tbuckley/cabot-search huggingface dataset:
Enhanced collagen synthesis and transcription by peak E, a contaminant of L-tryptophan preparations associated with the eosinophilia myalgia syndrome epidemic.
Authors: H Takagi, M S Ochoa, L Zhou, T Helfman, H Murata, V Falanga
Journal: Journal of Clinical Investigation (1995)

The pathogenesis of the eosinophilia myalgia syndrome (EMS) remains unclear. Several abnormal constituents have been found in the L-tryptophan lots responsible for the illness, particularly, 1,1-ethylidenebis[L-tryptophan], also called peak E or EBT, and 3-phenylamino-alanine or peak 5. However, the role of these contaminants in the pathogenesis of EMS and in the development of fibrosis is unknown. We now report that peak E, a dimer of L-tryptophan, is a potent stimulus for human dermal fibroblast DNA and collagen synthesis. Peak E (0.1-1.0 microM) increased DNA synthesis up to four-fold (P = 0.0001) in a dose-dependent manner (r = 0.987). When added to monolayer cultures for 2 to 24 h, peak E (0.5 to 100 microM) caused a progressive, more than threefold increase in alpha 1(I) procollagen mRNA levels and collagenous protein. No increase in procollagen mRNA levels was found after the addition of another major L-tryptophan contaminant, peak 5, or with L-tryptophan itself. Transient transfection with a 2.5-kb alpha 1(I) procollagen promoter-luciferase construct showed that peak E causes a twofold upregulation of promoter activity (P = 0.022). Contraction of collagen gels, consisting of human dermal fibroblasts incorporated into a type I collagen lattice, was enhanced two-fold by exposure to peak E (P = 0.001). We conclude that a major constituent of contaminated batches of L-tryptophan, peak E, is a potent stimulus for fibroblast activation and collagen synthesis. This stimulatory action of peak E may provide a direct mechanism for the development of fibrosis in EMS.
New consultants' contract sees pay bill rise by 38% in Scotland
Authors: Christie Bryan
Journal: BMJ (2006)

Implementation of the new UK contract for consultants has cost £235m (€345m; $410m) in Scotland, yet so far there is no clear evidence that it is helping to improve the care of patients.

Audit Scotland has carried out the first independent examination in the United Kingdom of the effect of the new contract, which was introduced in April 2004. The contract was the first major change in consultants' terms and conditions since the NHS began in 1948.

Audit Scotland's report has found that the pay bill for consultants has increased by 38% as a result of the contract. It says the contract offers an opportunity to focus the work of consultants on priorities …
STUDIES ON THE PATHOGENESIS OF FEVER WITH INFLUENZAL VIRUSES
Authors: Elisha Atkins, Wei Cheng Huang
Journal: The Journal of Experimental Medicine (1958)

Observations have been made on the fever-inducing properties of an endogenous pyrogen found in the circulation of rabbits after the intravenous inoculation of Newcastle disease virus (NDV). When endogenous pyrogen was given to a normal recipient, a biphasic fever was produced which simulated that seen with bacterial endotoxins. With the use of a technique of serial passive transfer, it has been shown that the "double-humped" response results from two separate actions of the injected pyrogen. The first of these appears to be a direct stimulation of the thermoregulatory centers. The second involves the release of further endogenous pyrogen in the normal recipient to cause, in turn, the second fever peak. Since the injection of endogenous pyrogen did not produce a significant change in the number of circulating leukocytes, it is inferred that this substance is different from either bacterial or tissue polysaccharides. In rabbits rendered tolerant by a previous injection of virus the second fever peak failed to appear and the response to endogenous pyrogen was monophasic. Evidence indicates that the absence of a second fever peak in the tolerant recipient was not due to rise in temperature on the preceding day of virus injection or to the development of either serum inhibitors or tolerance to virus itself. It is postulated that prior mobilization of endogenous pyrogen by virus may have modified the ability of the tolerant recipient to liberate further amounts of this substance in response to an injection of endogenous pyrogen.
Updated consensus statement on tumour necrosis factor blocking agents for the treatment of rheumatoid arthritis (May 2000)
Authors: D E FURST
Journal: Annals of the Rheumatic Diseases (2000)

As last year, a consensus group to consider the use of tumour necrosis factor (TNF) blocking agents was formed by an organising committee constituted of rheumatologists from the Universities of Erlangen, Leiden and Vienna in Europe in cooperation with universities in the United States. Pharmaceutical support was obtained from a number of companies, but these institutions had no part in the decisions regarding this specific programme nor with regard to the participants or attendees at this conference.

