tbuckley/cabot-search huggingface dataset:
Re-assessing the evidence about inhaled corticosteroids in chronic obstructive pulmonary disease
Authors: P M A CALVERLEY
Journal: Thorax (1999)

“For now we see through a glass darkly;”

Corinthians I: 13 v.12

Research into chronic obstructive pulmonary disease (COPD), for so long the Cinderella disorder of respiratory medicine, has undergone something of a renaissance in the last 10 years, with an increased awareness of its high prevalence1 as well as its growing importance as a cause of death in the developing world.2Having achieved a measure of consensus on the most appropriate definition,3-5 more mechanistic studies have shown that inflammatory cell infiltration in the walls of large airways6 and the presence of pro-inflammatory cytokines in induced sputum are frequent findings in patients with COPD.7 8 The characteristics of the cellular and biochemical changes differ from those seen in asthma with a predominance of alveolar macrophages and a relative neutrophilia, whilst the lymphocytes in the airway wall show no evidence of the CD4+ predominance seen in asthmatic airways.6 Data from a variety of groups using different sampling methods confirm that active inflammation is present in the airways and in the alveoli9of patients with COPD at almost any stage of the disease. Inevitably, this begs the question of whether these processes can be modified and, given the substantial benefits seen in bronchial asthma, what might be the role of inhaled corticosteroids in the patient with COPD.

Data on the inflammatory changes seen in the airways of patients with COPD have been available for many years,10 although the scientific importance was not fully appreciated. Clinicians were aware that some patients with COPD improved dramatically after a course of oral corticosteroids—not just for exacerbations11 but even when clinically stable—and, as a result, empirical trials of corticosteroids have been recommended.12 Between 10% and 20% of patients show a “response” to this therapy with a …
Puerperal Infection in Private Practice.
Authors: C. S. Bacon
Journal: JAMA (1902)

Chicago, April 22, 1902. <h3>To the Editor:</h3> —Your editorial inThe Journalof April 19 on "Puerperal Infection in Private Practice" calls attention to a very important subject and one that will bear much discussion to bring and keep it properly before the profession. A careful inspection of the mortality reports of the various city boards of health will confirm the content of your statement, which I believe is also in agreement with the impression of physicians who are particularly interested in obstetric work: that puerperal infection in private practice is still much larger than it should be and not on the decline. In your statement of the causes of this unfortunate state of obstetric practice, however, it may be that you have not dwelt with sufficient fulness nor with sufficient emphasis on the chief factors. At any rate further consideration of these factors is desirable if we expect to
505. Analysis of AAV Genome Conversion and Stabilization
Authors: Bernd Hauck, Jing Xie, Weidong Xiao
Journal: Molecular Therapy (2005)

Recombinant adeno-associated virus (rAAV) vectors have been widely used to deliver a variety of therapeutic genes in both in vitro and in vivo experiments. The administration of AAV vectors usually gives rise to persistent transgene expression. However, the doses required for meaningful gene expression are usually much higher than other viral vectors. Because AAV genomes are single-stranded DNA (ss), we examined the conversion and stability of AAV genomes in both tissue cultured cells and in vivo animal experiments. The special AAV vectors labeled with BrdU molecules were generated and an anti-BrdU antibody was used to specifically track free ss AAV DNA genomes. Although single stranded AAV genomes were detected by conventional Southern Blot anaylsis, the antibody tracking, which recognizes ssDNA labeled with BrdU but not double stranded (ds) DNA with BrdU, revealed no free ss DNA molecules after AAV transduction. We concluded that ss DNA accumulation is not an essential step for transduction. In addition, we observed significant AAV genome losses during AAV transduction. Overall, less than 0.1% of AAV genomes survive the degradation in the stages of intracellular trafficking, ss DNA to double stranded DNA conversion, and ds DNA to final stabilized forms. Through a quantitative analysis of newly synthesized ds AAV genomes, we discovered that more than 90% of these molecules did not persist although they were fully functional in expressing transgenes (such as lacZ or GFP) in both tissue culture cells and mouse liver. The long term expression of transgene products observed in vivo was therefore coming from a small amount of stabilized AAV genomes. Our results suggest that improving the AAV genome stability post transduction is critical for enhancing AAV transduction efficacy.
Research press releases need better policing
Authors: M. McCartney
Journal: BMJ (2014)

Blaming the media for bad reporting is good sport. It’s easy to find headlines in the broadsheets as well as the tabloids breaking health news with overstated research findings. Caveats of scientific conclusions are often abbreviated or absent. Scientific uncertainties can be left diminished or invisible.

