1031-35 Value of Ibopamine as Adjunct to Maximal Oral Medication in Patients with Moderately Severe Congestive Heart Failure; a Double-Blind, Placebo-controlled Study

Multiple drug therapy, including ACE inhibitors, diuretics, vasodilators and digoxin is currently used to reduce signs and symptoms of chronic heart failure (CHF). Optimal treatment of these patients (pts) is a major clinical problem, as the prevalence of CHF increases. Ibopamine, a novel oral dopamine agonist with peripheral vasodilating and neurohumoral inhibiting effects, may have additive value in the treatment of pts with moderately severe CHF, already treated with ACE-inhibitors.To evaluate the additive value of ibopamine as adjunctive to maximal CHF treatment we studied 60 pts with NYHA class III-IV CHF, who were assigned to treatment with ibopamine (3 dd 100mg) or placebo in a double-blind, randomized fashion.We examined the effect of ibopamine on peak oxygen consumption (VO2), neurohumoral factors and cardiac arrhythmias during 48 hrs ECG monitoring. Neurohumoral parameters were determined at rest and during exercise and included serum norepinephrine, epinephrine, aldosterone and plasma renin activity. All assessments were made at baseline and after 12 weeks of study treatment.Baseline dataOf the 60 pts, 40 pts (67%) had ischemic heart disease andlor old myocardial infarction, and 20 (33%) non-ischemic heart disease (16 pts (27%) dilated myocardiopathy). Mean age was 63±10 years, left ventricular ejection fraction 0.23±0.08, peak VO2 15.0±2.4 ml/min/kg and 44 of the patients (73%) were male. Background CHF therapy included ACE-inhibitors (100%), diuretics (100%), and digoxin, nitrates, amiodarone when required. At baseline resting serum norepinephrine was 724±78pg/ml, epinephrine 68±17pg/ml, aldosterone 0.50±0.08nmol/l and plasma renin activity 5.7±0.9ng/ml/hr.ResultsThe study was recently completed, the study data are currently analyzed and the results will be presented at the meeting

Sex Differences in the Association Between Serum Testosterone and Kidney Function in the General Population

Introduction: Testosterone might prevent kidney function decline, although evidence is limited in men and lacking in women from the general population. We investigated the association between serum testosterone and kidney function in men and women from a large population-based cohort study. Methods: Participants aged ≥45 years with available measurements of serum testosterone, sex hormone-binding globulin (SHBG), creatinine, and cystatine C were included. Assessments of kidney function included baseline assessments of the estimated glomerular filtration rate (eGFR) based on serum creatinine (eGFRcreat) or serum cystatin C (eGFRcys), and the urine albumin-to-creatinine ratio (ACR), and repeated assessments of eGFRcreat. Linear regression and linear mixed models were used to assess the associations of serum free and total testosterone with kidney function, stratified for sex. Results: A total of 4095 men and 5389 women (mean age 65.2 years) were included. In men, higher free testosterone was associated with lower eGFRcreat (beta −0.63, 95% confidence interval [CI]: −1.05; −0.21), higher eGFRcys (beta 0.56, 95% CI: 0.07; 1.05), and lower ACR (beta −0.25, 95% CI: −0.35; −0.16) at baseline. Higher total testosterone was associated with higher baseline and follow-up eGFRcreat, and with lower eGFRcreat when additionally adjusted for SHBG. In women, higher free testosterone was associated with lower baseline eGFRcreat and eGFRcys (beta −1.03, 95% CI: −1.36; −0.71; beta −1.07, 95% CI: −1.44; −0.70; respectively) and lower eGFRcreat over time (beta −0.78, 95% CI: −1.10; −0.46), but not with ACR. Conclusions: eGFRcys might be a better parameter than eGFRcreat for the association of testosterone with kidney function, although further studies investigating this are needed. Furthermore, we identified sex differences in the association between testosterone and kidney function, with a positive association in men and a negative association in women.</p

Effects of correcting metabolic acidosis on muscle mass and functionality in chronic kidney disease:a systematic review and meta-analysis

