Passage and concentration-dependent effects of Indomethacin on tendon derived cells

<p>Abstract</p> <p>Background</p> <p>Non-steroidal anti-inflammatory drugs (NSAID) are commonly used in the treatment of tendinopathies such as tendonitis and tendinosis. Despite this, little is known of their direct actions on tendon-derived cells. As NSAIDs have been shown to delay healing in a number of mesenchymal tissues we have investigated the direct effects of indomethacin on the proliferation of tendon-derived cells.</p> <p>Results and Discussion</p> <p>The results obtained were dependent on both the type of cells used and the method of measurement. When measured using the Alamar blue assay, a common method for the measurement of cell proliferation and viability, no effect of indomethacin was seen regardless of cell source. It is likely that this lack of effect was due to a paucity of mitochondrial enzymes in tendon cells.</p> <p>However, when cell number was assessed using the methylene blue assay, which is a simple nuclear staining technique, an Indomethacin-induced inhibition of proliferation was seen in primary cells but not in secondary subcultures.</p> <p>Conclusion</p> <p>These results suggest that firstly, care must be taken when deciding on methodology used to investigate tendon-derived cells as these cells have a quite different metabolism to other mesenchymal derive cells. Secondly, Indomethacin can inhibit the proliferation of primary tendon derived cells and that secondary subculture selects for a population of cells that is unresponsive to this drug.</p

Determining the Effects of Transcranial Direct Current Stimulation on Tinnitus, Depression, and Anxiety: A Systematic Review

(1) Background: Tinnitus is the awareness of a sound in the absence of an external source. It affects around 10–15% of people, a significant proportion of whom also experience symptoms such as depression or anxiety that negatively affect their quality of life. Transcranial direct current stimulation (tDCS) is a technique involving constant low-intensity direct current delivered via scalp electrodes. It is a potential treatment option for tinnitus, as well as tinnitus-related conditions such as depression and anxiety. This systematic review estimates the effects of tDCS on outcomes relevant to tinnitus. In addition, it sheds light on the relationship between stimulation parameters and the effect of tDCS on these outcomes; (2) Methods: Exhaustive searches of electronic databases were conducted. Randomised controlled trials were included if they reported at least one of the following outcomes: tinnitus symptom severity, anxiety, or depression. Where available, data on quality of life, adverse effects, and neurophysiological changes were also reviewed. GRADE was used to assess the certainty in the estimate; (3) Results: Meta-analyses revealed a statistically significant reduction in tinnitus (moderate certainty) and depression (low certainty)-but not anxiety-following active tDCS compared to sham control. Network meta-analyses revealed potential optimal stimulation parameters; (4) Conclusions: The evidence synthesised in this review suggests tDCS has the potential to reduce symptom severity in tinnitus and depression. It further narrows down the number of potentially optimal stimulation parameters

Superheated Microdrops as Cold Dark Matter Detectors

It is shown that under realistic background considerations, an improvement in Cold Dark Matter sensitivity of several orders of magnitude is expected from a detector based on superheated liquid droplets. Such devices are totally insensitive to minimum ionizing radiation while responsive to nuclear recoils of energies ~ few keV. They operate on the same principle as the bubble chamber, but offer unattended, continuous, and safe operation at room temperature and atmospheric pressure.Comment: 15 pgs, 4 figures include

The effectiveness and cost-effectiveness of assistive technology and telecare for independent living in dementia: a randomised controlled trial

