Formation of the high-affinity agonist state of the α1-adrenergic receptor at cold temperatures does not require a G-protein

AbstractTwo methods were employed to uncouple hepatic α1-adrenergic receptors from their associated G-protein (termed Gp) in order to determine wether locking of the α1-receptor in a high-affinity agonist state at cold temperatures (2°C) represents formation of a ternary complex. Uncoupling is defined as the inability to observe the GppNHp-sensitive, high-affinity agonist state of the receptor in [3H]prazosin competition binding studies performed at 25°C. The first method for achieving uncoupling involved brief alkalinization and resulted in greater 95% loss of several G-proteins. The second method involved proteolytic cleavage of either part or all of the α1-receptor coupling domain from the binding domain. Following either treatment, receptors were converted to the high-affinity agonist state at 2°C. Thus, while formation of the high-affinity state of the receptor at higher temperatures may require Gp, formation of this state at 2°C does not require Gp or even the entire α1-adregenic receptor

Application of a Fast Isoprene Sensor (FIS) for measuring isoprene production from marine samples

Research into isoprene production from marine sources traditionally relies on gas chromatography techniques which are labor intensive, provide a slow sample turnover, and require significant method training. An alternative method is the use of a Fast Isoprene Sensor (FIS), a chemiluminescence‐based approach that provides real time isoprene analysis, but is relatively simple to run and also portable. Until now, the FIS has been used in terrestrial but not aquatic isoprene studies. Due to the added difficulties with marine compared with terrestrial sampling, particularly potential interference from dimethyl sulfide (DMS), we have developed a new protocol that allows accurate and reliable data to be obtained from FIS analysis. The detection limit of our modified system to standard gas was 0.02 nM (0.5 ppbv), while minimum isoprene production detected by the FIS was 0.59 nmol h−1 (for Thalassiosira weissflogii). We also compared our FIS‐based approach with GC analysis of isoprene emission from marine samples of micro‐ and macro‐algae, and demonstrated a strong similarity (r2 = 0.910, slope = 1.003). The ability to use FIS analysis with marine samples will significantly broaden the scope of isoprene research in marine environments, permitting remote field work, and allow previously unanswered questions to be addressed.</jats:p

