Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of capacitative calcium entry on glutamate‐induced calcium influx in type‐I rat cortical astrocytes

Capacitative calcium entry (CCE) has been described in a variety of cell types. To date, little is known about its role in the CNS, and in particular in the cross‐talk between glia and neurons. We have first analyzed the properties of CCE of astrocytes in culture, in comparison with that of the rat basophilic leukemia cell line (RBL‐2H3), a model where calcium release‐activated Ca2+ (CRAC) channels have been unambiguously correlated with CCE. We here show that (i) in astrocytes CCE activated by store depletion and Ca2+ influx induced by glutamate share the same pharmacological profile of CCE in RBL‐2H3 cells and (ii) glutamate‐induced Ca2+ influx in astrocytes plays a primary role in glutamate‐dependent intracellular Ca2+ concentration ([Ca2+]i) oscillations, being these latter reduced in frequency and amplitude by micromolar concentrations of La3+. Finally, we compared the expression of various mammalian transient receptor potential genes (TRP) in astrocytes and RBL‐2H3 cells. Despite the similar pharmacological properties of CCE in these cells, the pattern of TRP expression is very different. The involvement of CCE and TRPs in glutamate dependent activation of astrocytes is discussed.
Role of hypoxia‐induced fibronectin‐integrin β1 expression in embryonic stem cell proliferation and migration: Involvement of PI3K/Akt and FAK

Cell migration is largely dependent on integrin (IN) binding to the extracellular matrix, and several signaling pathways involved in these processes have been shown to be modified by hypoxia. Therefore, the aim of this study was to determine the influence of hypoxia on fibronectin (FN) and IN β1 expression in mouse embryonic stem cells (mESCs) and their signaling pathways to modulate proliferation. FN and IN β1 expression were significantly increased in hypoxic mESCs by 24 h. Hypoxia also increased cell attachment, which was accompanied by concomitant increases in the binding level of FN and IN β1. Hypoxia‐induced FN expression was mediated by increased phosphatidylinositol 3 kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) phosphorylation, and hypoxia‐inducible factor‐1α (HIF‐1α) expression. Moreover, under hypoxic conditions, focal adhesion kinase (FAK) and Src phosphorylation were increased in a time‐dependent fashion; these increases were blocked by IN β1 antibody. In addition, the hypoxia induced increase of F‐actin distribution and cell migration (activation of matrix metalloproteinase‐2 and ‐9) was inhibited by IN β1 antibody. Indeed, hypoxia increased the level of cell‐cycle regulatory protein and DNA synthesis. In conclusion, hypoxia increases the proliferation and migration of mESCs via FN‐IN β1 production through the PI3K/Akt, mTOR, and HIF‐1α pathways, followed by FAK activation. J. Cell. Physiol. 226: 484–493, 2011. © 2010 Wiley‐Liss, Inc.
Thyroid function and the response to liothyronine in depression.

Longitudinal studies of thyroid function during a four-week comparative trial of imipramine hydrochloride andL-tryptophan in 30 depressed patients showed a significant fall in the free thyroxine index during the first week of the trial, but otherwise measures of thyroid activity were within normal limits and showed no change during clinical recovery. Administration of 25µg ofL-triiodothyronine (T 3 , liothyronine sodium) for 14 days was sufficient to cause some suppression of endogenous thyroid function and demonstrated that the pituitary-thyroid axis remains responsive during depressive illness. Ankle reflex time estimated prior to treatment was very significantly correlated with response to imipramine therapy, ie, the patients with faster ankle reflex times showed a greater improvement than those with a slower ankle reflex time. A similar correlation was found between a low serum cholesterol level and a good clinical response to imipramine treatment.
The challenge of complexity in health care

