. Conclusions: Patients with coronary artery disease and left ventricular dysfunction carrying ACE D and AT1 C alleles are at increased risk for development of malignant ventricular arrhythmias. Because of available pharmacological inhibitors, these results may have clinical implications for the prevention of sudden cardiac death.
Emergency Coronary Artery Bypass Surgery in the Contemporary Percutaneous Coronary Intervention Era
Authors: Niranjan Seshadri, Patrick L. Whitlow, Naveen Acharya, Penny Houghtaling, Eugene H. Blackstone, Stephen G. Ellis
Journal: Circulation (2002)

Since the advent of percutaneous coronary interventions (PCIs), technological advances, adjunctive pharmacotherapy, and increasing operator experience have contributed to lowering the occurrence of major complications. However, emergency coronary artery bypass surgery (CABG) for failed PCI is still associated with important morbidity and mortality, even in the era of coronary stenting. We sought to determine the prevalence, indications, predictors, and complications of emergency CABG after PCI in the past decade.We reviewed 18 593 PCIs performed from 1992 through 2000. There was a need for emergency CABG in 113 (0.61%) cases. The major indications were extensive dissection (n=61, 54%), perforation/tamponade (n=23, 20%), and recurrent acute closure (n=23, 20%). Prevalence of emergency CABG decreased from 1.5% of PCIs in 1992 to 0.14% in 2000 (P<0.001). Independent predictors of the need for emergency CABG included the worst ACC/AHA scoring of the intervened lesion (P<0.001) and female sex (P= 0.028), whereas history of prior bypass surgery and use of stents resulted in a decreased need for emergency CABG (P<0.001 for both). In patients undergoing emergency CABG, there were 17 (15%) in-hospital deaths, 14 (12%) perioperative Q-wave myocardial infarctions, and 6 (5%) cerebrovascular accidents.The need for emergency CABG has considerably decreased over time. Risk factors include female sex and a higher ACC/AHA score of the intervened lesion. However, morbidity and mortality of emergency CABG remain high even in the new millennium.
NT-proBNP–guided and clinically guided treatment reduced short-term but not long-term mortality in chronic HF
Authors: Sabesan Karuppiah
Journal: Annals of Internal Medicine (2010)

Source Citation Lainchbury JG, Troughton RW, Strangman KM, et al. N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial. J Am Coll Cardiol 2009;55:53-60. 20117364
Expression of transglutaminase 1 in human hair follicles, sebaceous glands and sweat glands
Authors: None Yoneda, None Akiyama, None Morita, None Shimizu, None Imamura, None Kim
Journal: British Journal of Dermatology (1998)

To explore the function of the enzyme transglutaminase 1 (TGase 1), its distribution was analysed by immunofluorescence microscopy, postembedding immunoelectron microscopy and in situ hybridization. TGase 1 was expressed in the outer root sheath (ORS) cells in the distal portion of the isthmus and infundibulum of human hair follicles. In the level of the proximal and middle portion of the isthmus, TGase 1 was observed in the keratinized area of the inner root sheath (IRS) and ORS cells. In the bulbar and suprabulbar portions, TGase 1 was present in the ORS and IRS cells. The cortex and medulla cells in these regions also contained TGase 1. A high level of fluorescence was observed at the cuticle of the cortex. Sebaceous and sweat gland cells contained abundant TGase 1. Possible functions of TGase 1 in these epidermal appendages are discussed.
Gaps between UK social groups in infant mortality are widening
Authors: Sally Hargreaves
Journal: BMJ (2007)

Despite an overall improvement in infant mortality in the United Kingdom, inequalities between different social and ethnic groups are widening, says a Department of Health report published this week.

A department spokesman said, “Infant mortality is at an all time low, and the rate continues to fall. However, there remains a gap between the routine and manual classes and the general population.

“Our target is to reduce the infant mortality gap by at least 10% by 2010. We are not complacent. This remains a challenging target.”

Previous research has shown that people in routine and manual occupations—such as porters and cleaners—and in ethnic minorities show consistently poorer health outcomes than the general population. 

