Effect of site of lactate infusion on regional lactate exchange in pigs

Background The rate of extra-hepatic lactate production and the route of influx of lactate to the liver may influence both hepatic and extra-hepatic lactate exchange. We assessed the dose-response of hepatic and extra-hepatic lactate exchange during portal and central venous lactate infusion. Methods Eighteen pigs randomly received either portal (n=5) or central venous (n=7) lactate infusion or saline (n=6). Sodium lactate was infused at 33, 66, 99, and 133 µmol kg−1 min−1 for 20 min each. Systemic and regional abdominal blood flows and plasma lactate were measured at 20 min intervals until 1 h post-infusion, and regional lactate exchange was calculated (area under lactate uptake-time curve). Results Total hepatic lactate uptake [median (95% confidence interval)] during the experimental protocol (140 min) was higher during portal [8198 (5487-12 798) µmol kg−1] than during central venous lactate infusion [4530 (3903-5514) µmol kg−1, P<0.05]. At a similar hepatic lactate delivery (∼400 µmol kg−1 min−1), hepatic lactate uptake [mean and standard deviation (sd)] was higher during portal [118 (sd 55) µmol kg−1 min−1] than during central venous lactate infusion [44 (12) µmol kg−1 min−1, P<0.05]. Time courses of arterial lactate concentrations and lactate uptake at other measured regions were similar in both groups. Conclusions Higher hepatic lactate uptake during portal compared with central venous lactate infusion at a similar total hepatic lactate influx underlines the role of portal vein lactate concentration in total hepatic lactate uptake capacity. Arterial lactate concentration does not depend on the site of lactate infusion. At higher arterial lactate concentrations, all regions participated in lactate uptak

Photodynamische Therapie bei altersbedingter Makuladegeneration am schlechteren und besseren Auge

Zusammenfassung: Hintergrund: Die PDT ist die Standardbehandlung vieler Formen der exsudativen bzw. neovaskulären Makuladegeneration (AMD). Trotz Therapie fällt die Sehschärfe häufig in den Low-vision-Bereich ab. Die Kosteneffizienz der Therapie am schlechteren Auge wird daher kontrovers diskutiert. Patienten und Methoden: Retrospektive Fallkontrollstudie aller Patienten, welche zwischen September 1999 und November 2004 am Universitätsspital Zürich eine PDT erhalten haben. Die Situation bei Präsentation und der Verlauf unter Therapie wurden bei ersten (schlechteren) und zweiten (besseren) Augen verglichen. Ergebnisse: In 117/228Fällen (51,3%) war der Visus am behandelten Auge bei Präsentation besser (oder gleich) als der Visus am Partnerauge. Der Visus vor Behandlung betrug bei den besseren Augen im Mittel 0,58±0,27logMAR [Snellen: 0,26 (0,14-0,49)] und 0,69±0,4logMAR [Snellen 0,20 (0,08-0,51)] bei den schlechteren Augen (p=0,015). Nach Behandlung bestand zwischen den Gruppen weder bezüglich Visus bzw. Visusveränderung noch bezüglich Membrangröße bzw. Größenveränderung der Membran ein signifikanter Unterschied. Schlussfolgerung: Die Resultate nach PDT sind beim zweiten (bzw. besseren) Auge nicht signifikant besser als beim ersten (bzw. schlechteren) Aug

Endocrine hormone imbalance in heart failure with reduced ejection fraction: A cross-sectional study

BACKGROUND AND AIMS Sustained neurohormonal activation plays a central role in the progression of heart failure (HF). Other endocrine axes may also be affected. It was the aim of this study to examine the endocrine profile (thyroid, parathyroid, glucocorticoid, and sex hormones) in a contemporary sample of patients with HF and reduced ejection fraction (EF) on established disease-modifying therapy. METHODS This study prospectively measured morning fasting hormones in 52 ambulatory and stable HF patients with EF < 50% on disease-modifying therapy (mean age 63 ± 11 years, 29% female, mean LVEF 32 ± 9.6%) and compared them to 54 patients at elevated risk for HF (61 ± 12 years, 28% female) and 62 healthy controls (HC; 61 ± 13 years, 27% female). Main comparisons were performed using one-way analysis of variance. Associations with biomarkers were studied with linear regression. RESULTS HF patients showed a reduced free triiodothyronine (fT3)/free thyroxine (fT4) ratio compared to HC (0.30 ± 0.06 vs. 0.33 ± 0.05, p = 0.046). Parathyroid hormone (PTH) and cortisol were increased in HF compared to both HC (median [IQR] 59 [50-84] vs. 46 [37-52] ng/L, p < 0.001 and 497 ± 150 vs. 436 ± 108 nmol/L, p = 0.03, respectively) and patients at risk (both p < 0.001). Total testosterone was reduced in male HF compared to HC (14.4 ± 6.6 vs. 18.6 ± 5.3 nmol/L; p = 0.01). No differences in TSH, estradiol, progesterone, and prolactin were found. Lower fT3 levels were found in HF with EF < 40% versus EF 40%-49% (4.6 ± 0.3 vs. 5.2 ± 0.7 pmol/L, p = 0.009). In HF patients, fT3 was an independent predictor of NT-proBNP and high-sensitivity troponin T in multiple regression analysis. PTH was positively associated with NT-proBNP. CONCLUSION There is evidence of endocrine hormonal imbalance in HF with reduced EF beyond principal neurohormones and despite the use of disease-modifying therapy

