tbuckley/cabot-search huggingface dataset:
Prolonged mechanical ventilation in humans impairs diaphragm muscle fiber contractility and reduces myofilament protein expression
Authors: Celine Guichon, Auday Al Khunaizi, Felipe de Souza, Annabelle Cornachione, Mahroo Mofarrahi, Peter Goldberg, Dilson Rassier, Sabah Hussain
Journal: European Respiratory Journal (2014)

In this study, we assessed diaphragm myofilament contractility and myofilament protein levels in humans undergoing prolonged MV. Diaphragm biopsies were obtained from 10 control subjects and 8 brain-dead organ donors. MV durations for the two groups averaged 1.1 and 49.3 hours, respectively. Specific active and passive forces produced by diaphragm myofibrils were measured with atomic force cantilevers. Rate of force development (Kact), the rate of force re-development after a shortening-stretching protocol (Ktr), and the rate of relaxation (Krel) in fully activated myofibrils were also assessed. Protein levels of myosin, troponin I, T, and C, tropomyosin and sarcomeric actin were measured with SDS immunoblotting. Titin and nebulin protein levels were measured with agarose electrophoresis. Prolonged MV was associated with significant decline in active and passive forces produced by diaphragm myofibrils. The decrease in active force was accompanied by a decrease in the Kact, Ktr and Krel, suggesting an impairment of myosin cross-bridge kinetics. Prolonged MV significantly reduced troponin T and tropomyosin protein levels. Titin levels declined in three diaphragm samples obtained from brain-dead organ donors. Nebulin protein levels were similar to control subjects. We conclude that prolonged MV in humans triggers significant impairment of diaphragm myofilament contractility and this dysfunction is mediated through impaired myosin-actin interactions. The mechanisms behind this impairment remain unclear but we propose that it may be due to selective degradation of myofilament proteins including troponin T and tropomyosin that regulate this interaction.
Efficacy and safety of bevacizumab (BEV) plus chemotherapy in Chinese patients (pts) with metastatic colorectal cancer (mCRC): Results from the ARTIST study.
Authors: Z. Guan, J. Xu, R. Luo, F. Feng, L. Wang, L. Shen, S. Yu, Y. Ba, J. Liang, D. Wang
Journal: Journal of Clinical Oncology (2010)

e14002 Background: BEV inhibits tumor angiogenesis by targeting vascular endothelial growth factor (VEGF). This randomized open-label multicenter study (ARTIST) evaluated the efficacy and safety of BEV in combination with modified IFL (mIFL) as first-line treatment for Chinese pts with mCRC. Methods: Pts >18 years with histologically confirmed, previously untreated, measurable mCRC and ECOG PS 0 or 1 were randomized 2:1 to BEV + mIFL or mIFL alone until disease progression, death, or unacceptable toxicities. mIFL (irinotecan 125 mg/m2, leucovorin 20 mg/m2 bolus, and 5-FU 500 mg/m2) was given weekly for 4 weeks every 6 weeks. BEV 5 mg/kg was given on Day 1 with chemotherapy, then every 2 weeks. Primary objectives were progression-free survival (PFS) and 6-month PFS rate; secondary objectives included overall survival (OS), overall response rate (ORR), response duration, and safety. Results: Between Jul 07 and Aug 08, 214 pts were enrolled at 12 centers in China (203 pts evaluable); final analysis was performed 10 months after the last pt was enrolled. Pt characteristics were balanced between arms. Addition of BEV to chemotherapy significantly improved PFS, 6-month PFS, OS, and ORR (table); risk of disease progression or death was reduced by 56% and risk of death by 38%. BEV plus mIFL was well tolerated; no grade 4/5 adverse events (AEs) of special interest, wound-healing complications, or episodes of congestive heart failure were reported (for grade 3 AEs see Table). Conclusions: The ARTIST study has shown that BEV plus mIFL is effective and well tolerated as first-line therapy for mCRC. The clinical benefit and safety profiles of BEV in Chinese pts are consistent with those observed in pivotal phase III multinational studies. Outcome (95% CI) BEV + mIFL mIFL p value Efficacy Evaluable patients 139 64 6-month PFS, % 62.6 (54.5–70.6) 25.0 (14.4–35.6) p<0.001 Median PFS, months 8.3 (7.4–8.9) 4.2 (3.7–4.9) p<0.001 HR=0.44 (0.31–0.63) Median OS, months 18.7 (15.8–19.6) 13.4 (9.7–17.2) p=0.014 HR=0.62 (0.41–0.95) ORR, % 35.3 (27.5–43.5) 17.2 (8.4–27.7) p=0.013 Safety Evaluable patients 141 70 Grade 3 hypertension, % 3.5 0 Grade 3 bleeding, % 0.7 1.4 Grade 3 GI perforation, % 0.7 0 No significant financial relationships to disclose.
Denial of memory deficit in Alzheimer's disease
Authors: S Sevush, N Leve
Journal: American Journal of Psychiatry (1993)