This is the first in a series of four articles Across all disciplines, at all levels, and throughout the world, health care is becoming more complex. Just 30 years ago the typical general practitioner in the United Kingdom practised from privately owned premises with a minimum of support staff, subscribed to a single journal, phoned up a specialist whenever he or she needed advice, and did around an hour's paperwork per week. The specialist worked in a hospital, focused explicitly on a particular system of the body, was undisputed leader of his or her “firm,” and generally left administration to the administrators. These individuals often worked long hours, but most of their problems could be described in biomedical terms and tackled using the knowledge and skills they had acquired at medical school. You used to go to the doctor when you felt ill, to find out what was wrong with you and get some medicine that would make you better. These days you are as likely to be there because the doctor (or the nurse, the care coordinator, or even the computer) has sent for you. Your treatment will now be dictated by the evidence—but this may well be imprecise, equivocal, or conflicting. Your declared values and preferences may be used, formally or informally, in a shared management decision about your illness. The solution to your problem is unlikely to come in a bottle and may well involve a multidisciplinary team. Not so long ago public health was the science of controlling infectious diseases by identifying the “cause” (an alien organism) and taking steps to remove or contain it. Today's epidemics have fuzzier boundaries (one is even known as “syndrome X”1): they are the result of the interplay of genetic predisposition, environmental context, and lifestyle choices. The experience of …
An aerobic walking programme versus muscle strengthening programme for chronic low back pain: a randomized controlled trial

Objective: To assess the effect of aerobic walking training as compared to active training, which includes muscle strengthening, on functional abilities among patients with chronic low back pain. Design: Randomized controlled clinical trial with blind assessors. Setting: Outpatient clinic. Subjects: Fifty-two sedentary patients, aged 18–65 years with chronic low back pain. Patients who were post surgery, post trauma, with cardiovascular problems, and with oncological disease were excluded. Intervention: Experimental ‘walking’ group: moderate intense treadmill walking; control ‘exercise’ group: specific low back exercise; both, twice a week for six weeks. Main measures: Six-minute walking test, Fear-Avoidance Belief Questionnaire, back and abdomen muscle endurance tests, Oswestry Disability Questionnaire, Low Back Pain Functional Scale (LBPFS). Results: Significant improvements were noted in all outcome measures in both groups with non-significant difference between groups. The mean distance in metres covered during 6 minutes increased by 70.7 (95% confidence interval (CI) 12.3–127.7) in the ‘walking’ group and by 43.8 (95% CI 19.6–68.0) in the ‘exercise’ group. The trunk flexor endurance test showed significant improvement in both groups, increasing by 0.6 (95% CI 0.0–1.1) in the ‘walking’ group and by 1.1 (95% CI 0.3–1.8) in the ‘exercise’ group. Conclusions: A six-week walk training programme was as effective as six weeks of specific strengthening exercises programme for the low back.
Widespread Expression of Arginase I in Mouse Tissues: Biochemical and Physiological Implications

Arginase I (AI), the fifth and final enzyme of the urea cycle, detoxifies ammonia as part of the urea cycle. In previous studies from others, AI was not found in extrahepatic tissues except in primate blood cells, and its roles outside the urea cycle have not been well recognized. In this study we undertook an extensive analysis of arginase expression in postnatal mouse tissues by in situ hybridization (ISH) and RT-PCR. We also compared arginase expression patterns with those of ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT). We found that, outside of liver, AI was expressed in many tissues and cells such as the salivary gland, esophagus, stomach, pancreas, thymus, leukocytes, skin, preputial gland, uterus and sympathetic ganglia. The expression was much wider than that of arginase II, which was highly expressed only in the intestine and kidney. Several co-localization patterns of AI, ODC, and OAT have been found: (a) AI was co-localized with ODC alone in some tissues; (b) AI was co-localized with both OAT and ODC in a few tissues; (c) AI was not co-localized with OAT alone in any of the tissues examined; and (d) AI was not co-localized with either ODC or OAT in some tissues. In contrast, AII was not co-localized with either ODC or OAT alone in any of the tissues studied, and co-localization of AII with ODC and OAT was found only in the small intestine. The co-localization patterns of arginase, ODC, and OAT suggested that AI plays different roles in different tissues. The main roles of AI are regulation of arginine concentration by degrading arginine and production of ornithine for polyamine biosynthesis, but AI may not be the principal enzyme for regulating glutamate biosynthesis in tissues and cells.
Effects of biological control on long‐term population dynamics: identifying unexpected outcomes