The approximately 100 rheumatologists and bioscientists from 25 countries who attended the consensus conference were chosen from a worldwide group of people felt to have experience or interest in the use of TNF blocking treatment for rheumatoid arthritis (RA). Unfortunately, the number of attendees and participants were limited so that not everyone who might have been appropriate could be invited.

During the past year increasing amounts of data on the use of TNF blocking agents in RA have been published. Consequently it was felt appropriate to update the provisional consensus statement published last year (Ann Rheum Dis 1999;58 (suppl 1):I129–30).

During this revision it became clear that there are still large areas where knowledge is lacking. In an effort to clarify, for the readers, evidence on which the consensus statement is based, statements with supporting data have been referenced.

When a statement is not referenced it will have arisen from the consensus process: small group discussions, large group discussions and repeated drafts of the consensus statement to allow input from all participants. We feel that this statement represents an updated, although still provisional, consensus view of the use of TNF blockade in RA. However, it will …
Serial transplantation of mismatched donor hematopoietic cells between HLA-identical sibling pairs with congenital immunodeficiency: in vivo tolerance permits rapid immune reconstitution following T-replete transplantation without GVHD in the secondary recipient
Authors: Jonathan M. Cohen, Valerie Rogers, H. Bobby Gaspar, Alison Jones, E. Graham Davies, Kanchan Rao, Daniel J. McCloskey, Kimberley Gilmour, Robert Wynn, Persis J. Amrolia, Paul Veys
Journal: Blood (2006)
Intra-CSF Rituximab for Lymhomatous Meningitis
Authors: Marc C. Chamberlain, Michael J. Glantz
Journal: Journal of Clinical Oncology (2007)

We appreciate the comments of Dr Miksad and colleagues.We agree that economic analyses can provide very important information in translating the results of clinical trials into health care delivery policies.This is particularly relevant in this setting because, to our knowledge, this trial of gemcitabine plus erlotinib is the first to demonstrate a significant, albeit small, overall survival benefit in advanced pancreatic cancer. 1 Overall, the treatment is well tolerated, but there is some additional toxicity.Determination of the cost effectiveness and cost utility of this new treatment therefore is of interest to inform clinical decision making at both the patient and policy level.Similar to clinical trials, economic analyses need to be conducted in a rigorous manner.We are in the process of considering the merits and methodological issues associated with conducting a formal economic evaluation of the results of our trial.While there will be debate about utility for health care policies, our data do confirm biologic activity of erlotinib that translated into superior disease control in the population studied.We would point out that median survival is a single point on the survival curve and may not be representative of the average difference in survival that occurs for all patients on the study.Also, that our rash and disease control analyses suggest that there is a subset of patients who experience a larger benefit from erlotinib.Identification of prospective molecular markers that will allow an enrichment of the patient population treated would be both clinically and economically attractive, and is a focus of further studies we are conducting.
Hypersensitivity Pneumonitis Associated with Environmental Mycobacteria
Authors: William Beckett, Michael Kallay, Akshay Sood, Zhengfa Zuo, Donald Milton
Journal: Environmental Health Perspectives (2005)

A previously healthy man working as a machine operator in an automotive factory developed respiratory symptoms. Medical evaluation showed abnormal pulmonary function tests, a lung biopsy showed hypersensitivity pneumonitis, and his illness was traced to his work environment. His physician asked the employer to remove him from exposure to metalworking fluids. Symptoms reoccurred when he was later reexposed to metalworking fluids, and further permanent decrement in his lung function occurred. Investigation of his workplace showed that five of six large reservoirs of metalworking fluids (cutting oils) grew Mycobacterium chelonae (or Mycobacterium immunogenum), an organism previously associated with outbreaks of hypersensitivity pneumonitis in automaking factories. His lung function remained stable after complete removal from exposure. The employer, metalworking fluid supplier, union, and the National Institute for Occupational Safety and Health were notified of this sentinel health event. No further cases have been documented in this workplace.
THE MITOTIC RATE AND DURATION IN LESIONS OP PSORIASIS AND ICHTYOSIS*
Authors: L. B. FISHER, G. C. WELLS
Journal: British Journal of Dermatology (1968)