OBJECTIVES: The use of assistive technology and telecare (ATT) has been promoted to manage risks associated with independent living in people with dementia but with little evidence for effectiveness. METHODS: Participants were randomly assigned to receive an ATT assessment followed by installation of all appropriate ATT devices or limited control of appropriate ATT. The primary outcomes were time to institutionalisation and cost-effectiveness. Key secondary outcomes were number of incidents involving risks to safety, burden and stress in family caregivers and quality of life. RESULTS: Participants were assigned to receive full ATT (248 participants) or the limited control (247 participants). After adjusting for baseline imbalance of activities of daily living score, HR for median pre-institutionalisation survival was 0.84; 95% CI, 0.63 to 1.12; P = 0.20. There were no significant differences between arms in health and social care (mean -£909; 95% CI, -£5,336 to £3,345, P = 0.678) and societal costs (mean -£3,545; 95% CI, -£13,914 to £6,581, P = 0.499). ATT group members had reduced participant-rated quality-adjusted life years (QALYs) at 104 weeks (mean - 0.105; 95% CI, -0.204 to -0.007, P = 0.037) but did not differ in QALYs derived from proxy-reported EQ-5D. DISCUSSION: Fidelity of the intervention was low in terms of matching ATT assessment, recommendations and installation. This, however, reflects current practice within adult social care in England. CONCLUSIONS: Time living independently outside a care home was not significantly longer in participants who received full ATT and ATT was not cost-effective. Participants with full ATT attained fewer QALYs based on participant-reported EQ-5D than controls at 104 weeks

The impact of assistive technology on burden and psychological well-being in informal caregivers of people with dementia (ATTILA Study)

INTRODUCTION: Assistive technology and telecare (ATT) may alleviate psychological burden in informal caregivers of people with dementia. This study assessed the impact of ATT on informal caregivers’ burden and psychological well‐being. METHODS: Individuals with dementia and their informal caregivers were recruited to a randomized‐controlled trial assessing effectiveness of ATT. Caregivers were allocated to two groups according to their cared‐for person's randomization to a full or basic package of ATT and were assessed on caregiver burden, state anxiety, and depression. Caregivers’ data from three assessments over 6 months of the trial were analyzed. RESULTS: No significant between‐ or within‐group differences at any time point on caregivers’ burden, anxiety, and depression levels were found. DISCUSSION: Full ATT for people with dementia did not impact caregivers’ psychological outcomes compared to basic ATT. The length of follow up was restricted to 6 months

High-risk mammographic parenchymal patterns and anthropometric measures: a case–control study

Mammographic parenchymal patterns are related to breast cancer risk and are also affected by anthropometric measure. We carried out a case–control study comprising 200 cases with high-risk (P2 and DY) mammographic parenchymal pattern and 200 controls with low-risk (N1 and P1) patterns in order to investigate the effect of body size and shape and breast size on mammographic patterns. Women in the highest quartile of body mass index (BMI) distribution were significantly less likely to have a high-risk pattern (odds ratio (OR) = 0.21, 95% confidence interval (CI) 0.08–0.52, P-value for trend = 0.001) compared to those in the lowest quartile. Relative to women with a waist to hip ratio (WHR) of less than 0.75, the OR of having a high-risk pattern in women with a WHR greater than 0.80 was 0.30 (95% CI 0.14–0.63). Breast size as measured by cup size was significantly and negatively related to high-risk pattern. Our study indicates that both BMI and WHR are negatively associated with high-risk patterns. However, both phenomena are associated with increased risk of breast cancer in post-menopausal women. This negative confounding of two positive risk factors means that the effect of parenchymal patterns on risk will tend to be underestimated when not adjusted for BMI and WHR and vice versa. Thus we may have underestimated the importance of BMI and mammographic parenchymal patterns in the past. Further studies are needed to determine a measure of parenchymal density that is independent of anthropometric measures and breast size. © 1999 Cancer Research Campaig

Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial

Background High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. Methods We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UKbased ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053. Findings Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants’ systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (p<0·0001), and diastolic blood pressure was lowered by 2·6 mm Hg (p=0·0026) at hospital admission. We found no difference in mRS between the groups in participants with a final diagnosis of stroke or transient ischaemic stroke (cohort 1): 3 (IQR 2–5; n=420) in the GTN group versus 3 (2–5; n=408) in the sham group, adjusted common odds ratio for poor outcome 1·25 (95% CI 0·97–1·60; p=0·083); we also found no difference in mRS between all patients (cohort 2: 3 [2–5]; n=544, in the GTN group vs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups. Interpretation Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultraacute prehospital setting

Impairment of Rat Fetal Beta-Cell Development by Maternal Exposure to Dexamethasone during Different Time-Windows

Glucocorticoids (GCs) take part in the direct control of cell lineage during the late phase of pancreas development when endocrine and exocrine cell differentiation occurs. However, other tissues such as the vasculature exert a critical role before that phase. This study aims to investigate the consequences of overexposure to exogenous glucocorticoids during different time-windows of gestation for the development of the fetal endocrine pancreas

The effectiveness and cost-effectiveness of assistive technology and telecare for independent living in dementia: a randomised controlled trial.

