tbuckley/cabot-search huggingface dataset:
Larger dispersion of INa in female dog ventricle as a mechanism for gender-specific incidence of cardiac arrhythmias
Authors: H. Barajas-Martinez, V. Haufe, C. Chamberland, M.-J. B. Roy, M. H. Fecteau, J. M. Cordeiro, R. Dumaine
Journal: Cardiovascular Research (2008)

Women have a higher incidence of long QT-related arrhythmias, whereas men exhibit a higher incidence of Brugada syndrome (BrS). The cardiac sodium current (INa) is associated with arrhythmias in BrS and long QT-syndrome (LQTS) and conduction disease. Although a great deal of work has been performed to explain how heterogeneous distribution of repolarizing currents triggers arrhythmias, the transmural distribution of INa within the cardiac ventricle and its contribution to generate the arrhythmogenic substrate remain unknown. We undertook to determine whether INa was heterogeneously distributed within the ventricular wall of canine heart, an animal model close to humans. Using patch-clamp and molecular biology techniques, we tested whether gender differences exist in the ventricular distribution and amplitude of INa in the canine heart model. Our results show that the INa amplitude is smaller in the female epicardial and endocardial layers of the left ventricle, but similar to male in the mid-myocardium. Exposure of female cardiomyocytes to testosterone increased the amplitude of INa to levels similar to male in epicardium, but had no effects in mid-myocardial and endocardial cells. Castrated male dogs displayed INa amplitudes similar to what was found in female hearts. The larger dispersion of INa amplitude within the female cardiac ventricle may contribute to the higher risk of arrhythmias in females. Testosterone modulates this dispersion. By decreasing the transmural dispersion of INa, testosterone may exert a protective effect against LQTS-related arrhythmias in males.
PPARγ Agonists, Modulation of Ion Transporters, and Fluid Retention
Authors: Charity Nofziger, Bonnie L. Blazer-Yost
Journal: Journal of the American Society of Nephrology (2009)

Peroxisome proliferator-activated receptor γ (PPARγ) agonists, also known as thiazolidinediones (TZDs), are used as insulin-sensitizing agents to treat type 2 diabetes. Examples include pioglitazone (Actos®), rosiglitazone (Avandia®), and others such as troglitazone, farglitazar (GI262570), and GW7845. Side effects of TZD therapy include fluid retention and peripheral edema. The weight gain from fluid retention is undesirable from a cosmetic standpoint but more seriously can adversely affect comorbidity in the diabetic state.1

Reported effects of PPARγ agonists on cardiovascular function are mixed. One recent high-profile study found that rosiglitazone increases the risk of death from cardiovascular disease,2 although other studies observe beneficial effects of pioglitazone on major cardiovascular events in humans3 and protection against ischemia–reperfusion injury and reduction of myocardial infarct size in animal models.4 Regardless of the risk–benefit relationships of PPARγ agonist therapy, it is clear that fluid retention exacerbates compromised cardiac function and lessens patient compliance with drug treatment. Unfortunately, PPARγ-agonist-induced fluid retention is refractory to most first-line diuretic therapies.5

The nature of PPARγ-agonist-induced fluid retention suggests an integrated physiologic response that includes a primary effect on renal regulation of salt and water balance. PPARγ is expressed in the collecting duct, suggesting that ligands for this receptor modulate salt and water homeostasis through ion transport systems in this nephron segment. The epithelial Na+ channel (ENaC) expressed in collecting duct principal cells is regulated by steroid (aldosterone) and peptide hormones (insulin, IGF-1, and vasopressin) and represents a key control point for the modulation of salt reabsorption and, consequently, BP. It is logical, therefore, to postulate that ENaC is a likely target of a PPARγ agonist effect. Unfortunately, studies performed to substantiate this relationship are contradictory, and it is difficult to establish a consensus as to potential mechanisms.

