tbuckley/cabot-search huggingface dataset:
Physiologically based pharmacokinetic models for trichloroethylene and its oxidative metabolites.
Authors: J W Fisher
Journal: Environmental Health Perspectives (2000)

Trichloroethylene (TCE) pharmacokinetics have been studied in experimental animals and humans for over 30 years. Compartmental and physiologically based pharmacokinetic (PBPK) models have been developed for the uptake, distribution, and metabolism of TCE and the production, distribution, metabolism, and elimination of P450-mediated metabolites of TCE. TCE is readily taken up into systemic circulation by oral and inhalation routes of exposure and is rapidly metabolized by the hepatic P450 system and to a much lesser degree, by direct conjugation with glutathione. Recent PBPK models for TCE and its metabolites have focused on the major metabolic pathway for metabolism of TCE (P450-mediated metabolic pathway). This article briefly reviews selected published compartmental and PBPK models for TCE. Trichloroacetic acid (TCA) is considered a principle metabolite responsible for TCE-induced liver cancer in mice. Liver cancer in mice was considered a critical effect by the U.S. Environmental Protection Agency for deriving the current maximum contaminant level for TCE in water. In the literature both whole blood and plasma measurements of TCA are reported in mice and humans. To reduce confusion about disparately measured and model-predicted levels of TCA in plasma and whole blood, model-predicted outcomes are compared for first-generation (plasma) and second-generation (whole blood) PBPK models published by Fisher and colleagues. Qualitatively, animals and humans metabolize TCE in a similar fashion, producing the same metabolites. Quantitatively, PBPK models for TCE and its metabolites are important tools for providing dosimetry comparisons between experimental animals and humans. TCE PBPK models can be used today to aid in crafting scientifically sound public health decisions for TCE.
Role of Nitric Oxide in the Local Regulation of Pulmonary Vascular Resistance in Humans
Authors: Christopher J. Cooper, Michael J. Landzberg, Todd J. Anderson, Francois Charbonneau, Mark A. Creager, Peter Ganz, Andrew P. Selwyn
Journal: Circulation (1996)

Background Endothelium-derived nitric oxide (NO) may be an important mediator of vascular resistance in the pulmonary circulation. We tested the hypotheses that in conscious adults the endothelium, through NO production, is important in maintaining basal pulmonary vascular resistance and that it can increase NO production further in response to receptor-mediated stimulation, leading to further vasodilation. Methods and Results Pulmonary arterial resistance vessel function was studied within the distribution of a segmental lower lobe pulmonary artery in eight conscious adults 37 to 76 years old who were undergoing cardiac catheterization. Segmental blood flow was determined with use of a Doppler-tip guide wire and quantitative angiography. Drugs were administered locally within the segmental artery through an infusion catheter. N G -Monomethyl- l -arginine (L-NMMA) was used as a specific inhibitor of NO production, whereas acetylcholine (ACh) was used to test receptor-mediated vasodilation. To demonstrate that vasodilation to ACh was NO dependent, ACh response was tested alone, in the presence of L-NMMA, and in the presence of a control constrictor phenylephrine. Basal pulmonary vascular resistance was NO dependent because L-NMMA infusion resulted in a dose-dependent decrease in local flow velocity ( P &lt;.005), with flow decreasing 33% at the highest dose of L-NMMA. ACh infusion resulted in a dose-dependent increase in flow velocity ( P =.001). The ACh response was at least in part NO dependent because it was diminished by the presence of L-NMMA ( P &lt;.05). The effect of L-NMMA on the ACh response was not due to nonspecific preconstriction because L-NMMA diminished the ACh response significantly more than did the endothelium-independent constrictor phenylephrine ( P &lt;.05) despite comparable preconstriction. Conclusions In healthy conscious adults, (1) normal basal pulmonary resistance is maintained in part by continuous local production of NO and (2) the local NO production is responsive to receptor-mediated stimulation, leading to further vasodilation, and can be tested with ACh.
Complement C5 Mediates Experimental Tubulointerstitial Fibrosis
Authors: Peter Boor, Andrzej Konieczny, Luigi Villa, Anna-Lisa Schult, Eva Bu[Combining Diaeresis]cher, Song Rong, Uta Kunter, Claudia R.C. van Roeyen, Thomas Polakowski, Heiko Hawlisch, Sonja Hillebrandt, Frank Lammert, Frank Eitner, Ju[Combining Diaeresis]rgen Floege, Tammo Ostendorf
Journal: Journal of the American Society of Nephrology (2007)

