tbuckley/cabot-search huggingface dataset:
PTEN Depletion Decreases Disease Severity and Modestly Prolongs Survival in a Mouse Model of Spinal Muscular Atrophy
Authors: Daniel Little, Chiara F Valori, Chantal A Mutsaers, Ellen J Bennett, Matthew Wyles, Basil Sharrack, Pamela J Shaw, Thomas H Gillingwater, Mimoun Azzouz, Ke Ning
Journal: Molecular Therapy (2014)

Spinal muscular atrophy (SMA) is the second most common genetic cause of death in childhood. However, no effective treatment is available to halt disease progression. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene. We previously reported that PTEN depletion leads to an increase in survival of SMN-deficient motor neurons. Here, we aimed to establish the impact of PTEN modulation in an SMA mouse model in vivo. Initial experiments using intramuscular delivery of adeno-associated vector serotype 6 (AAV6) expressing shRNA against PTEN in an established mouse model of severe SMA (SMNΔ7) demonstrated the ability to ameliorate the severity of neuromuscular junction pathology. Subsequently, we developed self-complementary AAV9 expressing siPTEN (scAAV9-siPTEN) to allow evaluation of the effect of systemic suppression of PTEN on the disease course of SMA in vivo. Treatment with a single injection of scAAV9-siPTEN at postnatal day 1 resulted in a modest threefold extension of the lifespan of SMNΔ7 mice, increasing mean survival to 30 days, compared to 10 days in untreated mice. Our data revealed that systemic PTEN depletion is an important disease modifier in SMNΔ7 mice, and therapies aimed at lowering PTEN expression may therefore offer a potential therapeutic strategy for SMA. Spinal muscular atrophy (SMA) is the second most common genetic cause of death in childhood. However, no effective treatment is available to halt disease progression. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene. We previously reported that PTEN depletion leads to an increase in survival of SMN-deficient motor neurons. Here, we aimed to establish the impact of PTEN modulation in an SMA mouse model in vivo. Initial experiments using intramuscular delivery of adeno-associated vector serotype 6 (AAV6) expressing shRNA against PTEN in an established mouse model of severe SMA (SMNΔ7) demonstrated the ability to ameliorate the severity of neuromuscular junction pathology. Subsequently, we developed self-complementary AAV9 expressing siPTEN (scAAV9-siPTEN) to allow evaluation of the effect of systemic suppression of PTEN on the disease course of SMA in vivo. Treatment with a single injection of scAAV9-siPTEN at postnatal day 1 resulted in a modest threefold extension of the lifespan of SMNΔ7 mice, increasing mean survival to 30 days, compared to 10 days in untreated mice. Our data revealed that systemic PTEN depletion is an important disease modifier in SMNΔ7 mice, and therapies aimed at lowering PTEN expression may therefore offer a potential therapeutic strategy for SMA.
Neutral endopeptidase inhibitors potentiate substance P- and capsaicin-induced cough in awake guinea pigs.
Authors: H Kohrogi, P D Graf, K Sekizawa, D B Borson, J A Nadel
Journal: Journal of Clinical Investigation (1988)

To study the roles of substance P and endogenous neutral endopeptidase in mediating cough, we measured cough responses in awake guinea pigs in response to exogenous substance P and capsaicin aerosols in the presence and absence of the neutral endopeptidase inhibitors leucine-thiorphan and phosphoramidon. Substance P stimulated cough in very low concentrations (10(-17)-10(-16) M). In a second study where the investigator did not know whether substance P or diluent alone was aerosolized, substance P (10(-16) M) caused cough. Leucine-thiorphan (10(-5) M) and phosphoramidon (10(-5) M) potentiated substance P-induced cough; NEP inhibitors also potentiated capsaicin-induced cough significantly. These findings suggest that substance P is a potent stimulator of cough responses, that capsaicin-induced cough is mediated by substance P or another similar neuropeptide, and that cough responses are modulated by endogenous neutral endopeptidase.
Osteoclastogenesis in peripheral blood mononuclear cell cultures of periprosthetic osteolysis patients and the phenotype of T cells localized in periprosthetic tissues
Authors: Ilaria Roato, Davide Caldo, Lucia D’Amico, Patrizia D’Amelio, Laura Godio, Salvatore Patanè, Franco Astore, Guido Grappiolo, Maurizio Boggio, Roberto Scagnelli, Luigi Molfetta, Riccardo Ferracini
Journal: Biomaterials (2010)
Torsade de pointes after astemizole overdose.
Authors: T M Craft
Journal: BMJ (1986)

