tbuckley/cabot-search huggingface dataset:
The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain
Authors: Anne-Sophie Carlo, Camilla Gustafsen, Guido Mastrobuoni, Morten Nielsen, Stefan Kempa, Claus Munck Petersen, Thomas Willnow
Journal: Molecular Neurodegeneration (2013)

Sortilin is a member of the VPS10P domain receptor gene family, a class of sorting and signalling receptors in neurons. This gene family also includes SORLA/LR11, the neuronal sorting factor for APP. Sortilin has been shown to constitute an essential component of the receptor complex that transmits pro-neurotrophin-dependent death signals in neurons. In previous studies, sortilin-dependent pro-neurotrophin signalling has been implicated in regulation of neuronal viability during normal development and aging. Also, sortilin activity has been shown to control neuronal cell death and survival in spinal cord injury. Remarkably, up-regulation of pro-neurotrophins has been observed under conditions of neurodegeneration. These findings led us to hypothesize that sortilin signaling may not only control neuronal viability during acute but also during chronic distress of the nervous system as in Alzheimer’s disease (AD). Here, we have used mice with targeted sortilin gene disruption to address the consequences of impaired receptor activity for APP processing, structural and functional integrity of the brain, as well as AD pathology in vivo. When crossed with two different AD models (PDAPP, 5xFAD), sortilin-deficient mice showed a robust increase in Aβ levels in brain compared with control animals. Surprisingly, the levels of soluble APP products were not altered in sortilin-deficient mice, nor were the levels of Aβ-degrading enzymes, neprilysin and insulin-degrading enzyme, suggesting an impairment of Aβ clearance pathways. Apolipoprotein (APO) E is the major risk factor for sporadic Alzheimer disease. Among other functions, APOE is proposed to sequester neurotoxic amyloid-β peptides (Aβ) in the brain, delivering them to cellular catabolism via neuronal APOE receptors. In this study, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of apoliporotein E (APOE)/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain, and in aggravated plaque burden. Also, primary neurons lacking sortilin exhibit significantly impaired uptake of APOE/Aβ complexes despite proper expression of other APOE receptors. In spite of higher than normal brain APOE levels, sortilin-deficient animals display anomalies in brain lipid metabolism seen in APOE-deficient mice, indicating functional deficiency in cellular APOE uptake pathways. Taken together, our findings identified sortilin as an essential neuronal pathway for APOE-containing lipoproteins in vivo and suggest an intriguing link between Aβ catabolism and pro-neurotrophin signaling converging on this receptor.
Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma.
Authors: E Bajetta, A Di Leo, M G Zampino, M R Sertoli, G Comella, M Barduagni, B Giannotti, P Queirolo, G Tribbia, M G Bernengo
Journal: Journal of Clinical Oncology (1994)

PURPOSE Some phase II studies have suggested that the combination of interferons (IFNs) with dacarbazine (DTIC) in the treatment of malignant melanoma (MM) increases the antitumor activity of DTIC alone. In an attempt to confirm this hypothesis, a randomized study was performed with the further intent of observing whether low doses of recombinant interferon alfa-2a (rIFN alpha 2a) could be as effective as intermediate doses. PATIENTS AND METHODS Two hundred sixty-six patients were randomized onto three different treatment arms: DTIC 800 mg/m2 intravenously (IV) days 1 and 21; DTIC plus rIFN alpha 2a 9 mIU intramuscularly (IM) daily; and DTIC plus rIFN alpha 2a 3 mIU IM three times per week. Major prognostic factors were well balanced among the three arms. Chemotherapy was administered for a maximum of eight cycles. After 6 months of therapy, rIFN alpha 2a was continued until disease progression at 3 mIU three times per week in responding patients who had received the combined treatment. RESULTS The percentage of objective responses did not differ among the three groups (20%, 28%, and 23%, respectively), although a significant prolongation of response duration was observed when rIFN alpha 2a was added to DTIC (2.6 v 8.4 v 5.5 months, respectively). However, this improvement in response duration did not translate into an amelioration of overall survival. The addition of rIFN alpha 2a led to the onset of flu-like syndrome, but in no case was it necessary to withdraw the treatment program and no toxic deaths or life-threatening toxicities were reported. CONCLUSION In this study, rIFN alpha 2a significantly prolonged response duration, whereas no effects on response rate and survival were observed; rIFN alpha 2a 3 mIU appeared to be equally effective and better tolerated than 9 mIU.
Concurrent Epstein Barr Virus Viremia and Hodgkin Lymphoma In Two Patients With Chronic Lymphocytic Leukemia
Authors: Samir Dalia, Jason B. Brayer, Julio C Chavez, Celeste M. Bello, Bijal D. Shah, Pedro Horna, Hailing Zhang, Lubomir Sokol, Eduardo M. Sotomayor, Javier Pinilla-Ibarz
Journal: Blood (2013)
Survivor Treatment Selection Bias in Observational Studies: Examples from the AIDS Literature
Authors: Marshall J. MD, Glesby
Journal: Annals of Internal Medicine (1996)

