tbuckley/cabot-search huggingface dataset:
Genetic Deletion of Rnd3/RhoE Results in Mouse Heart Calcium Leakage Through Upregulation of Protein Kinase A Signaling
Authors: Xiangsheng Yang, Tiannan Wang, Xi Lin, Xiaojing Yue, Qiongling Wang, Guoliang Wang, Qin Fu, Xun Ai, David Y. Chiang, Christina Y. Miyake, Xander H.T. Wehrens, Jiang Chang
Journal: Circulation Research (2014)

Rnd3, a small Rho GTPase, is involved in the regulation of cell actin cytoskeleton dynamics, cell migration, and proliferation. The biological function of Rnd3 in the heart remains unexplored.To define the functional role of the Rnd3 gene in the animal heart and investigate the associated molecular mechanism.By loss-of-function approaches, we discovered that Rnd3 is involved in calcium regulation in cardiomyocytes. Rnd3-null mice died at the embryonic stage with fetal arrhythmias. The deletion of Rnd3 resulted in severe Ca(2+) leakage through destabilized ryanodine receptor type 2 Ca(2+) release channels. We further found that downregulation of Rnd3 attenuated β2-adrenergic receptor lysosomal targeting and ubiquitination, which in turn resulted in the elevation of β2-adrenergic receptor protein levels leading to the hyperactivation of protein kinase A (PKA) signaling. The PKA activation destabilized ryanodine receptor type 2 channels. This irregular spontaneous Ca(2+) release can be curtailed by PKA inhibitor treatment. Increases in the PKA activity along with elevated cAMP levels were detected in Rnd3-null embryos, in neonatal rat cardiomyocytes, and noncardiac cell lines with Rnd3 knockdown, suggesting a general mechanism for Rnd3-mediated PKA signaling activation. β2-Adrenergic receptor blocker treatment reduced arrhythmia and improved cardiac function.Rnd3 is a novel factor involved in intracellular Ca(2+) homeostasis regulation in the heart. Deficiency of the protein induces ryanodine receptor type 2 dysfunction by a mechanism that attenuates Rnd3-mediated β2-adrenergic receptor ubiquitination, which leads to the activation of PKA signaling. Increased PKA signaling in turn promotes ryanodine receptor type 2 hyperphosphorylation, which contributes to arrhythmogenesis and heart failure.
"Blue bodies" in a case of cryptogenic fibrosing alveolitis (desquamative type) an ultra-structural study.
Authors: I T Gardiner, J S Uff
Journal: Thorax (1978)

A patient with cryptogenic fibrosing alveolitis, with both mural and desquamative features, had two lung biopsies at the times of coronary artery surgery. These lung specimens were studied, using light and electron microscopy, with immunofluorescence techniques and electron microanalysis. In addition to the typical changes of cryptogenic fibrosing alveolitis previously reported, we found "blue-staining bodies" within alveolar macrophages and giant cells. These bodies were 15--25 micrometer in diameter with an iron rich outer rim and core of connective tissue mucin--possibly chondroitin sulphate or dermatan sulphate. It seems unlikely that these "blue bodies" were due to fibreglass dust to which the patients had had a trivial exposure, but their exact nature and significance remains unclear.
C-Reactive Protein, a Sensitive Marker of Inflammation, Predicts Future Risk of Coronary Heart Disease in Initially Healthy Middle-Aged Men
Authors: Wolfgang Koenig, Malte Sund, Margit Fröhlich, Hans-Günther Fischer, Hannelore Löwel, Angela Döring, Winston L. Hutchinson, Mark B. Pepys
Journal: Circulation (1999)