Repositioning for pressure injury prevention in adults

BACKGROUND: A pressure injury (PI), also referred to as a 'pressure ulcer', or 'bedsore', is an area of localised tissue damage caused by unrelieved pressure, friction, or shearing on any part of the body. Immobility is a major risk factor and manual repositioning a common prevention strategy. This is an update of a review first published in 2014. OBJECTIVES: To assess the clinical and cost effectiveness of repositioning regimens(i.e. repositioning schedules and patient positions) on the prevention of PI in adults regardless of risk in any setting. SEARCH METHODS: We searched the Cochrane Wounds Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid Embase, and EBSCO CINAHL Plus on 12 February 2019. We also searched clinical trials registries for ongoing and unpublished studies, and scanned the reference lists of included studies as well as reviews, meta-analyses, and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication, or study setting. SELECTION CRITERIA: Randomised controlled trials (RCTs), including cluster-randomised trials (c-RCTs), published or unpublished, that assessed the effects of any repositioning schedule or different patient positions and measured PI incidence in adults in any setting. DATA COLLECTION AND ANALYSIS: Three review authors independently performed study selection, 'Risk of bias' assessment, and data extraction. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We identified five additional trials and one economic substudy in this update, resulting in the inclusion of a total of eight trials involving 3941 participants from acute and long-term care settings and two economic substudies in the review. Six studies reported the proportion of participants developing PI of any stage. Two of the eight trials reported within-trial cost evaluations. Follow-up periods were short (24 hours to 21 days). All studies were at high risk of bias. Funding sources were reported in five trials. Primary outcomes: proportion of new PI of any stage Repositioning frequencies: three trials compared different repositioning frequencies We pooled data from three trials (1074 participants) comparing 2-hourly with 4-hourly repositioning frequencies (fixed-effect; I² = 45%; pooled risk ratio (RR) 1.06, 95% confidence interval (CI) 0.80 to 1.41). It is uncertain whether 2-hourly repositioning compared with 4-hourly repositioning used in conjunction with any support surface increases or decreases the incidence of PI. The certainty of the evidence is very low due to high risk of bias, downgraded twice for risk of bias, and once for imprecision. One of these trials had three arms (967 participants) comparing 2-hourly, 3-hourly, and 4-hourly repositioning regimens on high-density mattresses; data for one comparison was included in the pooled analysis. Another comparison was based on 2-hourly versus 3-hourly repositioning. The RR for PI incidence was 4.06 (95% CI 0.87 to 18.98). The third study comparison was based on 3-hourly versus 4-hourly repositioning (RR 0.20, 95% CI 0.04 to 0.92). The certainty of the evidence is low due to risk of bias and imprecision. In one c-RCT, 262 participants in 32 ward clusters were randomised between 2-hourly and 3-hourly repositioning on standard mattresses and 4-hourly and 6-hourly repositioning on viscoelastic mattresses. The RR for PI with 2-hourly repositioning compared with 3-hourly repositioning on standard mattress is imprecise (RR 0.90, 95% CI 0.69 to 1.16; very low-certainty evidence). The CI for PI include both a large reduction and no difference for the comparison of 4-hourly and 6-hourly repositioning on viscoelastic foam (RR 0.73, 95% CI 0.53 to 1.02). The certainty of the evidence is very low, downgraded twice due to high risk of bias, and once for imprecision. Positioning regimens: four trials compared different tilt positions We pooled data from two trials (252 participants) that compared a 30° tilt with a 90° tilt (random-effects; I² = 69%). There was no clear difference in the incidence of stage 1 or 2 PI. The effect of tilt is uncertain because the certainty of evidence is very low (pooled RR 0.62, 95% CI 0.10 to 3.97), downgraded due to serious design limitations and very serious imprecision. One trial involving 120 participants compared 30° tilt and 45° tilt with 'usual care' and reported no occurrence of PI events (low certainty evidence). Another trial involving 116 ICU patients compared prone with the usual supine positioning for PI. Reporting was incomplete and this is low certainty evidence. Secondary outcomes No studies reported health-related quality of life utility scores, procedural pain, or patient satisfaction. Cost analysis Two included trials also performed economic analyses. A cost-minimisation analysis compared the costs of 3-hourly and 4-hourly repositioning with 2-hourly repositioning schedule amongst nursing home residents. The cost of repositioning was estimated at CAD 11.05 and CAD 16.74 less per resident per day for the 3-hourly or 4-hourly regimen, respectively, compared with the 2-hourly regimen. The estimates of economic benefit were driven mostly by the value of freed nursing time. The analysis assumed that 2-, 3-, or 4-hourly repositioning is associated with a similar incidence of PI, as no difference in incidence was observed. A second study compared the nursing time cost of 3-hourly repositioning using a 30° tilt with standard care (6-hourly repositioning with a 90° lateral rotation) amongst nursing home residents. The intervention was reported to be cost-saving compared with standard care (nursing time cost per patient EUR 206.60 versus EUR 253.10, incremental difference EUR -46.50, 95% CI EUR -1.25 to EUR -74.60). AUTHORS' CONCLUSIONS: Despite the addition of five trials, the results of this update are consistent with our earlier review, with the evidence judged to be of low or very low certainty. There remains a lack of robust evaluations of repositioning frequency and positioning for PI prevention and uncertainty about their effectiveness. Since all comparisons were underpowered, there is a high level of uncertainty in the evidence base. Given the limited data from economic evaluations, it remains unclear whether repositioning every three hours using the 30° tilt versus "usual care" (90° tilt) or repositioning 3-to-4-hourly versus 2-hourly is less costly relative to nursing time

British Association of dermatologists guidelines for biologic therapy for psoriasis 2020 – a rapid update

The overall aim of the guideline is to provide up‐to‐date, evidence‐based recommendations on the use of biologic therapies targeting TNF (adalimumab, etanercept, certolizumab pegol, infliximab), IL12/23p40 (ustekinumab), IL17A (ixekizumab, secukinumab), IL17RA (brodalumab) and IL23p19 (guselkumab, risankizumab, tildrakizumab) in adults, children and young people for the treatment of psoriasis; consideration is given to the specific needs of people with psoriasis and psoriatic arthritis

Effect of organ site on nuclear matrix protein composition

The nuclear matrix has been linked to several important cellular functions within cells, such as DNA organization and replication, as well as regulation of gene expression. It has been reported that the nuclear matrix protein composition is altered in cells grown on different extracellular matrices in vitro. This study examined the nuclear matrix protein composition of tumors produced by MAT-LyLu (MLL) rat prostate tumor cells implanted at different organ sites within the rat. When high resolution two-dimensional gels were utilized to compare nuclear matrix protein composition to the prostate orthotopic tumor, it was found that there were distinct protein differences depending upon where the tumor grew. In particular, there were 14 proteins found in the lung, six proteins found in intramuscular, 17 proteins is the heart, and five proteins in the tail vein tumor tissue that were not present in the prostate orthotopic tumor tissue. Therefore, this study adds evidence to support that the nuclear matrix composition of a cell is dependent, at least in part, by the extracellular matrix and/or different cellular environments and may have a role in site-specific differences in tumor properties. © 1996 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38462/1/14_ftp.pd

