tbuckley/cabot-search huggingface dataset:
Sterol synthesis in the human arterial intima
Authors: Aram V. Chobanian
Journal: Journal of Clinical Investigation (1968)

Intimal sterol synthesis was examined in isolated human arterial segments obtained at surgery or at postmortem examination. The tissues were incubated with acetate-1-(14)C and mevalonate-2-(14)C and the incorporation of these precursors into sterols was determined. Intimal sterols were isolated by multiple chromatographic techniques and purified by bromination and oxidation procedures. The results indicate that the arterial intima can incorporate acetate and mevalonate into cholesterol, cholestanol, and squalene. Cholestanol was the major sterol synthesized by the arterial wall, but cholesterol production was also consistently observed. The findings suggest that local synthesis is a potential source of sterol accumulation within the arterial wall. The conversion of cholesterol to other sterols was also studied in terminally ill patients receiving labeled cholesterol before death. Tissue analyses revealed the presence of labeled cholestanol as well as cholesterol in the tissue 5-104 days after labeled cholesterol administration. The results demonstrate the conversion of cholesterol to cholestanol in man and suggest that the exchange of cholestanol between the blood and tissues is similar to that of cholesterol.
AFTER-EFFECTS OF INTRAUTERINE RADIUM FOR THE PRODUCTION OF ARTIFICIAL MENOPAUSE: REPORT OF AN INVESTIGATION
Authors: M. L. Kreitmayer
Journal: BMJ (1930)

TDICnptmsn 815ence in patients who are treate(l ov,er the age of 40, buit that in the younger :patients tl-e symptoms tend to be niioere sevelre.A question ofteni asked bv patients before siubmitting to tlis teattiiet is, " Shall I get fat?" It woild appeal fromii tihis serics that 50 per cent.definitely piut on weight, but t; details of lhow much are not recorded(l.Aniothier ifnfportant symptom is the question of dys- pareuiiia, which occurred in only 7 cases out of the 93; and loss of inclination was experienced in 8.In 31 cases it is definitely stated that the relations wer-c unaltere(d.FoIrty of the remaining patients, lhowever, were spinsters olr iilows, and in 5 the answers were too indefinite to be of value.The small nuimber of cases suiffe ringg fromn dysparcunia suggests that there is no rcal troufble cauised by cicatriiation or adlhesions in th-e vaginia, in spite of the large dose.thatis, 3,600 mg.houirs.TREATMENT OF FIBROIDS IIY RAPTOTHERAPY.Thlie treatment of fibroids may be divided under thlee head(ings-surgical, radiological, and palliative.A tew years ago the palliative treatment was frequently emn)loyed, especially when the patient was over 40 aii(l
Generalized Arterial Calcification of Infancy
Authors: A. C. Hunt, D. G. Leys
Journal: BMJ (1957)

In some 40 reported cases of arterial calcification of infancy the proved occurrence in siblings has been described once (Menten and Fetterman, 1948).We report a further example of siblings affected by this disease.It has been described in children of either sex from the age of 1 day to 27 months, usually in the first six months of life.The clinical history and post-mortem appearances in most of the reported examples in early infancy are very similar.The children are born to apparently healthy young parents.The pregnancy and birth are normal, and there is no evidence of abnormal consumption by mother or child of poisons or poisonous dosages of calcifying substances.The infant thrives at first, then, after a few hours, or at the most a few days, of acute symptoms, succumbs from cardiac ischaemia.The symptoms are refusal of feeds, painful rapid respiration, abdominal distension, and heart failure.Occasionally, as in the first of our cases, an electrocardiogram may show the picture typical of coronary occlusion.Although the clinical manifestations are usually
A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury
Authors: Keiji Kuba, Yumiko Imai, Shuan Rao, Hong Gao, Feng Guo, Bin Guan, Yi Huan, Peng Yang, Yanli Zhang, Wei Deng, Linlin Bao, Binlin Zhang, Guang Liu, Zhong Wang, Mark Chappell, Yanxin Liu, Dexian Zheng, Andreas Leibbrandt, Teiji Wada, Arthur S Slutsky, Depei Liu, Chuan Qin, Chengyu Jiang, Josef M Penninger
Journal: Nature Medicine (2005)