Unlike patients in a randomized, clinical trial, patients in an observational study choose if and when to begin treatment. Patients who live longer have more opportunities to select treatment; those who die earlier may be untreated by default. These facts are the essence of an often overlooked bias, termed "survivor treatment selection bias," which can erroneously lead to the conclusion that an ineffective treatment prolongs survival. Unfortunately, misanalysis of survivor treatment selection bias has been prevalent in the recent literature on the acquired immunodeficiency syndrome. Approaches to mitigating this bias involve complex statistical models. At a minimum, initiation of therapy should be treated as a time-dependent covariate in a proportional hazards model. Investigators and readers should be on the alert for survivor treatment selection bias and should be cautious when interpreting the results of observational treatment studies.
Prognostic factors in necrotizing soft-tissue infections (NSTI): A cohort study
Authors: Camille Hua, Emilie Sbidian, Francois Hemery, Jean Winoc Decousser, Romain Bosc, Roland Amathieu, Alain Rahmouni, Pierre Wolkenstein, Laurence Valeyrie-Allanore, Christian Brun-Buisson, Nicolas de Prost, Olivier Chosidow
Journal: Journal of the American Academy of Dermatology (2015)
Ethnicity, social inequality, and mental illness
Authors: K. Lloyd
Journal: BMJ (1998)

The relative prevalence and treatment of mental illness among different ethnic groups in Britain is probably one of the most controversial issues in the field of health variations. The Policy Studies Institute, in a study commissioned by the Department of Health, has tackled these complexities and openly addressed the difficulties in the cross cultural assessment of mental illness.1

The study is based on a national community survey of 5196 people of Caribbean or Asian origin and 2867 white Britons. Ethnicity was assigned on the basis of country of family origin, though the limitations of this approach are acknowledged.2 In a two stage interviewing process, initial assessment of mental health relied on structured questionnaires: a cut down clinical interview schedule3 for neurotic disorders and the psychosis screening questionnaire4 for psychotic disorders. Second stage interviewing was conducted by ethnically and linguistically matched interviewers using the appropriate translation of version 9 of the …
The efficacy of a rifabutin-containing regimen for rifabutin-susceptible multidrug-resistant tuberculosis
Authors: Kyung-Wook Jo, Wonjun Ji, Jiwon Lyu, Young Ju Jung, Sang-Do Lee, Woo Sung Kim, Dong Soon Kim, Tae Sun Shim
Journal: European Respiratory Journal (2012)

OBJECTIVE: We investigated the efficacy of a rifabutin (RBU)-containing regimen for the treatment of RBU-susceptible multidrug-resistant tuberculosis (MDR-TB).

METHODS: From 256 patients diagnosed with MDR-TB at Asan Medical Center in South Korea between January 2006 and December 2010, 39 patients (15.2%) were susceptible to RBU. Of these 39 patients, nine patients who were appropriately treated with a RBU-containing regimen were included. Twenty-seven MDR-TB patients who were resistant to RBU, were selected as a control group, and the outcomes of both groups were retrospectively compared.

RESULTS: In the nine patients with RBU-susceptible MDR-TB, their mean age was 43.7 years and the proportion of extensively drug-resistant TB (XDR-TB) was 44.4% (4/9). Baseline characteristics and the drug resistance pattern (except RBU) did not differ between the two groups. Treatment success was achieved in all nine patients in the RBU group: cure in six (66.7%) and treatment completion in three (33.3%). On the other hand, the treatment success rate was 48.1% (13/27) and treatment failed in 14 (51.9%) of the 27 patients in the control group ( p = 0.012).