Metabolic acidosis unfavourably influences the nutritional status of patients with non-dialysis dependent chronic kidney disease (CKD) including the loss of muscle mass and functionality, but the benefits of correction are uncertain. We investigated the effects of correcting metabolic acidosis on nutritional status in patients with CKD in a systematic review and meta-analysis. A search was conducted in MEDLINE and the Cochrane Library from inception to June 2023. Study selection, bias assessment, and data extraction were independently performed by two reviewers. The Cochrane risk of bias tool was used to assess the quality of individual studies. We applied random effects meta-analysis to obtain pooled standardized mean difference (SMD) and 95% confidence intervals (CIs). We retrieved data from 12 intervention studies including 1995 patients, with a mean age of 63.7 ± 11.7 years, a mean estimated glomerular filtration rate of 29.8 ± 8.8 mL/min per 1.73 m2, and 58% were male. Eleven studies performed an intervention with oral sodium bicarbonate compared with either placebo or with standard care and one study compared veverimer, an oral HCl-binding polymer, with placebo. The mean change in serum bicarbonate was +3.6 mEq/L in the intervention group and +0.4 mEq/L in the control group. Correcting metabolic acidosis significantly improved muscle mass assessed by mid-arm muscle circumference (SMD 0.35 [95% CI 0.16 to 0.54], P &lt; 0.001) and functionality assessed with the sit-to-stand test (SMD −0.31 [95% CI −0.52 to 0.11], P = 0.003). We found no statistically significant effects on dietary protein intake, handgrip strength, serum albumin and prealbumin concentrations, and blood urea nitrogen. Correcting metabolic acidosis in patients with CKD improves muscle mass and physical function. Correction of metabolic acidosis should be considered as part of the nutritional care for patients with CKD.</p

Early human brain development:insights into macroscale connectome wiring

BACKGROUND: Early brain development is closely dictated by distinct neurobiological principles. Here, we aimed to map early trajectories of structural brain wiring in the neonatal brain. METHODS: We investigated structural connectome development in 44 newborns, including 23 preterm infants and 21 full-term neonates scanned between 29 and 45 postmenstrual weeks. Diffusion-weighted imaging data were combined with cortical segmentations derived from T2 data to construct neonatal connectome maps. RESULTS: Projection fibers interconnecting primary cortices and deep gray matter structures were noted to mature faster than connections between higher-order association cortices (fractional anisotropy (FA) F = 58.9, p < 0.001, radial diffusivity (RD) F = 28.8, p < 0.001). Neonatal FA-values resembled adult FA-values more than RD, while RD approximated the adult brain faster (F = 358.4, p < 0.001). Maturational trajectories of RD in neonatal white matter pathways revealed substantial overlap with what is known about the sequence of subcortical white matter myelination from histopathological mappings as recorded by early neuroanatomists (mean RD 68 regions r = 0.45, p = 0.008). CONCLUSION: Employing postnatal neuroimaging we reveal that early maturational trajectories of white matter pathways display discriminative developmental features of the neonatal brain network. These findings provide valuable insight into the early stages of structural connectome development

Successful control of a hospital-wide outbreak of OXA-48 producing Enterobacteriaceae in the Netherlands, 2009 to 2011

On 31 May 2011, after notification of Klebsiella pneumoniae(KP)(OXA-48);(CTX-M-15) in two patients, nosocomial transmission was suspected in a Dutch hospital. Hospital-wide infection control measures and an outbreak investigation were initiated. A total of 72,147 patients were categorised into groups based on risk of OXA-48 colonisation or infection, and 7,527 were screened for Enterobacteriaceae(OXA-48) by polymerase chain reaction (PCR). Stored KP isolates (n=408) were retrospectively tested for OXA-48 and CTX-M-1 group extended-spectrum beta-lactamases (ESBL). 285 KP isolates from retrospective and prospective patient screening were genotyped by amplified fragment length polymorphism (AFLP). 41 isolates harbouring different Enterobacteriaceae species were analysed by plasmid multilocus sequence typing (pMLST). No nosocomial transmission of Enterobacteriaceae(OXA-48) was detected after 18 July 2011. Enterobacteriaceae(OXA-48) were found in 118 patients (KP (n=99), Escherichia coli (n=56), >= 1 Enterobacteriaceae(OXA-48) species (n=52)),of whom 21 had clinical infections. 39/41 (95%) of OXA-48 containing plasmids were identical in pMLST. Minimum inhibitory concentrations (MICs) of KPOXA-48 and E. coli(OXA-48) for imipenem and meropenem ranged from = 16 mg/L, and 153/157 (97%) had MIC >0.25mg/L for ertapenem. AFLP identified a cluster of 203 genetically linked isolates (62 KPOXA-48;(CTX-M15); 107 KPCTX-M-15; 34 KPOXA-48). The 'oldest' KPCTX-M-15 and KPOXA-48 clonal types originated from February 2009 and September 2010, respectively. The last presumed outbreak-related KPOXA-48 was detected in April 2012. Uncontrolled transmission of KP (CTX-M-15) evolved into a nosocomial outbreak of KPOXA-48; CTX-M15 with large phenotypical heterogeneity. Although the outbreak was successfully controlled, the contribution of individual containment measures and of the hospital relocating into a new building just before outbreak notification was impossible to quantify

Subunit-selective proteasome activity profiling uncovers uncoupled proteasome subunit activities during bacterial infections