Summary 1. Attempts to control natural systems through management have often met with success but have also led to unexpected and often undesirable outcomes. Unfortunately, the ultimate result of such management programmes may not be apparent until long after the control efforts have begun. This is particularly true for forest-defoliating species that exhibit longperiod cycles such as the invasive gypsy moth Lymantria dispar, which causes widespread damage in some years but is rare in other years. 2. We studied the effects of two commonly employed biocontrol agents on gypsy moth dynamics using a series of field-tested and empirically parameterized mathematical models, which allowed us to examine various potential control strategies and assess long-term effects. 3. In a non-spatial model, addition of either a manufactured version of the same baculovirus involved in natural epizootics, or a general bioinsecticide Bacillus thuringiensis var. kurstaki (Btk), which directly kills a fraction of the population, decreases the amplitude between boom and bust portions of the cycle. 4. However, ill-planned biocontrol applications can result in increased gypsy moth densities over the long term. Thus, control efforts may maintain pest populations at unexpectedly high numbers, which could result in constant forest defoliation. 5. In a spatial two-patch model, where one patch is sprayed and the other is left untreated, there is also considerable danger that migration between patches may drive the unsprayed population to levels that could result in constant forest defoliation. 6. Synthesis and applications: Perturbations to host–pathogen systems may have unexpected results, driving and maintaining populations at multiple levels including those far from desired management goals. It is often assumed that any control strategy that decreases pest populations in the short term is beneficial, but our results show that undesirable outcomes may often occur. The mechanisms we describe apply to many systems that undergo population cycles or outbreaks regulated by density-dependent processes, and in which disease or pesticide application is used for pest control. We suggest that successful management strategies should closely monitor population responses immediately following the control application to ensure that pest populations are not being maintained at artificially high levels compared with historic data.
Targeted approaches to childhood cancer: progress in drug discovery and development

Introduction: Cancer is a leading cause of death in childhood. Encouraging progress has been made in the treatment of childhood malignancies, but there is an unmet need for new drugs to improve survival and reduce treatment-associated toxicities. Drug development in paediatric oncology has specific requirements with regard to the patient population and the regulatory background and presents several unique challenges that need addressing. Areas covered: This review discusses the current framework of paediatric oncology drug development and some of the specific challenges in pre-clinical and clinical research. The authors discuss the recent developments in the targeting of various signalling pathways. These pathways represent a selection of targets that have been identified by pre-clinical and clinical investigators to be highly relevant in paediatric malignancies. Expert opinion: The development of targeted agents in paediatric oncology must be driven by knowledge of tumour biology. Predictive and pharmacodynamic biomarkers should be incorporated within paediatric early clinical trials wherever possible. Faster dose-escalation, limited numbers of cohorts and novel adaptive designs can help to make paediatric early clinical trials more efficient. Close collaboration between academic/clinical researchers, the pharmaceutical industry, regulatory bodies and parent groups are crucial in overcoming the challenges associated with paediatric oncology drug development.
Nicotine delivery systems

Due to the profound mortality associated with tobacco use, effective treatments for tobacco dependence are needed. Currently, the most widely available pharmacotherapy is nicotine replacement therapy (NRT). This paper will review the state of the science and public health policy regarding NRT.Several formulations have been developed for delivering nicotine into the body, including nicotine patch, gum, oral inhaler, nasal spray, and lozenge. Nicotine patches deliver nicotine at a relatively steady rate and are applied once daily. All other forms are taken on a periodic basis, multiple times per day. All of these products, except the nasal spray, deliver nicotine through the oral mucosa. New formulations are currently in the development phase. There are also several ways in which currently available formulations could be modified to improve delivery. The future of NRT may include the development of a true pulmonary inhaler, products for long-term maintenance, products for reduced smoking, products for acute use, and the tailoring of treatments for individual smokers. Nicotine replacement medications have been shown to be efficacious in dozens of clinical trials, and have had an impact on public health by assisting thousands of smokers to quit smoking. The over-the-counter marketing of nicotine patches and gum allows smokers ready access to these medications, and has led to an increase in product use and successful cessation compared with prescription-only marketing. The wide menu of NRT medications for smoking cessation gives patients and healthcare professionals options for treatment. However, whereas NRT medications double quit rates compared with unassisted attempts, there is clearly much to be done to improve the proportion of quitters who use evidence-based treatment, their use of the products, and the usability and inherent efficacy of NRT.
Vascular Endothelial Growth Factor Polymorphisms in Relation to Breast Cancer Development and Prognosis