OBJECTIVES: The use of assistive technology and telecare (ATT) has been promoted to manage risks associated with independent living in people with dementia but with little evidence for effectiveness. METHODS: Participants were randomly assigned to receive an ATT assessment followed by installation of all appropriate ATT devices or limited control of appropriate ATT. The primary outcomes were time to institutionalisation and cost-effectiveness. Key secondary outcomes were number of incidents involving risks to safety, burden and stress in family caregivers and quality of life. RESULTS: Participants were assigned to receive full ATT (248 participants) or the limited control (247 participants). After adjusting for baseline imbalance of activities of daily living score, HR for median pre-institutionalisation survival was 0.84; 95% CI, 0.63 to 1.12; P = 0.20. There were no significant differences between arms in health and social care (mean -£909; 95% CI, -£5,336 to £3,345, P = 0.678) and societal costs (mean -£3,545; 95% CI, -£13,914 to £6,581, P = 0.499). ATT group members had reduced participant-rated quality-adjusted life years (QALYs) at 104 weeks (mean - 0.105; 95% CI, -0.204 to -0.007, P = 0.037) but did not differ in QALYs derived from proxy-reported EQ-5D. DISCUSSION: Fidelity of the intervention was low in terms of matching ATT assessment, recommendations and installation. This, however, reflects current practice within adult social care in England. CONCLUSIONS: Time living independently outside a care home was not significantly longer in participants who received full ATT and ATT was not cost-effective. Participants with full ATT attained fewer QALYs based on participant-reported EQ-5D than controls at 104 weeks

The peroxisome proliferator-activated receptor (PPAR) alpha agonist fenofibrate maintains bone mass, while the PPAR gamma agonist pioglitazone exaggerates bone loss, in ovariectomized rats

<p>Abstract</p> <p>Background</p> <p>Activation of peroxisome proliferator-activated receptor (PPAR)gamma is associated with bone loss and increased fracture risk, while PPARalpha activation seems to have positive skeletal effects. To further explore these effects we have examined the effect of the PPARalpha agonists fenofibrate and Wyeth 14643, and the PPARgamma agonist pioglitazone, on bone mineral density (BMD), bone architecture and biomechanical strength in ovariectomized rats.</p> <p>Methods</p> <p>Fifty-five female Sprague-Dawley rats were assigned to five groups. One group was sham-operated and given vehicle (methylcellulose), the other groups were ovariectomized and given vehicle, fenofibrate, Wyeth 14643 and pioglitazone, respectively, daily for four months. Whole body and femoral BMD were measured by dual X-ray absorptiometry (DXA), and biomechanical testing of femurs, and micro-computed tomography (microCT) of the femoral shaft and head, were performed.</p> <p>Results</p> <p>Whole body and femoral BMD were significantly higher in sham controls and ovariectomized animals given fenofibrate, compared to ovariectomized controls. Ovariectomized rats given Wyeth 14643, maintained whole body BMD at sham levels, while rats on pioglitazone had lower whole body and femoral BMD, impaired bone quality and less mechanical strength compared to sham and ovariectomized controls. In contrast, cortical volume, trabecular bone volume and thickness, and endocortical volume were maintained at sham levels in rats given fenofibrate.</p> <p>Conclusions</p> <p>The PPARalpha agonist fenofibrate, and to a lesser extent the PPARaplha agonist Wyeth 14643, maintained BMD and bone architecture at sham levels, while the PPARgamma agonist pioglitazone exaggerated bone loss and negatively affected bone architecture, in ovariectomized rats.</p