During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world1,2,3. A new coronavirus (SARS-CoV) was identified as the SARS pathogen4,5,6,7, which triggered severe pneumonia and acute, often lethal, lung failure8. Moreover, among infected individuals influenza such as the Spanish flu9,10 and the emergence of new respiratory disease viruses11,12 have caused high lethality resulting from acute lung failure13. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor14. The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.
The Ph.D. to M.D. Program
Authors: William M. Awad, William J. Harrington, Emanuel M. Papper
Journal: New England Journal of Medicine (1979)

Abstract The Ph.D. to M.D. Program, a two-year, accelerated medical curriculum for Ph.D. scientists, has been in operation at the University of Miami for over seven years. Two hundred and nine students from a broad range of scientific disciplines have been admitted, and attrition has been remarkably low (less than 1 per cent). One hundred and thirty-five of the entering candidates (65 per cent) were nonbiologists, but their achievements in the curriculum were virtually equivalent to those of their biologically oriented peers. All graduates have commenced house-staff training, the vast majority at university or university-affiliated hospitals. Of the 46 graduates who have completed some aspect of postgraduate training, 22 are in private practice, 20 are in teaching and research positions and four are scientific administrators in industry. The record indicates that through intensive medical education, the program is able to bring a group of scientists with unusual talents to the theory and practice of medicine. (N Engl J Med 301:863–867, 1979)
Lehrbuch und Atlas der laparoskopischen Diagnostik
Authors: Ernst G. Maasz
Journal: JAMA (1967)

This contribution to the field of peritoneoscopy presents the author's extensive personal experience with this valuable diagnostic procedure. There is a 128-page text followed by an atlas devoted to roentgenograms after pneumoperitoneum, and 63 case presentations with illustrative color drawings, endophotographs, and photomicrographs. In the text section, detailed discussions of the technique and clinical applications of peritoneoscopy are accentuated by sketches of instruments and procedures, and varying methods are compared and evaluated. The interested clinician will appreciate the extensive list of indications, contraindications, and complications, as well as the emphasis on differential diagnostic aspects of postprocedural pain. Gross morphologic changes of diseased intra-abdominal organs are correlated with etiology, pathophysiology and histology. Particular attention is directed to the effect of infections, nutritional deficiencies, and biliary tract diseases on liver function, and there are candid discussions of the normal and abnormal portal circulation, retrograde cholecystography, and splenoportography.  In the atlas section, differentiation
Tuberculosis immunodiagnosis: delving below the surface
Authors: Ajit Lalvani, David W Connell
Journal: Thorax (2013)

It is one hundred and thirty years since Franz Ziehl and Friedrich Neelsen developed the rapid stain for acid-fast bacilli;1 ,2 accurate point-of-care diagnosis of active tuberculosis (TB) remains a major unmet clinical need. With the sensitivity of the Ziehl–Neelsen stain in sputum less than 50% and more than 20% of TB cases negative on both acid-fast stain and culture for Mycobacterium tuberculosis , there has long been a yawning gap in the diagnostic toolkit for TB. New rapid molecular methods have recently improved detection of M tuberculosis nucleic acids in sputum providing diagnostic sensitivity that is much higher than sputum-smear microscopy but lower than culture.3 

The longstanding diagnostic gap has stimulated decades of research into immunodiagnosis, mostly serological. Although serological tests for TB are point-of-care, they lack diagnostic accuracy and are devoid of clinical utility. After thorough review of the evidence, and on account of their continued widespread misuse in many high-burden countries, WHO recently tried to bury current commercial serological test kits with a negative endorsement warning against their use.4 

Research into cellular immunodiagnosis has been more fruitful, delivering a tangible advance in clinical practice in the form of interferon-gamma release-assays (IGRA).5 IGRA detect M tuberculosis infection, providing a new standard-of-care for diagnosis of latent TB infection (LTBI), but they cannot distinguish active TB from LTBI. Hence, their potential role in evaluation of patients with suspected active TB is limited to that of a possible rule-out test of TB, yet currently available IGRA lack sufficient diagnostic sensitivity for this indication, as discussed elsewhere in this issue of Thorax .6 ,7 