Purpose: Angiogenesis is a necessary step in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a major mediator of breast cancer angiogenesis. Therefore, we investigated the association of polymorphisms in the VEGF gene with breast cancer risk and prognostic characteristics of the tumors in a large case-control study. Experimental Design: We examined three polymorphisms in the VEGF gene (−2578C/A, −1154G/A, and +936C/T) in 571 familial breast cancer cases from Poland and Germany and −2578C/A, −634G/C, and +936C/T polymorphisms in 974 unselected breast cancer cases from Sweden together with ethnically and geographically selected controls. Results: None of the polymorphisms or any haplotype was significantly associated with either familial or unselected breast cancers. Our study suggests that the +936C/T polymorphism is unlikely to be associated with breast cancer. We also analyzed the unselected cases for genotypes or haplotypes that associated with tumor characteristics. The −634CC genotype and the −2578/−634 CC haplotype were significantly associated with high tumor aggressiveness (large tumor size and high histologic grade, P < 0.01) and the −2578AA genotype and the −2578/−634 AG haplotype with low histologic grade tumors (P = 0.04). The genotypes and haplotypes were not related with other tumor characteristics such as regional or distant metastasis, stage at diagnosis, or estrogen or progesterone receptor status. Conclusions: Although none of the polymorphisms studied in the VEGF gene was found to influence susceptibility to breast cancer significantly, some of the VEGF genotypes and haplotypes may influence tumor growth through an altered expression of VEGF and tumor angiogenesis.
Projecting Primary Care Use in the Medicaid Expansion Population

Millions of low-income adults are beginning to gain Medicaid coverage under the Affordable Care Act. To forecast the resulting need for primary care providers, we estimate the effect of Medicaid take-up on visits to office-based primary care providers, including clinics. We estimate that adults with Medicaid coverage at any point in the year have an average of 1.32 visits per year to primary care providers, 0.48 more visits than low-income adults without Medicaid. Consequently, we project a need for 2,113 additional primary care providers (range: 1,130-3,138) if all states expand Medicaid. Our estimates are somewhat lower than several recent forecasts, which may not have controlled adequately for selection bias, and which used non-representative samples for forecasting. Our findings shed light on disparities in access to care, particularly in counties with relatively few primary care providers per capita. Efforts to expand access to primary care should focus on where providers practice, rather than simply training more providers.
The Prognostic Value of E-cadherin Expression in Breast Cancer.