from that among normal controls and patients with osteoarthritis.Im- mobility per se does not seem to be a primary factor as the patients with osteoarthritis did not show an increased prevalence compared with the control group.Certain medical conditions, including pure iron deficiency, uraemia, pregnancy, gastrectomy, and carcinoma, are associated with the syndrome, providing potential clues about its mechanism.3Interestingly, these con- ditions lead to either pure iron deficiency or anaemia of chronic disease, and anaemic patients experience more severe symptoms.4As patients with rheumatoid arthritis characteristically develop the anaeniia of chronic disease the increased prevalence of the syndrome observed in the group with rheumatoid arthritis may relate to this secondary complication.5The combination of the restless leg syndrome and rheumatoid arthritis contributes considerably to discomfort and anxiety, and in our experience few doctors are aware of this condition.
Fate of the thiomalate part after intramuscular administration of aurothiomalate in rheumatoid arthritis.
Authors: E Jellum, E Munthe
Journal: Annals of the Rheumatic Diseases (1982)

The excretory fate and plasma level of thiomalate were studied after intramuscular administration of auro-14C-thiomalate to 3 patients with rheumatoid arthritis. The gold and the thiomalate parts separated in vivo, and the free thiomalate was excreted in the urine, rapidly at first and then slowly. After one day about 60% of the 14C-label had been recovered in the urine. The plasma level also declined rapidly. The results are in complete agreement with those previously described in animal experiments.
Loss of employment and mortality
Authors: J. K Morris, D. G Cook, A G. Shaper
Journal: BMJ (1994)

<h3>Abstract</h3> <b>Objective</b>: To assess effect of unemployment and early retirement on mortality in a group of middle aged British men. <b>Design</b>: Prospective cohort study (British Regional Heart Study). Five years after initial screening, information on employment experience was obtained with a postal questionnaire. <b>Setting</b>: One general practice in each of 24 towns in Britain. <b>Subjects</b>: 6191 men aged 40-59 who had been continuously employed for at least five years before initial screening in 1978-80: 1779 experienced some unemployment or retired during the five years after screening, and 4412 remained continuously employed. <b>Main outcome measure</b>: Mortality during 5.5 years after postal questionnaire. <b>Results</b>: Men who experienced unemployment in the five years after initial screening were twice as likely to die during the following 5.5 years as men who remained continuously employed (relative risk 2.13 (95% confidence interval 1.71 to 2.65). After adjustment for socioeconomic variables (town and social class), health related behaviour (smoking, alcohol consumption, and body weight), and health indicators (recall of doctor diagnoses) that had been assessed at initial screening the relative risk was slightly reduced, to 1.95 (1.57 to 2.43). Even men who retired early for reasons other than illness and who appeared to be relatively advantaged and healthy had a significantly increased risk of mortality compared with men who remained continuously employed (relative risk 1.87 (1.35 to 2.60)). The increased risk of mortality from cancer was similar to that of mortality from cardiovascular disease (adjusted relative risk 2.07 and 2.13 respectively). <b>Conclusions</b>: In this group of stably employed middle aged men loss of employment was associated with an increased risk of mortality even after adjustment for background variables, suggesting a causal effect. The effect was non-specific, however, with the increased mortality involving both cancer and cardiovascular disease.
Renal-Vein Thrombosis in Newborn Infants of Diabetic Mothers
Authors: Mary Ellen Avery, Ella H. Oppenheimer, Harry H. Gordon
Journal: New England Journal of Medicine (1957)

THROMBOSIS of the renal veins in infancy is an unusual occurrence, and is commonly attributed to dehydration or sepsis. Sometimes, however, it occurs without any apparent predisposing cause, and under these circumstances it has been referred to as primary renal-vein thrombosis.1 The 2 patients discussed below were the infants of diabetic mothers. A review of the literature reveals 2 other infants with renal-vein thrombosis, also the offspring of diabetic mothers.2 , 3 In addition, there are reports of several infants weighing over 4 kg. with thrombosis of the renal veins in the newborn period in the absence of dehydration or sepsis.4 , 5 Usually, . . .
The Prevalence of Retinal Vein Occlusion: Pooled Data from Population Studies from the United States, Europe, Asia, and Australia
Authors: Sophie Rogers, Rachel L. McIntosh, Ning Cheung, Lyndell Lim, Jie Jin Wang, Paul Mitchell, Jonathan W. Kowalski, Hiep Nguyen, Tien Y. Wong
Journal: Ophthalmology (2009)
ANOMALOUS SCARLET FEVERA REPORT OF THREE EPIDEMICS
Authors: WILLIAM THOMAS CORLETT
Journal: JAMA (1910)