Are there immune responses that differ sufficiently between active TB and LTBI to enable development of an immunodiagnostic test that is specific for active TB? Quantifying genome-wide host gene-expression yielded a …
Nuclear Translocation of the Tumor Marker Pyruvate Kinase M2 Induces Programmed Cell Death
Authors: Attila Steták, Réka Veress, Judit Ovádi, Péter Csermely, György Kéri, Axel Ullrich
Journal: Cancer Research (2007)

Abstract Cancer cells often fail to respond to stimuli that normally activate their intrinsic apoptotic machinery. Moreover, they are able to adapt to hypoxia by changing their glycolytic rate. Pyruvate kinase (PK) is a rate-limiting enzyme in glycolysis that is converted to a less active dimer form of PKM2 isoenzyme during oncogenesis. Here, we show that both somatostatin and the structural analogue TT-232 interact with the PKM subtype. We further show that the PKM2 is translocated to the nucleus in response to TT-232 and different apoptotic agents. Nuclear translocation of PKM2 is sufficient to induce cell death that is caspase independent, isoform specific, and independent of its enzymatic activity. These results show that the tumor marker PKM2 plays a general role in caspase-independent cell death of tumor cells and thereby defines this glycolytic enzyme as a novel target for cancer therapy development. [Cancer Res 2007;67(4):1602–8]
Is transplantation tolerable?
Authors: Terry B. Strom
Journal: Journal of Clinical Investigation (2004)

To test the hypothesis that chronic stimulation of T cells with a weak agonistic antigen will generate regulatory T cells and immune tolerance, a study reported in this issue employed the redesign of a minor histocompatibility antigen. Using knowledge of residues at which the antigen contacts the T cell receptor, a weak agonist was produced. Pretreatment with this altered antigen produced transplant tolerance, generation of regulatory T cells, and a loss of many antigen-reactive T cells.
Performance of classification criteria for gout in early and established disease
Authors: William J Taylor, Jaap Fransen, Nicola Dalbeth, Tuhina Neogi, H Ralph Schumacher, Melanie Brown, Worawit Louthrenoo, Janitzia Vazquez-Mellado, Maxim Eliseev, Geraldine McCarthy, Lisa K Stamp, Fernando Perez-Ruiz, Francisca Sivera, Hang-Korng Ea, Martijn Gerritsen, Carlo Scire, Lorenzo Cavagna, Chingtsai Lin, Yin-Yi Chou, Anne-Kathrin Tausche, Geraldo da Rocha Castelar-Pinheiro, Matthijs Janssen, Jiunn-Horng Chen, Ole Slot, Marco Cimmino, Till Uhlig, Tim L Jansen
Journal: Annals of the Rheumatic Diseases (2014)

To compare the sensitivity and specificity of different classification criteria for gout in early and established disease.This was a cross-sectional study of consecutive rheumatology clinic patients with joint swelling in which gout was defined by presence or absence of monosodium urate crystals as observed by a certified examiner at presentation. Early disease was defined as patient-reported onset of symptoms of 2 years or less.Data from 983 patients were collected and gout was present in 509 (52%). Early disease was present in 144 gout cases and 228 non-cases. Sensitivity across criteria was better in established disease (95.3% vs 84.1%, p<0.001) and specificity was better in early disease (79.9% vs 52.5%, p<0.001). The overall best performing clinical criteria were the Rome criteria with sensitivity/specificity in early and established disease of 60.3%/84.4% and 86.4%/63.6%. Criteria not requiring synovial fluid analysis had sensitivity and specificity of less than 80% in early and established disease.Existing classification criteria for gout have sensitivity of over 80% in early and established disease but currently available criteria that do not require synovial fluid analysis have inadequate specificity especially later in the disease. Classification criteria for gout with better specificity are required, although the findings should be cautiously applied to non-rheumatology clinic populations.
Kenneth Walter William Henry Walton
Authors: G. Born
Journal: BMJ (2009)

Kenneth Walton was a leading experimental pathologist. His wide-ranging research at Birmingham University, covering both atherosclerosis and rheumatoid arthritis, is still cited, and he did much to shape our contemporary scientific approach to rheumatology.