Renal fibrosis is the final common pathway of most progressive renal diseases. C5 was recently identified as a risk factor for liver fibrosis. This study investigated the role of C5 in the development of renal tubulointerstitial fibrosis by (1) induction of renal fibrosis in wild-type and C5(-/-) mice by unilateral ureteral ligation (UUO) and (2) investigation of the effects of a C5a receptor antagonist (C5aRA) in UUO. In C5(-/-) mice, when compared with wild-type controls, markers of renal fibrosis (Sirius Red, type I collagen, fibronectin, alpha-smooth muscle actin, vimentin, and infiltrating macrophages) were significantly reduced on day 5 of UUO. On day 10, fibronectin mRNA and protein expression were still reduced in the C5(-/-) mice. Cortical mRNA of all PDGF isoforms and of TGF-beta(1) (i.e., central mediators of renal disease) were significantly reduced in C5(-/-) mice when compared with controls. Renal tubular cell expression of the C5aR was sparse in normal cortex but markedly upregulated after UUO. Treatment of wild-type UUO mice with C5aRA also led to a significant reduction of cortical Sirius Red staining, fibronectin protein expression, and PDGF-B mRNA expression on day 5. Neither genetic C5 deficiency nor C5aRA treatment caused any histologic changes in the nonobstructed kidneys. In cultured murine cortical tubular cells, C5a stimulated production of TGF-beta(1), and this was inhibited by C5aRA. Using a combined genetic and pharmacologic approach, C5, in particular C5a, is identified as a novel profibrotic factor in renal disease and as a potential new therapeutic target.
Poole and Bournemouth hospitals should have another chance to put the case for a merger, charity says
Authors: G. Iacobucci
Journal: BMJ (2014)

NHS trusts that are seeking to merge or reconfigure services must produce evidence of benefits to patients “from the outset” to avoid having their plans blocked, an independent analysis has concluded.1

But the report by the health charity the Health Foundation said that the collapse of the proposed merger of Poole Hospital NHS Foundation Trust and the Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust last year was an avoidable and costly process that suffered from bad timing. The proposed merger was blocked by the Competition Commission after the watchdog concluded that the evidence provided by the trusts was not strong enough to indicate that a merger …
New Cases of G.P.I
Authors: S. Bockner, N. Coltart
Journal: BMJ (1961)

Is general paralysis of the insane (G.P.I.) becoming increasingly common to-day ?This question has commanded our attention in recent months owing to the increasing number of cases we have seen.For some years now G.P.I. has been a rare disease.At one time it was relatively common, and wards full of these cases could be seen in most mental hospitals.To-day, of course, it is difficult to find cases of G.P.I. in mental hospitals.However, our experience in a busy psychiatric observation ward suggests that the disease is becoming more frequent.This ward is situated in a busy working- class north London district, drawing its patients from London, Middlesex, Essex, and Hertford.It has twelve beds and there are approximately 500 admissions per annum.Until two years ago only one, or perhaps two, cases of G.P.I. were admitted to this ward each year; these were invariably of long standing, had been treated, and were still showing psychiatric disturbance.However, during 1959 nine cases of G.P.I. were admitted to the observation ward.Steel (1960) described 14 cases of G.P.I. admitted to a 70-bed observation ward in the period April, 1957, to September, 1958.Our nine cases in a smaller unit and over a shorter period suggest that the frequency of G.P.I. is still increasing.Most cases of G.P.I. present as psychiatric problems.In this paper the nine cases are described, particular attention being paid to the psychiatric picture.
Interaction between the regulatory domain of cardiac troponin C and the acidosis-resistant cardiac troponin I A162H
Authors: Sandra E. Pineda-Sanabria, Ian M. Robertson, Monica X. Li, Brian D. Sykes
Journal: Cardiovascular Research (2012)