Two different collecting-duct-specific PPARγ null mouse models showed …
Using Health Technology Assessment to Identify Gaps in Evidence and Inform Study Design for Comparative Effectiveness Research
Authors: Sean R. Tunis, Charles Turkelson
Journal: Journal of Clinical Oncology (2012)

Health technology assessment (HTA) is primarily used as a tool to ensure that clinical and policy decisions are made with the benefit of a systematic analysis of all completed research. This article describes the progress and potential for HTA reports to improve the quality and relevance of future research and to better serve the information needs of patients, clinicians, payers, and other decision makers. We conducted a review of the current published literature and working papers describing past, ongoing, and future initiatives that rely on HTA reports to identify gaps in evidence and improve the design of future research. Although still in a developmental stage, significant progress is under way to improve methods for using HTA reports for the systematic identification of research gaps, prioritization of future research, and improvement of study designs. Several well-defined frameworks have been developed to assist those who produce HTA to become more effective in these additional domains of work. A recurring element of this work is the importance of meaningfully involving stakeholders in the process of defining future research needs and designing studies to address them. Patients, clinicians, and payers are important audiences for completed research and are now recognized as serving an important role in determining what future research is needed. There are substantial opportunities to improve the quality, relevance, and efficiency of clinical research. Recent efforts are beginning to demonstrate the potential to build on the work invested in developing HTA reports to provide a roadmap toward these objectives.
Increased frequency of HLA-DRB1*0401 in patients with RA and bronchiectasis
Authors: E TOUSSIROT
Journal: Annals of the Rheumatic Diseases (2000)

CoVee consumption, RF, and the risk of RAStress is one of the factors that can trigger the onset of rheumatoid arthritis (RA).People working under deadline pressure, and people characterised as hard driving, "type A" personalities may be most likely to experience stress.These are the same people who may consume large quantities of coVee in order to stay at peak performance for longer periods of time.Possibly, therefore, the correlation reported by Heliövaara et al 1 between coVee consumption and RA may, in part, be due to the association between stress and RA.
Early [18F]Fluorodeoxyglucose–Positron Emission Tomography Responses in Metastatic Melanoma: What Do They Mean?
Authors: Michael J. Millward
Journal: Journal of Clinical Oncology (2012)

Inhibition of oncogenic BRAF signaling has shown substantial benefit in the approximately 50% of patients with metastatic melanoma whose tumors harbor an activating mutation. Vemurafenib, a selective and potent inhibitor of mutated BRAF kinase, has rapidly moved from early clinical trials to status as an approved drug on the basis of significant improvements in progression-free survival (PFS), overall survival, and response rate compared with standard dacarba
New Topoisomerase I mutations are associated with resistance to camptothecin
Authors: Céline Gongora, Nadia Vezzio-Vie, Sandie Tuduri, Vincent Denis, Annick Causse, Céline Auzanneau, Gwenaëlle Collod-Beroud, Arnaud Coquelle, Philippe Pasero, Philippe Pourquier, Pierre Martineau, Maguy Del Rio
Journal: Molecular Cancer (2011)

Abstract Background Topoisomerase I (TOP1) is a nuclear enzyme that catalyzes the relaxation of supercoiled DNA during DNA replication and transcription. TOP1 is the molecular target of camptothecin and related drugs such as irinotecan and SN38 (irinotecan's active metabolite). Irinotecan is widely used as an anti-cancer agent in the treatment of metastatic colon cancer. However, its efficacy is often limited by the development of resistance. Methods We previously established several SN38 resistant HCT116-derived clones to study the mechanisms underlying resistance to SN38. Here, we investigated whether resistance to SN38 in these cell lines could be linked to the presence of TOP1 mutations and changes in its expression and activity. Functional analyses were performed on these cell lines challenged with SN38 and we specifically monitored the double strands breaks with γH2AX staining and replication activity with molecular combing. Results In SN38 resistant HCT116 clones we identified three new TOP1 mutations, which are located in the core subdomain III (p.R621H and p.L617I) and in the linker domain (p.E710G) and are packed together at the interface between these two domains. The presence of these TOP1 mutations in SN38 resistant HCT116 cells did not modify TOP1 expression or intrinsic activity. Conversely, following challenge with SN38, we observed a decrease of TOP1-DNA cleavage complexes and a reduction in double-stranded break formation). In addition, we showed that SN38 resistant HCT116 cells present a strong decrease in the SN38-dependent asymmetry of replication forks that is characteristic of SN38 sensitive HCT116 cells. Conclusions These results indicate that the TOP1 mutations are involved in the development of SN38 resistance. We hypothesize that p.L617, p.R621 and p.E710 TOP1 residues are important for the functionality of the linker and that mutation of one of these residues is sufficient to alter or modulate its flexibility. Consequently, linker fluctuations could have an impact on SN38 binding by reducing the enzyme affinity for the drug.
Can acetylcysteine slow lung function decline in idiopathic pulmonary fibrosis?
Authors: T Toma
Journal: Thorax (2006)