During the past decade there have occurred in Lakeside Hospital three epidemics of what is thought to be anomalous scarlet fever. In each of these epidemics the disease might have passed unrecognized or at least some doubt might have been entertained as to its nature, had not one or more typical cases occurred which acted as a diagnostic control. These epidemics were characterized by the mildness of the attack, the benign course of the disease together with the suppression or complete absence of the exanthem together with some other of the more important symptoms.  The first epidemic occurred in the winter of 1904-5 and started in the children's ward, but before strict quarantine and disinfection terminated its spread, the medical and surgical wards likewise contributed until eighteen cases were observed.  REPORTS OF CASES Case 1.—  A child admitted with some slight ailment was observed to have a faint rash on the
Thiocholesterol-based lipids for ordered assembly of bioresponsive gene carriers
Authors: Zhaohua Huang, Weijun Li, J. Andrew MacKay, Francis C. Szoka
Journal: Molecular Therapy (2004)

A series of thiocholesterol-based cationic lipids (TCL) has been designed and synthesized by the attachment of thiocholesterol to a cationic amine via a disulfide bond. TCL can be incorporated into liposomes and used to package DNA into a lipoplex, thereby protecting it from DNase digestion. DNA is rapidly released from the complex in the presence of low concentrations of reducing agents. The lipoplex mediated efficient transfection activity and had low cytotoxicity. To improve the biocompatibility of the cationic lipoplex, TCL were used as a component in the assembly of a nanolipoparticle (NLP). The particle surface was subsequently modified by disulfide exchange to replace the cationic group with a negatively charged (glutathione) or zwitterionic (cysteine) reducing agent. A cell-binding ligand (TAT peptide, sequence GRKKRRQRRRGYG) was then incorporated onto the particle surface to enhance the particle-cell recognition. The sequentially assembled cell-binding NLP with a zwitterionic surface gave a larger transfection yield than the cationic NLP at all concentrations tested. At low DNA concentrations, the enhancement was 80-fold. The disulfide cationic lipids and the sequential assembly strategy enable one to tailor the surface charge, hydrophilicity, and recognition elements of a nanosized gene carrier. This results in increased gene transfer activity in a biocompatible particle.
US doctors say sex selection acceptable for non-medical reasons
Authors: S. Gottlieb
Journal: BMJ (2001)

The American Society for Reproductive Medicine has ruled that it is proper and ethical to help couples to choose the sex of their babies.

In a recent letter of advice to an infertility specialist, the acting chairman of the society's ethics committee, John Robertson, said that sex selection was acceptable for reasons of “gender variety.” If a couple already had a child of one sex, it could ethically select embryos that were of the opposite sex, he said.

The group, which sets the rules for the field of reproductive medicine, has previously said that the practice was justified when parents were aiming to avoid the incidence of certain sex linked genetic …
Antithrombin reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation through promotion of prostacyclin production
Authors: Akio Mizutani, Kenji Okajima, Mitsuhiro Uchiba, Hirotaka Isobe, Naoaki Harada, Sachiko Mizutani, Takayuki Noguchi
Journal: Blood (2003)
Contribution of isolated general practitioner maternity units.
Authors: A J Cavenagh, K M Phillips, B Sheridan, E M Williams
Journal: BMJ (1984)

A postal survey of isolated general practitioner maternity units in England and Wales showed that just under 4% of deliveries take place in them. Eight per cent of general practitioners are on the staffs, and in 87% of units midwives are integrated with the community midwifery service. Sixty two per cent of units have visiting consultant cover. Fifty seven per cent of patients are booked and delivered in the unit, 28% are booked and deliberately delivered elsewhere, 5% are transferred in the antenatal period, and 10% transferred as emergencies. The perinatal mortality rate for cases booked and delivered in the units is 1.1 per 1000. The number of emergency transfers was appreciably less for those units that were prepared to do their own operations. Thirty five per cent of these units are liable to be cut off in bad weather, and they will continue to fulfil an essential role in the midwifery services.
Functional Studies of Left Upper Quadrant Mass Aid Management of Idiopathic Thrombocytopenic Purpura
Authors: STEVEN J. HARWOOD, ROBERT G. CARROLL
Journal: Clinical Nuclear Medicine (1992)

