tbuckley/cabot-search huggingface dataset:
Proximal muscle rehabilitation is effective for patellofemoral pain: a systematic review with meta-analysis
Authors: Simon Lack, Christian Barton, Oliver Sohan, Kay Crossley, Dylan Morrissey
Journal: British Journal of Sports Medicine (2015)

Background Proximal muscle rehabilitation is commonly prescribed to address muscle strength and function deficits in individuals with patellofemoral pain (PFP). This review (1) evaluates the efficacy of proximal musculature rehabilitation for patients with PFP; (2) compares the efficacy of various rehabilitation protocols; and (3) identifies potential biomechanical mechanisms of effect in order to optimise outcomes from proximal rehabilitation in this problematic patient group. Methods Web of Knowledge, CINAHL, EMBASE and Medline databases were searched in December 2014 for randomised clinical trials and cohort studies evaluating proximal rehabilitation for PFP. Quality assessment was performed by two independent reviewers. Effect size calculations using standard mean differences and 95% CIs were calculated for each comparison. Results 14 studies were identified, seven of high quality. Strong evidence indicated proximal combined with quadriceps rehabilitation decreased pain and improved function in the short term, with moderate evidence for medium-term outcomes. Moderate evidence indicated that proximal when compared with quadriceps rehabilitation decreased pain in the short-term and medium-term, and improved function in the medium term. Limited evidence indicated proximal combined with quadriceps rehabilitation decreased pain more than quadriceps rehabilitation in the long term. Very limited short-term mechanistic evidence indicated proximal rehabilitation compared with no intervention decreased pain, improved function, increased isometric hip strength and decreased knee valgum variability while running. Conclusions A robust body of work shows proximal rehabilitation for PFP should be included in conservative management. Importantly, greater pain reduction and improved function at 1 year highlight the long-term value of proximal combined with quadriceps rehabilitation for PFP.
Inhibition of sympathetic neurotransmission in canine blood vessels by adenosine and adenine nucleotides.
Authors: R H Verhaeghe, P M Vanhoutte, J T Shepherd
Journal: Circulation Research (1977)

Adenosine and the adenine nucleotides caused a greater relaxation of strips of canine saphenous vein and tibial artery when they had been contracted by nerve stimulation than by exogenous norepinephrine. An infusion of adenosine into the dogs' lateral saphenous vein, perfused at constant flow, caused a greater relaxation of this vein when constricted by electrical stimulation of the lumbar sympathetic chain than by exogenous norepinephrine. That this difference was due to inhibition by these compounds of the output of neurotransmitter from the sympathetic nerve endings was demonstrated by column chromatographic analysis of the radioactivity in the superfusion fluid of vein strips, previously incubated with tritiated norepinephrine. Both adenosine and adenosine triphosphate (10(-5) M) reduced the efflux of 3H-norepinephrine during nerve stimulation with electrical impulses. Adenosine also reduced the efflux caused by potassium (30 mM), but not that caused by tyramine (6 X 10(-6) M). Theophylline antagonized the inhibitory effect of adenosine on the sympathetic neurotransmission. We found that at 4 X 10(-4) M adenosine triphosphate still caused a decreased efflux of neurotransmitter during electrical stimulation, but with adenosine the 3H-norepinephrine efflux no longer decreased and the overflow of deaminated compounds increased. Furthermore, the same concentration of adenosine increased the efflux of 3H-norepinephrine and deaminated compounds in unstimulated strips, and the increase of 3H-norepinephrine was enhanced after monoamine oxidase inhibition. Thus, we conclude that at higher concentrations adenosine increases the intraneuronal leakage of norepinephrine out of the storage vesicles.
Second-Line Chemotherapy With Irinotecan Plus Carmustine in Glioblastoma Recurrent or Progressive After First-Line Temozolomide Chemotherapy: A Phase II Study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)
Authors: Alba A. Brandes, Alicia Tosoni, Umberto Basso, Michele Reni, Francesco Valduga, Silvio Monfardini, Pietro Amistà, Linda Nicolardi, Guido Sotti, Mario Ermani
Journal: Journal of Clinical Oncology (2004)