The government introduced targets in 2003 to reduce the gap in infant mortality across social groups, as well as to raise life expectancy …
Abstract 5540: Targeting type 1 insulin-like growth factor receptor enhances radiosensitivity in human liposarcoma cell lines
Authors: Jonathan Kuang, Tony Z. Knittel, David Goldstein, Jia Lin Yang
Journal: Cancer Research (2010)

Abstract Soft tissue sarcoma (STS) is currently treated by surgery and adjuvant or neoadjuvant radiotherapy. About 20 - 30% of patients develop local recurrence and 50% will eventually die of their disease. Adjuvant cytotoxic therapies improve disease free survival but overall survival is minimally effected. New treatments are required. As with many cancers there is an imbalance between cell growth and cell death and this also the case with STS. Cell growth signals such as those from the insulin-like growth factor receptor (IGF-1R) increases resistance to radiotherapy. We proved that IGF-1R family members are highly expressed in sarcoma tissue samples, particularly IGF-1R 80% positive, which is also significantly associated with histologic grade. This study investigates whether inhibiting IGF-1R can improve the sensitivity of radiotherapy in liposarcomas. Expression of IGF-1R and/or activated IGF-1R in 3 liposarcoma cell lines was detected by western blot and immunoprecipitation respectively. Crystal violet staining and/or clonogenic assays were used to assess anti-proliferative effects of irradiation and IGF-1R inhibitor (tyrphostin AG1024) or IGF-1R downstream pathway inhibitors (LY294002 and SB202190). Irradiation was performed using Therapax DXT300 Orthovoltage Radiation System. We found that the IGF-1R inhibitor can enhance radiotherapy, particularly in the 2 radio-insensitive sarcoma cell lines (combination index &amp;lt;1 = synergism, CI &amp;lt;0.1 for 449B; CI 0.1-0.3 for 778). The drug reduction index (DRI) at IC50 measures how much the dose of x-ray may be reduced when drug and x-ray were combined at the IC50 effect level compared with the dose of x-ray alone. The DRI for 449B and 778 was 3 and 5 fold for x-ray reduction respectively. In addition, we found that radiation can induce activation of IGF-1R in the sarcoma cell line detected with peak time at 4 hours. Using the IGF-1R inhibitor pre-treatment achieved more inhibitory effect than concurrent inhibitor plus X-ray or X-ray alone group. The greatest enhancement of radiosensitivity was observed with pre-treatment of AG1024 followed by combination therapy, resulting in an 80% decrease in cell survival fraction at the highest dose combination. We also used PI3K and p38 pathway inhibitors singly or together compared with the IGF-1R inhibitor in the presence or absence of X-ray or IGF-1 and discovered that both pathways are involved in radioresistance and the inhibition is at least partially IGF-1R dependent. Targeting the IGF-1R to radiosensitize liposarcomas is a novel treatment strategy that can potentially improve the prognosis of some patients with low radiosensitive liposarcoma. 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 5540.
Book Review Gastrointestinal and nutritional Manifestations of the Acquired Immunodeficiency Syndrome Edited by Donald P. Kotler. 310 pp., illustrated. New York, Raven Press, 1991. $89. ISBN 0–88167–780–9 . Approach to Pulmonary Infections in the Immunocompromised Host Edited by Michael F. Tenholder. 338 pp., illustrated. Mt. Kisco, N.Y., Futura, 1991. $79. ISBN 0–87993–505–7 .
Authors: James T. Noble
Journal: New England Journal of Medicine (1992)
Prevalence and characteristics of anemia in the elderly: Cross‐sectional study of three urban Korean population samples
Authors: Chul Won Choi, Juneyoung Lee, Kyong Hwa Park, So Young Yoon, In Keun Choi, Sang Cheul Oh, Jae Hong Seo, Byung Soo Kim, Sang Won Shin, Yeul Hong Kim, Jun Suk Kim
Journal: American Journal of Hematology (2004)

