tbuckley/cabot-search huggingface dataset:
A new design for registration trials in rheumatoid arthritis allowing secondary head-to-head comparisons with standard of care treatment including biologicals: Figure 1
Authors: Maarten Boers
Journal: Annals of the Rheumatic Diseases (2009)

Current drug development programs produce high quality data on the efficacy of new drugs, substantial data on safety, but little data on actual applicability of the new product compared to standard of care. After successful registration and launch, such data require years to accumulate and often remain incomplete. This viewpoint proposes a new trial design for phase 2 and 3 drug trials in rheumatoid arthritis. In this design the trial starts conventionally: patients that are inadequate responders to standard treatment (usually methotrexate) are randomised to receive the experimental drug or placebo on the background of continued (methotrexate) treatment. However, after 3 months all patients in the placebo group are additionally treated with one and the same standard of care treatment (usually an inhibitor of tumour necrosis factor) and all patients in the experimental group are additionally treated with a placebo corresponding to the chosen standard of care treatment. This design allows primary assessment of efficacy and safety of the experimental drug compared with placebo at the ethically acceptable limit of 3 months, followed by secondary assessments of efficacy (including durability) and safety compared to standard of care. The secondary assessments are observational and thus more prone to bias, but it is argued that the potential for bias is limited in this setting. Widespread adoption of the design will greatly help to determine the place of a new product in the spectrum of treatment possibilities of rheumatoid arthritis.
Inhaled insulin is approved in Europe and United States
Authors: Jeanne Lenzer
Journal: BMJ (2006)

An inhaled form of human insulin, Exubera, has been approved in Europe and the United States for the treatment of type 1 and 2 diabetes in adults. The drug, to be marketed jointly by Pfizer and Sanofi-Aventis, was hailed by the US Food and Drug Administration as the “first new insulin delivery option introduced since the discovery of insulin in the 1920s.”

Both the FDA and the European Agency for the Evaluation of Medicinal Products have specified that the drug, which will not be available for several months, is contraindicated in smokers and in patients who have smoked in the preceding six months. It is “not recommended” in patients with asthma, bronchitis, or emphysema.

The European agency has also specified that Exubera is indicated only for “adult patients with …
Postnatal developmental changes in the electrophysiological properties of cat right ventricular papillary muscles
Authors: DESMOND J SHERIDAN
Journal: Cardiovascular Research (1980)

Cellular electrophysiological properties of cat right ventricular papillary muscles were studied during postnatal development using intracellular microelectrodes. Animals were studied in the neonatal period (less than 75 h of age), in infancy (16 to 18 days old) and in adult life (1.8 to 2.3 kg body weight). Resting membrane potential, action potential amplitude, Vmax and action potential duration increased significantly with age. The age related changes in action potential duration were independent of stimulation frequency. Conduction velocity was measured using two simultaneous impalements and increased significantly with age. Exposure to low [Ca]o (0.2 mmol X litre-1) caused a prolongation in action potential duration which was greater in infant and adult than neonatal myocardium, and was greatest at low stimulation frequencies. High [Ca]o shortened action potential duration and this was also greater in infant and adult tissue. Action potential duration was prolonged by low [K]o (0.5 mmol X litre-1) and shortened by high [K]o. Both of these effects appeared to be independent of age. Exposure to ouabain, 10(-8) and 10(-7) mol X litre-1 caused a dose related shortening of action potential duration. This effect was significantly greater in adult and infant than neonatal myocardium. The results indicate that the electrophysiological properties of the cat myocardium continue to develop during early postnatal life. These findings are discussed in relation to changes in morphology and transmembrane ionic gradients occurring at this time.
Masking Syphilis with Penicillin
Authors: T. E. Osmond
Journal: BMJ (1945)