Patients with probable Alzheimer's disease often deny or underestimate the severity of their memory impairment. The authors examined the relationships between denial and severity of cognitive impairment and between denial and the presence of depressed mood and sad affect in 128 patients with probable Alzheimer's disease.Denial of memory deficit was evaluated by structured interview. Cognition was evaluated with a quantitative examination that assessed performance on 16 subtests. Depression was rated by using a scale that included patients' self-ratings as well as caregivers' and examiners' assessments of the patient's mood and affect. Pearson correlation coefficients were used to quantify the relationship between denial and demographic, cognitive, and depression variables. Stepwise multiple regression analysis was used to further examine the relationship between denial and individual cognitive subset scores.Denial did not correlate with age at onset of Alzheimer's disease, duration of illness, or educational background. It did correlate with gender: women exhibited greater denial than men. A significant correlation was found between denial and overall severity of cognitive deficit and particularly with impairment in object naming. A negative correlation was found between denial and depression.The association between denial and cognitive impairment may suggest that denial of probable Alzheimer's disease results from disruption of cognitive abilities needed for awareness of illness. The negative association between denial and depression may suggest that depression in Alzheimer's disease is in part reactive in nature.
Bedaquiline: finding the pores on the pot
Authors: Prasanta Raghab Mohapatra
Journal: European Respiratory Journal (2015)

Salfinger and Migliori [1] discussed some important issues of bedaquiline, the most promising drug for treating multidrug-resistant (MDR) tuberculosis (TB) in the early twenty-first century. I am afraid of some issues that could be detrimental to the future of TB control. Bedaquiline should be used with caution, bacause of some methodological flaws in a few of the published landmark studies. In one study, Diacon et al. [2], the authors, without doing drug-sensitivity testing on isoniazid and rifampicin (criteria of MDR-TB), firmly concluded the effectiveness of their new regimen on MDR-TB patients. By using a regimen containing bedaquiline for susceptible patients to the tested drug does not predict bedaquiline's effectiveness in MDR-TB patients, as the pharmacokinetics and probability of pharmacodynamic target attainment (area under the time curve minimum inhibitory concentration ratio) are likely to be altered in MDR patients [3]. We need a better drug to control drug resistant tuberculosis (MDR TB) <http://ow.ly/MTcSu>
Imaging the dynamic platelet‐neutrophil response in sterile liver injury and repair in mice
Authors: Ingrid Slaba, Jing Wang, Elzbieta Kolaczkowska, Braedon McDonald, Woo‐Yong Lee, Paul Kubes
Journal: Hepatology (2015)

