tbuckley/cabot-search huggingface dataset:
Challenges to Human Subject Protections in US Medical Research
Authors: Beverly Woodward
Journal: JAMA (1999)

United States regulations governing federally supported research with human subjects derive in part from 2 international codes, the Nuremberg Code and the Declaration of Helsinki. The Declaration of Helsinki states that "concern for the interests of the subject must always prevail over the interests of science and society." The concept of minimal risk and the principle of informed consent are the key means by which US federal regulations seek to protect the rights and welfare of the individual in the research setting. Current trends in medical research—including increased funding, ever-greater capabilities of computers, development of new clinical tools that can also be used in research, and new research tools developed through research itself—are creating greater demand for human subjects, for easier recruitment and conscription of these subjects, and for unimpeded access to patient medical records and human biological materials. Nationally and internationally, there are new pressures to subordinate the interests of the subject to those of science and society. The National Bioethics Advisory Commission, which is about to undertake a comprehensive review of the US system of human subject protections, faces a daunting task.
IMMUNOLOGICAL TOLERANCE IN BONE MARROW-DERIVED LYMPHOCYTES
Authors: David H. Katz, Toshiyuki Hamaoka, Baruj Benacerraf
Journal: The Journal of Experimental Medicine (1972)

Administration of the 2,4-dinitrophenyl (DNP) derivative of the copolymer of D-glutamic acid and D-lysine (D-GL) to inbred mice induces a state of DNP-specific tolerance in such animals irrespective of their immune status at the time of treatment. Taking advantage of the relative ease with which DNP-D-GL can induce tolerance in an animal previously primed with an immunogenic DNP-carrier conjugate, we have established conditions for tolerance induction in an adoptive cell transfer system. Thus, the adoptive secondary anti-DNP antibody response of DNP-keyhole limpet hemocyanin (KLH)-primed spleen cells was completely, or almost completely, abolished by exposure of such cells to DMP-D-GL either in vivo or in vitro. Tolerance induction in vivo occurred irrespective of whether the DNP-primed cells were exposed to DNP-D-GL in the donor animal before adoptive transfer or in recipient mice after transfer. In the latter situation, it was possible to show that tolerance induction in this model occurs very rapidly (1 hr) and with relatively low doses of tolerogen (50 microg). Incubation of DNP-KLH-primed cells with DNP-D-GL in vitro under varying culture conditions also resulted in depression of the adoptive secondary response of such cells, although the kinetics and degree of tolerance induction in this way were slightly different from that obtained by in vivo tolerization. Utilizing the adoptive transfer tolerance system, it was possible to approach certain questions concerning the mechanism of tolerance induction and fate of tolerant bone marrow-derived (B) lymphocytes in the DNP-D-GL model. The possibility that suppression of anti-DNP antibody from the DNP-D-GL reflects blocking of surface receptor molecules on B lymphocytes has been ruled out by several experimental observations. The most conclusive evidence on this point derives from the failure of enzymatic treatment with trypsin to reverse the tolerant state induced by in vitro exposure of primed cells to DNP-D-GL, whereas trypsinization completely restored the immunocompetence of DNP-KLH-primed cells rendered unresponsive by exposure to DNP-ovalbumin in vitro. The present studies also demonstrate that the tolerant state induced by DNP-D-GL represents a predominantly irreversible inactivation of specific B lymphocytes. This conclusion is derived from experiments in which it was found that tolerance was maintained through as many as two serial adoptive transfers performed over a period of time of at least 24 days from the single exposure of such cells to the tolerogen. Moreover, the possibility that maintenance of tolerance through such serial transfers was due to inadvertent transfer of tolerogenic doses of DNP-D-GL was definitively ruled out. It appears, therefore, that DNP-specific tolerance induced by DNP-D-GL is an example of irreversible inhibition of cell reactivity to antigen reflecting yet-to-be-determined events at the intra- and subcellular levels.
A Role for CD4 in Peripheral T Cell Differentiation
Authors: Daniel R. Brown, Naomi H. Moskowitz, Nigel Killeen, Steven L. Reiner
Journal: The Journal of Experimental Medicine (1997)