The media have been repeatedly blamed for misinformation and health scares, and no wonder: when patients voice or act on misconceptions in the press, trying to redress the balance can eat up scarce clinical time.

I confess a previous secret pleasure in playing the dissing bad headlines game. My own crossness with bad health reporting was the reason I started writing. But the rules were never fair, I now realise.

Doctors and scientists are …
Metoclopramide in young children.
Authors: J A Sills, E J Glass
Journal: BMJ (1978)

myocardial infarction so that any arrhythmia that developed could be treated promptly.However, there is evidence that hospital care may actually cause some of the arrhythmias that then have to be treated.More than 20 years ago Dr Klaus Jarvinen' observed that a disproportionate number of patients dying in hospital after acute myocardial infarction did so during or shortly after ward rounds.That interaction with hospitals and staff can significantly affect a patient's heart rate and rhythm is also well documented.2Although no one would suggest that there is no place for specialised coronary care units it is tempting to speculate that they have to be so well equipped and expertly staffed to compensate for the arrhythmias precipitated by the fear and isolation experienced by a patient in hospital.A study comparing the incidence of arrhythmias after myocardial infarction at home and in hospital would be most interesting.
Cellular electrophysiological effects of flecainide on human atrial fibres
Authors: B. Le Grand, J.-Y. Le Heuzey, P. Perier, P. Peronneau, T. Lavergne, S. Hatem, L. Guize
Journal: Cardiovascular Research (1990)

Study objective – The aim of the study was to examine the electrophysiological characteristics of human atrial specimens collected during heart surgery and to investigate the effects of the class I antiarrhythmic agent flecainide on their electrical activity. Design – Atrial specimens were studied using standard microelectrode techniques, with and without superfused flecainide (5 × 10−7 M) or the transient outward current inhibitor 4-aminopyridine (0.5 mM). Experimental material – Atrial fragments 0.5-1.0 cm2 were obtained at operation from 34 patients, mean age 30 years. There was no history of previous atrial arrhythmia in any patient and drug therapy was stopped 24 h before surgery. Measurements and main results – Two types of transmembrane action potential were identified: (1) triangular shaped potentials (group A, classically found in animal models); (2) potentials with a large plateau preceded by a notch (group B). The effect of flecainide was compared on the the two types of action potential. In both, flecainide lessened the depolarisation rate. In group B, but not in group A, it increased the action potential duration at 50% and 90% repolarisation (APD50, APD90) and the effective refractory period. The notch in group B action potentials is generated by transient outward currents (Ito). Inhibition of these currents, either by increasing the pacing rate or by adding 4-aminopyridine, limited the increase in APD50, APD90, and effective refractory period generated by the presence of flecainide. Conclusions – The effects of flecainide on the atrial repolarisation process depend on the shape of the action potential. These effects are more marked in cells with a plateau, where Ito is activated.
A dose-response study of UVB-induced suppression of contact photosensitivity in the mouse
Authors: G.M. SHIVJI, W.R. BROWN, C.A. RAMSAY
Journal: British Journal of Dermatology (1990)

A marked contact photosensitivity (CPS) response to 3, 3′, 4′, 5 tetrachlorosalicylanilide (TCSA) plus UVA was induced in mice. Cyclophosphamide (Cy), given prior to sensitization, caused a further increase in ear swelling. When UVB radiation was given at a site distant from that used for sensitization it caused a dose‐related suppression of CPS. Cy did not eliminate the UVB‐induced suppression.
Impaired contact hypersensitivity in untreated psoriasis and the effects of photochemotherapy and dithranol/UV-B
Authors: CELIA MOSS, P.S. FRIEDMANN, SAM SHUSTER
Journal: British Journal of Dermatology (1981)

