Assessment of Acute and Chronic Pharmacological Effects on Energy Expenditure and Macronutrient Oxidation in Humans: Responses to Ephedrine

Evidence of active brown adipose tissue in human adults suggests that this may become a pharmacological target to induce negative energy balance. We have explored whole-body indirect calorimetry to detect the metabolic effects of thermogenic drugs through administration of ephedrine hydrochloride and have assessed ephedrine's merits as a comparator compound in the evaluation of novel thermogenic agents. Volunteers randomly given ephedrine hydrochloride 15 mg QID (n = 8) or placebo (n = 6) were studied at baseline and after 1-2 and 14-15 days of treatment. We demonstrate that overnight or 23-hour, 2% energy expenditure (EE) and 5% fat (FO) or CHO oxidation effects are detectable both acutely and over 14 days. Compared to placebo, ephedrine increased EE and FO rates overnight (EE 63 kJ day 2, EE 105 kJ, FO 190 kJ, day 14), but not over 23 h. We conclude that modest energy expenditure and fat oxidation responses to pharmacological interventions can be confidently detected by calorimetry in small groups. Ephedrine should provide reliable data against which to compare novel thermogenic compounds

Differential changes in serum uric acid concentrations in sibutramine promoted weight loss in diabetes: results from four weeks of the lead-in period of the SCOUT trial

<p>Abstract</p> <p>Background and aims</p> <p>Elevated levels of serum uric acid are associated with an increased risk of cardiovascular morbidity and mortality. The response of uric acid to weight loss therapy (lifestyle plus sibutramine) in an overweight and obese cardiovascular high risk population was studied.</p> <p>Methods and results</p> <p>Data from a four week single-blind lead-in period of the Sibutramine Cardiovascular OUTcomes (SCOUT) study were analyzed. 2584 patients (24%) had diabetes mellitus (DM) only, 1748 (16%) had cardiovascular disease (CVD) only and 6397 (60%) had both DM + CVD. Uric acid concentrations (mean ± standard deviation) at screening were significantly higher among patients with CVD compared to patients without CVD (p < 0.0001): 369 ± 86 μmol/L, 374 ± 98 μmol/L and 342 ± 87 μmol/L in CVD only, CVD+DM and DM only groups, respectively. During treatment uric acid decreased significantly more in patients without DM (p < 0.0001): -15.0 μmol/L (95% confidence interval -17.7;-12.4), -4.6 μmol/L (-6.2;-3.0), and -6.6 μmol/L (-8.7;-4.5) in CVD only, CVD+DM, and DM only groups, respectively. In patients who failed to lose weight, sibutramine induced lower uric acid levels, but greater weight loss and diabetes were associated with smaller falls in blood uric acid levels; decreasing fasting and urinary glucose concentrations in diabetes were associated with increases in uric acid levels.</p> <p>Conclusion</p> <p>A four week daily intake of sibutramine and life style changes was associated with significant reductions in mean uric acid levels. Changes in renal glucose load in diabetes seem to counteract a potential uricosuric effect of sibutramine.</p> <p>Trial Registration</p> <p>The trial is registered at ClinicalTrial.gov number: NCT00234832.</p

An evaluation of a pilot of daily testing of SARS-CoV-2 contacts in acute hospital and ambulance trusts in England

OBJECTIVES: Healthcare worker (HCW) SARS-CoV-2 contacts in England have been required to quarantine, creating staff shortages. We piloted daily contact testing (DCT) to assess its feasibility as an alternative. STUDY DESIGN: Observational service evaluation. METHODS: We conducted an observational service evaluation of seven-day daily contact testing using antigen lateral flow devices, (LFDs) at four acute hospital trusts and one ambulance trust in England. Mixed methods were employed, utilising aggregate and individual-level test monitoring data, semi-structured interviews, and a survey of eligible contacts. RESULTS: In total, 138 HCWs were identified as contacts of a confirmed SARS-CoV-2 case. Of these, 111 (80%) consented to daily LFD testing, of whom 82 (74%) completed the required programme without interruption, and 12 (11%) completed with interruption. Fifty-eight (52%) participants and two (7·4%) non-participants completed the survey. In total, 28 interviews were conducted with participants, site and infection control leads, and union representatives. One participant tested positive on LFD and polymerase chain reaction (PCR) test. Three participants tested positive on PCR but not LFD. DCT was well-accepted by trusts and staff. Participants reported no relaxation of their infection prevention and control behaviours. No incidents of transmission were detected. An estimated 729 potential days of work absence were averted. CONCLUSIONS: DCT can be acceptably operated in a healthcare setting, averting quarantine-related work absences in HCW SARS-CoV-2 contacts

