tbuckley/cabot-search huggingface dataset:
Thomas Kuhn's ‘Structure of Scientific Revolutions’ applied to exercise science paradigm shifts: example including the Central Governor Model
Authors: Flávio de Oliveira Pires
Journal: British Journal of Sports Medicine (2012)

According to Thomas Kuhn, the scientific progress of any discipline could be distinguished by a pre-paradigm phase, a normal science phase and a revolution phase. The science advances when a scientific revolution takes place after silent period of normal science and the scientific community moves ahead to a paradigm shift. I suggest there has been a recent change of course in the direction of the exercise science. According to the 'current paradigm', exercise would be probably limited by alterations in either central command or peripheral skeletal muscles, and fatigue would be developed in a task-dependent manner. Instead, the central governor model (GCM) has proposed that all forms of exercise are centrally-regulated, the central nervous system would calculate the metabolic cost required to complete a task in order to avoid catastrophic body failure. Some have criticized the CGM and supported the traditional interpretation, but recently the scientific community appears to have begun an intellectual trajectory to accept this theory. First, the increased number of citations of articles that have supported the CGM could indicate that the community has changed the focus. Second, relevant journals have devoted special editions to promote the debate on subjects challenged by the CGM. Finally, scientists from different fields have recognized mechanisms included in the CGM to understand the exercise limits. Given the importance of the scientific community in demarcating a Kuhnian paradigm shift, I suggest that these three aspects could indicate an increased acceptance of a centrally-regulated effort model, to understand the limits of exercise.
Trans Fatty Acids and Their Effects on Lipoproteins in Humans
Authors: Martijn B. Katan, Peter L. Zock, Ronald P. Mensink
Journal: Annual Review of Nutrition (1995)

Trans fatty acids raise plasma low-density lipoprotein (LDL) cholesterol levels in volunteers when exchanged for cis unsaturated fatty acids in the diet. In addition, trans fatty acids may lower high-density lipoprotein (HDL) cholesterol levels and raise triglyceride and lipoprotein(a) levels in plasma. Trans and cis unsaturated fatty acids are thus not equivalent, and diets aimed at reducing the risk of coronary heart disease should be low in both trans and saturated fatty acids.
Identification of Lethal microRNAs Specific for Head and Neck Cancer
Authors: Marlon Lindenbergh-van der Plas, Sanne R. Martens-de Kemp, Michiel de Maaker, Wessel N. van Wieringen, Bauke Ylstra, Reuven Agami, Francesco Cerisoli, C. René Leemans, Boudewijn J.M. Braakhuis, Ruud H. Brakenhoff
Journal: Clinical Cancer Research (2013)

Abstract Purpose: The prognosis of head and neck squamous cell carcinomas (HNSCC) remains disappointing and the development of novel anti-cancer agents is urgently awaited. We identified by a functional genetic screen microRNAs that are selectively lethal for head and neck cancer cells but not for normal cells. We further investigated the genes targeted by these microRNAs. Experimental Design: A retroviral expression library of human microRNAs was introduced in HNSCC cell lines and normal oropharyngeal keratinocytes to identify tumor-selective lethal microRNAs. Potential downstream gene targets of these microRNAs were identified by gene expression profiling and validated by functional assays. Results: We identified six microRNAs that selectively inhibit proliferation of head and neck cancer cells. By gene expression profiling and 3′-untranslated region (UTR) luciferase reporter assays, we showed that the ataxia telangiectasia mutated (ATM) gene is a common target for at least two and likely three of these microRNAs. Specific inhibition of ATM resulted in a similar tumor-specific lethal effect, whereas the phenotype was reverted in rescue experiments. Conclusions: These six microRNAs might be developed as novel anti-cancer agents and highlight ATM as an interesting novel therapeutic target for head and neck cancer. Clin Cancer Res; 19(20); 5647–57. ©2013 AACR.
Abstract #LB-215: Antiproliferative effects of a novel mTOR inhibitor (Temsirolimus) provide the prolonged survival in a pleural dissemination model using non-small cell lung cancer cells
Authors: Toshiaki Ohara, Yoshio Naomoto, Yasuko Tomono, Shinichi Toyooka, Toshio Nishikawa, Kazufumi Sakurama, Seishi Nishitani, Huifang Hao, Xiaohong Bao, Shunsuke Tanabe, Yasuhiro Fujiwara, Takayuki Motoki, Munenori Takaoka, Yasuhiro Shirakawa, Tomoki Yamatsuji, Junji Matsuoka, Noriaki Tanaka
Journal: Cancer Research (2009)