CONCLUSIONS: RBU seems to be useful in the treatment of MDR-TB in patients who are susceptible to RBU.
Antifungal stewardship in a tertiary-care institution: a bedside intervention
Authors: M. Valerio, P. Muñoz, C.G. Rodríguez, B. Caliz, B. Padilla, A. Fernández-Cruz, M. Sánchez-Somolinos, P. Gijón, J. Peral, J. Gayoso, I. Frias, M. Salcedo, M. Sanjurjo, E. Bouza
Journal: Clinical Microbiology and Infection (2015)
Giving gentamicin once daily for neutropenic fever has proved to be simple
Authors: R P D Cooke, R J Grace, P A Gover
Journal: BMJ (1996)

EDITOR,—Michael Barza and colleagues' meta-analysis of single versus multiple daily doses of aminoglycosides1 confirms the view that once daily dosing is safe and clinically effective.2 However, specific experience with gentamicin (the most commonly prescribed aminoglycoside in Britain) is extremely limited because most trials have compared either netilimicin or amikacin.1 Only three trials of aminoglycosides in the management of febrile neutropenic patients were referenced, none of which used gentamicin. Haematology units that treat neutropenic fever with gentamicin may therefore be reluctant …
Airway wall responses to tidal breathing and deep inspiration
Authors: Thomas K Ansell, Peter B. Noble, Howard W. Mitchell, Peter McFawn
Journal: European Respiratory Journal (2012)

Introduction   Mechanical stretch attenuates airway smooth muscle (ASM) force production, which may explain the reversal of bronchoconstriction (i.e. bronchodilation) following a deep inspiration (DI) in vivo. We measured the effect of simulated DI on both narrowing and ASM force in isolated bronchi.   Methods   Bronchial segments were dissected from pig lungs and maintained in organ bath chambers. Airway narrowing (% volume) to acetylcholine (ACh, 10 -7 M - 3x10 -3 M) was measured under static transmural pressure (P tm ) conditions and during fixed P tm  oscillations simulating tidal breathing (Δ5cmH 2 O) with intermittent DI (Δ25cmH 2 O). In a separate group of experiments, the above protocols were repeated using fixed volume oscillations to simulate tidal and DI breathing whilst measuring the increase in P tm  produced by ASM contraction. Under each condition, airway wall stiffness was measured from the change in P tm  and volume during tidal oscillations.   Results   Under static conditions, maximal response to ACh was 92.3±4.3% narrowing (n=6) and 73.5±9.2cmH 2 O P tm  (n=4). DI to Δ25cmH 2 O reversed ∼60% narrowing at low doses of ACh but had no affect at moderate or high doses, whereas fixed volume DI attenuated ASM force to 12.7±5.6cmH 2 O (t-test, p tm  conditions but reversed 60.9±4.4% (p   Conclusions   The mechanical loading conditions present during tidal breathing and DI influence the airway response to mechanical stretch. Inhibition of bronchoconstriction to mechanical stretch is minimal during fixed Ptm oscillations particularly at high levels of ASM activation.
Extrapolation of methacholine log-dose response curves with a Cumulative Gaussian Distribution function
Authors: JG Aerts, JM Bogaard, SE Overbeek, AF Verbraak, P Thio
Journal: European Respiratory Journal (1994)

Methacholine provocation tests are aimed at determining bronchial responsiveness. Recent investigations stress the importance of considering the entire log-dose response curve, yielding not only the provocative dose producing a 20% change in forced expiratory volume in one second (FEV1) (PC20), but also the plateau value and the steepest slope of the curve (reactivity). In three control subjects and seven patients with mild to moderate asthma, we have obtained methacholine log-dose response curves in which a plateau was reached. A new model, the Cumulative Gaussian Distribution (CGD) function was fitted to the whole curve. The upper part of the curve was also analysed with the Hofstee equation, which has been used in a number of other investigations and aimed at plateau estimation. The plateau values obtained by the fits were compared with the values actually measured (average response of last 3 points with a variation coefficient < 5% of the mean value) by using the coefficient of determination (R2) (Applied Statistics. Sachs). If all data points were considered, both fits yielded a plateau which slightly overestimated the measured plateau values. R2 for the CGD fit ranged from 0.93-0.99, indicating a highly significant correlation between actual and fitted data points. If the curves were truncated, such that the last four provocative doses were omitted from the analysis, the CGD fit still yielded plateau values; the mean difference from the measured plateaux, in % of the measured plateau values, was -2.6% (SD 18.2). In only three out of the 10 cases did the Hofstee equation yield plateau values with a deviation from 'measured' < 47% of the measured value.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of insulin on muscle glutamate uptake
Authors: T. T. Aoki, M. F. Brennan, W. A. Müller, F. D. Moore, G. F. Cahill
Journal: Journal of Clinical Investigation (1972)