Kenneth Walter William Henry Walton was born in Lahore in 1919; his father was a British serviceman who later became a cotton exporter. His grandfather on his mother’s side was a general practitioner, and he was encouraged by his parents to study medicine. He trained at University College and University College Hospital, London, where he became a demonstrator in pathology while still a student under his great mentor, Sir Roy Cameron. As a keen cricketer, he was a member of his college cricket team and also found time for dinghy sailing on the Thames. He qualified in 1942, aged 23.

As a house officer at St John and Elizabeth Hospital, he dealt with bomb casualties in London. He subsequently served in the Royal Army Medical Corps. He travelled to India, Burma, and Hong Kong and ended his service career in 1947 with the rank of a major and as assistant director of pathology in the Hong Kong command. His experiences in British India and as an army pathologist equipped him with a much broader perspective than can be readily achieved today.

Once demobbed, he returned to the department …
Extreme poverty: an obligation ignored
Authors: J. Kevany
Journal: BMJ (1996)

The world's biggest killer and the greatest cause of ill health and suffering across the globe is listed almost at the end of the International Classification of Diseases. It is given code Z59.5—extreme poverty.1

Extreme poverty is defined as a level of income or expenditure below which people cannot afford a minimum, nutritionally adequate diet and essential non-food requirements.2 The effects of poverty on health are never more clearly expressed than in poor communities of the developing world. The absence of safe water, environmental sanitation, adequate diet, secure housing, basic education, income generating opportunities, and access to health care act in obvious and direct ways to produce ill health, particularly from infectious disease, malnutrition, and reproductive hazards.3

Today the number of people in extreme poverty is estimated at 1.1 billion—a fifth of the world's population. The wealthiest fifth of the world's population now controls 85% of global gross national product and 85% of world trade, leaving the poorest quintile with …
Hormone-sensitive fat cell adenylate cyclase in the rat. Influences of growth, cell size, and aging.
Authors: B Cooper, R I Gregerman
Journal: Journal of Clinical Investigation (1976)

The possibility has been explored that decreases of adenylate cyclase may explain diminished hormone sensitivity of adipose tissue with aging. Isolated cells were prepared from epididymal fat pads of rats 1-, 2-, 6-, 12-, and 24-mo old, fixed in OSO4, and sized and counted with a Coulter apparatus. Adenylate cyclase was assayed in cell membranes (ghosts) using [alpha-32P] ATP as substrate and expressed as cyclic [32P] AMP/10 min per mg protein or per 10(6) cells. Enzyme activity was determined for the basal state and in the presence of varying concentrations of glucagon, ACTH, epinephrine, and fluoride. Basal activity per cell increased in threefold between 1 and 2 mo with a comparable increase in cell surface area, suggesting synthesis of enzyme along with new cell membrane. Although epinephrine stimulated adenylate cyclase 8-fold and fluoride 12-fold throughout the life-span of the rat, stimulated activity paralleled basal levels, decreasing 60% between 2 and 24 mo per mg protein and 40% between 6 and 24 mo per cell. Glucagon stimulated adenylate cyclase 4.5-fold relative to basal in the 1-mo-old rat, but its effect then rapidly decreased and was absent by 12 mo. The fourfold stimulation by ACTH noted in the 1-mo-old animals decreased gradually with age but was still twice basal at 24 mo. Since no significant change of cell size occurred after 6 mo, diminished hormone sensitivity with senescence cannot be related to cell size. Similar age-related patterns of hormonal activation were evoked by 5'-guanylyl-imidodiphosphate [GMP-P(NH)P], a nucleotide analogue which increased both basal- and hormone-activated enzyme at all ages studied. Dose-response curves to hormones, fluoride, and GMP-P (NH)P were not affected by age. High Mg++ (50 mM) in the presence of GMP-P-(NH)P stimulated adenylate cyclase to levels greater than with fluoride, but a similar loss of activity with aging was still observed. Loss of hormone receptors may partially explain the age-related decreases of glucagon and ACTH-sensitive adenylate cyclase, but decreased basal-, epinephrine-, fluoride-, and GMP-P-(NH) P-stimulated responses suggest loss of the catalytic component of the adenylate cyclase enzyme complex in the aging fat cell membranes.
Dealing With Complexity in Clinical Diabetes
Authors: Richard Kahn
Journal: Diabetes Care (2003)