Background —Inflammatory reactions in coronary plaques play an important role in the pathogenesis of acute atherothrombotic events; inflammation elsewhere is also associated with both atherogenesis generally and its thrombotic complications. Recent studies indicate that systemic markers of inflammation can identify subjects at high risk of coronary events. Methods and Results —We used a sensitive immunoradiometric assay to examine the association of serum C-reactive protein (CRP) with the incidence of first major coronary heart disease (CHD) event in 936 men 45 to 64 years of age. The subjects, who were sampled at random from the general population, participated in the first MONICA Augsburg survey (1984 to 1985) and were followed for 8 years. There was a positive and statistically significant unadjusted relationship, which was linear on the log-hazards scale, between CRP values and the incidence of CHD events (n=53). The hazard rate ratio (HRR) of CHD events associated with a 1-SD increase in log-CRP level was 1.67 (95% CI, 1.29 to 2.17). After adjustment for age, the HRR was 1.60 (95% CI, 1.23 to 2.08). Adjusting further for smoking behavior, the only variable selected from a variety of potential confounders by a forward stepping process with a 5% change in the relative risk of CRP as the selection criterion, yielded an HRR of 1.50 (95% CI, 1.14 to 1.97). Conclusions —These results confirm the prognostic relevance of CRP, a sensitive systemic marker of inflammation, to the risk of CHD in a large, randomly selected cohort of initially healthy middle-aged men. They suggest that low-grade inflammation is involved in pathogenesis of atherosclerosis, especially its thrombo-occlusive complications.
Lymphogranuloma venereum; epidemiological, clinical, surgical and therapeutic aspects based on a study in the Caribbean.
Authors: W. D. Mortimer Harris
Journal: JAMA (1963)

This book, which presents a general review of lymphogranuloma venereum and an interesting picture of the incidence of this disease in Jamaica, was written by a team of authors who have made an on-the-spot study over a period of years in this Caribbean island. The authors start with a general background of the island and its residents and the occurrence and distribution of the disease in the population. The clinical, pathologic, laboratory, and epidemiologic features are discussed rather fully, and a frank comparison is made of the authors' findings and those of other authors. Use of chemotherapy is explored at length, and indications for certain types of surgical therapy are discussed. Of course, the details of surgical procedures are not presented. Differential diagnosis and possible complications are also described. The chapters are written individually by different members of the team, and there is a certain degree of repetition. The black
Uniform Presentation of Enzyme Determinations
Authors: Harry L. Gerstbrein
Journal: JAMA (1974)

To the Editor.—  The method of presentation of clinical laboratory data sometimes complicates their interpretation. The number of enzyme tests has proliferated to the point that interpretation has become a problem for the average physician. We have adopted a system of data handling that simplifies this.  We have corrected all enzyme chemistry values so that the upper normal is 100. At our hospital the upper normal is interpreted as the 95th percentile for healthy adults. To avoid confusion these units are designated centinormalized units (CU).  The conversion is done by taking the upper normal value and dividing each value in the usual units by this factor, ie, 350/100 = 3.5 as the factor. If the normal range in international units is 70 to 350 IU, then in our units the normal range would be 20 to 100 CU.  These conversions are done in the laboratory and the clinician does not have
Cerebral Embolization Complicating Hyperthyroidism-Reply
Authors: Martin I. Surks
Journal: JAMA (1979)

<h3>In Reply.—</h3> The points raised by Drs Hydovitz, Lippe, and Melada appear well taken. We can supply additional information regarding our patient. Thrombocytopenia was not observed during the patient's hospital course. We cannot, however, exclude aberrations in the coagulation mechanism. We agree with Hydovitz and colleagues that there are always risks involved in the administration of anticoagulants. I would point out that the elevations in levels of serum free thyroxine that have been recorded in patients receiving intravenous heparin therapy are not associated with changes in distributions of hormone between the plasma compartment and the tissues.<sup>1</sup>As indicated in our report, we believe that without overt contraindications to their use, anticoagulants do have a role in the management of hyperthyroidism associated with perceptible cardiac arrhythmias.
Misdiagnosis in the time of meningitis
Authors: T. W Bourke, M. D Shields
Journal: BMJ (2009)

Distinguishing viral illness from serious bacterial infection is notoriously difficult. Many of the symptoms currently recommended as “screening” questions for A/H1N1 flu such as fever, coryza, sore throat, headache, muscle aches, vomiting, and diarrhoea may also be present …
Wasting time with people
Authors: Simon Challand
Journal: BMJ (2004)

“Waste time with people,” advised the African bishop with a smile. “You Europeans are always concerned about projects and budgets. The African does not worry about them—just waste time with people.” He gave me this advice in 1996 shortly before I came out to work in Uganda. Since then his words have kept coming back to me, and I reflect on their truth and wisdom and how difficult it has been for me, as someone with European values and attitudes, to apply them.

I supervise eight rural health centres in the west of Uganda, scattered among the foothills of the Rwenzori mountains. I love driving out on winding dirt tracks, past steep fields planted with cassava and coffee, and dodging the ubiquitous goats, to an isolated health centre run by two or three nurses and community health workers, a centre with few drugs but many patients. The dedication and perseverance of the staff are a real inspiration to me.