Although platelets have been extensively studied in hemostasis and inflammation, their role is not well understood in sterile liver injury and repair. Using a thermally induced focal liver injury and repair model and multichannel spinning disk confocal microscopy allowed visualization of the dynamic behavior of platelets and neutrophils in this insult. Platelets instantaneously adhered to molecularly altered sinusoidal endothelium adjacent to the afflicted area, paving approximately 200 µm abutting the injury. Platelets remained adherent for at least 4 hours, but dissipated by 8 hours. The early recruitment occurred by GPIIbIIIa (CD41) and the later recruitment was dependent upon both GPIIbIIIa and GPIb (CD42B). Platelets did not occlude the vessels, but rather paved the altered endothelium. Endothelin‐induced vasoconstriction by hepatic stellate cells, and not platelet accumulation or coagulation, was responsible for temporarily restricted perfusion around the injury. Neutrophils crawled into the injury from significant distances through the sinusoids. The crawling neutrophils required the platelet‐paved endothelium given that very little neutrophil recruitment was noted in thrombocytopenic or CD41‐deficient mice. As platelets slowly dissipated, neutrophil recruitment was also halted. Previous work suggested that platelets binding to immobilized neutrophils induced neutrophil extracellular trap (NET) formation in response to infection as well as during thrombosis and other forms of sterile injury. In this model of neutrophils crawling on immobilized platelets, very few NETs were observed and no additional injury was noted. In fact, GPIIbIIIa‐deficient mice had delayed repair. Conclusion : In a liver model of sterile injury and repair, platelets play a critical role in forming a substratum and pave the way for neutrophils to enter the injured site for subsequent repair. (H epatology 2015;62:1593–1605)
Bortezomib-based therapy combined with high cut-off hemodialysis is highly effective in newly diagnosed multiple myeloma patients with severe renal impairment
Authors: Beatrice Anna Zannetti, Elena Zamagni, Marisa Santostefano, Lucia Barbara De Sanctis, Paola Tacchetti, Elena Mancini, Lucia Pantani, Annamaria Brioli, Raffaella Rizzo, Katia Mancuso, Serena Rocchi, Annalisa Pezzi, Enrica Borsi, Carolina Terragna, Giulia Marzocchi, Antonio Santoro, Michele Cavo
Journal: American Journal of Hematology (2015)

Multiple myeloma (MM) is often associated with renal insufficiency (RI) which adversely influences the prognosis. Several studies demonstrated that bortezomib can improve both renal function and outcome. We prospectively evaluated 21 newly diagnosed MM patients with severe renal impairment secondary to tubular-interstitial damage, most of them due to myeloma kidney, who were primarily treated with bortezomib-based therapy combined with high cut-off hemodialysis (HCOD). The median serum creatinine level at baseline was 6.44 mg dL(-1) and calculated median estimated glomerular filtration rate (eGFR), according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, was 8 mL/min/1.73 m(2) . Serum free light chain (sFLC) median concentration was 6,040 mg L(-1) . Post induction and best stringent complete response rates were 19 and 38%, respectively. Responses were fast, occurring within a median of 1.4 months. The combination of bortezomib and HCOD led to a prompt and remarkable (>90%) decrease in sFLC levels. Sixteen patients (76%) became dialysis independent within a median of 32 days. With a median follow up of 17.2 months, the 3-year PFS and OS were 76 and 67%, respectively. No early deaths were observed. This study demonstrates that incorporation of bortezomib into induction therapy combined with HCOD is a highly effective strategy in rescuing renal function and improving outcomes in patients with MM and RI.
Current status of pig heart xenotransplantation
Authors: Muhammad M. Mohiuddin, Bruno Reichart, Guerard W. Byrne, Christopher G.A. McGregor
Journal: International Journal of Surgery (2015)