Glioblastoma multiforme (GBM), the most frequent brain tumor in adults, is not considered chemosensitive. Nevertheless, there is widespread use of first-line chemotherapy, often with temozolomide, as a therapeutic option in patients with progressive disease after surgery and radiotherapy. However, at the time of second recurrence and/or progression, active and noncross-resistant chemotherapy regimens are required. The aim of the present multicenter phase II trial, therefore, was to ascertain the efficacy of second-line carmustine (BCNU) and irinotecan chemotherapy.Patients with histologically confirmed GBM, recurring or progressing after surgery, standard radiotherapy and a first-line temozolomide-based chemotherapy, were considered eligible. The primary end-point was progression-free survival at 6 months (PFS-6), and secondary end-points included response rate, toxicity, and survival. All patients were on enzyme-inducing antiepileptic prophylaxis. Chemotherapy consisted of BCNU (100 mg/m2 on day 1) plus irinotecan (175 mg/m2/weekly for 4 weeks), every 6 weeks, for a maximum of eight cycles. In the absence of grade 2 toxicity, the irinotecan dose was increased to 200 mg/m2.A total of 42 patients (median age, 53.4 years; median Karnofsky performance status, 80; range, 60 to 90) were included in the study. PFS-6 was 30.3% (95% CI, 18.5% to 49.7%). Median time to progression was 17 weeks (95% CI, 11.9 to 23.9). Nine partial responses (21.4%; 95% CI, 9% to 34%) were obtained. Toxicity was manageable.The BCNU plus irinotecan regimen seems active and non-cross-resistant in patients with GBM with recurrence after temozolomide-based chemotherapy.
Fluid Shear Stress Activates Ca <sup>2+</sup> Influx Into Human Endothelial Cells via P2X4 Purinoceptors
Authors: Kimiko Yamamoto, Risa Korenaga, Akira Kamiya, Joji Ando
Journal: Circulation Research (2000)

Abstract —Ca 2+ signaling plays an important role in endothelial cell (EC) responses to shear stress generated by blood flow. Our previous studies demonstrated that bovine fetal aortic ECs showed a shear stress–dependent Ca 2+ influx when exposed to flow in the presence of extracellular ATP. However, the molecular mechanisms of this process, including the ion channels responsible for the Ca 2+ response, have not been clarified. Here, we demonstrate that P2X4 purinoceptors, a subtype of ATP-operated cation channels, are involved in the shear stress–mediated Ca 2+ influx. Human umbilical vein ECs loaded with the Ca 2+ indicator Indo-1/AM were exposed to laminar flow of Hanks’ balanced salt solution at various concentrations of ATP, and changes in [Ca 2+ ] i were monitored with confocal laser scanning microscopy. A stepwise increase in shear stress elicited a corresponding stepwise increase in [Ca 2+ ] i at 250 nmol/L ATP. The shear stress–dependent increase in [Ca 2+ ] i was not affected by phospholipase C inhibitor (U-73122) but disappeared after the chelation of extracellular Ca 2+ with EGTA, indicating that the Ca 2+ increase was due to Ca 2+ influx. Antisense oligonucleotides designed to knockout P2X4 expression abolished the shear stress–dependent Ca 2+ influx seen at 250 nmol/L ATP in human umbilical vein ECs. Human embryonic kidney 293 cells showed no Ca 2+ response to flow at 2 μmol/L ATP, but when transfected with P2X4 cDNA, they began to express P2X4 purinoceptors and to show shear stress–dependent Ca 2+ influx. P2X4 purinoceptors may have a “shear-transducer” property through which shear stress is perceived directly or indirectly and transmitted into the cell interior via Ca 2+ signaling.
Changes in brain morphology in patients with obstructive sleep apnoea
Authors: M. J. Morrell, M. L. Jackson, G. L. Twigg, R. Ghiassi, D. W. McRobbie, R. A. Quest, H. Pardoe, G. S. Pell, D. F. Abbott, P. D. Rochford, G. D. Jackson, R. J. Pierce, F. J. O'Donoghue, D. R. Corfield
Journal: Thorax (2010)

