The role of plasma concentrations and drug characteristics of beta-blockers in fall risk of older persons.

Beta-blocker usage is inconsistently associated with increased fall risk in the literature. However, due to age-related changes and interindividual heterogeneity in pharmacokinetics and dynamics, it is difficult to predict which older adults are more at risk for falls. Therefore, we wanted to explore whether elevated plasma concentrations of selective and nonselective beta-blockers are associated with an increased risk of falls in older beta-blocker users. To answer our research question, we analyzed samples of selective (metoprolol, n = 316) and nonselective beta-blockers (sotalol, timolol, propranolol, and carvedilol, n = 179) users from the B-PROOF cohort. The associations between the beta-blocker concentration and time to first fall were assessed using Cox proportional hazard models. Change of concentration over time in relation to fall risk was assessed with logistic regression models. Models were adjusted for potential confounders. Our results showed that above the median concentration of metoprolol was associated with an increased fall risk (HR 1.55 [1.11-2.16], p = .01). No association was found for nonselective beta-blocker concentrations. Also, changes in concentration over time were not associated with increased fall risk. To conclude, metoprolol plasma concentrations were associated with an increased risk of falls in metoprolol users while no associations were found for nonselective beta-blockers users. This might be caused by a decreased ß1-selectivity in high plasma concentrations. In the future, beta-blocker concentrations could potentially help clinicians estimate fall risk in older beta-blockers users and personalize treatment.

Are higher antidepressant plasma concentrations associated with fall risk in older antidepressant users?

PURPOSE: Antidepressants are well-established fall-risk increasing drugs (FRIDs) and therefore falls should be considered an important adverse drug event (ADE) of antidepressants. However, not all antidepressant users experience fall incidents and factors associated with increased fall risk among antidepressant users are incompletely understood. Our objective was to explore whether antidepressant plasma concentrations are associated with falls in older antidepressant users. METHODS: For this study, we included antidepressant users of the multicenter B-PROOF study. Fall incidents were recorded prospectively using fall calendars. Antidepressant plasma concentrations were analyzed by Liquid chromatography-mass spectrometry (LC-MS) at baseline and at 2 years follow-up. The associations between the observed antidepressant concentration and fall risk were assessed using Cox proportional hazard and logistic regression models and adjusted for potential confounders. RESULTS: In total 93 selective serotonin reuptake inhibitor (SSRI) and 41 antidepressant (TCA) users were identified. There was a significant association between baseline TCA plasma concentration and fall risk within users (HR 2.50, 95% CI 1.07-5.87, crude model). In the adjusted model, there were no significant associations between concentrations of SSRIs and fall risk. CONCLUSION: There might be an association between plasma concentrations of TCAs and the risk of falling in older users. However, these results needs to be interpreted with caution considering the small sample size and accompanying limitation of confinement to crude analyses. Therefore, these novel findings need to replicated in a larger cohort, preferably including adjustment for potential confounders and more frequent measures of plasma concentrations is needed.

Treatment of third-degree burn wounds in animal specimens: acellular dermis or partial-thickness skin graft.

Several dermal products have been introduced to substitute dermal tissues. In this study we review the effects of these products on repairing third-degree burn wounds and managing complications in animal specimens. Using an interventional approach, rats were randomly assigned to four groups (G1 to G4). Two wounds were created on the back of each rat. An open wound was left on the back of rats in G1; in G2, wounds were covered with a thick rat derived-ADM product and overlying thin skin graft; on G3 rats, similar third degree ulcers were made with one ulcer covered with harvested thin skin graft. In G4, ulcers were covered with a thin rat derived-ADM product and thin graft. Factors such as take rate, histopathological score, wound contracture and graft contracture were compared on the 7th, 15th, 21st and 30th day. Mean graft take rate on the 30th day in the thick ADM, thin ADM and graft group showed a significant difference (p=0.015). Histopathological score on the 30th day in the thin ADM, thick ADM and graft group showed no considerable difference. Mean graft take rate was significantly better in the thin ADM and graft group than in the thick ADM group. Wound contracture was significantly more severe in the thick ADM and control group than in the thin ADM and graft group.