Significant progress in understanding and overcoming cardiac xenograft rejection using a clinically relevant large animal pig-to-baboon model has accelerated in recent years. This advancement is based on improved immune suppression, which attained more effective regulation of B lymphocytes and possibly newer donor genetics. These improvements have enhanced heterotopic cardiac xenograft survival from a few weeks to over 2 years, achieved intrathoracic heterotopic cardiac xenograft survival of 50 days and orthotopic survival of 57 days. This encouraging progress has rekindled interest in xenotransplantation research and refocused efforts on preclinical orthotopic cardiac xenotransplantation.
Effect of cromolyn inhaler on resistant neutrophilic cough variant of asthma, A phase two clinical trial
Authors: Majid Mirsadraei, Zahra Sabbagh Sajadieh, Saeedeh Sabbagh Sajadieh
Journal: European Respiratory Journal (2014)

Introduction: Cromolyn inhaler was used to treat mild asthma but its usage was decreased with introduction of inhaled corticosteroids (ICS) and antileukotriens. Aim of this study was to evaluate the effectiveness of cromolyn in subjects whom resistant to ICS and antileukotriens and determine the proposed mechanism of action.  Materials and methods:Three hudered subjects suffered from cough variant of asthma were treated with ICS, antileukotriens, proton pomp inhibitors and nasal corticosteroids in four stages by step by step approach. Sixty eight subjects whom were not responded to treatment with drugs mentioned above after four two months were enrolled in this phase two clinical trial. All subjects signed the informed consent. The study was accepted in our local ethical committee.  Methods: The subjects were randomly divided in to two groups including case group treated with Cromolyn MDI inhaler and placebo. The physician and pharmacist were blind to the type of treatment. Clinical findings, spirometry, Exhaled Nitric Oxide (FENO), asthma control test (ACT) and sputum cytology obtained by sputum induction were the main variables evaluated before and after the trial.  Results: Cough, dyspnea and sputum were decreased significantly and ACT score was increased significantly in Cromolyn compared to placebo group. Spirometry parameters were not changed significantly. FENO was decreased in cromolyn group with significant difference with placebo group. Neutrophile was the most frequent inflammatory cell and it was significantly decreased in Cromolyn group.  Conclusion: Cromolyn showed promising result in resistant cough variant of asthma especialy in the neutrphilic asthma.
Abstract 12: Direct Mechanical Ventricular Actuation Significantly Augments Left Ventricular Function in Failing Rabbit Heart Model
Authors: Subbaraju Budharaju, Anthony J Pothoulakis, Scott A Kerns, Benjamin Schmitt, Rebecca J Darner, Lawrence J Prochaska, Peer M Portner, Mark P Anstadt
Journal: Circulation (2008)

Introduction: Direct Mechanical Ventricular Actuation (DMVA) is a unique non-blood contacting cardiac support device that augments ventricular function during both systole and diastole. The purpose...
Abstract MP08: Cardiovascular Health and Incident Cardiovascular Disease and Cancer
Authors: Randi Foraker, Mahmoud Abdel-Rasoul, Lewis Kuller, Rebecca Jackson, Linda Van Horn, Rebecca Seguin, Monika Safford, Robert Wallace, Anna Kucharska-Newton, Jennifer Robinson, Lisa Martin, Golareh Agha, Lifang Hou, Norrina Allen, Hilary Tindle
Journal: Circulation (2013)