Health centres in Uganda, even those built and …
Proteus Infections in a General Hospital. II. Some Clinical and Epidemiological Characteristics
Authors: JONATHAN L. ADLER
Journal: Annals of Internal Medicine (1971)

In a clinical analysis of 87 patients with nonbacteremic proteus infections and of 71 patients with proteus bacteremia, about two thirds of all the infections were acquired in the hospital. Proteus infections of the urinary tract were somewhat more frequently acquired in the community than in the hospital. Two thirds of the nosocomial infections occurred on surgical wards; 68% of community-acquired infections were in general medical ward patients. Most strains of Proteus mirabilis proticine types 6 and 9 were from hospital-acquired infections; some of the patients with these types were clustered in medical and neurosurgical wards. Most of the respiratory infections occurred within the first 10 days in the hospital; most of the wound infections occurred after the third week. About 30% of all proteus infections and of the bacteremias were first apparent after the fourth week. In 85% of the nosocomial bacteremias, antibiotics had been administered before the first positive blood culture.
ASSOCIATION OF HEART FAILURE BELIEFS AND SELF-CARE ADHERENCE IN PATIENTS TREATED IN AN EMERGENCY DEPARTMENT FOR ACUTE DECOMPENSATED HEART FAILURE
Authors: Nancy M. Albert, Phillip Levy, Elizabeth Langlois, Benjamin Nutter, Dongsheng Yang, Vijaya Arun Kumar, Patrick Medado, Elizabeth Nykun
Journal: Journal of the American College of Cardiology (2010)
Role of <i>I</i> <sub>Kur</sub> in Controlling Action Potential Shape and Contractility in the Human Atrium
Authors: Erich Wettwer, Ottó Hála, Torsten Christ, Jürgen F. Heubach, Dobromir Dobrev, Michael Knaut, András Varró, Ursula Ravens
Journal: Circulation (2004)

Background— The ultrarapid outward current I Kur is a major repolarizing current in human atrium and a potential target for treating atrial arrhythmias. The effects of selective block of I Kur by low concentrations of 4-aminopyridine or the biphenyl derivative AVE 0118 were investigated on right atrial action potentials (APs) in trabeculae from patients in sinus rhythm (SR) or chronic atrial fibrillation (AF). Methods and Results— AP duration at 90% repolarization (APD 90 ) was shorter in AF than in SR (300±16 ms, n=6, versus 414±10 ms, n=15), whereas APD 20 was longer (35±9 ms in AF versus 5±2 ms in SR, P &lt;0.05). 4-Aminopyridine (5 μmol/L) elevated the plateau to more positive potentials from −21±3 to −6±3 mV in SR and 0±3 to +12±3 mV in AF. 4-Aminopyridine reversibly shortened APD 90 from 414±10 to 350±10 ms in SR but prolonged APD 90 from 300±16 to 320±13 ms in AF. Similar results were obtained with AVE 0118 (6 μmol/L). Computer simulations of I Kur block in human atrial APs predicted secondary increases in I Ca,L and in the outward rectifiers I Kr and I Ks , with smaller changes in AF than SR. The indirect increase in I Ca,L was supported by a positive inotropic effect of 4-aminopyridine without direct effects on I Ca,L in atrial but not ventricular preparations. In accordance with the model predictions, block of I Kr with E-4031 converted APD shortening effects of I Kur block in SR into AP prolongation. Conclusions— Whether inhibition of I Kur prolongs or shortens APD depends on the disease status of the atria and is determined by the level of electrical remodeling.
Ethics behind closed doors: do research ethics committees need secrecy?
Authors: R. Ashcroft
Journal: BMJ (2001)

Biomedical research involving human subjects must be reviewed by an independent ethics committee.1–3 In the United Kingdom, such committees are normally NHS local or multicentre research ethics committees.4–6 There is currently widespread frustration in the research community, in the regulatory authorities, and in the pharmaceutical industry with the efficiency of such committees. 7 8 At the same time there are doubts about the effectiveness of these independent committees in protecting patients.9–11 Doubts have arisen in the aftermath of some high profile scandals in the ethics of research in the United Kingdom and United States.12 13 Guidance on research governance within the public sector to parallel governance within the pharmaceutical industry is therefore welcome. 2 6 14

An important reason for the contention surrounding research ethics committees is the secrecy that surrounds them and their decision making. We argue that this secrecy is rarely justified. To investigate this, we reviewed the guidelines regulating research ethics committees in common law jurisdictions and searched the literature on research ethics committees.