Legislator dissent as a valence signal

Existing research suggests that voters tend to respond positively to legislator independence due to two types of mechanism. First, dissent has an indirect effect, increasing a legislator’s media coverage and personal recognition among constituents (profile effects). Second, constituents react positively to dissent when this signals that the legislator has matching political or representational preferences (conditional evaluation). We argue for a third effect: dissent acts as a valence signal of integrity and trustworthiness. Consistent with the valence signalling mechanism, we use new observational and experimental evidence to show that British voters have a strong and largely unconditional preference for legislators who dissent. Our findings pose a dilemma for political systems which rely on strong and cohesive parties

Assessment of Acute and Chronic Pharmacological Effects on Energy Expenditure and Macronutrient Oxidation in Humans: Responses to Ephedrine

Evidence of active brown adipose tissue in human adults suggests that this may become a pharmacological target to induce negative energy balance. We have explored whole-body indirect calorimetry to detect the metabolic effects of thermogenic drugs through administration of ephedrine hydrochloride and have assessed ephedrine&apos;s merits as a comparator compound in the evaluation of novel thermogenic agents. Volunteers randomly given ephedrine hydrochloride 15 mg QID (n = 8) or placebo (n = 6) were studied at baseline and after 1-2 and 14-15 days of treatment. We demonstrate that overnight or 23-hour, 2% energy expenditure (EE) and 5% fat (FO) or CHO oxidation effects are detectable both acutely and over 14 days. Compared to placebo, ephedrine increased EE and FO rates overnight (EE 63 kJ day 2, EE 105 kJ, FO 190 kJ, day 14), but not over 23 h. We conclude that modest energy expenditure and fat oxidation responses to pharmacological interventions can be confidently detected by calorimetry in small groups. Ephedrine should provide reliable data against which to compare novel thermogenic compounds

Tobacco Arp3 is localized to actin-nucleating sites in vivo

The polarity of actin is a central determinant of intracellular transport in plant cells. To visualize actin polarity in living plant cells, the tobacco homologue of the actin-related protein 3 (ARP3) was cloned and a fusion with the red fluorescent protein (RFP) was generated. Upon transient expression of these fusions in the tobacco cell line BY-2 (Nicotiana tabacum L. cv. Bright Yellow 2), punctate structures were observed near the nuclear envelope and in the cortical plasma. These dots could be shown to decorate actin filaments by expressing RFP–ARP3 in a marker line, where actin was tagged by GFP (green fluorescent protein)–FABD (fimbrin actin-binding domain 2). When actin filaments were disrupted by latrunculin B or by prolonged cold treatment, and subsequently allowed to recover, the actin filaments reformed from the RFP–ARP3 structures, that therefore represented actin nucleation sites. The intracellular distribution of these sites was followed during the formation of pluricellular files, and it was observed that the density of RFP–ARP3 increased in the apex of the polarized, terminal cells of a file, whereas it was equally distributed in the central cells of a file. These findings are interpreted in terms of position-dependent differences of actin organization

Management of obesity in adults: European clinical practice guidelines

Stworzenie jednolitych wytycznych postępowania w otyłości jest złożone. Obejmują one zarówno zalecenia diagnostyczne, lecznicze, jak i działania w zakresie prewencji. Wobec wielu publikacji i różnic poglądów oraz świadomości krótkotrwałości efektu odchudzającego u poszczególnych osób wielu uważa, że trudno jest ustalić właściwe postępowanie w otyłości. Różnorodność zasad postępowania w kraju oraz pomiędzy regionami Europy utrudnia ustalenie i wprowadzenie standardów. W ustalaniu obecnych wytycznych za podstawę brano wiedzę opartą na dowodach (EBM), a w razie wątpliwości uzupełniano na podstawie doświadczenia klinicznego i różnorodności regionalnej oraz uzgodnionego stanowiska zespołu. W podsumowaniu stwierdzono, że: 1) lekarz jest odpowiedzialny za rozpoznanie otyłości jako choroby oraz pomoc w odpowiedniej prewencji i leczeniu; 2) leczenie powinno być oparte na dobrej praktyce klinicznej i EBM; 3) leczenie otyłości powinno wyznaczać indywidualne realne cele i dożywotnie postępowanie.The development of consensus guidelines for obesity is complex. It involves recommending both treatment interventions and interventions related to screening and prevention. With so many publications and claims, and with the awareness that success for the individual is short-lived, many find it difficult to know what action is appropriate in the management of obesity. Furthermore, the significant variation in existing service provision both within countries as well as across the regions of Europe makes a standardised approach, even if evidence-based, difficult to implement. In formulating these guidelines, we have attempted to use an evidence based approach while allowing flexibility for the practicing clinician in domains where evidence is currently lacking and ensuring that in treatment there is recognition of clinical judgment and of regional diversity as well as the necessity of an agreed approach by the individual and family. We conclude that 1) physicians have a responsibility to recognise obesity as a disease and help obese patients with appropriate prevention and treatment, 2) treatment should be based on good clinical care and evidence- based interventions and 3) obesity treatment should focus on realistic goals and lifelong management