Cardiovascular disease (CVD) and cancer are leading causes of morbidity and mortality. A favorable risk factor and behavior profile, reflected by a metric of cardiovascular health (CV health) recently introduced by the AHA, predict a lower risk of CVD in younger populations, yet has not been well-characterized in older adults. Achieving ideal CV health may also lower cancer risk, since cancer and CVD share common risk factors. We used multivariable Cox regression to estimate hazard ratios (HR) for the association between CV health and incident CVD and cancer, respectively, among Women’s Health Initiative (WHI) participants. We characterized CV health as the number [0 (worst) - 7 (best)] of ideal CV health behaviors and factors at baseline: 1) never smoking, or quit for &gt;1 yr; 2) body mass index &lt;25 kg/m 2 ; 3) physical activity of ≥150 min/wk moderate, ≥75 min/wk vigorous, or ≥150 min/wk moderate and vigorous; 4) at least 4 of 5 healthy diet components (≥4.5 cups/day of fruits and vegetables; ≥3.5 oz servings/wk of fish; ≥3 1-oz servings/day of whole grains; &lt;1,500 mg/day of sodium; and ≤36 oz/wk of sugar-sweetened beverages); 5) total cholesterol (untreated) &lt;200 mg/dL; 6; blood pressure (untreated) &lt;120 mmHg / &lt;80 mmHg; and 7) fasting glucose (untreated) &lt;100 mg/dL. Approximately 300 women (&lt;1%) had a CV health score of 7 (best) in both CVD- and cancer-free groups at baseline. Among 115,302 women free of CVD at baseline, the hazard of CVD was inversely related to CV health (Figure 1a), controlling for age, race/ethnicity, family history, marital status, and education. Among 129,145 women free of cancer at baseline (Figure 1b), we observed a similar pattern, controlling for the same factors, although HRs were of smaller magnitude. Lower CV health is associated with an increased risk of CVD and cancer in older post-menopausal women, emphasizing the importance of prevention efforts among older adults. Figure 1. HRs and 95% CIs for (a) incident CVD and (b) incident cancer by ideal CV health score: WHI observational study participants
Anaphylaxis: past, present and future
Authors: M. Ben-Shoshan, A. E. Clarke
Journal: Allergy (2010)

Anaphylaxis is a clinical emergency, and recent reports suggest increased prevalence. A diverse set of primary genetic and environmental influences may confer susceptibility to anaphylactic reactions. Anaphylaxis presents diagnostic and therapeutic challenges. It often manifests with a broad array of symptoms and signs that might be similar to other diseases. The management of anaphylaxis consists of emergency treatment of acute episodes as well as preventive strategies to avoid recurrences. Treatment is complicated by its rapid onset and progression, presence of concurrent diseases or medications, and need for long-term allergen avoidance. Health care professionals must be able to recognize the signs of anaphylaxis, treat an episode promptly and appropriately, and provide preventive recommendations. Recognizing the gaps in our understanding and management of anaphylaxis may help identify promising targets for future treatment and prevention and areas that require further study.
Abstract 5275: Kruppel-Like Factor 15 Regulates the Cardiovascular Response to Angiotensin II
Authors: Saptarsi M Haldar, Yuan Lu, Yingjie Cui, Darwin Jeyaraj, Osama A Ibrahim, Manjusri Das, Caili Hao, Sam J Eapen, Daiji Kawanami, Yong Qiu Doughman, Michiko Watanabe, Junichi Sadoshima, Mukesh K Jain
Journal: Circulation (2008)

Background : Angiotensin II (A-II) causes pathologic remodeling of the heart and vasculature through gene-regulatory pathways that are incompletely understood. We and others have identified Kruppel-Like Factor 15 (KLF15) as a transcription factor that may exert beneficial effects in the cardiovascular system, however, its role in A-II signaling remains unknown. We hypothesize that KLF15 can modulate the deleterious effects of A-II on the heart and blood vessel. Methods and Results : A-II downregulates KLF15 expression in heart and vascular tissues in vitro and in vivo . Mice with systemic KLF15 deficiency (male, age 10 wks) have baseline abnormalities of the heart (increased cardiac mass, LV thickness, fetal gene expression) and vasculature (thickened aortic media with elastin breakdown). In response to chronic A-II infusion (1.4 mg/kg/D x 14D), KLF15 KO mice develop severe degenerative changes in both the heart and vessel compared to wild-type controls. In the heart, KLF15 KO mice develop pronounced heart failure characterized by augmented cardiac mass, eccentric LV remodeling, profound LV systolic dysfunction, increased fibrosis, enhanced fetal gene expression and apoptotic cell loss. Dramatic degenerative changes also occur in the aorta of KLF15 KO mice including medial destruction with elastin degradation, outward remodeling with vessel dilation, augmented inflammatory gene expression, and foci of severe smooth muscle apoptosis. Mechanistically, there is exaggerated accumulation of p53 and its direct pro-apoptotic targets in the heart (Bax) and aorta (Bax, p21) of KLF15 KO mice. As p53-mediated degradation of HIF1α has been implicated in cardiac decompensation, we show that KLF15 KO hearts have decreased HIF1α levels and fail to mount an angiogenic response to A-II. Finally, we provide evidence that KLF15 can directly inhibit p53 protein accumulation in a proteasome-dependent manner. Conclusion : KLF15 deficiency renders the cardiovascular system exquisitely sensitive to A-II stimulation and leads to degenerative remodeling of the heart and blood vessel with exaggerated p53 accumulation in these tissues. These findings suggest that manipulation of KLF15 function may provide novel approaches to inhibit the pathologic effects of A-II.
Awareness of negative social conditions among mentally retarded, emotionally disturbed outpatients
Authors: Steven Reiss, Betsey A. Benson
Journal: American Journal of Psychiatry (1984)