SUMMARY. The epidermal mitotic rate in psoriatic lesions is 3 or 4 times greater than that in normal epidermis as established by using 0.5% colcemid effective during a 5 hr. period. The mitotic duration in psoriasis is about 4 hr. compared with the normal 11/2hr. The colcemid mitotic rate in various forms of ichthyosis was found to be within the range of normal.
Wallerian Degeneration, Wld<sup>S</sup>, and Nmnat
Authors: Michael P. Coleman, Marc R. Freeman
Journal: Annual Review of Neuroscience (2010)

Traditionally, researchers have believed that axons are highly dependent on their cell bodies for long-term survival. However, recent studies point to the existence of axon-autonomous mechanism(s) that regulate rapid axon degeneration after axotomy. Here, we review the cellular and molecular events that underlie this process, termed Wallerian degeneration. We describe the biphasic nature of axon degeneration after axotomy and our current understanding of how Wld S —an extraordinary protein formed by fusing a Ube4b sequence to Nmnat1—acts to protect severed axons. Interestingly, the neuroprotective effects of Wld S span all species tested, which suggests that there is an ancient, Wld S -sensitive axon destruction program. Recent studies with Wld S also reveal that Wallerian degeneration is genetically related to several dying back axonopathies, thus arguing that Wallerian degeneration can serve as a useful model to understand, and potentially treat, axon degeneration in diverse traumatic or disease contexts.
Abstract 2753: The Relationship Between Pulmonary Vein Antrum Scarring Following Atrial Fibrillation Ablation and Procedural Success: Does Pulmonary Vein Isolation Matter?
Authors: Troy J Badger, Robert S Oakes, Akram Shabaan, Nazem W Akoum, Nathan M Segerson, Eric N Fish, Swati N Rao, Nathan S Burgon, Yaw Adjei-Poku, Eugene G Kholmovski, Sathya Vijayakumar, Edward V DiBella, Rob S MacLeod, Nassir F Marrouche
Journal: Circulation (2008)

Background. A mechanism of atrial fibrillation (AF) recurrence following ablation may be incomplete pulmonary vein antrum (PVA) scarring that allows for conduction between the pulmonary veins (PV) and the left atrium (LA). We report the relationship between circumferential PV scarring detected by delayed enhancement MRI (DE-MRI) and AF recurrence following PVAI. Methods. Eighty-six patients presenting for PVAI underwent DE-MRI 3 months post ablation. Circumferential ablation with posterior wall debulking was performed in all patients. PV ostia were marked on 3D images generated from the MRI data and assessed by consensus of two independent reviewers for the extent of scarring. Complete PVA scarring was defined as a continuous ring of enhancement surrounding the PVA. For patients with incomplete scarring, the degree of scarring was estimated. Results. The figure shows two patients from the cohort, Patient 1 exhibits successful scarring of all PVA. Patient 2 shows scarring of 1 PVA. At three months post ablation, complete circumferential lesion was seen on 131/335 PVA (39.1%). Complete scarring of 4 PVA was seen in 9 patients (10.5%), scarring of 3 PVA in 11 patients (12.8%) and scarring of 2 PVA was seen in 17 patients (19.8). Twenty-nine patients (33.7%) exhibited complete scarring in 1 PVA while 20 patients (23.3%) exhibited scarring in 0 PVA. Kaplan Meier analysis (Figure [E] ), suggests that PVA isolation may be important for long-term procedural success. Conclusion: Complete pulmonary vein antrum scarring exists in a very limited number of patients, despite its apparent importance for long-term procedural success.
Developing Safety Criteria for Introducing New Agents into Neoadjuvant Trials
Authors: Angela DeMichele, Donald A. Berry, JoAnne Zujewski, Sally Hunsberger, Larry Rubinstein, Joseph E. Tomaszewski, Gary Kelloff, Jane Perlmutter, Meredith Buxton, Julia Lyandres, Kathy S. Albain, Chris Benz, A. Jo Chien, Paul Haluska, Brian Leyland-Jones, Minetta C. Liu, Pamela Munster, Olufunmilayo Olopade, John W. Park, Barbara A. Parker, Lajos Pusztai, Debu Tripathy, Hope Rugo, Douglas Yee, Laura Esserman
Journal: Clinical Cancer Research (2013)