[Introduction] Growth factor receptor signalings are aberrantly regulated in cancers and mammalian target of rapamycin (mTOR) plays a center role in this stimulated growth/survival signals. mTOR is often upregulated in many types of cancers including non small cell lung cancer (NSCLC). Temsirolimus, an analogue of rapamycin, was recently synthesized to specifically inhibit mTOR and has provided a better outcome to patients with renal cell carcinoma. It was also reported that temsirolimus showed a certain antitumor effect on other types of malignancies such as breast cancer and brain tumors. In this study, we aimed to obtain a potential application of temsirolimus to NSCLC, especially a therapeutic strategy for pleural dissemination of NSCLC, which is a severe state of clinical NSCLC without yet any effective treatments. [Methods] Cultured human NSCLC cell lines (A549, H1299, and H358) were used in this study. The cells were treated with temsirolimus for 48 hours and its effect on cell proliferation was determined by calculating a concentration of 50% growth inhibition (IC 50 ) and cell cycle analysis was done by flowcytometry. Western blot was carried out to examine the protein expressions of mTOR and related molecules. Three million of cultured cancer cells were subcutaneously inoculated in nude mice and 10mg/kg of temsirolimus were weekly administered in an intraperitoneal cavity ( i.p. ) to assess its antitumor effect. To further assess the effect of temsirolimus on the survival periods of tumor-bearing animals, a pleural dissemination model was established by an intrapleural injection of cancer cells, followed by a weekly  i.p .-administration of 10mg/kg-temsirolimus. Tumors were obtained from the animals for immunohistochemistry. [Results] Temsirolimus suppressed in vitro cell proliferation of A549, H1299, and H358 cells in a dose-dependent  manner with accumulation of cell population at the G1 phase and their IC 50 s were 0.76nM, 0.75nM, and 0.64nM, respectively. 1nM of temsirolimus effectively inhibited the activations of mTOR and its downstream effectors. Next, when 10mg/kg of temsirolimus was weekly administered to the animals, a significant delay of A549 subcutaneous tumor growth was observed (tumor volume: vehicle vs temsirolimus = 698cm 3  vs 1239cm 3 ;  p  i.p.  with 10mg/kg of temsirolimus) revealed a prolonged survival period of a pleural dissemination model (median survival: vehicle vs temsirolimus = 53.5days vs 72.5days;  p    Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-215.
Cautious epoprostenol therapy is a safe bridge to lung transplantation in pulmonary veno-occlusive disease
Authors: D. Montani, X. Jaïs, L. C. Price, L. Achouh, B. Degano, O. Mercier, S. Mussot, E. Fadel, P. Dartevelle, O. Sitbon, G. Simonneau, M. Humbert
Journal: European Respiratory Journal (2009)

Pulmonary veno-occlusive disease (PVOD) carries a poor prognosis and lung transplantation is the only curative treatment. In PVOD, epoprostenol therapy is controversial, as this condition may be refractory to specific therapy with an increased risk of pulmonary oedema. We retrospectively reviewed clinical, functional and haemodynamic data of 12 patients with PVOD (10 with histological confirmation) treated with continuous intravenous epoprostenol and priority listed for lung transplantation after January 1, 2003. All PVOD patients had severe clinical, functional and haemodynamic impairment at presentation. Epoprostenol was used at low dose ranges with slow dose increases and high dose diuretics. Only one patient developed mild reversible pulmonary oedema. After 3–4 months, improvements were seen in the New York Heart Association functional class (class IV to III in seven patients), cardiac index (1.99±0.68 to 2.94±0.89 L·min −1 ·m −2 ) and indexed pulmonary vascular resistance (28.4±8.4 to 17±5.2 Wood units·m −2 ; all p&lt;0.01). A nonsignificant improvement in the 6-min walk distance was also observed (+41 m, p = 0.11). Two patients died, one patient was alive on the transplantation waiting list on December 1, 2008 and nine patients were transplanted. Cautious use of continuous intravenous epoprostenol improved clinical and haemodynamic parameters in PVOD patients at 3–4 months without commonly causing pulmonary oedema, and may be a useful bridge to urgent lung transplantation.
Fumaric acid esters for severe psoriasis: a retrospective review of 58 cases
Authors: M.J. Harries, R.J.G. Chalmers, C.E.M. Griffiths
Journal: British Journal of Dermatology (2005)