BACKGROUND Breast cancer continues to be a major cause of morbidity and mortality throughout the world. The behavior of breast cancer varies widely. Several parameters have been investigated to predict the prognosis in breast cancer. But still there is no single parameter that can predict prognosis in an individual patient. Among the novel prognostic markers is E-cadherin; a calcium-dependent epithelial cell adhesion molecule. Its loss has been associated with metastases, thereby providing evidence for its role as an invasion suppressor. The objective of the present study was to assess the prognostic value of E-cadherin expression in breast cancer cases, and its correlations with the other studied prognostic parameters. METHODS The study comprised 54 breast cancer patients admitted at King Fahd Specialist Hospital, Qassim during the period 2001-2006. The median tumor size was 3cms. Fifty cases (92.6%) had invasive ductal carcinoma, four cases had lobular carcinomas, and most were grade II (82%), stage II (48%), and the majority of cases had positive axillary lymph nodes (70.3%). Representative sections from formalin-fixed paraffin embedded tissue blocks were taken from the 54 cases of breast cancer, and were stained for E-cadherin expression by immunohistochemical technique (monoclonal E-cadherin (NCL-E-cad), Novocastra). All the lobular carcinoma cases were negative for membranous expression of E-cadherin while 72% of invasive ductal carcinomas were positive for the marker. RESULTS A significant correlation was found between strong E-cadherin expression and node negative cases. Node negative cases were found to be an independent predictor of strong E-cadherin expression while node positive cases predicted negative expression of E-cadherin (P = 0 .026). Also loss of E-cadherin was noted in advanced stages of breast cancer supporting the view that loss of E-cadherin expression is a marker of aggressiveness. However, there was no correlation between the E-cadherin and other prognostic parameters as tumor size, tumor grade, ER, PR, and HER-2 expression. CONCLUSION A significant correlation was found between strong E-cadherin expression and node negative cases.
Combining Attributes in Rapid Serial Visual Presentation Tasks

A series of three exploratory experiments sought to compare and contrast two broad classes of theory pertaining to visual information pick-up. One theoretical approach, exemplified by Keele and Neill (1978) and by Treisman (1977) emphasizes the relatively passive, parallel development of information codes, with subsequent attentional integration of contiguous codes into a percept. Another theoretical approach, exemplified by Broadbent (1977a) emphasizes the relatively active, sequential, recursive interrogation of a visual display in which the pick-up of each piece of information guides the perceptual system in its quest for more information. The manner in which separable attributes of visual information are picked up and combined was studied by manipulating the roles of different attributes in a rapid serial visual presentation (RSVP) paradigm. Observers were asked to report the name of a letter in a specified target colour; to report the colour of a specified target letter; to report the colour of a specified target numeral embedded in a list of letters; to report the colour of an unspecified numeral embedded in a list of letters; and to perform the latter two tasks without knowing in which of two alternating spatial positions the target might appear. Examination of the patterns of mis-combinations of attributes from target and non-target stimuli yields evidence both for and against each theoretical position, and suggests that the two might better be considered as modes of processing available to the perceptual system, rather than as intrinsic properties of that system.
Interscanner variation in brain MRI lesion load measurements in MS: Implications for clinical trials

We evaluated the effect of interscanner variation on brain MRI-measured lesion volumes and measurement reproducibility in MS. Twenty clinically definite MS patients were each scanned on two or three scanners (a total of 14 scanners were used). In addition, a formalin-fixed MS brain was studied on eight scanners from different manufacturers and with different field strengths. For the formalin-fixed MS brain, on each machine we obtained two scans with slice thicknesses of 5 and 3 mm. Only 5-mm-thick slices were obtained from patients. The lesion volume present on each scan was evaluated three times by a single observer in random order, using a local thresholding technique. In two groups of eight patients scanned on machines with different field strengths, the mean lesion volumes present on scans obtained at 1.5 T were significantly higher than those measured on scans obtained with machines operating at 0.5 and 1.0 T (p < 0.01). When a single observer repeatedly evaluated the same scan, a median intraobserver agreement of 98.7%(95% CI, 97.9 to 99.1) was achieved. However, when the observer evaluated the scans from different MRI scanners, the agreement (an interscanner agreement) fell to 91.1% (CI, 90.2 to 94.1). When only scanners operating at 1.5 T were considered, the median interscanner agreement was 96.7% (CI, 95 to 97.5). Also, for the formalin-fixed MS brain, the intraobserver agreements obtained with both slice thicknesses were significantly higher than the corresponding interscanner agreements. The interscanner agreement, but not the intraobserver agreement, obtained with a slice thickness of 3 mm was higher than that obtained with a slice thickness of 5 mm. Our results indicate that lesion volume measurements in MS are influenced significantly by the use of different MR scanners and that a patient included in a serial study should be always scanned with the same MR machine using 3-mm thick slices.