Age-dependent impairment of the erythropoietin response to reduced central venous pressure in HFpEF patients

Despite growing research interest in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), it remains unknown whether central hemodynamic alterations inherently present in this condition do affect blood pressure and blood volume (BV) regulation. The present study sought to determine hemodynamic and endocrine responses to prolonged orthostatic stress in HFpEF patients. Central venous pressure (CVP) assessed via the internal jugular vein (IJV) aspect ratio with ultrasonography, arterial pressure and heart rate were determined at supine rest and during 2 hours of moderate (25-30°) head-up tilt (HUT) in 18 stable HFpEF patients (71.2 ± 7.3 years), 14 elderly (EC), and 10 young (YC) healthy controls. Parallel endocrine measurements comprised main BV-regulating hormones: pro-atrial natriuretic peptide, copeptin, aldosterone, and erythropoietin (EPO). At supine rest, the IJV aspect ratio was higher (>30%) in HFpEF patients compared with EC and YC, while mean arterial pressure was elevated in HFpEF patients (98.0 ± 13.1 mm Hg) and EC (95.6 ± 8.3 mm Hg) versus YC (87.3 ± 5.0 mm Hg) (P < 0.05). HUT increased heart rate (+10%) and reduced the IJV aspect ratio (-52%), with similar hemodynamic effects in all groups (P for interaction ≥ 0.322). The analysis of endocrine responses to HUT revealed a group×time interaction for circulating EPO, which was increased in YC (+10%) but remained unaltered in HFpEF patients and EC. The EPO response to a given reduction in CVP is similarly impaired in HFpEF patients and elderly controls, suggesting an age-dependent dissociation of EPO production from hemodynamic regulation in the HFpEF condition

Local and global modes of drug action in biochemical networks

It becomes increasingly accepted that a shift is needed from the traditional target-based approach of drug development to an integrated perspective of drug action in biochemical systems. We here present an integrative analysis of the interactions between drugs and metabolism based on the concept of drug scope. The drug scope represents the set of metabolic compounds and reactions that are potentially affected by a drug. We constructed and analyzed the scopes of all US approved drugs having metabolic targets. Our analysis shows that the distribution of drug scopes is highly uneven, and that drugs can be classified into several categories based on their scopes. Some of them have small scopes corresponding to localized action, while others have large scopes corresponding to potential large-scale systemic action. These groups are well conserved throughout different topologies of the underlying metabolic network. They can furthermore be associated to specific drug therapeutic properties

Three-year treatment outcomes of Aflibercept versus Ranibizumab for diabetic macular edema:: Data from the Fight Retinal Blindness! Registry

PURPOSE Compare the 3-year outcomes of ranibizumab versus aflibercept in eyes with diabetic macular edema in daily practice. METHODS This was a retrospective analysis of naive diabetic macular edema eyes starting intravitreal injections of ranibizumab (0.5 mg) or aflibercept (2 mg) from January 1, 2013 to December 31, 2017 that were collected in the Fight Retinal Blindness! Registry. RESULTS We identified 534 eyes (ranibizumab-267 and aflibercept-267) of 402 patients. The adjusted mean (95% confidence interval) visual acuity change of +1.3 (-0.1 to 4.2) letters in the ranibizumab group and +2.4 (-0.2 to 5.1) letters (P = 0.001) in the aflibercept group at 3 years was not clinically different. However, the adjusted mean CST change seemed to remain significantly different throughout the 3-year period with higher reductions in favor of aflibercept (-87.8 [-108.3 to -67.4] µm for ranibizumab vs. -114.4 [-134.4 to -94.3] for aflibercept; P < 0.01). When baseline visual impairment was moderate (visual acuity ≤68 Early Treatment Diabetic Retinopathy Study letters), we found a faster improvement in visual acuity in eyes treated with aflibercept up until 18 months of treatment than eyes treated with ranibizumab, which then stayed similar until 36 months of treatment, whereas there was no apparent difference when baseline visual impairment was mild (visual acuity ≥69 Early Treatment Diabetic Retinopathy Study letters). The rate of serious adverse events was low. CONCLUSION Aflibercept and ranibizumab were both effective and safe for diabetic macular edema over 3 years