New approaches to drug development are critically needed to lessen the time, cost, and resources necessary to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process, such as the neoadjuvant setting. The U.S. Food and Drug Administration (FDA) has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathologic response, can be used to identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. However, this approach has unique challenges. In particular, issues of patient safety are paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience. Key components to safe drug development in the neoadjuvant setting include defining a study population at sufficiently poor prognosis with standard therapy to justify exposure to investigational agents, defining the extent and adequacy of safety data from phase I, detecting potentially harmful interactions between investigational and standard therapies, improving study designs, such as adaptive strategies, that limit patient exposure to ineffective agents, and intensifying safety monitoring in the course of the trial. The I-SPY2 trial is an example of a phase II neoadjuvant trial of novel agents for breast cancer in which these issues have been addressed, both in the design and conduct of the trial. These adaptations of phase II design enable acceleration of drug development by reducing time and cost to screen novel therapies for activity without compromising safety.
Effects of Various Chemical Agents on Sister Chromatid Exchanges, Chromosome Aberrations, and DNA Repair in Normal and Abnormal Human Lymphoid Cell Lines&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Y Shiraishi, A A Sandberg
Journal: JNCI Journal of the National Cancer Institute (1979)

Cells from a line (SN1029) derived from a case of chronic lymphocytic leukemia (CLL) were highly sensitive to the killing effects of chemical agents [4-nitroquinoline 1-oxide (4NQO), methyl methanesulfonate, ethyl methanesulfonate (EMS), mitomycin C (MMC), daunomycin (DM), bleomycin, and cytosine arabinoside], as compared to the lack of sensitivity of a normal lymphocytic cell line treated with these agents. Cells treated with N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) were a possible exception to this pattern. Among the chemicals tested, SN1029 cells were extremely sensitive to MMC with regard to frequency of sister chromatid exchange(s) (SCE), even though MMC did not greatly increase the incidence of chromosome aberrations. Reverse results were obtained with the 6 other chemicals, i.e., no significant increase in SCE but a definite rise in chromosome aberrations. However, some contrasting results were obtained; e.g., DM induced a high frequency of chromosome aberrations in normal and SN1029 cells without a concomitant increase in SCE frequency. Unscheduled DNA synthesis (USD) in normal and SN1029 cells was examined following UV radiation (200 ergs/ mm2) and chemical treatments with EMS, MNNG, MMC, and 4NQO for 90 minutes at 6.0 µg/ml (expt I) and for 48 hours at 0.003, 0.03, 0.3, and 6.0 µg/ml (expt II). Almost no detectable levels of USD were seen with MMC in experiment I or with MMC, EMS, MNNG, and 4-NQO in experiment II, whereas USD did occur following 4-NQO, EMS, MNNG, and UV radiation in experiment I. The repair level did not differ between normal and SN1029 cells when exposed to EMS, MNNG, 4-NQO, and UV radiation, in spite of hypersensitivity of the SN1029 cells to the killing effects of 4-NQO and EMS. Comparison of SCE breakpoints and USD (shown by the g rain distribution) indicated that the SCE breakpoints within chromosome #1 in MMC- and 4-NQO-treated normal cells were nonrandom, whereas the silver grains were distributed randomly over the chromatids in cells treated with 4-NQO. The results indicate that SCE and excision repair are not closely linked and that the high SCE sensitivity and cell death of the CLL cell line are independent of the quantitative capacity of excision repair.
Use of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for Improving the Accuracy of the Risk Classification of Type 1 Diabetes
Authors: Jay M. Sosenko, Jay S. Skyler, Jeffrey Mahon, Jeffrey P. Krischer, Carla J. Greenbaum, Lisa E. Rafkin, Craig A. Beam, David C. Boulware, Della Matheson, David Cuthbertson, Kevan C. Herold, George Eisenbarth, Jerry P. Palmer
Journal: Diabetes Care (2014)