Fumaric acid esters (FAE) have been used to treat severe psoriasis in northern Europe for over 20 years. A recent systematic review has shown FAE to be an effective systemic treatment for severe psoriasis. However, FAE remain unlicensed in the U.K.To present data relating to the efficacy and tolerability of FAE in severe psoriasis and report our experiences of FAE therapy at one U.K. centre.Patients who had received FAE for severe psoriasis at one U.K. regional referral centre between June 1999 and October 2003 were identified from pharmacy records. Their records were analysed retrospectively.Fifty-eight patients (25 women, 33 men) were identified. Fifty-five (95%) of the 58 patients had previously used other systemic antipsoriatic therapies with over 70% previously using two or more agents. Thirty-two patients (55%) showed improvement in their psoriasis with 10 (17%) being rated as 'clear' or 'virtually clear' by the attending physician. No improvement was seen in 28% patients and 16% showed worsening of their disease. Adverse events were common and were reported in 66% patients. These mainly consisted of abdominal pain (61%), diarrhoea (55%), flushing (45%), nausea (21%) and malaise (15%). They led to discontinuation of treatment in 15 patients after a mean period of 4.7 months. Lymphocytopenia developed during treatment in 57% of patients, all of whom had had a baseline value within the normal range. In only one patient was this considered severe enough to warrant withdrawal of treatment.Our study has shown that FAE are an effective therapy in selected patients with severe psoriasis, even in those who have previously been intolerant of systemic therapy or where it has failed.
680 URINARY TLR4: A NOVEL BIOMARKER TO IDENTIFY PATIENTS WITH ACUTE KIDNEY INJURY IN PATIENTS WITH ACUTE ON CHRONIC LIVER FAILURE
Authors: N. Shah, F.E.Z. Saleh Mohamed, M. Jover, J. Macnaughtan, N. Davies, R. Moreau, V. Paradis, K. Moore, R.P. Mookerjee, R. Jalan
Journal: Journal of Hepatology (2012)
Sodium supplementation is not required to maintain serum sodium concentrations during an Ironman triathlon
Authors: T D Hew-Butler, K Sharwood, M Collins, D Speedy, T Noakes
Journal: British Journal of Sports Medicine (2006)

Critical assessment of recommendations that athletes consume additional sodium during athletic events.To evaluate if sodium supplementation is necessary to maintain serum sodium concentrations during prolonged endurance activity and prevent the development of hyponatraemia.Prospective randomised trial of athletes receiving sodium (620 mg table salt), placebo (596 mg starch), or no supplementation during a triathlon. The sodium and placebo tablets were taken ad libitum, with the suggested range of 1-4 per hour.The 2001 Cape Town Ironman triathlon (3.8 km swim, 180 km cycle, 42.2 km run).A total of 413 triathletes completing the Ironman race.Sodium supplementation was not necessary to maintain serum sodium concentrations in athletes completing an Ironman triathlon nor required to prevent hyponatraemia from occurring in athletes who did not ingest supplemental sodium during the race.Subjects in the sodium supplementation group ingested an additional 3.6 (2.0) g (156 (88) mmol) sodium during the race (all values are mean (SD)). There were no significant differences between the sodium, placebo, and no supplementation groups with regard to age, finishing time, serum sodium concentration before and after the race, weight before the race, weight change during the race, and rectal temperature, systolic and diastolic blood pressure after the race. The sodium supplementation group consumed 14.7 (8.3) tablets, and the placebo group took 15.8 (10.1) tablets (p = 0.55; NS).Ad libitum sodium supplementation was not necessary to preserve serum sodium concentrations in athletes competing for about 12 hours in an Ironman triathlon. The Institute of Medicine's recommended daily adequate intake of sodium (1.5 g/65 mmol) seems sufficient for a healthy person without further need to supplement during athletic activity.
Effect of olfactory bulb ablation on spread of a neurotropic coronavirus into the mouse brain.
Authors: S Perlman, G Evans, A Afifi
Journal: The Journal of Experimental Medicine (1990)