AimsIschaemic heart disease is the leading cause of mortality worldwide. Acidosis is the main mediator of ischaemia and shielding against it might be possible. In this study, we characterize the nature of interaction between the regulatory domain of cardiac troponin C and the A162H-substituted cardiac troponin I (cTnI) that confers protection against acidosis.
CASES OF LITHOTRITY AND LITHOTOMY
Authors: D. Mackinder
Journal: BMJ (1856)

aOne is entitled to expect that so novel and startling a fit, so dangerous if false, so revolutionary if true, would be admitted only upon proof proportioned to its improbability.weighing exactly three drachms.The little fellow did well, and was cured in six weeks.REMARKS.Whilst this patient was under my care, he had two attacks of spasmodic croup, one a week or two prior to, and the other about a week after, the operation.The first, I referred to the irritation proa
Topical corticosteroid treatment: systemic side-effects
Authors: D. Kane, L. Barnes, O. Fitzgerald
Journal: British Journal of Dermatology (2003)

Journal Article Topical corticosteroid treatment: systemic side‐effects Get access D. Kane, D. Kane Department of Rheumatology, St Vincent's University Hospital and Dr David Kane. E‐mail: dk44a@clinmed.gla.ac.uk Search for other works by this author on: Oxford Academic Google Scholar L. Barnes, L. Barnes Department of Dermatology, St James's Hospital, Dublin 8, Ireland Search for other works by this author on: Oxford Academic Google Scholar O. Fitzgerald O. Fitzgerald Department of Rheumatology, St Vincent's University Hospital and Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 149, Issue 2, 1 August 2003, Page 417, https://doi.org/10.1046/j.1365-2133.2003.05356.x Published: 01 August 2003 Article history Accepted: 17 December 2002 Published: 01 August 2003
Faiza Bary Malik
Authors: H. R Choudhury, P. C Das
Journal: BMJ (2008)

Faiza Bary Malik (“Lipi”) took the unusual decision to train in the male dominated specialty of surgery. She arrived in Scotland in 1967, later pursuing training in paediatric surgery and working in various parts of England. Her interest gradually focused on general practice, and in 1979 she joined a long …
Insulin resistance in patients with depression and its changes during the clinical course of depression: Minimal model analysis
Authors: Fumio Okamura, Atsushi Tashiro, Atsushi Utumi, Towako Imai, Takatosi Suchi, Daisaku Tamura, Yoshinori Sato, Susumu Suzuki, Michio Hongo
Journal: Metabolism (2000)
Ureteral Dilatation and Oral Contraceptives
Authors: Sumner Marshall
Journal: JAMA (1970)

<h3>To the Editor.—</h3> In an excellent commentary on the effect of pregnancy and birth control pills in a case of surgically treated exstrophy of the bladder (<b>210:</b>1597, 1969), John K. Lattimer, MD, states that "with regard to contraceptive pills, while there is theoretical reason to worry about their increasing the flaccidity of the ureters, this has not yet been documented in clinical practice..." Reference might be made to the cases reported in the clinical note, "Ureteral Dilatation Following Use of Oral Contraceptives" (<b>198:</b>782, 1966). Results of experimental studies in animals and humans suggest that the "hydroureters of pregnancy" are secondary to both mechanical obstruction and hormonal influences, and that this ureteral dilatation can be produced by the progestogens contained in oral contraceptives. It is probable that the lesser amounts of progestogens contained in the newer oral contraceptives will decrease the chances of this occurrence.
Noncovalent stabilization of the factor VIII A2 domain enhances efficacy in hemophilia A mouse vascular injury models
Authors: Lilley Leong, Derek Sim, Chandra Patel, Katherine Tran, Perry Liu, Elena Ho, Thomas Thompson, Peter J. Kretschmer, Hironao Wakabayashi, Philip J. Fay, John E. Murphy
Journal: Blood (2014)
Outcomes of planned home births with certified professional midwives: large prospective study in North America
Authors: Kenneth C Johnson, Betty-Anne Daviss
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To evaluate the safety of home births in North America involving direct entry midwives, in jurisdictions where the practice is not well integrated into the healthcare system. <b>Design</b> Prospective cohort study. <b>Setting</b> All home births involving certified professional midwives across the United States (98% of cohort) and Canada, 2000. <b>Participants</b> All 5418 women expecting to deliver in 2000 supported by midwives with a common certification and who planned to deliver at home when labour began. <b>Main outcome measures</b> Intrapartum and neonatal mortality, perinatal transfer to hospital care, medical intervention during labour, breast feeding, and maternal satisfaction. <b>Results</b> 655 (12.1%) women who intended to deliver at home when labour began were transferred to hospital. Medical intervention rates included epidural (4.7%), episiotomy (2.1%), forceps (1.0%), vacuum extraction (0.6%), and caesarean section (3.7%); these rates were substantially lower than for low risk US women having hospital births. The intrapartum and neonatal mortality among women considered at low risk at start of labour, excluding deaths concerning life threatening congenital anomalies, was 1.7 deaths per 1000 planned home births, similar to risks in other studies of low risk home and hospital births in North America. No mothers died. No discrepancies were found for perinatal outcomes independently validated. <b>Conclusions</b> Planned home birth for low risk women in North America using certified professional midwives was associated with lower rates of medical intervention but similar intrapartum and neonatal mortality to that of low risk hospital births in the United States.
In Vivo Genetic Selection of Renal Proximal Tubules
Authors: Patrice K. Held, Muhsen Al-Dhalimy, Holger Willenbring, Yassmine Akkari, Shuguang Jiang, Yumi Torimaru, Susan Olson, William H. Fleming, Milton Finegold, Markus Grompe
Journal: Molecular Therapy (2005)