Naive CD4+ T helper cells (Th) differentiate into one of two well-defined cell types during immune responses. Mature Th1 and Th2 cells regulate the type of response as a consequence of the unique cytokines that they secrete. CD4 serves a prominent role in potentiating antigen recognition by helper T cells. We have examined the role of CD4 in peripheral T cell differentiation by studying helper T cells from mice with a congenital defect in CD4 expression. After protein immunization or infection with Leishmania major, CD4-deficient mice were incapable of mounting antigen-specific Th2 responses, but retained their Th1 potency. CD4-deficient, T cell receptor transgenic T cells were also incapable of Th2 differentiation after in vitro activation. Expression of a wild-type CD4 transgene corrected the Th2 defect of CD4-deficient mice in all immune responses tested. To investigate the role of the cytoplasmic domain, mice reconstituted with a truncated CD4 molecule were also studied. Expression of the tailless CD4 transgene could not rescue the Th2 defect of CD4-deficient mice immunized with protein or CD4-deficient transgenic T cells activated in vitro, raising the possibility that the cytoplasmic domain of CD4 may influence Th2 generation. Expression of the tailless transgene was, however, capable of restoring Th2 development in CD4-deficient mice infected with L. major or CD4-deficient transgenic T cells activated in the presence of recombinant IL-4, demonstrating that the cytoplasmic domain is not absolutely required for Th2 development. Together, these results demonstrate a previously undescribed role of the CD4 molecule. The requirement for CD4 in Th2 maturation reflects the importance of molecules other than cytokines in the control of helper T cell differentiation.
Alcohol Consumption and Risk for Development of Impaired Fasting Glucose or Type 2 Diabetes in Middle-Aged Japanese Men
Authors: Noriyuki Nakanishi, Kenji Suzuki, Kozo Tatara
Journal: Diabetes Care (2003)

OBJECTIVE—To investigate the association between alcohol consumption and risk for development of diabetes. RESEARCH DESIGN AND METHODS—We examined 2,953 Japanese male office workers aged 35–59 years who did not have impaired fasting glucose (IFG) (a fasting plasma glucose concentration of 6.1–6.9 mmol/l), type 2 diabetes (a fasting plasma glucose concentration of ≥7.0 mmol/l or receipt of hypoglycemic medication), medication for hypertension, or a history of cardiovascular disease. Fasting plasma glucose concentrations were measured at periodic annual health examinations from May 1994 through May 2001. RESULTS—There was a U-shaped association between alcohol consumption and the incidence of IFG or type 2 diabetes during 7 years of follow-up, with the lowest incidence at alcohol intake of 23.0–45.9 g ethanol/day. After controlling for age, family history of diabetes, BMI, cigarette smoking, and physical activity, the relative risk for development of IFG or type 2 diabetes compared with alcohol consumption of 23.0–45.9 g ethanol/day was 1.51 (95% CI, 1.07–2.13), 1.31 (95% CI, 0.93–1.84), 1.18 (95% CI, 0.87–1.61), and 1.43 (95% CI, 1.01–2.02) with alcohol consumption of 0, 0.1–22.9, 46.0–68.9, and ≥69.0 g ethanol/day, respectively (P for quadratic trend = 0.016). Analyses by presence or absence of a risk factor revealed that a U-shaped association was more evident in older men, men without a family history of diabetes, and nonsmokers. CONCLUSIONS—These results indicate that moderate alcohol consumption among apparently healthy Japanese men is associated with reduced risk for development of IFG or type 2 diabetes.
A NOTE ON ABDOMINAL HYSTERECTOMY FOR CANCER OF THE CERVIX, AND ITS IMMEDIATE MORTALITY: WITH AN ANALYSIS OF SEVENTEEN CASES
Authors: T. B. Henderson
Journal: BMJ (1908)