For decades, investigators concerned with protein metabolism in man have performed detailed amino acid analyses of human plasma obtained under a wide range of experimental situations. A large body of information has been used to calculated rates of protein synthesis and proteolysis. During the course of an investigation of the effect of intrabrachial artery infusion of insulin (70 μU/min per kg body weight) on glutamate uptake by human forearm muscle, it was discovered that plasma arterio-deep venous glutamate difference analysis failed to document any increase in the uptake of this amino acid, suggesting that insulin had little influence on glutamate uptake by muscle. However, whole blood glutamate analyses, performed on the same blood samples, revealed that (a) the resting muscle uptake of glutamate is smaller than previously reported and (b) insulin is capable of markedly increasing glutamate uptake by muscle from whole blood. Since the hematocrit was obtained on all samples, detailed analyses of the various compartments in which glutamate could be found were performed. It was determined that circulating blood cells have a dynamic role in glutamate transport. These data underscore the need for both whole blood and plasma amino acid analysis in investigations concerned with protein synthesis and/or amino acid flux, for analysis of plasma samples alone could be misleading as illustrated in the present study.
Lung sound monitoring in real time operation mode in diagnosis of exercise-induced asthma
Authors: Elena Kolganova, Sergey Glotov
Journal: European Respiratory Journal (2011)

Introduction:  Exercise-induced asthma is an actual problem of pulmonology and sports medicine. It is important to watch lung sounds evolution on physical activity.   Objective:  Assessment lung sounds evolution and detection wheezes on physical activity.   Materials and methods:  Clinical trial was conducted on 13 patients with diagnosis of bronchial asthma. The sensor of the electronic stethoscope was connected with the radio transmitter and placed at the patient9s neck over the trachea. Lung sounds were monitored at the field testing. The investigators got a lung sounds by radio receiver and analyzed it by computer program in real time operation mode.   Results:  Wheezes were registered in 6 patients on physical activity. Wheezes appeared again on the 12-th minute after the end of the field testing in 2 patients. The following changes in the form of an acoustic pattern were observed in all patients: amplitude of an acoustic signal and frequency of respiratory cycles were increased, a respiratory cycle was shortened.   Conclusions:  The use of lung sound monitoring in real time operation mode makes it possible to assess lung sound evolution and to detect wheezes during the field testing.
Magnetopneumography: a general review
Authors: V Le Gros, D Lemaigre, C Suon, JP Pozzi, F Liot
Journal: European Respiratory Journal (1989)

Magnetopneumography is the study of the remanent magnetism of foreign intrathoracic ferromagnetic particles after magnetization by an external magnetic field. Given knowledge of the magnetic characteristics of the inhaled particles, this highly sensitive and non-invasive technique allows the measurement of lung dust loads. Many groups of workers have been examined in this way, e.g. welders, coalminers, asbestos, foundry and steel workers. Magnetopneumography also allows analysis of the distribution of aerocontaminants in the different anatomical structures and, when repeated, the study of clearance speeds and migration from site to site of such particles. Emphasis has been laid on the importance of study of the fading of the remanent magnetic signal as time elapses. This short-term phenomenon, called relaxation, seems highly significant for the study of the dynamic properties of the immediate environment of extra pulmonary particles and especially for the study of macrophage activity.
The Shape of Training report: misreported evidence, unpersuasive excuses
Authors: Richard Wakeford
Journal: BMJ (2015)

So the “independent” Shape of Training report1 is tainted by political shenanigans, unsuccessful resorting to lawyers,2 and unpersuasive excuses.3 To support a major thesis, it also misreports evidence it received.