#### Summary points

Research ethics committees have a vital role in protecting the public and facilitating useful research but are increasingly under attack

In many countries, including the United Kingdom, research ethics committees meet confidentially, but no justification for this is normally offered

The possible justifications (protection of patients', researchers', commercial, or academic interests and the committee's independence) are weak and unconvincing

The minutes and meetings of research ethics committees should be open to the public except in a few special circumstances

Independence of review is an important element of good research governance. This is partly protected by lay membership of committees, clear lines of accountability to public authorities, and strict rules relating to conflicts of interest. However, this protection of patients' interests may …
Correction of Duncan's syndrome by allogeneic bone marrow transplantation
Authors: L.L. Williams, M.K. Brenner, R.A. Krance, H.E. Heslop, C.M. Rooney, M.E. Conley, M.E. Conley, M.K. Brenner, R.A. Krance, H.E. Heslop
Journal: The Lancet (1993)
Heterotopic Ossification of the Hips in a Patient With Guillain Barre Syndrome Demonstrated on SPECT/CT
Authors: Mohamed Shawgi
Journal: Clinical Nuclear Medicine (2012)

A 55-year-old man developed bilateral hip pain following admission with Guillain Barre syndrome. Hip radiographs showed minor degenerative changes. 99mTc-methylene diphosphonate bone scintigraphy showed bilateral abnormal activity extending from the acetabula to the trochanteric regions. SPECT/CT localized the abnormal activity to the soft tissues surrounding the hips. Heterotopic ossification is a rare complication of Guillain Barre syndrome.
Midshipman Aikin and Vivisection.
Authors: W. W. Keen
Journal: JAMA (1902)

Philadelphia, Dec. 5, 1902. Hon. Jacob H. Gallinger, Chairman of the Senate Committee on the District of Columbia, Washington, D. C. <h3>My Dear Sir:</h3> As you have repeatedly introduced bills into the Senate for the purpose nominally of regulating experiments on animals in the District of Columbia, which bills, however, if they had become laws, would in fact have prohibited many, if not all of them, I deem it my duty to call your attention to the case of Midshipman Aikin of the United States Naval Academy, who was recently injured in a football game. My reason for doing so is to show you by a single concrete example that knowledge gained by animal experimentation is an immense boon to humanity and that, therefore, such experiments should be heartily encouraged. The facts of Mr. Aikin's case are as follows: When I first saw him, three days after the accident, I
Assortative mating may explain spouses' risk of same disease
Authors: Gonneke Willemsen, Jacqueline M Vink, Dorret I Boomsma
Journal: BMJ (2003)

EDITOR—Hippisley-Cox et al observed significant similarities for disease between spouses in a large sample of 8386 couples recruited through general practice.1 They think that shared environmental factors may cause these similarities but reject assortative mating as an explanation.

In a sample from the Netherlands twin register we could not replicate their spouse similarities for asthma, depression, diabetes, and cardiovascular disease, possibly because of our smaller sample size of 2152 spouse pairs.2 When we examined health behaviour in a larger sample we found good associations between spouses for smoking, …
Hospital clinic care versus general practice care for type II diabetics
Authors: T. Hayes, J. Harries
Journal: BMJ (1985)

cancer becomes inappropriate as our patients approach death, but realistic and optimistic hopes are to be encouraged.One of our patients recently stated that the most important thing for her morale was having realistic short term goals.Even when patients are too weak to achieve goals there are still appropriate hopes: hopes for their family and loved ones, hopes for a reconciliation, hopes about the memories they will leave behind, or hopes for some kind of existence after death.The cnanges that we see occurring in families around this time can often be described as full of hope.
Unexpected dominance: Brugada syndrome SCN5A variants exert negative dominance via -subunit interaction
Authors: J.-S. Rougier, H. Abriel
Journal: Cardiovascular Research (2012)

This editorial refers to ‘Dominant-negative effect of SCN5A N-terminal mutations through the interaction of Nav1.5 α-subunits’ by J. Clatot et al ., pp. 53–63, this issue. 