Repopulation by transplanted cells can result in effective therapy for several regenerative organs including blood, liver, and skin. In contrast, cell therapies for renal diseases are not currently available. Here we developed an animal model in which cells genetically resistant to a toxic intermediate of tyrosine metabolism, homogentisic acid (HGA), were able to repopulate the damaged proximal tubule epithelium of mice with fumarylacetoacetate hydrolase (Fah) deficiency. HGA resistance was achieved by two independent mechanisms. First, Fah+ transplanted bone marrow cells produced significant replacement of damaged proximal tubular epithelium (up to 50%). The majority of bone marrow-derived epithelial cells were generated by cell fusion, not transdifferentiation. In addition to regeneration by fusion-derived epithelial cells, proximal tubular repopulation was also observed by host epithelial cells, which had lost the homogentisic acid dioxygenase gene. These data demonstrate that extensive regeneration of the renal proximal tubule compartment can be achieved through genetic selection of functional cells.
Phenotypic Correction of α-Sarcoglycan Deficiency by Intra-arterial Injection of a Muscle-specific Serotype 1 rAAV Vector
Authors: Francoise Fougerousse, Marc Bartoli, Jérôme Poupiot, Ludovic Arandel, Muriel Durand, Nicolas Guerchet, Evelyne Gicquel, Olivier Danos, Isabelle Richard
Journal: Molecular Therapy (2006)

α-Sarcoglycanopathy (limb-girdle muscular dystrophy type 2D, LGMD2D) is a recessive muscular disorder caused by deficiency in α-sarcoglycan, a transmembrane protein part of the dystrophin-associated complex. To date, no treatment exists for this disease. We constructed recombinant pseudotype-1 adeno-associated virus (rAAV) vectors expressing the human α-sarcoglycan cDNA from a ubiquitous or a muscle-specific promoter. Evidence of specific immune response leading to disappearance of the vector was observed with the ubiquitous promoter. In contrast, efficient and sustained transgene expression with correct sarcolemmal localization and without evident toxicity was obtained with the muscle-specific promoter after intra-arterial injection into the limbs of an LGMD2D murine model. Transgene expression resulted in restoration of the sarcoglycan complex, histological improvement, membrane stabilization, and correction of pseudohypertrophy. More importantly, α-sarcoglycan transfer produced full rescue of the contractile force deficits and stretch sensibility and led to an increase of the global activity of the animals when both posterior limbs are injected. Our results establish the feasibility for AAV-mediated α-sarcoglycan gene transfer as a therapeutic approach.
Acute care is "suboptimal," says Royal College of Physicians
Authors: C. McKenna
Journal: BMJ (2002)

The standard of care received by acutely ill medical inpatients in the United Kingdom is below acceptable standards, says a new report on the interface between acute general medicine and critical care, commissioned by the Royal College of Physicians.