<h3>Background</h3> Obstructive sleep apnoea (OSA) is a common disease that leads to daytime sleepiness and cognitive impairment. Attempts to investigate changes in brain morphology that may underlie these impairments have led to conflicting conclusions. This study was undertaken to aim to resolve this confusion, and determine whether OSA is associated with changes in brain morphology in a large group of patients with OSA, using improved voxel-based morphometry analysis, an automated unbiased method of detecting local changes in brain structure. <h3>Methods</h3> 60 patients with OSA (mean apnoea hypopnoea index 55 (95% CI 48 to 62) events/h, 3 women) and 60 non-apnoeic controls (mean apnoea hypopnoea index 4 (95% CI 3 to 5) events/h, 5 women) were studied. Subjects were imaged using T1-weighted 3-D structural MRI (69 subjects at 1.5 T, 51 subjects at 3 T). Differences in grey matter were investigated in the two groups, controlling for age, sex, site and intracranial volume. Dedicated cerebellar analysis was performed on a subset of 108 scans using a spatially unbiased infratentorial template. <h3>Results</h3> Patients with OSA had a reduction in grey matter volume in the right middle temporal gyrus compared with non-apnoeic controls (p&lt;0.05, corrected for topological false discovery rate across the entire brain). A reduction in grey matter was also seen within the cerebellum, maximal in the left lobe VIIIb close to XI, extending across the midline into the right lobe. <h3>Conclusion</h3> These data show that OSA is associated with focal loss of grey matter that could contribute to cognitive decline. Specifically, lesions in the cerebellum may result in both motor dysfunction and working memory deficits, with downstream negative consequences on tasks such as driving.
Tadalafil Therapy for Pulmonary Arterial Hypertension
Authors: Nazzareno Galiè, Bruce H. Brundage, Hossein A. Ghofrani, Ronald J. Oudiz, Gerald Simonneau, Zeenat Safdar, Shelley Shapiro, R. James White, Melanie Chan, Anthony Beardsworth, Lyn Frumkin, Robyn J. Barst
Journal: Circulation (2009)

Background— Treatment options for pulmonary arterial hypertension target the prostacyclin, endothelin, or nitric oxide pathways. Tadalafil, a phosphodiesterase type-5 inhibitor, increases cGMP, the final mediator in the nitric oxide pathway. Methods and Results— In this 16-week, double-blind, placebo-controlled study, 405 patients with pulmonary arterial hypertension (idiopathic or associated), either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan, were randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily. The primary end point was the change from baseline to week 16 in the distance walked in 6 minutes. Changes in World Health Organization functional class, clinical worsening, and health-related quality of life were also assessed. Patients completing the 16-week study could enter a long-term extension study. Tadalafil increased the distance walked in 6 minutes in a dose-dependent manner; only the 40-mg dose met the prespecified level of statistical significance ( P &lt;0.01). Overall, the mean placebo-corrected treatment effect was 33 m (95% confidence interval, 15 to 50 m). In the bosentan-naive group, the treatment effect was 44 m (95% confidence interval, 20 to 69 m) compared with 23 m (95% confidence interval, −2 to 48 m) in patients on background bosentan therapy. Tadalafil 40 mg improved the time to clinical worsening ( P =0.041), incidence of clinical worsening (68% relative risk reduction; P =0.038), and health-related quality of life. The changes in World Health Organization functional class were not statistically significant. The most common treatment-related adverse events reported with tadalafil were headache, myalgia, and flushing. Conclusions— In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening.
Clinical and Histopathologic Predictors of Survival in Patients With Malignant Melanoma: a Population-Based Study in Sweden
Authors: M. Thorn, F. Ponte, R. Bergstrom, P. Sparen, H.-O. Adami
Journal: JNCI Journal of the National Cancer Institute (1994)

Previous malignant melanoma studies regarding prognostic factors have often selected their patients from hospitals. Unfortunately, most of these studies have had small numbers of patients, consisted of short-term data sets, omitted important factors, did not optimize histopathologic classification, had too short or inadequate follow-up, and did not test their predictive models.Our study goals were to identify independent clinical and histopathologic determinants of survival in malignant melanoma, to analyze changes in prognostic value over follow-up time, and, finally to construct a prognostic index.A random sample from the Swedish Cancer Registry of the records of 498 (246 men and 252 women) patients defined by gender, five 5-year time periods of diagnosis from 1960 through 1984, and five anatomic sites formed the cohort on whom data were analyzed by univariate analyses. Multivariate analyses were based on data on 476 patients with complete information about all variables. All patients in the cohort had complete follow-up through December 31, 1989. Clinical information was abstracted and recorded as: date of diagnosis, stage at diagnosis, sex, age, anatomic site of primary tumor, date of death, and cause of death. Histopathologic slides were re-examined and classified with regard to histogenetic type, level of invasion, tumor thickness, ulceration, vascular invasion, regression, lymphocytic reaction, pre-existing nevus, and cell type.All variables, except pre-existing nevus and cell type, were significant predictors of survival. In the multivariate analyses including all variables, women still had a significant, 33% lower relative hazard than men. The prognosis was poor in the youngest age group. Patients with external ear, scalp-neck, and trunk-located melanoma had increasing relative hazard when all variables were included. Regional metastases and tumor thickness remained independent prognostic factors. No significant association between histogenetic type or level of invasion persisted. Patients whose tumors showed ulceration or vascular invasion had lower relative hazard when all variables were included. Level of invasion, tumor thickness, ulceration, and vascular invasion were significantly associated with the prognosis during both short- and long-term follow-up. The patients were subgrouped according to percentage fractions of their score on the prognostic index. Survival curves for these groups of patients were well separated, thus identifying patients with a low or high risk of death from malignant melanoma.The present population-based study identifies independent clinical and histopathologic predictors of survival in cutaneous malignant melanoma and emphasizes the role of histopathologic characteristics such as tumor thickness, ulceration, and vascular invasion besides anatomic site.
Increased gastric secretory capacity in smokers without gastrointestinal lesions.
Authors: S Massarrat, F Enschai, P M Pittner
Journal: Gut (1986)