Cell mediated immune reactivity was studied in eighty-five psoriasis patients and twenty-five healthy controls by an improved (quantitative) method for measuring contact hypersensitivity to 2,4 dinitrochlorobenzene (DNCB). Patients were sensitized with 500 μg DNCB, the lowest dose found to sensitize all healthy subjects. Responses to epicutaneous challenge with a series of concentrations of DNCB were measured as volumes calculated from diameter and thickness and the various groups were compared by the differences in the log dose-response curves. Patients with untreated psoriasis were less responsive than healthy controls; responses were less still in patients treated with dithranol/UV-B/tar and they were least of all in patients treated with photochemotherapy with 8-methoxypsoralen and UV-A (PUVA), particularly in those who pigmented least. Sensitization and challenge at different stages of treatment showed that both induction and elicitation of sensitization were impaired by PUVA. The possible relationship of these changes to DNCB metabolism, Langerhans cell damage and a decrease in circulating T cells is discussed. Although the clinical significance of the findings is unknown, treatment with dithranol/UV-B/tar has proved safe over many years of use.
US doctors debate refusing treatment to malpractice lawyers
Authors: Fred Charatan
Journal: BMJ (2004)

Animosity between doctors and medical malpractice lawyers has reached such a pitch in the United States that the American Medical Association last week debated a motion proposing that doctors should refuse medical treatment to such lawyers, their families, and employees except in emergencies.

Although the motion, brought by Dr Chris Hawk, a surgeon from South Carolina, was lost, some doctors felt the fact that it was proposed at all shows how bad relations between the professions have become. Doctors are angry, among other things, at the effect that malpractice awards are having on their insurance premiums.

Dr Clinton “Rick” Miller, a prominent neurosurgeon from New Hampshire, is one doctor who supports the idea of refusing treatment except in emergencies. In his 25 year …
Dense Alu clustering and a potential new member of the NFκB family within a 90 kilobase HLA Class III segment
Authors: François J.M. Iris, Lydie Bougueleret, Sylvie Prieur, Dominique Caterina, Gwenaël Primas, Virginie Perrot, Jerzy Jurka, Patricia Rodriguez-Tome, Jean Michel Claverie, Jean Dausset, Daniel Cohen
Journal: Nature Genetics (1993)
Neurological Complications of Acute Leukemia in Adults: Changing Rate
Authors: DAVID M. DAWSON
Journal: Annals of Internal Medicine (1973)

In a large series of adults with acute leukemia followed by the same hematology service, prior to 1970, there were only two instances of clinically apparent central nervous system involvement, in 230 cases of acute granulocytic leukemia and 38 cases of acute lymphoblastic leukemia. From 1970 to 1972, perhaps associated with an increased remission rate, 7 of 41 patients with acute granulocytic leukemia and 7 of 12 patients with acute lymphoblastic leukemia developed central nervous system involvement. Headaches, papilledema, and cranial nerve palsies were common in these cases. The patients with acute granulocytic leukemia also showed evidence of compression of neural structures by malignant cells.
Oncolytic Immunovirotherapy for Melanoma Using Vesicular Stomatitis Virus
Authors: Rosa Maria Diaz, Feorillo Galivo, Timothy Kottke, Phonphimon Wongthida, Jian Qiao, Jill Thompson, Mikael Valdes, Glen Barber, Richard G. Vile
Journal: Cancer Research (2007)

Abstract Relatively little attention has been paid to the role of virotherapy in promoting antitumor immune responses. Here, we show that CD8+ T cells are critical for the efficacy of intratumoral vesicular stomatitis virus virotherapy and are induced against both virally encoded and tumor-associated immunodominant epitopes. We tested three separate immune interventions to increase the frequency/activity of activated antitumoral T cells. Depletion of Treg had a negative therapeutic effect because it relieved suppression of the antiviral immune response, leading to early viral clearance. In contrast, increasing the circulating levels of tumor antigen–specific T cells using adoptive T cell transfer therapy, in combination with intratumoral virotherapy, generated significantly improved therapy over either adoptive therapy or virotherapy alone. Moreover, the incorporation of a tumor-associated antigen within the oncolytic vesicular stomatitis virus increased the levels of activation of naïve T cells against the antigen, which translated into increased antitumor therapy. Therefore, our results show that strategies which enhance immune activation against tumor-associated antigens can also be used to enhance the efficacy of virotherapy. [Cancer Res 2007;67(6):2840–7]
The Transsexual Phenomenon
Authors: Marjorie C. Meehan
Journal: JAMA (1967)