ITP (idiopathic thrombocytopeni purpura) causes rapid sequestration and destruction of thrombocytes by the spleen, liver, bone marrow, and reticuloendothelial elements of other organs. The usefulness of multiple radio-nuclide functional imaging procedures in the management of a 34-year-old woman with chronic ITP, two splenectomies (removal of the initial spleen and then a hypertrophied accessory spleen), and the failure of chemotherapy to control her thrombocytopenia, are discussed. A combination of in-111 oxine autologous platelet imaging, liver/spleen imaging, disofenin (liver/gallbladder) imaging, and glucoheptonate renal imaging demonstrated that her platelets were being sequestered by a markedly enlarged left hepatic lobe extending to the left lateral wall, with a small amount in the kidneys and lungs, and that there was no second accessory spleen.
Clap along if you feel like happiness is linked to money
Authors: N. Hawkes
Journal: BMJ (2014)

Surveying people’s wellbeing is unnecessary—GDP seems to be a good marker for happiness



This week, duty dictates that I should write about NHS England chief executive Simon Stevens’s plan for the next five years of the NHS.1 2 Its publication is a big event, raising lots of animated chatter among the policy makers and setting the scene for next year’s general election. Yet somehow it doesn’t excite: it’s altogether too sensible. So let’s cast duty aside and talk about happiness instead.

For many years it’s been an article of faith that gross national (or domestic) product measures everything except what makes life worthwhile, to borrow a phrase from Robert Kennedy. It does not include “the health of our children, the quality of their education, or the joy of their play,” he said in a speech in 1968. “It does not include the beauty of our poetry, the strength of our marriages, or the integrity of our public officials,” and so on. Disregarding the chutzpah of that claim about marriage from a Kennedy, his rhetoric was certainly stirring.

The idea of a better measure of national wellbeing hibernated until reinvented by the French. Secure in the belief that the French model for living was superior to that of the Anglo …
Scleroderma, Sjögren-like Syndrome, and Chronic Graft-Versus-Host Disease
Authors: THOMAS J. LAWLEY
Journal: Annals of Internal Medicine (1977)

A patient with acute myelogenous leukemia treated with an allogeneic bone marrow transplant developed acute graft-versus-host disease manifested by severe diarrhea, hepatitis, and a cutaneous eruption. As the graft-versus-host disease progressed to the chronic phase, the patient developed marked cutaneous sclerosis and symptoms of xerophthalmia and xerostomia. Biopsy of his indurated skin showed features of both graft-versus-host disease and scleroderma. Results of Schirmer's tests, corneal fluorescent studies, parotid flow-rate testing, and a lip biopsy were consistent with Sjögren's syndrome. Possibly, activated lymphocytes may have a role in the pathogenesis of graft-versus-host disease, scleroderma, and Sjögren's syndrome.
Farmer's lung precipitins in Doubs (a department of France): prevalence and diagnostic value
Authors: J. C. Dalphin, B. Toson, E. Monnet, D. Pernet, A. Dubiez, J. J. Laplante, J. M. Aiache, A. Depierre
Journal: Allergy (1994)

In a French region where farmer's lung (FL) is common, we determined the prevalence of FL precipitins in dairy farmers and analyzed the relation between the presence of FL precipitins and the clinical probability of the disease. All the exposed dairy farmers of both sexes ( n = 2555) from five districts of the Doubs department were asked to respond to a medical and professional questionnaire. A total of 1763 (69%) farmers agreed to participate. Precipitins tests were conducted in 551 (31%) farmers who showed any respiratory symptom and in a random sample of 100 asymptomatic farmers. Serum for each farmer was analyzed by both double diffusion and immunoelectrophoresis against Micropolyspora faeni (MF) and extracts of moldy hay (HE) from Doubs. The 651 farmers were then divided into four groups (G 1–4) with a decreasing probability of FL (G1: typical FL symptoms; G4: asymptomatic farmers). The estimated prevalence of precipitins in the whole population was as follows: 1) by double diffusion, against HE: 83%, against MF: 27%; 2) by immunoelectrophoresis, against HE: 26%, against MF: 19%. There was a close “linear” relation between the prevalence of precipitins detected by immunoelectrophoresis against HE and the symptoms: 51% in G1, 36% in G2, 29% in G3, and 13% in G4. Precipitins detected by immunoelectrophoresis were also related to exposure and geography (more immunization in tableland area than in plain or mountain area). Presence of precipitins detected by double diffusion was not related to symptoms, exposure, or geography. This study shows that the prevalence of precipitins is high in the exposed dairy farmers of Doubs, and suggests that immunoelectrophoresis (with the antigens used) is a more effective method for the diagnosis of FL than double diffusion.
GE-17 * ALTERATION OF THE p53 PATHWAY AND ANCESTRAL PROGENITORS ARE ASSOCIATED WITH TUMOR RECURRENCE IN GLIOBLASTOMA
Authors: H. Kim, S. Zheng, S. Amini, S. Virk, T. Mikkelsen, D. Brat, C. Sougnez, F. Muller, J. Hu, A. Sloan, M. Cohen, E. Van Meir, L. Scarpace, E. Lander, S. Gabriel, G. Getz, M. Meyerson, L. Chin, J. Barnholtz-Sloan, R. Verhaak
Journal: Neuro-Oncology (2014)