Doran received a false report of the patient's death, but on February 12th, 1908, a patient came to see him at the hospital.She complained of dyspepsia, due, it appeared, to excessive tea-drinking, but she added that she had gone on wonderfully well since her operation.Then, on looking into his notebook, Mr. Doran found she was Case ii, and there was a report of her death.On further inquiry it transpired that the report referred to some other patient with a similar name and complaint, who had never been under his care.The patient looked very healthy, just as she appeared before the operation, and had distinctly gained flesh.There had been no period since the operation, and the menopause symptoms had passed away soon after her last visit in 1905.On examination, the abdominal cicatrix was found to be perfectly healthy, and the parietes supple.There was no evidence of the existence of any abdominal tumour.The cervix had become very small, and was still fixed, the two fleshy wattles in the left fornix had almost disappeared.There was a little resistance above the left fornix just definable on bimanual palpation.The right and posterior fornices were free.Such was the patient's condition two years and seven months after the operation.Mr. Doran declared that in the whole of his operative experience he had never come across a case where the after-history so thoroughly belied operative and pathological evidence.These cases show the imperative necessity for careful observation of all patients from whom uterine fibroids have been removed.Only by such observation can we expect to gain anything like accurate knowledge as to the effects on the patient's organism of the removal of the fibroid uterus with or without cervical or ovarian tissue, so that we may see how far clinical experience agrees with the physiological experience of Blair Bell, Bond, Carmichael and Marshall, and others; and only by such observation can we expect to calculate with something like precision the chances of malignant, or apparently malignant, changes being overlooked or misinterpreted.
Measurement of Myocardial Blood Flow in Animals and Man by Selective Injection of Radioactive Inert Gas into the Coronary Arteries
Authors: RICHARD S. ROSS, KEIJI UEDA, PAUL R. LICHTLEN, J. RUSSELL REES, Redden Redden, Christa Kaelber
Journal: Circulation Research (1964)

1. Human myocardial blood flow has been measured by the determination of precordial radioactivity after the injection of solutions of radioactive gas directly into the coronary arteries following coronary arteriography. 2. The accuracy of radioactive gas measurements has been established in dog experiments by comparison with coronary blood flow simultaneously measured by rotameter. 3. This method has two major advantages over the existing methods of measuring human myocardial blood flow. Firstly, the right and left coronary circulations can be studied separately, this being the only method whereby the right circulation can be studied in man. Secondly, anatomical and physiological correlations are readily available as arteriography is an essential feature of the method.
Screening pelvic exams are of no benefit, US doctors' group says
Authors: M. McCarthy
Journal: BMJ (2014)

Screening pelvic exams should not be routinely performed on healthy, asymptomatic, women who are not pregnant, a new clinical guideline from the American College of Physicians has said.1

The guideline was prepared by the college’s Clinical Guidelines Committee and appeared in the 1 July issue of the Annals of Internal Medicine .

The college—whose membership includes 137 000 internists, internal medicine sub-specialists, and doctors in training—is the largest medical specialty organization and the second largest physician group in the United States. The committee rated its recommendation as “strong” and its evidence as “moderate quality.”

“Routine pelvic examination rarely detects important disease and does not reduce mortality,” said Linda Humphrey of the Veterans Affairs Medical Center in Portland, Oregon, and a guideline coauthor, in a statement accompanying its release. Moreover, the exam “is associated with discomfort for many …
Enhanced Antitumor Efficacy of Clinical-Grade Vasculature-Targeted Liposomal Doxorubicin
Authors: Fabio Pastorino, Daniela Di Paolo, Federica Piccardi, Beatrice Nico, Domenico Ribatti, Antonio Daga, Gabriella Baio, Carlo E. Neumaier, Chiara Brignole, Monica Loi, Danilo Marimpietri, Gabriella Pagnan, Michele Cilli, Eugene A. Lepekhin, Seema V. Garde, Renato Longhi, Angelo Corti, Theresa M. Allen, Jinzi J. Wu, Mirco Ponzoni
Journal: Clinical Cancer Research (2008)