Incidence, risk factors and outcomes of submacular haemorrhage with loss of vision in neovascular age-related macular degeneration in daily clinical practice: data from the FRB! registry

PURPOSE The main purpose of the study was to report the estimated incidence, cumulative rate, risk factors and outcomes of submacular haemorrhage (SMH) with loss of vision in neovascular age-related macular degeneration (nAMD) receiving intravitreal injections (IVT) of vascular endothelial growth factor (VEGF) inhibitor in routine clinical practice. METHODS Retrospective analysis of treatment-naïve eyes receiving IVTs of VEGF inhibitors (ranibizumab, aflibercept or bevacizumab) for nAMD from 1 January 2010 to 31 December 2020 that were tracked the Fight Retinal Blindness! registry. Estimated incidence, cumulative rate and hazard ratios (HR) of SMH with loss of vision during treatment were measured using the Poisson regression, Kaplan-Meier survival curves and Cox proportional hazard models. RESULTS We identified 7642 eyes (6425 patients) with a total of 135 095 IVT over a 10-year period. One hundred five eyes developed SMH with loss of vision with a rate of 1 per 1283 injections (0.08% 95% confidence interval [95% CI] [0.06; 0.09]). The estimated incidence [95% CI] was 4.6 [3.8; 5.7] SMH with loss of vision per year per 1000 treated patients during the study. The cumulative [95% CI] rate of SMH per patient did not increase significantly with each successive injection (p = 0.947). SMH cases had a mean VA drop of around 6 lines at diagnosis, which then improved moderately to a 4-line loss at 1 year. CONCLUSIONS Submacular haemorrhage (SMH) with loss of vision is an uncommon complication that can occur at any time in eyes treated for nAMD in routine clinical practice, with only limited recovery of vision 1 year later

Constraints from orbital motions around the Earth of the environmental fifth-force hypothesis for the OPERA superluminal neutrino phenomenology

It has been recently suggested by Dvali and Vikman that the superluminal neutrino phenomenology of the OPERA experiment may be due to an environmental feature of the Earth, naturally yielding a long-range fifth force of gravitational origin whose coupling with the neutrino is set by the scale M_*, in units of reduced Planck mass. Its characteristic length lambda should not be smaller than one Earth's radius R_e, while its upper bound is expected to be slightly smaller than the Earth-Moon distance (60 R_e). We analytically work out some orbital effects of a Yukawa-type fifth force for a test particle moving in the modified field of a central body. Our results are quite general since they are not restricted to any particular size of lambda; moreover, they are valid for an arbitrary orbital configuration of the particle, i.e. for any value of its eccentricity $e$. We find that the dimensionless strength coupling parameter alpha is constrained to |alpha| <= 1 10^-10-4 10^-9 for 1 R_e <= lambda <= 10 R_e by the laser data of the Earth's artificial satellite LAGEOS II, corresponding to M_* >= 4 10^9 -1.6 10^10. The Moon perigee allows to obtain |alpha| <= 3 10^-11 for the Earth-Moon pair in the range 15 R_e <= lambda = 3 10^10 - 4.5 10^10. Our results are neither necessarily limited to the superluminal OPERA scenario nor to the Dvali-Vikman model, in which it is M_* = 10^-6 at lambda = 1 R_e, in contrast with our bounds: they generally extend to any theoretical scenario implying a fifth-force of Yukawa-type.Comment: LaTex2e, 18 pages, 4 figures, 1 table, 81 reference

Time-varying signal analysis to detect high-altitude periodic breathing in climbers ascending to extreme altitude

This work investigates the performance of cardiorespiratory analysis detecting periodic breathing (PB) in chest wall recordings in mountaineers climbing to extreme altitude. The breathing patterns of 34 mountaineers were monitored unobtrusively by inductance plethysmography, ECG and pulse oximetry using a portable recorder during climbs at altitudes between 4497 and 7546 m on Mt. Muztagh Ata. The minute ventilation (VE) and heart rate (HR) signals were studied, to identify visually scored PB, applying time-varying spectral, coherence and entropy analysis. In 411 climbing periods, 30–120 min in duration, high values of mean power (MPVE) and slope (MSlopeVE) of the modulation frequency band of VE, accurately identified PB, with an area under the ROC curve of 88 and 89 %, respectively. Prolonged stay at altitude was associated with an increase in PB. During PB episodes, higher peak power of ventilatory (MPVE) and cardiac (MPLF HR) oscillations and cardiorespiratory coherence (MPLFCoher), but reduced ventilation entropy (SampEnVE), was observed. Therefore, the characterization of cardiorespiratory dynamics by the analysis of VE and HR signals accurately identifies PB and effects of altitude acclimatization, providing promising tools for investigating physiologic effects of environmental exposures and diseases.Peer ReviewedPostprint (author’s final draft