A paediatric bone index derived by automated radiogrammetry

Hand radiographs are obtained routinely to determine bone age of children. This paper presents a method that determines a Paediatric Bone Index automatically from such radiographs. The Paediatric Bone Index is designed to have minimal relative standard deviation (7.5%), and the precision is determined to be 1.42%. Introduction We present a computerised method to determine bone mass of children based on hand radiographs, including a reference database for normal Caucasian children. Methods Normal Danish subjects (1,867), of ages 7-17, and 531 normal Dutch subjects of ages 5-19 were included. Historically, three different indices of bone mass have been used in radiogrammetry all based on A = pi TW(1 - T/W), where T is the cortical thickness and W the bone width. The indices are the metacarpal index A/W-2, DXR-BMD=A/W, and Exton-Smith's index A/(WL), where L is the length of the bone. These indices are compared with new indices of the form A/((WLb)-L-a), and it is argued that the preferred index has minimal SD relative to the mean value at each bone age and sex. Finally, longitudinal series of X-rays of 20 Japanese children are used to derive the precision of the measurements. Results The preferred index is A/((WL0.33)-L-1.33), which is named the Paediatric Bone Index, PBI. It has mean relative SD 7.5% and precision 1.42%. Conclusions As part of the BoneXpert method for automated bone age determination, our method facilitates retrospective research studies involving validation of the proposed index against fracture incidence and adult bone mineral densit

Risk of Serious Infections in Patients with Psoriasis on Biologic Therapies: A Systematic Review and Meta-Analysis

A comprehensive evaluation of the risk of serious infections in biologic therapies for psoriasis is lacking. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) and prospective cohort studies reporting serious infections in people taking any licensed biologic therapy for psoriasis compared with those taking placebo, nonbiologic therapy, or other biologic therapies. The quality of the studies was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. No significant heterogeneity was detected in data from 32 RCTs (n = 13,359 participants) and one cohort study (n = 4,993 participants). In adults, low- to very-low-quality RCT data showed no significant difference between any biologic therapy and placebo at weeks 12–16 (overall pooled Peto odds ratio = 0.71, 95% confidence interval = 0.36–1.41) and weeks 20–30 (odds ratio = 2.27, 95% confidence interval = 0.45–11.49). No significant differences were found in any of the other comparisons in underpowered RCT data. Prospective cohort study data of low quality suggests that only adalimumab (adjusted hazard ratio [adjHR] = 2.52, 95% confidence interval = 1.47–4.32) was associated with a significantly higher risk of serious infection compared with retinoid and/or phototherapy in adults. No association between biologic therapies and serious infections in patients with psoriasis who were eligible for RCTs was detected. Further observational studies are needed to inform the uncertainty around this risk in the real world

Use of radiolabelled choline as a pharmacodynamic marker for the signal transduction inhibitor geldanamycin

There is an urgent need to develop non-invasive pharmacodynamic endpoints for the evaluation of new molecular therapeutics that inhibit signal transduction. We hypothesised that, when labelled appropriately, changes in choline kinetics could be used to assess geldanamycin pharmacodynamics, which involves inhibition of the HSP90 molecular chaperone→Raf1→Mitogenic Extracellular Kinase→Extracellular Signal-Regulated Kinase 1 and 2 signal transduction pathway. Towards identifying a potential pharmacodynamic marker response, we have studied radiolabelled choline metabolism in HT29 human colon carcinoma cells following treatment with geldanamycin. We studied the effects of geldanamycin, on net cellular accumulation of (methyl-14C)choline and (methyl-14C)phosphocholine production. In parallel experiments, the effects of geldanamycin on extracellular signal-regulated kinase 1 and 2 phosphorylation and cell viability were also assessed. Additional validation studies were carried out with the mitogenic extracellular kinase inhibitor U0126 as a positive control; a cyclin-dependent kinase-2 inhibitor roscovitine and the phosphatidylinositol 3-kinase inhibitor LY294002 as negative controls. Hemicholinium-3, an inhibitor of choline transport and choline kinase activity was included as an additional control. In exponentially growing HT29 cells, geldanamycin inhibited extracellular signal-regulated kinase 1 and 2 phosphorylation in a concentration- and time-dependent manner. These changes were associated with a reduction in (methyl-14C)choline uptake, (methyl-14C) phosphocholine production and cell viability. Brief exposure to U0126, suppressed phosphocholine production to the same extent as Hemicholinium-3. In contrast to geldanamycin and U0126, which act upstream of extracellular signal-regulated kinase 1 and 2, roscovitine and LY294002 failed to suppress phosphocholine production. Our results suggest that when labelled with carbon-11 isotope, (methyl-11C)choline may be a useful pharmacodynamic marker for the non-invasive evaluation of geldanamycin analogues

Support surfaces for pressure ulcer prevention.