▴ Demedts M, Behr J, Buhl R, et al and the IFIGENIA Study Group. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med2005;353:2229–42 [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] Efficient treatments in idiopathic pulmonary fibrosis (IPF) are elusive and patients die 3–5 years after diagnosis. The standard treatment for IPF includes prednisolone and azathioprine, but there is little evidence that these drugs alter the progress of the disease. This study suggests that the addition of high dose acetylcysteine … [1]: {openurl}?query=rft.jtitle%253DNew%2BEngland%2BJournal%2Bof%2BMedicine%26rft.stitle%253DNEJM%26rft.issn%253D0028-4793%26rft.aulast%253DDemedts%26rft.auinit1%253DM.%26rft.volume%253D353%26rft.issue%253D21%26rft.spage%253D2229%26rft.epage%253D2242%26rft.atitle%253DHigh-Dose%2BAcetylcysteine%2Bin%2BIdiopathic%2BPulmonary%2BFibrosis.%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMoa042976%26rft_id%253Dinfo%253Apmid%252F16306520%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1056/NEJMoa042976&link_type=DOI [3]: /lookup/external-ref?access_num=16306520&link_type=MED&atom=%2Fthoraxjnl%2F61%2F4%2F289.atom [4]: /lookup/external-ref?access_num=000233434500006&link_type=ISI
PinX1 the tail on the chromosome
Authors: F. Brad Johnson
Journal: Journal of Clinical Investigation (2011)

The PinX1 protein inhibits telomerase, an enzyme that lengthens telomeres - the structures that protect the ends of chromosomes. Loss of PinX1 leads to increased telomere length along with defects in chromosome dynamics. In this issue of the JCI, Zhou et al. present novel evidence from human tumors and mouse models indicating that PinX1 is a clinically significant tumor suppressor. Importantly, the genome-destabilizing effects of PinX1 loss appear to depend on telomerase activity, raising new models and questions for how telomeres and telomerase contribute to the development of cancer.
Comparative Effectiveness of Peer Leaders and Community Health Workers in Diabetes Self-management Support: Results of a Randomized Controlled Trial
Authors: Tricia S. Tang, Martha Funnell, Brandy Sinco, Gretchen Piatt, Gloria Palmisano, Michael S. Spencer, Edith C. Kieffer, Michele Heisler
Journal: Diabetes Care (2014)

To compare a peer leader (PL) versus a community health worker (CHW) telephone outreach intervention in sustaining improvements in HbA1c over 12 months after a 6-month diabetes self-management education (DSME) program.One hundred and sixteen Latino adults with type 2 diabetes were recruited from a federally qualified health center and randomized to (1) a 6-month DSME program followed by 12 months of weekly group sessions delivered by PLs with telephone outreach to those unable to attend or (2) a 6-month DSME program followed by 12 months of monthly telephone outreach delivered by CHWs. The primary outcome was HbA1c. Secondary outcomes were cardiovascular disease risk factors, diabetes distress, and diabetes social support. Assessments were conducted at baseline, 6, 12, and 18 months.After DSME, the PL group achieved a reduction in mean HbA1c (8.2-7.5% or 66-58 mmol/mol, P < 0.0001) that was maintained at 18 months (-0.6% or -6.6 mmol/mol from baseline [P = 0.009]). The CHW group also showed a reduction in HbA1c (7.8 vs. 7.3% or 62 vs. 56 mmol/mol, P = 0.0004) post-6 month DSME; however, it was attenuated at 18 months (-0.3% or -3.3 mmol/mol from baseline, within-group P = 0.234). Only the PL group maintained improvements achieved in blood pressure at 18 months. At the 18-month follow-up, both groups maintained improvements in waist circumference, diabetes support, and diabetes distress, with no significant differences between groups.Both low-cost maintenance programs led by either a PL or a CHW maintained improvements in key patient-reported diabetes outcomes, but the PL intervention may have additional benefit in sustaining clinical improvements beyond 12 months.
IMMUNOLOGIC RESPONSE OF NEONATAL AND OLDER RABBITS TO ANTIGENS OF RABBIT LEUCOCYTES
Authors: T. N. Harris, Susanna Harris, Miriam B. Farber
Journal: The Journal of Experimental Medicine (1962)