In this issue of Diabetes Care , two articles by Eddy and Schlessinger (1,2) describe a new type of mathematical model of diabetes known as Archimedes. Many readers might think that mathematical models are too abstract or simplistic to have any relevance to real clinical practice. Others may be skeptical because they have difficulty understanding how the model can do what the articles describe, and may be tempted to dismiss it as a black box.

Both of these responses would be natural and understandable, but incorrect. The significance of this new model, and the potential it can provide for helping us improve the quality of diabetes care, is quite remarkable. For the first time, there is a model written at the level of biological and clinical detail at which clinicians make day-to-day decisions. And for the first time, there is a model that has been validated against real clinical trials, and many of them.

To truly appreciate the potential value of Archimedes, it is necessary to address the two main sources of skepticism. First, why are mathematical models needed at all? And second, why is this particular model so special? The answers to both these questions rest on a single issue—complexity.

Diabetes care is complex. If all we had to do was lower blood glucose levels in everyone with the disease, the answer would be clear-cut and simple. But when we begin to consider the risk of hypoglycemia, the side effects of medications, and the uncertainties of “adherence to treatment,” decision-making becomes more difficult. Now add hypertension, dyslipidemia, and obesity, many or all of which are found in most people with diabetes, and the treatment options become even more complex. Next add age, race, gender, duration of disease, life expectancy, quality of life, comorbid conditions, and all of …
Management of rheumatoid arthritis.
Authors: P. J. Holt
Journal: BMJ (1969)

Rheumatoid arthritis affects at least 1 % of all males and 3% of all females, the incidence rising with increasing age.In mild cases little disability results, but in more severe cases a progres- sive destruction of joints, tendons, and other tissues is associated with a systemic illness and constitutional symptoms, of fluctuating and very variable degree, eventually leading to deformed and crippled limbs when the inflammation has sub- sided.Since there is no definitive treatment the object of
Response of Severe HIV-Associated Thrombocytopenia to Highly Active Antiretroviral Therapy Including Protease Inhibitors
Authors: S. Carbonara, G. Fiorentino, G. Serio, P. Maggi, G. Ingravallo, L. Monno, F. Bruno, S. Coppola, G. Pastore, G. Angarano
Journal: Journal of Infection (2001)
Multifunctional receptor model for dioxin and related compound toxic action: possible thyroid hormone-responsive effector-linked site.
Authors: J D McKinney
Journal: Environmental Health Perspectives (1989)

Molecular/theoretical modeling studies have revealed that thyroid hormones and toxic chlorinated aromatic hydrocarbons of environmental significance (for which dioxin or TCDD is the prototype) have similar structural properties that could be important in molecular recognition in biochemical systems. These molecular properties include a somewhat rigid, sterically accessible and polarizable aromatic ring and size-limited, hydrophobic lateral substituents, usually contained in opposite adjoining rings of a diphenyl compound. These molecular properties define the primary binding groups thought to be important in molecular recognition of both types of structures in biochemical systems. Similar molecular reactivities are supported by the demonstration of effective specific binding of thyroid hormones and chlorinated aromatic hydrocarbons with four different proteins, enzymes, or receptor preparations that are known or suspected to be involved in the expression of thyroid hormone activity. These binding interactions represent both aromatic-aromatic (stacking) and molecular cleft-type recognition processes. A multiple protein or multifunctional receptor-ligand binding mechanism model is proposed as a way of visualizing the details and possible role of both the stacking and cleft type molecular recognition factors in the expression of biological activity. The model suggests a means by which hormone-responsive effector-linked sites (possible protein-protein-DNA complexes) can maintain highly structurally specific control of hormone action. Finally, the model also provides a theoretical basis for the design and conduct of further biological experimentation on the molecular mechanism(s) of action of toxic chlorinated aromatic hydrocarbons and thyroid hormones.