BACKGROUND: Pressure ulcers (also known as bedsores, pressure sores, decubitus ulcers) are areas of localised damage to the skin and underlying tissue due to pressure, shear or friction. They are common in the elderly and immobile and costly in financial and human terms. Pressure-relieving beds, mattresses and seat cushions are widely used as aids to prevention in both institutional and non-institutional settings. OBJECTIVES: This systematic review seeks to answer the following questions: to what extent do pressure-relieving cushions, beds, mattress overlays and mattress replacements reduce the incidence of pressure ulcers compared with standard support surfaces? how effective are different pressure-relieving surfaces in preventing pressure ulcers, compared to one another? SEARCH STRATEGY: The Specialised Trials Register of the Cochrane Wounds Group (compiled from regular searches of many electronic databases including MEDLINE, CINAHL and EMBASE plus handsearching of specialist journals and conference proceedings) was searched up to January 2004, Issue 3, 2004 of the Cochrane Central Register of Controlled Trials was also searched. The reference sections of included studies were searched for further trials. SELECTION CRITERIA: Randomised controlled trials (RCTs), published or unpublished, which assessed the effectiveness of beds, mattresses, mattress overlays, and seating cushions for the prevention of pressure ulcers, in any patient group, in any setting. RCTs were eligible for inclusion if they reported an objective, clinical outcome measure such as incidence and severity of new of pressure ulcers developed. Studies which only reported proxy outcome measures such as interface pressure were excluded. DATA COLLECTION AND ANALYSIS: Trial data were extracted by one researcher and checked by a second. The results from each study are presented as relative risk for dichotomous variables. Where deemed appropriate, similar studies were pooled in a meta analysis. MAIN RESULTS: 41 RCTs were included in the review. Foam alternatives to the standard hospital foam mattress can reduce the incidence of pressure ulcers in people at risk. The relative merits of alternating and constant low pressure devices, and of the different alternating pressure devices for pressure ulcer prevention are unclear.Pressure-relieving overlays on the operating table have been shown to reduce postoperative pressure ulcer incidence, although one study indicated that an overlay resulted in adverse skin changes. One trial indicated that Australian standard medical sheepskins prevented pressure ulcers. There is insufficient evidence to draw conclusions on the value of seat cushions, limb protectors and various constant low pressure devices as pressure ulcer prevention strategies.A study of Accident & Emergency trolley overlays did not identify a reduction in pressure ulcer incidence. There are tentative indications that foot waffle heel elevators, a particular low air loss hydrotherapy mattress and an operating theatre overlay are harmful. REVIEWERS' CONCLUSIONS: In people at high risk of pressure ulcer development, consideration should be given to the use of higher specification foam mattresses rather than standard hospital foam mattresses. The relative merits of higher-tech constant low pressure and alternating pressure for prevention are unclear. Organisations might consider the use of pressure relief for high risk patients in the operating theatre, as this is associated with a reduction in post-operative incidence of pressure ulcers. Seat cushions and overlays designed for use in Accident & Emergency settings have not been adequately evaluated

The role of nutrition in integrated programs to control neglected tropical diseases

There are strong and direct relationships between undernutrition and the disease caused by infectious organisms, including the diverse pathogens labeled as neglected tropical diseases (NTDs). Undernutrition increases the risk of infection, the severity of disease and the risk that children will die, while the physical damage, loss of appetite, and host responses during chronic infection can contribute substantially to undernutrition. These relationships are often synergistic. This opinion article examines the role of nutrition in controlling NTDs and makes the point that mass drug treatment - the major strategy currently proposed to control several diseases - is crucial to controlling disease and transmission, but is only the start of the process of physical recovery. Without adequate energy and nutrients to repair damaged tissues or recover lost growth and development, the benefits of treatment may not be evident quickly; the effects of control programs may be not appreciated by beneficiaries; while vulnerability to reinfection and disease may not be reduced. There is substantial potential for nutritional interventions to be added to large-scale programs to deliver drug treatments and thereby contribute, within a broad strategy of public health interventions and behavior change activities, to controlling and preventing NTDs in populations, and to restoring their health