The current emphasis on specialist training of doctors rather than generic skills is not the correct approach to intensive medical management, says the report. All doctors should be trained at senior house officer level in the care of …
We shouldn't fear social media
Authors: Margaret McCartney
Journal: BMJ (2011)

I thought Twitter was a superficial collection of 140 character messages, stuffed with celebrity spats and thus entirely irrelevant to real life and medicine. I was wrong. The governing bodies of medicine and nursing have taken note of their tweeting membership and their Facebook friends. The Royal College of Nursing says that you should “keep your personal and professional life separate as far as possible” and “do not discuss work related issues online.”⇑

The BMA has issued guidance saying that although “medical professionals should be free to take advantage” of social media, “it is important that they are aware of the potential risks involved.” And of course …
Are we at risk of being at risk?
Authors: F. Godlee
Journal: BMJ (2010)

Who decides what constitutes a disease and what is normality? Over the centuries such decisions have been the preserve of the medical profession, aided more recently by modern medical science. But the profession has grown too close to those who profit from developing drugs for new diseases and is no longer fit to make these decisions. This in brief is Ray Moynihan’s thesis, developed over years of reporting on the relationship between doctors and the drug industry, and vigorously reprised in this week’s journal (doi:10.1136/bmj.c4442).

Moynihan’s target this time is prehypertension, a condition that along with preosteoporosis and prediabetes has the potential …
Vascular Access in Patients Receiving Hemodialysis-Reply
Authors: Glenn M. Chertow
Journal: JAMA (1997)

<h3>In Reply.</h3> —Dr Qureshi rightly points out that a tunneled catheter may be an optimal "bridge" to an AVF, even in the case of late referral or urgent initiation of dialysis. I agree that a trend toward use of fistulas rather than grafts might have been expected over time, in contrast to what was observed, had this catheter-to-fistula strategy been commonly used. The results of Dr Tokars and Ms Miller highlight 2 key points: prevalence of graft use over time exceeds its "incidence" at 30 days, and the marked degree of regional variation observed by Hirth et al<sup>1</sup>is attenuated over time. These findings indicate that grafts are even more likely to be used as secondary accesses after failure of a primary graft or fistula. Drs Tesi and O'Donovan describe an alternative "philosophy," which I strongly support, in which creation of an AVF is attempted in all patients, even those with
Methods report on the development of the 2013 revision and update of the <scp>EAACI</scp>/<scp>GA<sup>2</sup>LEN</scp>/<scp>EDF</scp>/<scp>WAO</scp> guideline for the definition, classification, diagnosis, and management of urticaria
Authors: T. Zuberbier, W. Aberer, R. Asero, C. Bindslev‐Jensen, Z. Brzoza, G. W. Canonica, M. K. Church, L. F. Ensina, A. Giménez‐Arnau, K. Godse, M. Gonçalo, C. Grattan, J. Hebert, M. Hide, A. Kaplan, A. Kapp, A. H. Abdul Latiff, P. Mathelier‐Fusade, M. Metz, S. S. Saini, M. Sánchez‐Borges, P. Schmid‐Grendelmeier, F. E. R. Simons, P. Staubach, G. Sussman, E. Toubi, G. A. Vena, B. Wedi, X. J. Zhu, A. Nast, M. Maurer
Journal: Allergy (2014)

Abstract This methods report describes the process of guideline development in detail. It is the result of a systematic literature review using the ‘Grading of Recommendations Assessment, Development and Evaluation’ ( GRADE ) methodology and a structured consensus conference held on 28 and 29 November 2012, in Berlin. It is a joint initiative of the Dermatology Section of the European Academy of Allergy and Clinical Immunology ( EAACI ), the EU ‐funded network of excellence, the Global Allergy and Asthma European Network ( GA 2 LEN ), the European Dermatology Forum ( EDF ), and the World Allergy Organization ( WAO ) with the participation of delegates of 21 national and international societies. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence‐based diagnostic and therapeutic approaches for the different subtypes of urticaria. This guideline was acknowledged and accepted by the European Union of Medical Specialists ( UEMS ) and is published in Allergy 2014; 69 :868–887.