Recent announcement that Johns Hopkins has established a gender identity clinic to screen applicants for sex change surgery and that two such operations have been performed at that respected hospital, has stimulated interest in the problem of transsexuals. This term was chosen by Dr. Harry Benjamin to describe those rare individuals who feel that they belong to the opposite sex, wish to live as such, and consider their sex organs disturbing deformities which they want removed. He carefully distinguishes them from transvestites who wish to dress as members of the opposite sex but are satisfied to remain members of their own sex.  In this book, based largely on his own observations of 193 male and 27 female subjects, Benjamin discusses the problem at length. He considers the etiology obscure, although stating that childhood conditioning or imprinting may be significant in some cases. He expresses the belief that true transsexuals cannot
Suppression of Colorectal Cancer Growth Using an Adenovirus Vector Expressing an Antisense K-ras RNA
Authors: Masaru Nakano, Kazunori Aoki, Nobuyuki Matsumoto, Shumpei Ohnami, Kazuteru Hatanaka, Toshihumi Hibi, Masaaki Terada, Teruhiko Yoshida
Journal: Molecular Therapy (2001)

In human colorectal cancer, K-ras point mutations occur in approximately 40–50% of the cases, a frequency second only to pancreatic cancer (80–90%). Unlike pancreatic and lung cancers, however, the tumor-suppressive effect of antisense K-ras RNA expression has not been examined for colorectal cancers. A recombinant adenovirus vector expressing an antisense or sense K-ras gene fragment (AxCA-AS-K-ras or AxCA-S-K-ras) was first transduced into seven human colorectal cancer cell lines. Stable expression of antisense or sense K-ras RNA was detected by RNA blot analysis. Western blot analysis confirmed a reduction of up to 25% of K-ras-specific p21 protein in the antisense K-ras-transduced HCT-15 cells. In contrast to our previous findings on pancreatic cancer, the status of K-ras point mutations was not correlated with the growth-suppressive effect of the antisense K-ras vector: both the K-ras-mutation-positive and -negative colorectal cancer cell lines were suppressed for their growth in vitro. There was no growth-inhibitory effect on normal cells such as hepatocytes. Next, to test the efficacy in vivo, HCT-15 cells were inoculated subcutaneously into the left flank of SCID mice, and AxCA-AS-K-ras was injected intratumorally three times after the tumor mass was established. The infection of AxCA-AS-K-ras, but not the control AxCA-S-K-ras, significantly suppressed the growth of the HCT-15 subcutaneous tumor. This study shows that the adenovirus-mediated in vivo gene transfer of the antisense K-ras construct may be a useful therapeutic strategy for colorectal cancer.
Sunitinib (SU) in Combination with Trastuzumab (T) for the Treatment of Advanced Breast Cancer (ABC): Activity and Safety Results from a Phase II Study.
Authors: J. Blay, A. Lluch, M. Gutierrez, M. Martin, M. Kozloff, C. Prady, X. Huang, L. Verkh, C. Chen, V. Tassell, K. Kern, S. Verma
Journal: Cancer Research (2009)