Abstract We conducted a prospective study to assess the prevalence and clinical characteristics of anemia and to define the risk factors for anemia in older Koreans. From October 2002 to November 2002, 1,254 subjects over the age of 60 years were selected from a cross‐sectional study. All subjects underwent a complete medical history taking and laboratory testing, which included; a complete blood cell count, reticulocyte, liver and renal function tests, lipid profiles, and iron profiles. The median age was 70 years old (range, 60–95 years). The mean levels of hemoglobin (mean ± SD) were 14.5 ± 1.4 g/dL in men and 13.0 ± 1.1 g/dL in women, and the overall prevalence of anemia was 13.6% (171/1,254): 9.9% (27/273) in men and 14.7% (144/981) in women. We found that the prevalence of anemia differed significantly between those of age 60–69 and 70–79 years ( P &lt; 0.0001), those of age 60–69 and ≥80 ( P &lt; 0.0001), and those of age 70–79 and ≥80 ( P = 0.0474). Hemoglobin levels were significantly lower in subjects ≥80 years old. By logistic regression testing, female sex, old age, lower albumin level, higher creatinine level, and lower body mass index were identified as independent risk factors of anemia in elderly Koreans. In conclusion, the overall prevalence of anemia in our study group was 13.6% (171/1,254), and this increased with age. Am. J. Hematol. 77:26–30, 2004. © 2004 Wiley‐Liss, Inc.
Reversal of Global Apoptosis and Regional Stress Kinase Activation by Cardiac Resynchronization
Authors: Khalid Chakir, Samantapudi K. Daya, Richard S. Tunin, Robert H. Helm, Melissa J. Byrne, Veronica L. Dimaano, Albert C. Lardo, Theodore P. Abraham, Gordon F. Tomaselli, David A. Kass
Journal: Circulation (2008)

Background— Cardiac dyssynchrony in the failing heart worsens global function and efficiency and generates regional loading disparities that may exacerbate stress-response molecular signaling and worsen cell survival. We hypothesized that cardiac resynchronization (CRT) from biventricular stimulation reverses such molecular abnormalities at the regional and global levels. Methods and Results— Adult dogs (n=27) underwent left bundle-branch radiofrequency ablation, prolonging the QRS by 100%. Dogs were first subjected to 3 weeks of atrial tachypacing (200 bpm) to induce dyssynchronous heart failure (DHF) and then randomized to either 3 weeks of additional atrial tachypacing (DHF) or biventricular tachypacing (CRT). At 6 weeks, ejection fraction improved in CRT (2.8±1.8%) compared with DHF (−4.4±2.7; P =0.02 versus CRT) dogs, although both groups remained in failure with similarly elevated diastolic pressures and reduced dP/dtmax. In DHF, mitogen-activated kinase p38 and calcium-calmodulin–dependent kinase were disproportionally expressed/activated (50% to 150%), and tumor necrosis factor-α increased in the late-contracting (higher-stress) lateral versus septal wall. These disparities were absent with CRT. Apoptosis assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, caspase-3 activity, and nuclear poly ADP-ribose polymerase cleavage was less in CRT than DHF hearts and was accompanied by increased Akt phosphorylation/activity. Bcl-2 and BAD protein diminished with DHF but were restored by CRT, accompanied by marked BAD phosphorylation, enhanced BAD–14-3-3 interaction, and reduced phosphatase PP1α, consistent with antiapoptotic effects. Other Akt-coupled modulators of apoptosis (FOXO-3α and GSK3β) were more phosphorylated in DHF than CRT and thus less involved. Conclusions— CRT reverses regional and global molecular remodeling, generating more homogeneous activation of stress kinases and reducing apoptosis. Such changes are important benefits from CRT that likely improve cardiac performance and outcome.
Microvascular abnormalities in the mucosal prolapse syndrome.
Authors: B F Warren, J D Davies
Journal: Gut (1993)

Letters the appreciable differences seen in the results.The studies of Lauritsen et al, with faecal dialysates reflect only the intraluminal concen- trations but provide no information about the intramucosal concentrations.The information that results from both types of studies, how- ever, can be complementary.Finally, we totally agree that the very low mucosal concentrations of 5-ASA after Salazopyrin supports the hypothesis that Salazopyrin has pharmocological properties that are different from those of 5-ASA and contribute to its therapeutic efficacy.