Abstract Purpose: In vivo evaluation of good manufacturing practice-grade targeted liposomal doxorubicin (TVT-DOX), bound to a CD13 isoform expressed on the vasculature of solid tumors, in human tumor xenografts of neuroblastoma, ovarian cancer, and lung cancer. Experimental Design: Mice were implanted with lung, ovarian, or neuroblastoma tumor cells via the pulmonary, peritoneal, or orthotopic (adrenal gland) routes, respectively, and treated, at different days post inoculation, with multiple doses of doxorubicin, administered either free or encapsulated in untargeted liposomes (Caelyx) or in TVT-DOX. The effect of TVT-DOX treatment on tumor cell proliferation, viability, apoptosis, and angiogenesis was studied by immunohistochemical analyses of neoplastic tissues and using the chick embryo chorioallantoic membrane assay. Results: Compared with the three control groups (no doxorubicin, free doxorubicin, or Caelyx), statistically significant improvements in survival was seen in all three animal models following treatment with 5 mg/kg (maximum tolerated dose) of TVT-DOX, with long-term survivors occurring in the neuroblastoma group; increased survival was also seen at a dose of 1.7 mg/kg in mice bearing neuroblastoma or ovarian cancer. Minimal residual disease after surgical removal of neuroblastoma primary mass, and the enhanced response to TVT-DOX, was visualized and quantified by bioluminescence imaging and with magnetic resonance imaging. When treated with TVT-DOX, compared with Caelyx, all three tumor models, as assayed by immunohistochemistry and chorioallantoic membrane, showed statistically significant reductions in cell proliferation, blood vessel density, and microvessel area, showing increased cell apoptosis. Conclusion: TVT-DOX should be evaluated as a novel angiostatic strategy for adjuvant therapy of solid tumors.
Treatment with low-dose lansoprazole may reduce frequency of COPD exacerbations in older patients
Authors: L. Willis
Journal: Thorax (2009)

Colds caused by respiratory viruses can trigger exacerbations of chronic obstructive pulmonary disease (COPD). This Japanese study investigated whether lansoprazole reduces the frequency of COPD exacerbations by mitigating the effects of respiratory viruses.

One hundred and three patients with COPD (mean age 75 years, 95% male), but without evidence of …
Plasma levels of soluble tumour necrosis factor receptors are increased in coal miners with pneumoconiosis
Authors: RP Schins, PJ Borm
Journal: European Respiratory Journal (1995)

Among other cytokines, tumour necrosis factor (TNF)-alpha is considered to play a key role in the development of mineral dust related fibrosis. Previously, we showed that ex-vivo release of TNF by peripheral blood monocytes is a marker for progression of coal workers' pneumoconiosis (CWP). Since soluble TNF receptors (sTNF-Rs) are believed to play an important regulatory role in systemic effects of TNF, we measured plasma levels of sTNF-R55 and sTNF-R75 in coal miners with (n = 28) or without (n = 76) CWP and in nonexposed controls (n = 29). sTNF-R75 levels were significantly increased in miners with CWP (2.09 +/- 0.44 ng.mL-1) versus the nonexposed controls (1.86 +/- 0.23 ng.mL-1). Neither sTNF-R55 nor sTNF-R75 were related to exposure, stage of pneumoconiosis, smoking, or (spontaneous or ex-vivo induced) monocyte TNF-release. sTNF-R55 was increased in subjects with medication (especially those using cardiovascular drugs); upon exclusion of these subjects, sTNF-R55 was found also to be significantly increased in CWP. In conclusion, bearing in mind a confounding effect of medication, soluble TNF receptors are elevated in plasma of retired miners with coal workers' pneumoconiosis. These observations further support the important role of TNF-mediated pathways in the pathogenesis of mineral dust related fibrosis.
Cineradiographic Studies of the Early Systolic Click in Aortic Valve Stenosis
Authors: ELLIS J. EPSTEIN, J. MICHAEL CRILEY, EDWARD B. RAFTERY, J. O'NEAL HUMPHRIES, RICHARD S. ROSS
Journal: Circulation (1965)

