tbuckley/cabot-search huggingface dataset:
Nitric Oxide Can Increase Heart Rate by Stimulating the Hyperpolarization-Activated Inward Current, I <sub>f</sub>
Authors: Piotr Musialek, Ming Lei, Hilary F. Brown, David J. Paterson, Barbara Casadei
Journal: Circulation Research (1997)

Abstract We investigated the chronotropic effect of increasing concentrations of sodium nitroprusside (SNP, n=8) or 3-morpholinosydnonimine (SIN-1, n=6) in isolated guinea pig spontaneously beating sinoatrial node/atrial preparations. Low concentrations of NO donors (nanomolar to micromolar) gradually increased the beating rate, whereas high (millimolar) concentrations decreased it. The increase in rate was (1) enhanced by superoxide dismutase (50 to 100 U/mL, n=6), (2) prevented by the guanylyl cyclase inhibitors 6-anilino-5,8-quinolinedione (5 μmol/L, n=6) or 1 H -(1,2,4)oxadiazolo(4,3- a )quinoxalin-1-one (10 μmol/L, n=6), and (3) mimicked by 8-bromo-cGMP (n=6) with no additional positive chronotropic effect of SIN-1 (n=5). The response to 10 μmol/L SNP (n=28) or 50 μmol/L SIN-1 (n=16) was unaffected by I Ca-L antagonism with nifedipine (0.2 μmol/L) but was abolished after blockade of the hyperpolarization-activated inward current (I f ) by Cs + (2 mmol/L) or 4-( N -ethyl- N -phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride (1 μmol/L). The effect on I f was further evaluated in rabbit isolated patch-clamped sinoatrial node cells (n=21), where we found that 5 μmol/L SNP or SIN-1 caused a reversible Cs + -sensitive increase in this current (+130% at −70 mV and +250% at −100 mV). In conclusion, NO donors can affect pacemaker activity in a concentration-dependent biphasic fashion. Our results indicate that the increase in beating rate is due to stimulation of I f via the NO-cGMP pathway. This may contribute to the sinus tachycardia in pathological conditions associated with an increase in myocardial production of NO.
Primary care urgently needs resources to take on more care of chronic illness, say MPs
Authors: A. O'Dowd
Journal: BMJ (2014)

MPs have called for urgent recruitment and workforce planning in primary care to help deal with an anticipated shift of care of patients with long term conditions from hospitals.

In a report from the parliamentary health select committee, MPs said that the NHS system had to change to support better planning of care of people with chronic conditions.1 The report from the committee’s inquiry into managing the care of people with long term conditions, published on 3 July, said that the issue was not being dealt with properly at the moment and was only likely to get worse as demand grew.

An estimated 15 million NHS patients in England have long term conditions such as …
Universal sex differences across patriarchal cultures ≠ evolved psychological dispositions
Authors: Alice H. Eagly, Wendy Wood
Journal: Behavioral and Brain Sciences (2005)

Schmitt's findings provide little evidence that sex differences in sociosexuality are explained by evolved dispositions. These sex differences are better explained by an evolutionary account that treats the psychological attributes of women and men as emergent, given the biological attributes of the sexes, especially female reproductive capacity, and the economic and social structural aspects of societies.
Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera
Authors: Alessandro M. Vannucchi, Jean Jacques Kiladjian, Martin Griesshammer, Tamas Masszi, Simon Durrant, Francesco Passamonti, Claire N. Harrison, Fabrizio Pane, Pierre Zachee, Ruben Mesa, Shui He, Mark M. Jones, William Garrett, Jingjin Li, Ulrich Pirron, Dany Habr, Srdan Verstovsek
Journal: New England Journal of Medicine (2015)

Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea.We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging.The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two groups, respectively, had at least a 35% reduction in spleen volume. A complete hematologic remission was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therapy group (P=0.003); 49% versus 5% had at least a 50% reduction in the total symptom score at week 32. In the ruxolitinib group, grade 3 or 4 anemia occurred in 2% of patients, and grade 3 or 4 thrombocytopenia occurred in 5%; the corresponding percentages in the standard-therapy group were 0% and 4%. Herpes zoster infection was reported in 6% of patients in the ruxolitinib group and 0% of those in the standard-therapy group (grade 1 or 2 in all cases). Thromboembolic events occurred in one patient receiving ruxolitinib and in six patients receiving standard therapy.In patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera. (Funded by Incyte and others; RESPONSE ClinicalTrials.gov number, NCT01243944.).
RESPONSE OF HUMAN-IMMUNODEFICIENCY-VIRUS-ASSOCIATED NEUROLOGICAL DISEASE TO 3'-AZIDO-3'-DEOXYTHYMIDINE
Authors: Robert Yarchoan, Pim Brouwers, A. Robert Spitzer, Jordan Grafman, Bijan Safai, Carlo F. Perno, Steven M. Larson, Gary Berg, Margaret A. Fischl, Alison Wichman, Rose V. Thomas, Arturo Brunetti, Peter J. Schmidt, Charles E. Myers, Samuel Broder
Journal: The Lancet (1987)
Plasma-cell rich lymphangiosarcoma: an under-recognized variant and potential diagnostic pitfall
Authors: D. Govender, H-T. Wu, R. Chetty
Journal: British Journal of Dermatology (2011)

Journal Article Plasma‐cell rich lymphangiosarcoma: an under‐recognized variant and potential diagnostic pitfall Get access D. Govender, D. Govender Division of Anatomical Pathology, University of Cape Town and National Health Laboratory Service‐Groote Schuur Hospital, Cape Town, South AfricaDepartment of Cellular Pathology/Nuffield Department of Clinical Laboratory Sciences, Biomedical Research Centre, Oxford Hospitals Trust/University of Oxford, Oxford, U.K. E‐mail: dhiren.govender@uct.ac.za Search for other works by this author on: Oxford Academic Google Scholar H‐T. Wu, H‐T. Wu Division of Anatomical Pathology, University of Cape Town and National Health Laboratory Service‐Groote Schuur Hospital, Cape Town, South Africa Search for other works by this author on: Oxford Academic Google Scholar R. Chetty R. Chetty Department of Cellular Pathology/Nuffield Department of Clinical Laboratory Sciences, Biomedical Research Centre, Oxford Hospitals Trust/University of Oxford, Oxford, U.K. E‐mail: dhiren.govender@uct.ac.za Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 166, Issue 6, 1 June 2012, Pages 1364–1366, https://doi.org/10.1111/j.1365-2133.2011.10790.x Published: 01 June 2012
Familial systemic lupus erythematosus. Presence of a cross-reactive idiotype in healthy family members.
Authors: R Halpern, A Davidson, A Lazo, G Solomon, R Lahita, B Diamond
Journal: Journal of Clinical Investigation (1985)

Sera of 27 members of 3 human kindreds with familial systemic lupus erythematosus (SLE) were examined for expression of a cross-reactive idiotype present on anti-DNA antibodies of SLE patients. By radioimmunoassay, serum samples from 6 of 8 SLE patients and 15 of 19 family members had high-titered reactivity with the antiidiotype, 3I. Isoelectric focusing and Western blot analysis of 3I-reactive bands revealed two patterns of reactivity: either a pattern of bands present at pH 5-7, or bands present at pH 5-7 with additional bands present at pH 7-8.5. Cationic bands were found to correlate with the presence of anti-DNA antibodies, indicating that immunoglobulin charge may be a factor in determining specificity for DNA. Millipore filter analysis revealed anti-DNA antibodies in sera of 4 of 8 SLE patients and 2 of 19 family members without SLE. In 2 additional SLE patients and 2 additional family members, anti-DNA antibodies were revealed when sera were analyzed under conditions that dissociate immune complexes. This study indicates that expression of an idiotype associated with anti-DNA antibodies is significantly increased in relatives of SLE patients and usually occurs in the absence of anti-DNA activity.
Model of outcomes of screening mammography: information to support informed choices
Authors: Alexandra Barratt, Kirsten Howard, Les Irwig, Glenn Salkeld, Nehmat Houssami
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To provide easy to use estimates of the benefits and harms of biennial screening mammography for women aged 40, 50, 60, and 70 years. <b>Design</b> Markov process model, with data from BreastScreen Australia, the Australian Institute of Health and Welfare, and the Australian Bureau of Statistics. <b>Main outcome measure</b> Age specific outcomes expressed per 1000 women over 10 years. <b>Results</b> For every 1000 women screened over 10 years, 167-251 (depending on age) receive an abnormal result; 56-64 of these women undergo at least one biopsy, 9-26 have an invasive cancer detected by screening, and 3-6 have ductal carcinoma in situ (DCIS) detected by screening. More breast cancers (both invasive and DCIS) are diagnosed among screened than unscreened women. For example, among 1000 women aged 50 who have five biennial screens, 33 breast cancers are diagnosed: 28 invasive cancers (18 detected at screening and 10 interval cancers) and five DCIS (all detected at screening). By comparison, among 1000 women aged 50 who decline screening, 20 cancers are diagnosed over 10 years. There are about 0.5, 2, 3, and 2 fewer deaths from breast cancer over 10 years per 1000 women aged 40, 50, 60, and 70, respectively, who choose to be screened compared with women who decline screening at times determined by relevant policy. <b>Conclusion</b> Benefits and harms of screening mammography are relatively finely balanced. Quantitative estimates such as these can be used to support individual informed choices about screening.
Placebo-Controlled Trial of Oral Laquinimod for Multiple Sclerosis
Authors: Giancarlo Comi, Douglas Jeffery, Ludwig Kappos, Xavier Montalban, Alexey Boyko, Maria A. Rocca, Massimo Filippi
Journal: New England Journal of Medicine (2012)