Previous results suggested that, after intranasal inoculation, mouse hepatitis virus (MHV), a neurotropic coronavirus, entered the central nervous system (CNS) via the olfactory and trigeminal nerves. To prove this hypothesis, the effect of interruption of the olfactory pathway on spread of the virus was studied using in situ hybridization. Unilateral surgical ablation of this pathway prevented spread of the virus via the olfactory tract on the side of the lesion. MHV RNA could be detected, however, at distal sites on the operated side, indicating that the virus spread via well-described circuits involving the anterior commissure from the control (intact) side of the brain. Viral transport via the trigeminal nerve was not affected by removal of the olfactory bulb, showing that the surgical procedure was specific for the olfactory pathway. These results prove conclusively that MHV gains entry to the CNS via a transneuronal route, and spreads to additional sites in the brain via known neuroanatomic pathways.
11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study
Authors: Juha O Rinne, David J Brooks, Martin N Rossor, Nick C Fox, Roger Bullock, William E Klunk, Chester A Mathis, Kaj Blennow, Jerome Barakos, Aren A Okello, Sofia Rodriguez Martinez de LIano, Enchi Liu, Martin Koller, Keith M Gregg, Dale Schenk, Ronald Black, Michael Grundman
Journal: The Lancet Neurology (2010)
Prolonged survival in vivo of unprimed B cells responsive to a T-independent antigen.
Authors: Y Ron, J Sprent
Journal: The Journal of Experimental Medicine (1985)

Despite earlier evidence to the contrary, it has recently been claimed that most B lymphocytes, including lymph node (LN) and thoracic duct B cells, are short-lived cells of recent marrow origin. To seek direct information on this question, we transferred unprimed LN or thoracic duct B cells from normal mice to xid mice, i.e., mice unresponsive to the T-independent antigen, trinitrophenyl (TNP)-Ficoll. At varying periods after B cell transfer the recipients were challenged with TNP-Ficoll; anti-TNP plaque-forming cells were assayed in the spleen 6 d later. The results showed that the B cell recipients retained responsiveness to TNP-Ficoll for at least 3 mo after transfer. Responsiveness increased within the first 3 wk but then remained relatively constant. These findings imply that, at least for TNP-Ficoll-reactive cells, B cells residing in LN and thoracic duct lymph are not short-lived cells of recent marrow. Indeed, the data suggest that once the pool of recirculating B cells is fully formed in adult mice, further input of newly formed cells from the marrow into the recirculating pool is very limited.
Multiple Factors Influence Glomerular Albumin Permeability in Rats
Authors: Ruben M. Sandoval, Mark C. Wagner, Monica Patel, Silvia B. Campos-Bilderback, George J. Rhodes, Exing Wang, Sarah E. Wean, Sherry S. Clendenon, Bruce A. Molitoris
Journal: Journal of the American Society of Nephrology (2012)