The relationship between smoking and gastric secretory capacity was studied in 201 25-40 year old healthy subjects with normal laboratory data and no gastrointestinal lesions. Basal acid output (BAO) and peak acid output (PAO) were determined in all, and basal and stimulated pepsin outputs were measured in 85 participants. The accuracy of the patients' statements was checked by urinary nicotine assay. Basal acid output and PAO were significantly higher in male smokers (n = 55) than in male non-smokers (n = 49). In women PAO in smokers (n = 38) was higher than in non-smokers (n = 59). Female smokers (n = 38) had a higher pepsin output than female non-smokers (n = 23). Eight variables were considered in relation to BAO and PAO: age, height, weight, alcohol abuse, smoking habits, duration of smoking habit, number of cigarettes per day, and the product of years of smoking multiplied by daily number of cigarettes. The daily number of cigarettes X years of smoking was most closely correlated with BAO and PAO by stepwise multiple linear regression analysis. It was concluded that smoking is related to increased gastric acid capacity.
Development of Melanocytic Nevi in the First Three Years of Life
Authors: S. L. Harrison
Journal: JNCI Journal of the National Cancer Institute (2000)

Extract: Interest in melanocytic nevi (moles) stems from their clinical, histologic, and epidemiologic association with melanoma. Few studies of nevi have been longitudinal (1,2), and all, apart from our own (3), have involved subjects 3 years old or older. Hence, little is known about the age at which nevi begin to develop.

We compared rates of development of nevi from birth to 3 years of age in two cohorts of Caucasian children of similar ethnicity from the contrasting climates of Townsville, Australia [19° S; high levels of ambient UV radiation (4)], and Glasgow, U.K. [55° N; low levels of ambient UV radiation (5)]. The Australian cohort was recruited by approaching postpartum women at three maternity hospitals in Townsville during September and October 1994; 96.7% of the eligible mothers participated, resulting in a cohort of 115 babies of European ancestry. Scottish neonates were recruited from October 1993 through August 1994 by inviting postpartum women at the Queen Mother's Hospital, Glasgow, to participate in a randomized intervention trial focused on sun avoidance in infancy (consent rate for parents at Queen Mother's Hospital, Glasgow = 97.4%). From the latter group, only control subjects (no intervention; n = 157) were included in this study.
Significance of fibronectin in rheumatoid arthritis and osteoarthrosis.
Authors: D L Scott, A C Wainwright, K W Walton, N Williamson
Journal: Annals of the Rheumatic Diseases (1981)

Fibronectin is a glycoprotein secreted by connective tissue cells into their environment and into the blood. Plasma fibronectin has been isolated and used to prepare an antiserum. This has been shown to be specific for fibronectin and unreactive with fibrin(ogen) and collagen, to which fibronectin binds in vitro. The antiserum has been used to examine the distribution of this protein in the synovium in health, in rheumatoid arthritis, and in osteoarthrosis, and to estimate levels in plasma and synovial fluid. The results suggest that fibronectin is synthesised by synovial cells, and the synovial fluid level of fibronectin was found to be about twice the plasma level in rheumatoid arthritis. In long-standing arthritis fibronectin was also found to be codistributed with (presumably by adsorption upon) fibrin and immature collagen in intra-articular structures but was no longer demonstrable in areas where mature collagen had been formed in areas undergoing fibrosis. The possible significance of local fibronectin production within joints in relation to its possible effect on the resolution or continuance of arthritis is discussed.
MicroRNA-377 inhibited proliferation and invasion of human glioblastoma cells by directly targeting specificity protein 1
Authors: R. Zhang, H. Luo, S. Wang, W. Chen, Z. Chen, H.-W. Wang, Y. Chen, J. Yang, X. Zhang, W. Wu, S.-Y. Zhang, S. Shen, Q. Dong, Y. Zhang, T. Jiang, D. Lu, S. Zhao, Y. You, N. Liu, H. Wang
Journal: Neuro-Oncology (2014)