The proteasome is a nuclear‐cytoplasmic proteolytic complex involved in nearly all regulatory pathways in plant cells. The three different catalytic activities of the proteasome can have different functions, but tools to monitor and control these subunits selectively are not yet available in plant science. Here, we introduce subunit‐selective inhibitors and dual‐color fluorescent activity‐based probes for studying two of the three active catalytic subunits of the plant proteasome. We validate these tools in two model plants and use this to study the proteasome during plant–microbe interactions. Our data reveal that Nicotiana benthamiana incorporates two different paralogs of each catalytic subunit into active proteasomes. Interestingly, both β1 and β5 activities are significantly increased upon infection with pathogenic Pseudomonas syringae pv. tomato DC3000 lacking hopQ1‐1 [PtoDC3000(ΔhQ)] whilst the activity profile of the β1 subunit changes. Infection with wild‐type PtoDC3000 causes proteasome activities that range from strongly induced β1 and β5 activities to strongly suppressed β5 activities, revealing that β1 and β5 activities can be uncoupled during bacterial infection. These selective probes and inhibitors are now available to the plant science community, and can be widely and easily applied to study the activity and role of the different catalytic subunits of the proteasome in different plant species.Bio-organic Synthesi

Grafted ionomer complexes and their effect on protein adsorption on silica and polysulfone surfaces

We have studied the formation and the stability of ionomer complexes from grafted copolymers (GICs) in solution and the influence of GIC coatings on the adsorption of the proteins β-lactoglobulin (β-lac), bovine serum albumin (BSA), and lysozyme (Lsz) on silica and polysulfone. The GICs consist of the grafted copolymer PAA28-co-PAPEO22 {poly(acrylic acid)-co-poly[acrylate methoxy poly(ethylene oxide)]} with negatively charged AA and neutral APEO groups, and the positively charged homopolymers: P2MVPI43 [poly(N-methyl 2-vinyl pyridinium iodide)] and PAH∙HCl160 [poly(allylamine hydrochloride)]. In solution, these aggregates are characterized by means of dynamic and static light scattering. They appear to be assemblies with hydrodynamic radii of 8 nm (GIC-PAPEO22/P2MVPI43) and 22 nm (GIC-PAPEO22/PAH∙HCl160), respectively. The GICs partly disintegrate in solution at salt concentrations above 10 mM NaCl. Adsorption of GICs and proteins has been studied with fixed angle optical reflectometry at salt concentrations ranging from 1 to 50 mM NaCl. Adsorption of GICs results in high density PEO side chains on the surface. Higher densities were obtained for GICs consisting of PAH∙HCl160 (1.6 ÷ 1.9 chains/nm2) than of P2MVPI43 (0.6 ÷ 1.5 chains/nm2). Both GIC coatings strongly suppress adsorption of all proteins on silica (>90%); however, reduction of protein adsorption on polysulfone depends on the composition of the coating and the type of protein. We observed a moderate reduction of β-lac and Lsz adsorption (>60%). Adsorption of BSA on the GIC-PAPEO22/P2MVPI43 coating is moderately reduced, but on the GIC-PAPEO22/PAH∙HCl160 coating it is enhanced

Formation and structure of ionomer complexes from grafted polyelectrolytes

We discuss the structure and formation of Ionomer Complexes formed upon mixing a grafted block copolymer (poly(acrylic acid)-b-poly(acrylate methoxy poly(ethylene oxide)), PAA21-b-PAPEO14) with a linear polyelectrolyte (poly(N-methyl 2-vinyl pyridinium iodide), P2MVPI), called grafted block ionomer complexes (GBICs), and a chemically identical grafted copolymer (poly(acrylic acid)-co-poly(acrylate methoxy poly(ethylene oxide)), PAA28-co-PAPEO22) with a linear polyelectrolyte, called grafted ionomer complexes (GICs). Light scattering measurements show that GBICs are much bigger (~70–100 nm) and GICs are much smaller or comparable in size (6–22 nm) to regular complex coacervate core micelles (C3Ms). The mechanism of GICs formation is different from the formation of regular C3Ms and GBICs, and their size depends on the length of the homopolyelectrolyte. The sizes of GBICs and GICs slightly decrease with temperature increasing from 20 to 65 °C. This effect is stronger for GBICs than for GICs, is reversible for GICs and GBIC-PAPEO14/P2MVPI228, and shows some hysteresis for GBIC-PAPEO14/P2MVPI43. Self-consistent field (SCF) calculations for assembly of a grafted block copolymer (having clearly separated charged and grafted blocks) with an oppositely charged linear polyelectrolyte of length comparable to the charged copolymer block predict formation of relatively small spherical micelles (~6 nm), with a composition close to complete charge neutralization. The formation of micellar assemblies is suppressed if charged and grafted monomers are evenly distributed along the backbone, i.e., in case of a grafted copolymer. The very large difference between the sizes found experimentally for GBICs and the sizes predicted from SCF calculations supports the view that there is some secondary association mechanism. A possible mechanism is discussed