An early systolic click and a normal or accentuated aortic second sound have been found in cases of aortic valve stenosis characterized cineradiographically by a mobile, dome-shaped valve. Impaired valve mobility was usually associated with a systolic click of low intensity, and in the presence of an immobile aortic valve there was no systolic click. The aortic second sound was correspondingly diminished or absent. Early systolic clicks and loud aortic closure sounds were also present in patients in whom a diseased aortic valve had been replaced by three Teflon prosthetic leaflets. In most of these patients there was no systolic click before insertion of the prosthesis. In the patients studied, the systolic click occurred at the end of the opening movement of the aortic valve at the onset of left ventricular ejection. It followed the crossover point of the left ventricular and aortic pressure pulses by a time interval ranging from 15 to 45 msec. (average 33 msec.). The opening movement of the valve was thought to produce the systolic click by causing sudden tension of the valve membrane or sudden alteration in the velocity of blood flow. By analogy with the opening snap in mitral stenosis, the early systolic click may be regarded as the "opening snap" of the aortic valve. A systolic click is clinical evidence of a mobile aortic valve in patients with aortic valve disease.
Immunomodulatory drug costimulates T cells via the B7-CD28 pathway
Authors: Richard LeBlanc, Teru Hideshima, Laurence P. Catley, Reshma Shringarpure, Renate Burger, Nicholas Mitsiades, Constantine Mitsiades, Puneet Cheema, Dharminder Chauhan, Paul G. Richardson, Kenneth C. Anderson, Nikhil C. Munshi
Journal: Blood (2003)
Three Psychotherapies for Anorexia Nervosa: A Randomized, Controlled Trial
Authors: Virginia V.W. McIntosh, Jennifer Jordan, Frances A. Carter, Suzanne E. Luty, Janice M. McKenzie, Cynthia M. Bulik, Christopher M.A. Frampton, Peter R. Joyce
Journal: American Journal of Psychiatry (2005)

Few randomized, controlled trials have examined the efficacy of treatments for anorexia nervosa. Cognitive behavior therapy and interpersonal psychotherapy are effective in a related disorder, bulimia nervosa. There are theoretical and treatment indications for these therapies in anorexia nervosa.Fifty-six women with anorexia nervosa diagnosed by using strict and lenient weight criteria were randomly assigned to three treatments. Two were specialized psychotherapies (cognitive behavior therapy and interpersonal psychotherapy), and one was a control treatment combining clinical management and supportive psychotherapy (nonspecific supportive clinical management). Therapy consisted of 20 sessions over a minimum of 20 weeks.For the total study group (intent-to-treat group), there were significant differences among therapies in the primary global outcome measure. Nonspecific supportive clinical management was superior to interpersonal psychotherapy, while cognitive behavior therapy was intermediate, neither worse than nonspecific supportive clinical management nor better than interpersonal psychotherapy. For the women completing therapy, nonspecific supportive clinical management was superior to the two specialized therapies.The finding that nonspecific supportive clinical management was superior to more specialized psychotherapies was opposite to the primary hypothesis and challenges assumptions about the effective ingredients of successful treatments for anorexia nervosa.
The effect of dipyridamole and theophylline on hypercapnic ventilatory responses: the role of adenosine
Authors: TL Griffiths, JM Christie, ST Parsons, ST Holgate
Journal: European Respiratory Journal (1997)

The purine nucleoside, adenosine, has been implicated as a neuromodulator in central respiratory depression during prolonged exposure to hypoxia. It may also be a mediator of hypoxic hyperpnoea, acting on the carotid bodies. As there may be adenosine-sensitive mechanisms of hypoxic respiratory control, we sought to determine whether adenosine might be involved as a respiratory modulator in another central but non-oxygen-related control mechanism, the ventilatory response to hyperoxic hypercapnia. Twelve normal subjects were studied following 3 days of oral treatment with placebo, dipyridamole (which potentiates adenosine effects by inhibiting cellular uptake), and theophylline (a specific adenosine antagonist of cell surface receptors). The drugs were given in a random order, double-blind fashion. Resting end-tidal carbon dioxide tension (PET,CO2) and the maximum rate of isometric inspiratory pressure change at the mouth ((dP/dt) max), an index of respiratory drive, were determined in all subjects on each treatment. Hyperoxic, hypercapnic ventilatory responses were determined in seven of these subjects using a rebreathing technique. For each hypercapnic response, minute ventilation (V1E) and (dP/dt) max were plotted against PET,CO2 breath-by-breath. Resting PET,CO2 breathing room air was lower with theophylline (5.47 (SD 0.21) kPa) than with placebo (5.74 (0.26) kPa) or dipyridamole (5.86 (0.34) kPa), with no significant drug differences in resting (dP/dt)max. However, neither the slope nor the PET, CO2 intercept of the relationship between ventilation or respiratory drive and PET, CO2 were altered by the study drugs under hyperoxic conditions. We conclude that endogenous adenosine-related mechanisms are unlikely to be involved in determining either the sensitivity or the threshold of the ventilatory response to carbon dioxide under hyperoxic conditions. However, in normoxia, a centrally-acting, tonic, adenosine-mediated, respiratory modulation is not ruled out.