Increasing evidence has indicated that microRNAs (miRNAs) are strongly implicated in the initiation and progression of glioblastoma multiforme (GBM). Here, we identified a novel tumor suppressive miRNA, miR-377, and investigated its role and therapeutic effect for GBM. MiRNA global screening was performed on GBM patient samples and adjacent nontumor brain tissues. The expression of miR-377 was detected by real-time reverse-transcription PCR. The effects of miR-377 on GBM cell proliferation, cell cycle progression, invasion, and orthotopic tumorigenicity were investigated The therapeutic effect of miR-377 mimic was explored in a subcutaneous GBM model. Western blot and luciferase reporter assay were used to identify the direct and functional target of miR-377. MiR-377 was markedly downregulated in human GBM tissues and cell lines. Overexpression of miR-377 dramatically inhibited cell growth both in culture and in orthotopic xenograft tumor models, blocked G1/S transition, and suppressed cell invasion in GBM cells. Importantly, introduction of miR-377 could strongly inhibit tumor growth in a subcutaneous GBM model. Subsequent investigation revealed that specificity protein 1 (Sp1) was a direct and functional target of miR-377 in GBM cells. Silencing of Sp1 recapitulated the antiproliferative and anti-invasive effects of miR-377, whereas restoring the Sp1 expression antagonized the tumor-suppressive function of miR-377. Finally, analysis of miR-377 and Sp1 levels in human GBM tissues revealed that miR-377 is inversely correlated with Sp1 expression. These findings reveal that miR-377/Sp1 signaling that may be required for GBM development and may consequently serve as a therapeutic target for the treatment of GBM.
Application of a prediction model for work-related sensitisation in bakery workers
Authors: E. Meijer, E. Suarthana, J. Rooijackers, D. E. Grobbee, J. H. Jacobs, T. Meijster, J. G. R. de Monchy, E. van Otterloo, F. G. B. G. J. van Rooy, J. J. G. Spithoven, V. A. C. Zaat, D. J. J. Heederik
Journal: European Respiratory Journal (2010)

Identification of work-related allergy, particularly work-related asthma, in a (nationwide) medical surveillance programme among bakery workers requires an effective and efficient strategy. Bakers at high risk of having work-related allergy were indentified by use of a questionnaire-based prediction model for work-related sensitisation. The questionnaire was applied among 5,325 participating bakers. Sequential diagnostic investigations were performed only in those with an elevated risk. Performance of the model was evaluated in 674 randomly selected bakers who participated in the medical surveillance programme and the validation study. Clinical investigations were evaluated in the first 73 bakers referred at high risk. Overall 90% of bakers at risk of having asthma could be identified. Individuals at low risk showed 0.3–3.8% work-related respiratory symptoms, medication use or absenteeism. Predicting flour sensitisation by a simple questionnaire and score chart seems more effective at detecting work-related allergy than serology testing followed by clinical investigation in all immunoglobulin E class II-positive individuals. This prediction based stratification procedure appeared effective in detecting work-related allergy among bakers and can accurately be used for periodic examination, especially in small enterprises where delivery of adequate care is difficult. This approach may contribute to cost reduction.
Enzastaurin, a Protein Kinase Cβ–Selective Inhibitor, and Its Potential Application as an Anticancer Agent in Lung Cancer
Authors: Roy S. Herbst, Yun Oh, Asavari Wagle, Michael Lahn
Journal: Clinical Cancer Research (2007)

Abstract Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through protein kinase C (PKC)-β and the phosphatidylinositol 3-kinase/AKT pathway to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. In contrast to previous PKC inhibitors, enzastaurin is very well tolerated with a favorable safety profile, allowing it to be dosed for extended durations. In the present review, we summarize the rationale for targeting PKC in cancer, the preclinical experience of enzastaurin, and the clinical findings of the current phase I and II studies. Based on the combined information, we present the rationale for its future assessment in the treatment of lung cancer.