Two proof-of-concept clinical trials have provided evidence that laquinimod reduces disease activity in patients with relapsing–remitting multiple sclerosis.
Concomitant Involvement of the Shoulder Joints by Proliferative and Degenerative Arthritis
Authors: R. H. Ramsey
Journal: Annals of the Rheumatic Diseases (1951)

This record of an unusual case of arthritis involving both shoulders and both wrists in an elderly female patient emphasizes the difficulty of understanding and classifying the underlying disease process in the chronic arthritides, even when good pathologic material is available for study. Case ReportMrs. M.M. (B.H. 175892), a 75-year-old widow of Yugoslavian birth, entered Barnes Hospital on September 7, 1949, with the history of having insidiously developed inter- mittent pain and stiffness in both shoulders over a ten-year period.These symptoms gradually progressed and about two years before admission, the patient noticed swelling in both shoulders, and pain, swelling, and stiffness in both wrists.From this time on, the pain was moderately severe, almost constant, and aggravated by motion; and the patient became unablp to raise either hand up to her hair.Past history revealed that she had been in good general health and had actively done housework all her life.Physical Examination.-Thepatient was an alert, asthenic, elderly female in no acute distress and not appearing ill.There was a marked thoracic scoliosis to the right.There was a huge effusion of the right shoulder presenting anteriorly and laterally and a slight effusion of the left shoulder.There was pronounced atrophy of the muscles around both shoulders and both were subluxated upward although they could be passively moved completely around the margin of the glenoid with a coarse grating sensation.All active and passive motion was painful; there was slight peri-articular tenderness.Both wrists showed a prominent effusion with " ballooning " laterally and medially, and in these joints there was slight limitation of motion with pain and slight tenderness.The elbows, hips, knees, and ankles were normal.Heberden's nodes were present.No subcutaneous nodules were found.Head and neck, heart and lungs, abdomen, and neurological examinations were negative.Pelvic examination revealed a lesion on the right labia majora, 1 in. in diameter, which was diagnosed as epiderftoid carcinoma.Laboratory Findings.-Kahntest negative.Corrected sedimentation rate: 1*3 mm./min. (normal 01- 0-4 mm./min.).Haemoglobin: lO g.Red blood count: 4 million.White blood count: 8,500 with normal differential count.Urine analysis: negative.Culture of joint fluid revealed no growth; the fluid was of clear amber colour and of normal viscosity.
Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D <sub>3</sub> ) for prevention of fractures in primary care
Authors: Jill Porthouse, Sarah Cockayne, Christine King, Lucy Saxon, Elizabeth Steele, Terry Aspray, Mike Baverstock, Yvonne Birks, Jo Dumville, Roger Francis, Cynthia Iglesias, Suezann Puffer, Anne Sutcliffe, Ian Watt, David J Torgerson
Journal: BMJ (2005)

To assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.
MULTIPLICATION OF CERTAIN NEUROTROPIC VIRUSES IN THE RABBIT EYE FOLLOWING INTRAOCULAR INOCULATION
Authors: John R. Overman, William F. Friedewald
Journal: The Journal of Experimental Medicine (1950)

Lymphocytic choriomeningitis virus and Semliki Forest virus readily multiply in the rabbit eye following inoculation into the vitreous. Less than 10 mouse LD(50) of LCM virus was sufficient to induce multiplication in the eye, whereas, approximately 1000 LD(50) of SFV was required to initiate infection. Both viruses multiplied in the rabbit eye as an inapparent infection. Little or no virus could be recovered from the optic nerves or brains of the rabbits, although virus was present in high titer in the eyes. The animals showed no signs of illness other than a transitory fever. Large amounts of SFV induced a severe iritis followed by corneal opacity. This reaction appeared to be due to "toxic" properties of the virus. No ocular reactions have been observed with LCM virus other than a mild transitory hyperemia. The yield of virus from the eye following inoculation of large amounts of SFV was less than when more dilute inocula were used. Maximum multiplication of both viruses occurred about 48 hours after inoculation into the vitreous. SFV remained in high titer for about 4 days and thereafter could be recovered in variable amounts up to about 5 weeks after inoculation. LCM virus could be recovered in gradually decreasing amounts up to about 3 weeks after inoculation. Serum-neutralizing antibodies appeared in high titer (neutralization index up to 3000) following inoculation of SFV into the rabbit eye. However, only traces of antibody could be detected in extracts of the eyes. SFV was obtained irregularly and in low titer from the aqueous humor following inoculation into either the vitreous or anterior chamber. No significant difference in the virus content of the vitreous, an extract of the retinal cells, and an extract of the whole eye could be detected 48 hours after inoculation of SFV into the vitreous. The Lansing strain of poliomyelitis virus failed to cause any detectable reaction in the rabbit eye and no evidence of multiplication of the virus was obtained in these experiments.
Guideline for the diagnosis and management of vitiligo
Authors: D.J. Gawkrodger, A.D. Ormerod, L. Shaw, I. Mauri-Sole, M.E. Whitton, M.J. Watts, A.V. Anstey, J. Ingham, K. Young
Journal: British Journal of Dermatology (2008)

This detailed and user-friendly guideline for the diagnosis and management of vitiligo in children and adults aims to give high quality clinical advice, based on the best available evidence and expert consensus, taking into account patient choice and clinical expertise. The guideline was devised by a structured process and is intended for use by dermatologists and as a resource for interested parties including patients. Recommendations and levels of evidence have been graded according to the method developed by the Scottish Inter-Collegiate Guidelines Network. Where evidence was lacking, research recommendations were made. The types of vitiligo, process of diagnosis in primary and secondary care, and investigation of vitiligo were assessed. Treatments considered include offering no treatment other than camouflage cosmetics and sunscreens, the use of topical potent or highly potent corticosteroids, of vitamin D analogues, and of topical calcineurin inhibitors, and depigmentation with p-(benzyloxy)phenol. The use of systemic treatment, e.g. corticosteroids, ciclosporin and other immunosuppressive agents was analyzed. Phototherapy was considered, including narrowband ultraviolet B (UVB), psoralen with ultraviolet A (UVA), and khellin with UVA or UVB, along with combinations of topical preparations and various forms of UV. Surgical treatments that were assessed include full-thickness and split skin grafting, mini (punch) grafts, autologous epidermal cell suspensions, and autologous skin equivalents. The effectiveness of cognitive therapy and psychological treatments was considered. Therapeutic algorithms using grades of recommendation and levels of evidence have been produced for children and for adults with vitiligo.
Clinically Useful Genetic Markers of Antidepressant Response: How Do We Get There From Here?
Authors: Francis J. McMahon
Journal: American Journal of Psychiatry (2015)