<h3>Abstract</h3> <b>Objective</b> To describe the distribution of mortality among internally displaced persons during two and a half months after the Indian Ocean tsunami, 2004. <b>Design</b> Cross sectional household survey with retrospective cohort analysis of mortality. <b>Setting</b> Camps for internally displaced persons due to the tsunami in an eastern coastal district of Sri Lanka. <b>Participants</b> 3533 people from 859 households accommodated in 13 camps. <b>Main outcome measures</b> All cause death and number of missing people. <b>Results</b> 446 deaths and 11 missing people were reported after the 2004 tsunami, of which most (99%) occurred on the day of the tsunami or within three days thereafter. No deaths were reported for the two and a half month period starting one week after the tsunami. <b>Conclusions</b> Most mortality after the 2004 tsunami occurred within the first few days of the disaster and was low in the study area.
Idiocy in One of Monozygotic Twins
Authors: E. Hinden
Journal: BMJ (1956)

The presence of such separate tumours means that simple enucleation of the tumour may be followed by recurrence, not only in the capsule and scar but also by appearance of a new tumour.Such a possibility is a further reason why parotidectomy should replace all lesser procedures on these tumours.Patev (1953) felt that it was only necessary to remove the glandular tissue in the immediate neighbour- hood of the tumour, but examination of the specimen obtained in the second case reported here shows that this might still be inadequate.
Effects of exposure to low levels of environmental cadmium on renal biomarkers.
Authors: Curtis W Noonan, Sara M Sarasua, Dave Campagna, Steven J Kathman, Jeffrey A Lybarger, Patricia W Mueller
Journal: Environmental Health Perspectives (2002)

We conducted a study among residents of a small community contaminated with heavy metals from a defunct zinc smelter and residents from a comparison community to determine whether biologic measures of cadmium exposure were associated with biomarkers of early kidney damage. Creatinine-adjusted urinary cadmium levels did not differ between the smelter and comparison communities; thus we combined individuals from both communities (n = 361) for further analyses. The overall mean urinary cadmium level was low, 0.26 microg/g creatinine, similar to reference values observed in the U.S. general population. For children ages 6-17 years, urinary concentration of N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase (AAP), and albumin were positively associated with urinary cadmium, but these associations did not remain statistically significant after adjusting for urinary creatinine and other potential confounders. For adults ages 18 or older, urinary concentration of NAG, AAP, and albumin were positively associated with urinary cadmium. The associations with NAG and AAP but not with albumin remained statistically significant after adjusting for creatinine and other potential confounders. We found a positive dose-effect relationship between levels of creatinine-adjusted urinary cadmium and NAG and AAP activity, and statistically significant differences in mean activity for these two enzymes between the highest (> or =1.0 microg cadmium/g creatinine) and the lowest (< or =0.25 microg cadmium/g creatinine) exposure groups. The findings of this study indicate that biologic measures of cadmium exposure at levels below 2.0 microg/g creatinine may produce measurable changes in kidney biomarkers.
Drug-induced cardiovascular disease.
Authors: A M Breckenridge
Journal: BMJ (1979)

Adverse reactions to any group of drugs can be divided into those that occur as an exaggerated but otherwise normal response to the drug and those that represent aberrant effects unrelated to its therapeutic action. This review of drug-induced cardio vascular disease will deal principally with the second type of adverse reaction and will not discuss, in any depth, problems such as postural hypotension caused by antihypertensive agents, clinically important as they may be. In any survey of drug induced disease cardiovascular drugs are among the commonest agents incriminated. The most frequent drug-induced cardio vascular disorders are probably cardiac arrhythmias, heart failure, changes in blood pressure, and vascular spasm.
Evolutionary processes and mother-child attachment in intentional change
Authors: S. Shaun Ho, Adrianna Torres-Garcia, James E. Swain
Journal: Behavioral and Brain Sciences (2014)

Abstract Behavioral change may occur through evolutionary processes such as running stochastic evolutionary algorithms, with a fitness function to determine a winning solution from many. A science of intentional change will therefore require identification of fitness functions – causal mechanisms of adaptation – that can be acquired only with analytical approaches. Fitness functions may be subject to early-life experiences with parents, which influence some of the very same brain circuits that may mediate behavioral change through interventions.
The Use of Inflatable Plastic Splints
Authors: Milton Ginsberg
Journal: JAMA (1967)