Different laboratories recently reported incongruous results describing the quantification of albumin filtration using two-photon microscopy. We investigated the factors that influence the glomerular sieving coefficient for albumin (GSC(A)) in an effort to explain these discordant reports and to develop standard operating procedures for determining GSC(A). Multiple factors influenced GSC(A), including the kidney depth of image acquisition (10-20 μm was appropriate), the selection of fluorophore (probes emitting longer wavelengths were superior), the selection of plasma regions for fluorescence measurements, the size and molecular dispersion characteristics of dextran polymers if used, dietary status, and the genetic strain of rat. Fasting reduced the GSC(A) in Simonsen Munich Wistar rats from 0.035±0.005 to 0.016±0.004 (P<0.01). Frömter Munich Wistar rats had a much lower GSC(A) in both the fed and the fasted states. Finally, we documented extensive albumin transcytosis with vesicular and tubular delivery to and fusion with the basolateral membrane in S1 proximal tubule cells. In summary, these results help explain the previously conflicting microscopy and micropuncture data describing albumin filtration and highlight the dynamic nature of glomerular albumin permeability.
Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome
Authors: Danny Liaw, Debbie J. Marsh, Jing Li, Patricia L. M. Dahia, Steven I. Wang, Zimu Zheng, Shikha Bose, Katherine M. Call, Hui C. Tsou, Monica Peacoke, Charis Eng, Ramon Parsons
Journal: Nature Genetics (1997)
Early Repolarization in an Ambulatory Clinical Population
Authors: Abhimanyu Uberoi, Nikhil A. Jain, Marco Perez, Anthony Weinkopff, Euan Ashley, David Hadley, Mintu P. Turakhia, Victor Froelicher
Journal: Circulation (2011)

The significance of early repolarization, particularly regarding the morphology of the R-wave downslope, has come under question.We evaluated 29 281 resting ambulatory ECGs from the VA Palo Alto Health Care System. With PR interval as the isoelectric line and amplitude criteria ≥0.1 mV, ST-segment elevation is defined at the end of the QRS, J wave as an upward deflection, and slur as a conduction delay on the QRS downstroke. Associations of ST-segment elevation patterns, J waves, and slurs with cardiovascular mortality were analyzed with Cox analysis. With a median follow-up of 7.6 years, there were 1995 cardiac deaths. Of 29 281 subjects, 87% were male (55±14 years) and 13% were female (56±17 years); 13% were black, 6% were Hispanic, and 81% were white or other. Six hundred sixty-four (2.3%) had inferior or lateral ST-segment elevation: 185 (0.6%) in inferior leads and 479 (1.6%) in lateral leads, 163 (0.6%) in both, and 0.4% had global elevation. A total of 4041 ECGs were analyzed with enhanced display, and 583 (14%) had J waves or slurring, which were more prevalent in those with than in those without ST-segment elevation (61% versus 13%; P<0.001). ST-segment elevation occurred more in those with than in those without J waves or slurs (12% versus 1.3%; P<0.001). Except when involving only inferior leads, all components of early repolarization were more common in young individuals, male subjects, blacks, and those with bradycardia. All patterns and components of early repolarization were associated with decreased cardiovascular mortality, but this was not significant after adjustment for age.We found no significant association between any components of early repolarization and cardiac mortality.
Antibiotics at COPD exacerbations: the debate continues
Authors: J. A Wedzicha
Journal: Thorax (2008)

in animal studies has been shown to result in neuronal damage in wake promoting structures or disturbance in sleep architecture. 22 23Notwithstanding, one can also look at the issue of sleep hypoxaemia and daytime sleepiness from other angles.Why was desaturation more severe in the sleepy group despite similar AHI? Can the daytime sleepiness in those OSA individuals be a reflection of an overall propensity to sleep 9 11 with dimin- ished ventilatory response during nocturnal sleep, hence greater oxygen desaturation?Apart from hypoxaemia, is there any role for hypercarbia, the parameter in oblivion which is expected to be fluctuating alongside oxygen saturation?Barcelo ´'s article 3 has raised many more questions than it can answer.While researchers speculate on, and attempt to delineate, the complex relationships between OSA and its potential metabolic and neurobehavioural sequelae, it is important to confirm the findings of this work with further clinical trials.Furthermore, these two groups of subjects with similar severe OSA by AHI criteria and similar BMI, yet widely divergent degrees of daytime sleepiness, were probably highly selected for the purpose of addressing the authors' stated hypothesis.In our daily encounter, subjects would have a wide spectrum of severity of OSA, obesity and sleepiness.Given the numerous permutations in phenotypes and their underlying pathophysiological interactions, what demarcates clearly in the study sample may have very different consequences in the wider population of OSA subjects.This is perhaps the challenge of researchto search, and research.