Predicting who will respond to an antidepressant-and who will not-remains an urgent but unfulfilled need in psychiatry (1).Clinical indicators of response have a long history, but probably have low predictive value.This state of affairs has fueled an energetic search for biomarkers.Genetic markers are ideal biomarkers, since they do not suffer from reverse causation.Reverse causation arises when a biomarker value is actually the consequence of the outcome, rather than its cause.Genetic markers that represent the inherited sequence of DNA cannot reflect the result of a health outcome.The best genetic markers would identify individuals most likely to benefit from a particular treatment and least likely to suffer adverse events.Years of work with candidate genes have yielded some reproducible findings, but their individual effects are small, with little impact on clinical decision making (2).Studies that use genome-wide genotyping technology have implicated additional genes (3), but well-replicated findings that can help guide clinical decision making remain elusive.In this issue, Schatzberg et al. (4) report that common genetic markers in ABCB1 provide some information about which patients are most likely to respond to certain selective serotonin reuptake inhibitors.ABCB1 encodes P-glycoprotein, which influences the efficiency with which certain antidepressants (and other drugs) cross the blood-brain barrier.Common variants in ABCB1 have been associated with antidepressant outcome in some previous studies (5), so replication in an independent sample was the next logical step.Ten common markers in and around ABCB1 were tested in 683 patients with major depressive disorder who were treated for at least 2 weeks and an additional 576 patients who were treated for 8 weeks as part of the International Study to Predict Optimized Treatment in Depression (iSPOT-D) trial.The samples were carefully ascertained and evaluated, with prospective measures of efficacy and side effect burden, using standard instruments.General and emotional cognition were further assessed with a battery of 13 tests.Antidepressants included escitalopram, sertraline, and extended-release venlafaxine, all of which are known to bind P-glycoprotein.One singlenucleotide polymorphism (SNP) upstream of ABCB1 was associated with remission and subjective side effects, and the direction of the effect differed among the medications tested.How far does this take us, and what's next?Treatment assignment was randomized, but not blinded, and there were
Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?
Authors: CY Cheung, LLM Poon, AS Lau, W Luk, YL Lau, KF Shortridge, S Gordon, Y Guan, JSM Peiris
Journal: The Lancet (2002)
Association of systolic and diastolic blood pressure and all cause mortality in people with newly diagnosed type 2 diabetes: retrospective cohort study
Authors: E. P. Vamos, M. Harris, C. Millett, U. J. Pape, K. Khunti, V. Curcin, M. Molokhia, A. Majeed
Journal: BMJ (2012)

<b>Objective</b> To examine the effect of systolic and diastolic blood pressure achieved in the first year of treatment on all cause mortality in patients newly diagnosed with type 2 diabetes, with and without established cardiovascular disease. <b>Design</b> Retrospective cohort study. <b>Setting</b> United Kingdom General Practice Research Database, between 1990 and 2005. <b>Participants</b> 126 092 adult patients (age ≥18 years) with a new diagnosis of type 2 diabetes who had been registered with participating practices for at least 12 months. <b>Main outcome measure</b> All cause mortality. <b>Results</b> Before diagnosis, 12 379 (9.8%) patients had established cardiovascular disease (myocardial infarction or stroke). During a median follow-up of 3.5 years, we recorded 25 495 (20.2%) deaths. In people with cardiovascular disease, tight control of systolic (&lt;130 mm Hg) and diastolic (&lt;80 mm Hg) blood pressure was not associated with improved survival, after adjustment for baseline characteristics (age at diagnosis, sex, practice level clustering, deprivation score, body mass index, smoking, HbA<sub>1c</sub> and cholesterol levels, and blood pressure). Low blood pressure was also associated with an increased risk of all cause mortality. Compared with patients who received usual control of systolic blood pressure (130-139 mm Hg), the hazard ratio of all cause mortality was 2.79 (95% confidence interval 1.74 to 4.48, P&lt;0.001) for systolic blood pressure at 110 mm Hg. Compared with patients who received usual control of diastolic blood pressure (80-84 mm Hg), the hazard ratios were 1.32 (1.02 to 1.78, P=0.04) and 1.89 (1.40 to 2.56, P&lt;0.001) for diastolic blood pressures at 70-74 mm Hg and lower than 70 mm Hg, respectively. Similar associations were found in people without cardiovascular disease. Subgroup analyses of people diagnosed with hypertension and who received treatment for hypertension confirmed initial findings. <b>Conclusion</b> Blood pressure below 130/80 mm Hg was not associated with reduced risk of all cause mortality in patients with newly diagnosed diabetes, with or without known cardiovascular disease. Low blood pressure, particularly below 110/75 mm Hg, was associated with an increased risk for poor outcomes.