THE INFLATABLE plastic splint, which surrounds the extremity including the digits, is a good first aid measure for the immobilization of fractures but, when applied with an air pressure exceeding certain limits, may occlude the lumen of the small blood vessels of the digits. The risk of occlusion of the blood vessels becomes even greater in an extremity in which the blood supply is already impaired by disease or trauma. Effective immobilization of an extremity obtained by too high an air pressure may unwittingly lead to necrosis of the digits. A visual demonstration of the effect of various levels of air pressure on the circulation of the great toe was deemed advisable, therefore, to determine a safe but effective pressure for immobilization. Five normal individuals were studied and the results were similar. The results obtained in the reported instance are characteristic of all. <h3>Methods</h3> A transparent, inflatable plastic boot
Converting-enzyme inhibitor enalapril (MK421) in treatment of hypertension with renal artery stenosis.
Authors: G P Hodsman, J J Brown, D L Davies, R Fraser, A F Lever, J J Morton, G D Murray, J I Robertson
Journal: BMJ (1982)

Enalapril maleate (MK421), a new inhibitor of angiotensin converting enzyme, in single daily doses of 1.25-40 mg was assessed in five patients with hypertension and renal artery stenosis. Only small falls in plasma angiotensin II concentrations were seen at doses less than 10 mg; even with 10 and 20 mg, angiotensin II concentrations had risen again 24 hours from the last dose. During long-term treatment with 10-40 mg daily all patients achieved good blood-pressure control. No significant changes of body sodium or potassium values were seen. The drug was well tolerated with no serious side effects. These findings are evidence of the efficacy and acceptability of enalapril in the medical management of hypertension with renal artery stenosis.
Ankylosing spondylitis, HLA-B27, and Klebsiella: a study of lymphocyte reactivity of anti-Klebsiella sera.
Authors: B Singh, J D Milton, J C Woodrow
Journal: Annals of the Rheumatic Diseases (1986)

Twenty three anti-Klebsiella antisera were tested for their cytotoxic activity and four for their binding capacity for peripheral blood lymphocytes (PBL) from patients with HLA-B27 positive ankylosing spondylitis (AS+B27+) and from B27 positive (AS-B27+) and B27 negative (AS-B27-) healthy individuals. None of the antisera showed specific activity against PBL from any particular group. The antisera tested included two anti-Klebsiella K43 sera provided by an Australian group, who have reported them to be specifically cytotoxic for AS+B27+ PBL, four antisera raised against a Klebsiella K43 strain provided by this group, and an antiserum from another group, who have reported it as having increased binding capacity for AS+B27+ and AS-B27+ PBL compared with AS-B27- PBL. The results of other workers who have attempted to reproduce the results of either group are reviewed and the possible reasons for the repeated failure to confirm the reported findings are discussed.
THE PHYSIOLOGICAL ACTION OF COCAINE ON THE COMMON FROG, WITH SPECIAL REFERENCE TO ITS ACTION ON ORGANS AND TISSUES.
Authors: HERMAN M. BIGGS
Journal: JAMA (1885)

In the following experiments the hydrochlorate of cocaine, prepared by Merck, of Darmstadt, was used. It is uncrystallized, of a dull white color, has a slightly bitter taste, nearly neutral reaction, and is very soluble in water, alcohol, ether and chloroform. The solutions used were all made with water, and were i, 2 and 4 per cent. in strength. <i>Local Action</i>.—On the skin and mucous membrane: If the foot of a frog be immersed for a few minutes in a solution of cocaine (2 per cent.), very marked anæsthesia of the skin is produced; or, if a solution (2 or 4 per cent.) is applied to the mucous membrane of the mouth, the same action is observed. On the eye: When a few drops of a 4 per cent. solution are instilled into the eye of a frog, there is caused, after a short time, almost complete anæsthesia of the
Transplantable hematopoietic stem cells in human fetal liver have a CD34+ side population (SP)phenotype
Authors: Naoyuki Uchida, Tomoaki Fujisaki, Allen C. Eaves, Connie J. Eaves
Journal: Journal of Clinical Investigation (2001)