The field of cardiac channelopathies, i.e. dysfunction of ion channels caused by genetic defects, is one of the most fascinating areas of research for modern biomedical scientists. Indeed, these studies enable us to understand how a single genetic and molecular defect that can be recorded in one molecule, such as the bursting behaviour of one Nav1.5 long QT syndrome (LQTS) mutant channel,1 may lead to sudden cardiac death.2 Since 1995, this field has benefited from a prolific, interdisciplinary community of clinicians, geneticists, biophysicists, and biologists,3 as is the case in the study by Clatot et al. 4 published in this issue of Cardiovascular Research . Among the most striking examples is congenital LQTS, with hundreds of mutations found in a total of 13 genes. The LQTS genes KCNQ1 and KCNH2 code for the α-subunits of the K+ ion channels that are responsible for the I Ks and I Kr repolarizing cardiac currents.3 Genetic investigations have shown that most LQTS patients are carriers of a single mutated allele consistent with dominant transmission of the pathological trait.5

Early studies on LQTS missense mutations of KCNQ1 6 have demonstrated a dominant negative effect of the mutant α-subunits, which is consistent with the multimeric nature of voltage-gated K+ channels. Epidemiological studies7 subsequently demonstrated the worse outcome of patients carrying missense KCNQ1 mutations, exerting a dominant negative effect, when compared with …
Surgeon who carried out home circumcisions is struck off UK register after "blatant disregard" for patient safety
Authors: C. Dyer
Journal: BMJ (2015)

A “callous” surgeon who flouted basic hygiene rules in performing home circumcisions and showed a “blatant disregard” for patient safety has been struck off the UK medical register.

Mohammad Siddiqui operated a private mobile circumcision service while working for the NHS as a clinical fellow in paediatric surgery at University Hospital Southampton NHS Foundation Trust from June 2012 to November 2013.

A panel of the Medical Practitioners Tribunal Service found him guilty of a catalogue of failures in performing religious circumcisions in the homes of four babies. One, Baby D, was left with loss of …
Paratyphoid B Osteomyelitis of Frontal Bone
Authors: E. Peyser, M. Madorsky
Journal: BMJ (1952)

Although paratyphoid osteomyelitis has been described repeatedly in the literature we could find no case in which the skull bones were involved.Cases of typhoid infection of the skull, however, have been recorded by Winslow (1923), and by Lever and Barker (1945).Typhoid osteomyelitis occurs in almost 1 % of typhoid infections, while the incidence of this complication is much lower in cases of paratyphoid fever (Winslow, 1923 ; Keith and Keith, 1926; Rozansky, Ehrenfeld, and Matoth, 1948).Our observation of paratyphoid B osteomyelitis of the frontal bone deals with a hitherto unreported localization of paratyphoid osteomyelitis and is added to the 23 cases of bone involvement collected by Rozansky, Ehrenfeld, and Matoth (
Variability in the Androgen Response of Prostate Epithelium to 5α-Reductase Inhibition: Implications for Prostate Cancer Chemoprevention
Authors: Elahe A. Mostaghel, Linda Geng, Ilona Holcomb, Ilsa M. Coleman, Jared Lucas, Lawrence D. True, Peter S. Nelson
Journal: Cancer Research (2010)

Inhibitors of 5alpha-reductase (SRD5A) that lower intraprostatic levels of dihydrotestosterone (DHT) reduce the overall incidence of prostate cancer (PCa), but there is significant variation in chemopreventive activity between individual men. In seeking molecular alterations that might underlie this variation, we compared gene expression patterns in patients with localized PCa who were randomized to prostatectomy alone versus treatment with two different doses of the SRD5A inhibitor dutasteride. Prostatic levels of DHT were decreased by >90% in both dutasteride-treated patient groups versus the untreated patient group. Despite significant and uniform suppression of tissue DHT, unsupervised clustering based on prostatic gene expression did not discriminate these groups. However, subjects could be resolved into distinct cohorts characterized by high or low expression of genes regulated by the androgen receptor (AR), based solely on AR transcript expression. The higher-dose dutasteride treatment group was found to include significantly fewer cancers with TMPRSS2-ERG genetic fusions. Dutasteride treatment was associated with highly variable alterations in benign epithelial gene expression. Segregating subjects based on expression of AR and androgen-regulated genes revealed that patients are differentially sensitive to SRD5A inhibition. Our findings suggest that AR levels may predict the chemopreventive efficacy of SRD5A inhibitors.