OBJECTIVE We studied the utility of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for improving the accuracy of type 1 diabetes (T1D) risk classification in TrialNet Natural History Study (TNNHS) participants. RESEARCH DESIGN AND METHODS The cumulative incidence of T1D was compared between normoglycemic individuals with DPTRS values &amp;gt;7.00 and dysglycemic individuals in the TNNHS (n = 991). It was also compared between individuals with DPTRS values &amp;lt;7.00 or &amp;gt;7.00 among those with dysglycemia and those with multiple autoantibodies in the TNNHS. DPTRS values &amp;gt;7.00 were compared with dysglycemia for characterizing risk in Diabetes Prevention Trial-Type 1 (DPT-1) (n = 670) and TNNHS participants. The reliability of DPTRS values &amp;gt;7.00 was compared with dysglycemia in the TNNHS. RESULTS The cumulative incidence of T1D for normoglycemic TNNHS participants with DPTRS values &amp;gt;7.00 was comparable to those with dysglycemia. Among those with dysglycemia, the cumulative incidence was much higher (P &amp;lt; 0.001) for those with DPTRS values &amp;gt;7.00 than for those with values &amp;lt;7.00 (3-year risks: 0.16 for &amp;lt;7.00 and 0.46 for &amp;gt;7.00). Dysglycemic individuals in DPT-1 were at much higher risk for T1D than those with dysglycemia in the TNNHS (P &amp;lt; 0.001); there was no significant difference in risk between the studies among those with DPTRS values &amp;gt;7.00. The proportion in the TNNHS reverting from dysglycemia to normoglycemia at the next visit was higher than the proportion reverting from DPTRS values &amp;gt;7.00 to values &amp;lt;7.00 (36 vs. 23%). CONCLUSIONS DPTRS thresholds can improve T1D risk classification accuracy by identifying high-risk normoglycemic and low-risk dysglycemic individuals. The 7.00 DPTRS threshold characterizes risk more consistently between populations and has greater reliability than dysglycemia.
Three year residency produces equivalent of competent middle grade registrar
Authors: M. Nathanson, R. John
Journal: BMJ (1995)

patients' satisfaction but, more importantly, outcome.Indeed, anaesthetists and surgeons may also attach greater importance to pain relief and, in particular, regional anaesthesia if the promising results of recent research are borne out by larger controlled studies.'If a combination of new surgical techniques, high quality analgesia, and aggressive rehabilitation can reduce the mean length of stay after major surgery by half, then both providers and purchasers should be interested in the role of regional analgesia in the outcome of surgery.This will require a great change in clinicians' attitudes to postoperative care and an injection of new moneys in the short term.Whether either of these developments occurs remains to be seen.
Heterozygous -globin gene mutations as a risk factor for iron accumulation and liver fibrosis in chronic hepatitis C
Authors: M. Sartori, S. Andorno, M. Pagliarulo, C. Rigamonti, C. Bozzola, P. Pergolini, R. Rolla, A. Suno, R. Boldorini, G. Bellomo, E. Albano
Journal: Gut (2006)

Iron accumulation is a well-known risk factor for the progression of chronic hepatitis C (CHC) to fibrosis. However, the profibrogenic role of the genes controlling iron homeostasis is still controversial.
Beta-Blocker Use Is Associated With Improved Relapse-Free Survival in Patients With Triple-Negative Breast Cancer
Authors: Amal Melhem-Bertrandt, Mariana Chavez-MacGregor, Xiudong Lei, Erika N. Brown, Richard T. Lee, Funda Meric-Bernstam, Anil K. Sood, Suzanne D. Conzen, Gabriel N. Hortobagyi, Ana-Maria Gonzalez-Angulo
Journal: Journal of Clinical Oncology (2011)

To examine the association between beta-blocker (BB) intake, pathologic complete response (pCR) rates, and survival outcomes in patients with breast cancer treated with neoadjuvant chemotherapy.We retrospectively reviewed 1,413 patients with breast cancer who received neoadjuvant chemotherapy between 1995 and 2007. Patients taking BBs at the start of neoadjuvant therapy were compared with patients with no BB intake. Rates of pCR between the groups were compared using a χ² test. Cox proportional hazards models were fitted to determine the association between BB intake, relapse-free survival (RFS), and overall survival (OS).Patients who used BBs (n = 102) were compared with patients (n = 1,311) who did not. Patients receiving BBs tended to be older and obese (P < .001). The proportion of pCR was not significantly different between the groups (P = .48). After adjustment for age, race, stage, grade, receptor status, lymphovascular invasion, body mass index, diabetes, hypertension, and angiotensin-converting enzyme inhibitor use, BB intake was associated with a significantly better RFS (hazard ratio [HR], 0.52; 95% CI, 0.31 to 0.88) but not OS (P = .09). Among patients with triple-negative breast cancer (TNBC; n = 377), BB intake was associated with improved RFS (HR, 0.30; 95% CI, 0.10 to 0.87;P = .027) but not OS (HR, 0.35; 95% CI, 0.12 to 1.00;P = .05).In this study, BB intake was associated with improved RFS in all patients with breast cancer and in patients with TNBC. Additional studies evaluating the potential benefits of beta-adrenergic blockade on breast cancer recurrence with a focus on TNBC are warranted.