Many mentally retarded people experience negative social conditions for long periods in their lives. These include the stigmatizing effects of being labeled mentally retarded, rejection and ridicule, segregation, infantilization, social disruption, restricted opportunities, and victimization. Many mildly and some moderately retarded people are highly aware of these negative social realities and can articulate them in detail during psychotherapy interviews; the authors describe three such patients. There is a need for research on the possible effect of prolonged exposure to negative social conditions on the mental health of mentally retarded persons.
Peripheral neuropathy in chronic obstructive pulmonary disease
Authors: Walid Feki, Wajdi Ketata, Ines Hammami, Najla Bahloul, Wajdi Karim Rekik, Hajer Ayadi, Samy Kammoun
Journal: European Respiratory Journal (2014)

Introduction 

Chronic obstructive pulmonary disease (COPD) is currently regarded as a general disease with pulmonary starting point. Extra-thoracic manifestations are associated with the disease such as cachexia, skeletal muscle dysfonctionnment, cardiovascular diseases, osteoporosis and anemia. Very few studies have focused on evaluating the frequency of peripheral neuropathy in patients with COPD.

Methods 

Eighty subjects were included in the study. The COPD group comprised 40 male smokers with stable disease and 40 age-matched healthy, non smokers, male volunteers served as the control group. All subjects underwent pulmonary function testing and electroneuromyography. Individual patients in the COPD group having abnormal amplitude and/or conduction velocity in any one or more nerves beyond the range of mean ± 2 standard deviations were selected as having the significant peripheral neuropathy.

Results: Seven out of 40 COPD patients had peripheral nerve impairment on electrophysiological evaluation. In these patients, only one patient reported sensory symptoms of tingling kind to members. Peripheral neuropathy was often sensitive and predominated in the lower members. Its occurrence is correlated with the degree of smoking intoxication, the length of COPD and the depth of hypoxemia.

Conclusion 

Peripheral neuropathy is frequent in COPD patients and it is often subclinical.
Abstract 3964: GlObal Secondary Prevention StrategiEs to Limit Event Recurrence After Myocardial Infarction: The GOSPEL Study. A trial from the Italian Cardiac Rehabilitation Network: Final Results
Authors: Pantaleo Giannuzzi, Pier Luigi Temporelli, Aldo Maggioni, Vincenzo Ceci, Carmine Chieffo, Marinella Gattone, Raffaele Griffo, Roberto Marchioli, Carlo Schweiger, Luigi Tavazzi, Stefano Urbinati, Franco Valagussa, Diego Vanuzzo
Journal: Circulation (2006)

Cardiac rehabilitation programs (CRPs) are a proven treatment for pts with recent myocardial infarction (MI), resulting in reduced morbidity and mortality. However, following completion of a CRP, r...