A major recommendation is to register medical students a year earlier, based on information from the team’s site visits and from the Medical Schools Council. In its original evidence document (published in July 2013 but now removed from its website), the …
Decision analysis and screening for Down's syndrome
Authors: D. Murray, B. Tennison
Journal: BMJ (1995)

EDITOR,--J Fletcher and colleagues raise many important issues regarding the difficulties in making population policies for antenatal screening for Down's syndrome.1 Unlike in some previous studies, the authors give full attention to a wide range of outcome measures in their comparison of possible alternative policies rather than focusing simply on the number of cases of Down's syndrome detected. They also …
High-dose melphalan for multiple myeloma: long-term follow-up data.
Authors: D Cunningham, L Paz-Ares, M E Gore, J Malpas, T Hickish, M Nicolson, M Meldrum, C Viner, S Milan, P J Selby
Journal: Journal of Clinical Oncology (1994)

PURPOSE To present long-term follow-up data of patients with myeloma treated with high-dose melphalan HDM, including an assessment of prognostic factors. PATIENTS AND METHODS Between November 1981 and April 1986, 63 previously untreated patients with multiple myeloma received HDM 140 mg/m2 without autologous bone marrow transplantation. RESULTS The overall response rate was 82% (51 of 62), with 32% (20 of 62) patients entering complete remission (CR). The median duration of response was 18 months, and six patients remain alive and free from disease progression at 60+ to 84+ months. Improvements in quality of life associated with remission were immediate in terms of pain grade (89% of patients) and performance status (92%), and later in terms of bone healing (29%). Currently, at a median follow-up duration of 74 months (range, 63 to 100) since HDM, 23 patients are alive with a median survival duration of 47 months, and 35% of patients are expected to be alive at 9 years. Apart from early-stage disease, no factors were found to predict long-term survival. No second malignancies or other late side effects have been recorded. CONCLUSION Single-agent HDM without autologous bone marrow transplantation is a feasible therapeutic option in myeloma, and is associated with a high objective response rate, relatively long remission durations, and good symptom control.
Long-Term Cardiac Sequelae in Operable Breast Cancer Patients Given Adjuvant Chemotherapy With or Without Doxorubicin and Breast Irradiation
Authors: Milvia Zambetti, Angela Moliterni, Carlo Materazzo, Marco Stefanelli, Sonia Cipriani, Pinuccia Valagussa, Gianni Bonadonna, Luca Gianni
Journal: Journal of Clinical Oncology (2001)

To investigate long-term cardiac sequelae associated with anthracycline use in adjuvant chemotherapy of patients with early breast cancer.All 1,000 patients from three prospective trials of adjuvant chemotherapy containing doxorubicin (n = 637, median total dose of 294 mg/m(2)) or not containing the anthracycline (cyclophosphamide, methotrexate, and fluorouracil [CMF] regimen alone, n = 363) were analyzed for the relative incidence of congestive heart failure (CHF) and myocardial infarction (MI) during 14 years of follow-up. The 462 women continuously free of disease as of February 1996 were recalled, and 355 consented to undergo evaluation including 12-lead ECG and cardiac ultrasound with determination of left ventricular ejection fraction (LVEF) to assess the relative incidence of abnormalities in long-term survivors.Among the 1,000 patients, there were six cases of CHF and three cases of MI. Cumulative cardiac mortality accounted for 0.4% (doxorubicin-treated = 0.6%; CMF-treated = 0). Eighteen (5%) of the 355 patients undergoing cardiac evaluation after median 11 years of follow-up presented systolic dysfunction as defined by pathologic (< 50%, n = 8) or borderline (50% to 55%, n = 10) LVEF. Systolic dysfunction was higher in doxorubicin-treated (15 of 192; 8%) than in CMF-treated patients (three of 150; 2%). Breast irradiation had a significant impact on the occurrence of early CHF (four of 116; 3%), but not on systolic dysfunctions.At longer than 10 years of follow-up, the use of doxorubicin at a total dose commonly applied in regimens of adjuvant chemotherapy does not lead to cardiac clinical sequelae that counter-balance the benefit of treatment in patients with operable breast cancer who may be cured of their disease.