To evaluate evolutionary patterns of GBM recurrence, we analyzed whole genome sequencing (WGS) and multi-sector exome sequencing data from pairs of primary and posttreatment GBM. WGS on ten primary-recurrent pairs detected a median number of 12,214 mutations which we utilized to uncover clonal structures, by analyzing the distribution of mutation cellular frequencies (the fraction of tumor cells harboring a mutation). On average, 41 % of the mutations were shared by primary and recurrence. The majority of shared mutations were clonal in both primary and recurrence, but we also observed many clonal mutations that were uniquely detected in either the primary or the recurrence. This raises the intriguing possibility that major tumor clones in the primary tumor and disease relapse both evolved from a shared ancestral tumor cell population. At least one subclone was identified in the majority of WGS samples, and we observed groups of mutations that were at low cancer cell fractions in both primary and recurrence, suggesting that both subclones evolved from the same ancestral tumor cells separate from the major clone ancestral cells. To address the possibility that the lack of overlap between subsequent tumors was due to intratumoral heterogeneity, we analyzed exome sequencing from a second tumor sector of seven primary and six recurrent tumors. We found that the majority of "second biopsy" mutations were not conserved between time points, suggesting that intratumoral heterogeneity did not explain the large number of mutations uniquely detected in primary and recurrence. The limited overlap of mutations in primary and recurrence provides evidence for ancestral tumor cell populations that could not be eradicated by therapy, while offspring cell populations contained unique mutations, were selectively killed by treatment and could therefore no longer be detected after disease relapse. This study has provided new insights into patterns and dynamics of tumor evolution.
Public is asked to play free smartphone game to help cancer research
Authors: I. Torjesen
Journal: BMJ (2014)

Cancer Research UK has launched a free mobile phone game in which players help scientists to find patterns in genetic data from cancer patients. The aim is for the information to be used to improve the diagnosis and treatment of cancer.

At the start of Play to Cure: Genes in Space , players are shown an image of space and asked to map their intended course through the densest parts. They then fly their spaceship through the hazard strewn course, avoiding and shooting at asteroids, while picking up as much of the precious metal “Element Alpha” as possible. 

The image of space is actually a visual representation of real patient genetic data, and the players’ chosen routes are expected to …
QUANTITATIVE ASPECTS OF THE RED BLOOD CELL AGGLUTINATION TEST FOR INFLUENZA VIRUS
Authors: Gail Lorenz Miller, W. M. Stanley
Journal: The Journal of Experimental Medicine (1944)

A detailed study has been made of the nature of the variables inherent in the chicken red cell agglutination test for influenza virus in an effort to obtain a method of measurement of biological activity of sufficient accuracy that it might be employed as a reliable index of chemical purity of preparations of the virus. It was found that the temperature at which the test is conducted has a marked effect on the titer, whereas within the range of pH 6-8 the pH has a negligible effect. It was also found that a variation in results may be encountered due to a variation in the specific behavior of red cells from different chickens and to an instability of the red cells themselves. Preparations of purified influenza virus held at 4 degrees C., on the other hand, were found to be stable with respect to chicken red cell agglutinating activity for several months. This fact, together with the fact that in duplicate measurements upon different samples the accuracy was such that the chances were 19 out of 20 that differences of 8.4 per cent in the mean end points were significant, made it possible to establish a reproducible standard of CCA activity based on a unit weight of purified virus material. As a result, it was possible to devise a standardized procedure for carrying out with high accuracy quantitative measurements of influenza virus.