Cells with a verapamil-sensitive ability to efflux Hoechst 33342 (termed side population [SP] cells) have been identified in adult marrow from several species including humans and in several tissues from adult mice. In mice, the SP phenotype appears to be a common feature of stem cells, but human SP cells have been less well characterized. We show here, for the first time to our knowledge, that SP cells are present in the second-trimester human fetal liver. They include all of the transplantable human hematopoietic stem cell activity detectable in NOD/SCID mice and also certain other, more differentiated hematopoietic cell types. Notably, the stem cell activity was confined to the CD34+CD38– SP+ population, and isolation of these cells gave an approximately tenfold enrichment of transplantable stem cells. This subset was not, however, coenriched in hematopoietic progenitors detectable by either short- or long-term in vitro assays, indicating most of these to be distinct from transplantable stem cells. These findings suggest that the SP phenotype is an important and distinguishing property of human hematopoietic stem cells and that early in ontogeny they express CD34.
INFLUENCE OF HOST FACTORS ON NEUROINVASIVENESS OF VESICULAR STOMATITIS VIRUS
Authors: Albert B. Sabin, Peter K. Olitsky
Journal: The Journal of Experimental Medicine (1937)

1. Injection of vesicular stomatitis virus into the leg muscles of young mice gives rise to flaccid paralysis of the inoculated extremity as the first clinical sign of a disease which is invariably fatal; old mice similarly injected with the largest doses of virus survive without exhibiting any signs of illness. 2. In young mice the virus was shown to multiply at the site of inoculation and to invade the sciatic nerve and spinal cord; there was no evidence of multiplication of virus in the blood or viscera. 3. In old mice, after intramuscular injection of as much as 10 million M.C.L.D., there was no evidence of either local or systemic multiplication; in spite of the persistence of thousands of M.C.L.D. of virus at the site of inoculation for at least 4 days, there was no detectable invasion of the sciatic nerve or the central nervous system. 4. Injection of the virus directly into the sciatic nerve of old mice led to the typical paralytic disease in half the number of animals. 5. For 3 days after intrasciatic injection the virus could be demonstrated in the nerve but not in the spinal cord or brain. At the onset of paralysis (6th day) virus was detectable in the spinal cord but no longer in the inoculated nerve. 6. The capacity of the virus to invade the central nervous system from the nerve but not from the muscle suggested the existence of a barrier in the muscle or myoneural junction. 7. Injection of the virus into the vitreous humor of the eye is followed by a fatal encephalitis in 15 day old mice, but 1 year old mice, with few exceptions, survive without showing signs of disease. 8. The spread of virus in the brains of intraocularly injected, 15 day old mice was too rapid to indicate the pathways which were pursued, but in 21 day old mice there was evidence that the primary pathway was probably along the axons of the optic nerve with decussation to the contralateral diencephalon and mesencephalon, and subsequent early spread to the corresponding occipital cortex. In resistant, old mice, however, no virus was found in any part of the brain.
Patient–Physician Connectedness and Quality of Primary Care
Authors: Steven J. Atlas
Journal: Annals of Internal Medicine (2009)

Background: Valid measurement of physician performance requires accurate identification of patients for whom a physician is responsible. Among all patients seen by a physician, some will be more strongly connected to their physician than others, but the effect of connectedness on measures of physician performance is not known. Objective: To determine whether patient–physician connectedness affects measures of clinical performance. Design: Population-based cohort study. Setting: Academic network of 4 community health centers and 9 hospital-affiliated primary care practices. Patients: 155 590 adults with 1 or more visits to a study practice from 2003 to 2005. Measurements: A validated algorithm was used to connect patients to either 1 of 181 physicians or 1 of 13 practices in which they received most of their care. Performance measures included breast, cervical, and colorectal cancer screening in eligible patients; hemoglobin A1c measurement and control in patients with diabetes; and low-density lipoprotein cholesterol measurement and control in patients with diabetes and coronary artery disease. Results: Overall, 92 315 patients (59.3%) were connected to a specific physician, whereas 53 669 patients (34.5%) were connected only to a specific practice and 9606 patients (6.2%) could not be connected to a physician or practice. The proportion of patients in a practice who could be connected to a physician varied markedly (45.6% to 71.2% of patients per practice; P < 0.001). Physician-connected patients were significantly more likely than practice-connected patients to receive guideline-consistent care (for example, adjusted mammography rates were 78.1% vs. 65.9% [P < 0.001] and adjusted hemoglobin A1c rates were 90.3% vs. 74.9% [P < 0.001]). Receipt of preventive care varied more by whether patients were more or less connected to a physician than by race or ethnicity. Limitation: Patient–physician connectedness was assessed in 1 primary care network. Conclusion: Patients seen in primary care practices seem to be variably connected with a specific physician, and less connected patients are less likely to receive guideline-consistent care. Funding: National Cancer Institute.
Towards investing in health gain
Authors: J. Gabbay, A. Stevens
Journal: BMJ (1994)