Abstract Background: SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, FLT3, and CSF-1R, with single-agent activity in patients (pts) with heavily pretreated ABC (locally recurrent or metastatic breast cancer). T is approved for 2nd-line monotherapy and in combination with taxane-based therapies for 1st-line ABC. The combination of SU + T in HER2+ ABC pts was investigated.Materials and methods: Eligible pts with HER2+ ABC received a starting dose of oral SU 37.5 mg/d (continuous daily dosing [CDD]) and either T administered wkly (iv loading 4 mg/kg then wkly 2 mg/kg) or q3w (loading 8 mg/kg then q3w 6 mg/kg). Due to changing standard of care, the trial was amended to include pts having prior chemotherapy in the 1st-line setting. Previous treatment (tx) with T (± lapatinib) was permitted. The primary endpoint was objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), pharmacokinetics (PK) and quality of life (QoL).Results: As of April 2009, 60 pts were enrolled (6 on the original protocol and 54 under the amendment). Of 54 pts enrolled post-amendment, 6 pts continue on study and 48 have discontinued, 12 due to AEs. Most (n=31; 57%) pts received SU + T as 1st-line tx and 11/31 pts were completely tx-naïve. Pts received a median of 5 cycles (range: 1–16) of SU and 4 cycles (range: 1–15) of T. SU was dose reduced from 37.5 mg/d to 25 mg/d in 39% of pts. All pts were evaluable for safety and 52 pts were evaluable for efficacy. ORR was 34.6% and clinical benefit rate was 48% (2 CR; 16 PR; 7 SD ≥24 wks). Of the 18 responders, 5 pts were completely tx-naïve and 9 pts were 1st-line. Median PFS was 25.3 wks (95% CI, 19.3, 29.1). Most AEs were G1/2. G3 non-hematologic AEs in ≥10% pts were asthenia (17%) and hypertension (11%) and 3 G4 events occurred (LVEF decline, pulmonary embolism, and pancreatitis). Hematologic AEs (G3/4 in ≥10% pts) were neutropenia (22%) and thrombocytopenia (17%). One G5 event (cardiogenic shock) was reported. LVEF decline/LV dysfunction occurred in 21 pts (6 pts had ≥G3 AEs); 18/21 pts (86%) had received prior anthracycline and 12 pts (57%) prior T. There was no significant on-tx change from baseline in the QoL domain. Mean (SD) steady state level for SU was 46.1 (25.9) ng/mL in agreement with prior observations.Conclusions: The combination of SU (37.5 mg/d; CDD schedule) + T (wkly or q3w) showed acceptable tolerability and antitumor activity in HER2+ ABC pts without adversely affecting overall QoL. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 201.
Pathophysiology of Shock, Anoxia, and Ischemia
Authors: Francis L. Abel
Journal: JAMA (1982)

This book is designed to provide a comprehensive picture of the areas of shock, ischemia, and anoxia, specifically covering new developments since 1965. It is divided into four sections, with 76 contributing authors. Section 1 deals with basic pathophysiological alterations at the level of the cell and in the microcirculation. An additional chapter on disseminated intravascular coagulation is included. Alterations in transport of calcium and other ions are emphasized. The second section is devoted specifically to shock, primarily at the organ level, and to its current therapy. Endotoxic, hemorrhagic, and septic shock are covered along with shock models, the use of computer registries, and consideration of such therapeutic modes as fluorocarbons and hyperbaric oxygen. The lung as a shock organ is extensively covered. Unfortunately, similar coverage is not given to the heart. Section 3 deals with injury to the CNS, both brain and spinal cord. While this topic seems to
Enhancing Reproducibility in Cancer Drug Screening: How Do We Move Forward?
Authors: Christos Hatzis, Philippe L. Bedard, Nicolai J. Birkbak, Andrew H. Beck, Hugo J.W.L. Aerts, David F. Stern, Leming Shi, Robert Clarke, John Quackenbush, Benjamin Haibe-Kains
Journal: Cancer Research (2014)

Large-scale pharmacogenomic high-throughput screening (HTS) studies hold great potential for generating robust genomic predictors of drug response. Two recent large-scale HTS studies have reported results of such screens, revealing several known and novel drug sensitivities and biomarkers. Subsequent evaluation, however, found only moderate interlaboratory concordance in the drug response phenotypes, possibly due to differences in the experimental protocols used in the two studies. This highlights the need for community-wide implementation of standardized assays for measuring drug response phenotypes so that the full potential of HTS is realized. We suggest that the path forward is to establish best practices and standardization of the critical steps in these assays through a collective effort to ensure that the data produced from large-scale screens would not only be of high intrastudy consistency, so that they could be replicated and compared successfully across multiple laboratories.
Neville Lawn Birkett
Authors: H. Shaer
Journal: BMJ (2013)

Neville Lawn Birkettt was born in Ulverston and attended Ulverston Grammar School before going up to Emmanuel College, Cambridge, to study medicine. He trained at St Bartholomew’s Hospital in London.

During the war he joined the Royal Air Force’s medical services and in 1946, after he was demobbed, he took a house …