The immunologic response of neonatal and of older rabbits to the tissue (transplantation) antigens of pooled rabbit leucocytes was studied, the test system being the suppression of formation of agglutinin to Shigella paradysenteriae by transferred lymph node cells which had been incubated with Shigella antigen. In the active induction of the suppressive effect on the transferred cells it was found that neonatal rabbits reacted as vigorously as 1 kg rabbits to the prior injection of a given number of rabbit leucocytes pooled from prospective donors of lymph node cells. The suppressive effect was dose-related, and within the range of number of leucocytes used was similar for both age groups of recipients. An attempt to detect a difference in the response during the first few days after leucocyte injection, before the full suppressive effect is reached, failed to show any difference between rabbits of the two age groups. Since it had been found possible to transfer the suppressive effect passively with sera obtained from older rabbits injected with rabbit leucocytes, attempts were made to do so with sera obtained from neonatal rabbits injected with similar numbers of pooled adult rabbit leucocytes. No consistent suppression of transferred lymph node cells was observed with sera from neonatal rabbits, even with relatively large amounts of such serum. In sera of rabbits which had been injected with rabbit leucocytes at the age of 4 to 6 weeks, suppressive antibody could be detected. When anti-rabbit-leucocyte serum obtained in adult rabbits was injected into neonatal and 1 kg recipients at a given volume per gram of animal weight the suppressive effect of the serum was of similar extent in the two groups of recipients. In the adoptive transfer of the lymph node cell suppressive effect, by cells of lymph nodes draining the sites of injection of pooled rabbit leucocytes, it was found that the popliteal lymph node cells of neonatal rabbits were as effective as those of 1 kg rabbits. Splenic cells of neonatal rabbits were also effective, when an adequate number of rabbit leucocytes had been injected intravenously. Thus, in conferring adoptive immunologic response, as in active immunization, the neonatal rabbits were as effective as the older rabbits in their response to homotransplantation antigens, in contrast to the considerable difference in concentration of the suppressive antibody in sera of neonatal and older rabbits injected with rabbit leucocytes.
Respiratory Rate as an Indicator of Acute Respiratory Dysfunction
Authors: Thomas R. Gravelyn
Journal: JAMA (1980)

To assess respiratory rate as an indicator of acute respiratory dysfunction, we studied 58 consecutive patients four times daily during the postoperative period. Of 825 measurements of respiratory rate, 726 (89%) were normal (24/min or less). Elevations in respiratory rate without respiratory dysfunction were found in only 4% of all measurements. Patients without lung disease had a mean respiratory rate of 18 +/- 4/min, while patients with an abnormal respiratory rate and respiratory dysfunction had a mean of 27 +/- 5/min. Our study demonstrates that respiratory rate, if carefully measured, is a sensitive and reasonably specific marker of acute respiratory dysfunction.
Severe illness associated with appearance of antibody to human immunodeficiency virus in an African.
Authors: R J Biggar, B K Johnson, S S Musoke, J B Masembe, D M Silverstein, M M Warshow, S Alexander
Journal: BMJ (1986)