SVP in glass ampoules are manufactured using two main different technological production processes: the open-ampoule process (O) and the closed-ampoule process (C). In principle, the open-ampoule production technology should lead to better controlled production process. To test this hypothesis and quantify the possible qualitative differences in the manufactured ampoules, a suitable experimental design was set up. The two ampoule production processes have been compared on the basis of the visible particulate burden. Two batches of ampoules filled with water for injections were produced for each type of process, following conventional industrial procedures. Two samples of 20,000 units were taken from each batch and inspected with different automatic inspection systems: two Brevetti CEA machines (S1, S2—light scattering) and two EISAI machines (S3, S4—light absorbtion). The comparison between the processes was based on the rejection percentage. On both inspection machines the open-ampoule production samples present rejection percentages (ranging from 0.154% to 1.248% rejection percentages) which, on average, are lower than those detected in closed-ampoule production (ranging from 1.434% to 3.86% rejection percentages). The difference between the two processes is even more marked if we also consider the data obtained using inspection machines S3 and S4. The substantial differences in performance of the four inspection machines stress the need to provide for adequate validation procedures.
Targeted Prostaglandin E2 Inhibition Enhances Antiviral Immunity through Induction of Type I Interferon and Apoptosis in Macrophages
Authors: François Coulombe, Joanna Jaworska, Mark Verway, Fanny Tzelepis, Amir Massoud, Joshua Gillard, Gary Wong, Gary Kobinger, Zhou Xing, Christian Couture, Philippe Joubert, Jörg H. Fritz, William S. Powell, Maziar Divangahi
Journal: Immunity (2014)

Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic, 50 years prior to the demonstration of their inhibitory action on prostaglandins. Here, we show that during influenza A virus (IAV) infection, prostaglandin E2 (PGE2) was upregulated, which led to the inhibition of type I interferon (IFN) production and apoptosis in macrophages, thereby causing an increase in virus replication. This inhibitory role of PGE2 was not limited to innate immunity, because both antigen presentation and T cell mediated immunity were also suppressed. Targeted PGE2 suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE2 receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE2 administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE2 pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE2 signaling might serve as a treatment for IAV.
Tuberculosis screening for immigrants and refugees. Diagnostic outcomes in the state of Hawaii.
Authors: P L Zuber, N J Binkin, A C Ignacio, K L Marshall, S P Tribble, M A Tipple, R L Vogt
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

The effectiveness of the required overseas tuberculosis (TB) screening for immigrants and refugees to the United States has not been evaluated since new guidelines were introduced in 1991. Using data from the Hawaii State TB register for 1992-1993, patient records, and data from the U.S. government notifications of suspect TB among aliens, we determined the percentage of persons either classified as having active TB (B1), inactive TB (B2), or considered "normal" overseas, who were evaluated and subsequently diagnosed with active TB within 1 yr of arrival in the United States. Of the 124 TB cases among immigrants and refugees evaluated within 1 yr of arrival, 78 (63%) had been classified overseas as B1, 17 (14%) as B2, and 29 (23%) as "normal." The proportion of TB cases diagnosed after arrival in the United States was 14.0% for B1s and 2.1% for B2s. This proportion decreased with increasing age. A positive skin test was a strong predictor (OR: 10.7; 95% CI: 1.4-80.1) of culture-confirmed TB. These data document that immigrants and refugees with B1 and B2 TB status have a high prevalence of active TB. They should be promptly evaluated after arrival in the United States to determine the need for curative or preventive therapy.