A case report is presented of severe illness associated with appearance of antibody to human immunodeficiency virus in an African.  A previously healthy 35-year-old African man became ill in November 1984 (day 0) with vague malaise and fatigue.  The next day he developed joint pains and a fever of 39 degrees Centigrade which persisted over the next 13 days.  Additional problems observed on the 2nd day included pharyngitis diarrhea and vomiting and a pruritic maculopapular rash on the face.  By the 3rd day the rash extended to the trunk and occipital lymphadenopathy was noted.  On day 4 shallow ulcers were observed on the palatal and gingival mucosa and on the penis and scrotum.  During the next 5 days the patient became progressively obtunded to the extent that he was unable to speak or to recognize people.  This state persisted until day 15 when all the patients symptoms dramatically improved.  He was released from the hospital on day 19.  Although the patients condition continued to improve during the 3 weeks following discharge from the hospital he developed generalized lymphadenopathy.  Biopsy revealed nonspecific reactive hyperplasia.  At his last visit at 14 months the patient was working full time and had regained all lost weight.  The lymphadenopathy had gradually lessened from the end  of the 4th month but was still present.  The results of Western blot analyses and enzyme linked immunosorbent assay showed that antibody to HIV was present in the serum by day 11.  From day 11 onward conincident with the development of antibodies lymphocytes (up to 10%) were consistently described as reactive.  Results of liver function studies were abnormal during the 2nd week of illness.  The patient did not know of any exposure to patients with the acquired immune deficiency syndrome or to needlesticks during the past year.  He denied homosexuality and drug abuse and had never received a blood transfusion.  The patient had not traveled outside of Kenya since 1982.  During the year before his illness he had had many female sexual partners but no contact with prostitutes or venereal disease.  No other report has documented the acquisition of antibodies in relation to clinical symptoms in similar detail.  Antibody against p24 and p55 appeared earliest and before day 11 of illness coincident with the appearance of activated lymphocytes.  Antienvelope protein antibodies p41 and gp120/160 were first detected faintly at day 16 coincident with clinical improvement.  Antibodies against other antigens appeared before day 27 coincident with the development of persistent generalized lymphadenopathy.  Thus severe symptoms may occur as a consequence of primary HIV infection.
5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression
Authors: Lukas Pezawas, Andreas Meyer-Lindenberg, Emily M Drabant, Beth A Verchinski, Karen E Munoz, Bhaskar S Kolachana, Michael F Egan, Venkata S Mattay, Ahmad R Hariri, Daniel R Weinberger
Journal: Nature Neuroscience (2005)
Cough, fatigue and fever
Authors: S. De Weerdt, M. Noppen, E. De Boosere, A. Goossens, L. Remels, M. Meysman, A. Pletinckx, W. Vincken
Journal: European Respiratory Journal (2004)

A 37‐yr‐old male complained of a dry cough, fever, nocturnal sudation and dyspnoea. On lung auscultation, his general practitioner noticed right-sided expiratory wheezing and the diagnosis of tracheitis was withheld. Clarithromycin and a cough syrup were given and a slight amelioration was noticed, except for the persistence of dry cough. Bronchial hyperreactivity was suspected and a combination of budesonide and formoterol was added to the treatment.

During the following 2 months, symptomatology varied; cough and dyspnoea were intermittently present until the patient started complaining of right thoracic pain and important fatigue. Fever re-appeared reaching 39°C, and, after consulting his general practitioner, cefuroxime and paracetamol were prescribed.

Once again the fever disappeared, but a very invalidating cough with mucopurulent sputum, fatigue and chest pain persisted. After the antibiotic was stopped, fever reappeared and the patient was hospitalised.

In his past history the patient was treated at the age of 12 yrs by immunotherapy for an allergic rhinitis caused by dust allergy. There was no particular familial history. He had never smoked and worked in an office.

On clinical examination, the patient was pale, sweaty and thin. His blood pressure was 125/65, pulse 100·min−1 and temperature 38.7°C. On lung auscultation, breath sounds were diminished at the right lung base. Otherwise, physical examination was normal.

Laboratory studies demonstrated a white blood cell count of 16×109·L−1, with 83% neutrophils, haemoglobin 131 g·L−1 …