Plusieurs produits ont été introduits dans le but de substituer le derme. Dans cette étude, nous avons étudié l'effet de ces produits sur la cicatrisation et la gestion des complications après brûlure expérimentale. Nous avons étudié 4 groupes (G1 à G4) de rats ayant subi deux brûlures du dos. Celles de G1 étaient laissées à l'air, G2 recevaient un Derme Artificiel Acellulaire (DAA) dérivé de rats épais recouvert d'une greffe fine, G3 recevaient une greffe conservée, G4 recevaient DAA fin et greffe fine. Le taux de prise de greffe, le score histologique, la rétraction de la brûlure et de la greffe ont été comparés à J7, J15, J21 et J30. A J30, les taux de prise de greffe étaient significativement différents entre G2, G3 et G4 (p=0,015), étant moins bons en cas d'utilisation de DAA en couche épaisse. De même, la rétraction était plus intense après utilisation de DAA en couche épaisse qu'en couche fine ou après greffe seule. Les résultats histologiques étaient comparables.

BMI and Body Fat Mass Is Inversely Associated with Vitamin D Levels in Older Individuals.

OBJECTIVE: To assess the association between obesity (measured by Body Mass Index (BMI) and fat percentage) and serum 25(OH)D levels in older persons. DESIGN: Cross-sectional analysis of data from 'the B-PROOF study' (B-vitamins for the Prevention Of Osteoporotic Fractures). PARTICIPANTS: 2842 participants aged 65 years and older. MEASUREMENTS: BMI and fat percentage, measured by Dual Energy X-ray, and serum 25(OH)D levels. RESULTS: Mean age was 74 years (6.5 SD), with 50% women. Mean serum 25(OH)D levels were 55.8 nmol/L (25 SD). BMI and total body fat percentage were significant inversely associated with serum 25(OH)D levels after adjustment for confouders (ß-0.93; 95% CI [-1.15; -0.71], p<0.001 and ß-0.84; 95% CI [-1.04; -0.64], p<0.001). This association was most prominent in individuals with a BMI in the 'overweight' and 'obesity' range (ß -1.25 and -0.96 respectively) and fat percentage in the last two upper quartiles (ß-1.86 and -1.37 respectively). CONCLUSION: In this study, higher BMI and higher body fat percentage were significantly associated with lower serum 25(OH)D levels in older persons. This association was particularly present in individuals with overweight, and higher fat percentages, suggesting that these persons are at increased risk of vitamin D insufficiency.

Statistical physics of loopy interactions: independent-loop approximation and beyond.

We consider an interacting system of spin variables on a loopy interaction graph, identified by a tree graph and a set of loopy interactions. We start from a high-temperature expansion for loopy interactions represented by a sum of non-negative contributions from all the possible frustration-free loop configurations. We then compute the loop corrections using different approximations for the nonlocal loop interactions induced by the spin correlations in the tree graph. For distant loopy interactions, we can exploit the exponential decay of correlations in the tree interaction graph to compute loop corrections within an independent-loop approximation. Higher orders of the approximation are obtained by considering the correlations between the nearby loopy interactions involving larger number of spin variables. In particular, the sum over the loop configurations can be computed "exactly" by the belief propagation algorithm in the low orders of the approximation as long as the loopy interactions have a tree structure. These results might be useful in developing more accurate and convergent message-passing algorithms exploiting the structure of loopy interactions.

Patterned and disordered continuous Abelian sandpile model.

We study critical properties of the continuous Abelian sandpile model with anisotropies in toppling rules that produce ordered patterns on it. Also, we consider the continuous directed sandpile model perturbed by a weak quenched randomness, study critical behavior of the model using perturbative conformal field theory, and show that the model has a random fixed point.

Direct evidence for conformal invariance of avalanche frontiers in sandpile models.

Appreciation of stochastic Loewner evolution (SLE_{kappa}) , as a powerful tool to check for conformal invariant properties of geometrical features of critical systems has been rising. In this paper we use this method to check conformal invariance in sandpile models. Avalanche frontiers in Abelian sandpile model are numerically shown to be conformally invariant and can be described by SLE with diffusivity kappa=2 . This value is the same as value obtained for loop-erased random walks. The fractal dimension and Schramm's formula for left passage probability also suggest the same result. We also check the same properties for Zhang's sandpile model.

Simplifying random satisfiability problems by removing frustrating interactions.

How can we remove some interactions (generate shorter clauses) in a constraint satisfaction problem (CSP) such that it still remains satisfiable? In this paper we study a modified survey propagation algorithm that enables us to address this question for a prototypical CSP, i.e., random K-satisfiability problem. The average number of removed interactions is controlled by a tuning parameter in the algorithm. If the original problem is satisfiable then we are able to construct satisfiable subproblems ranging from the original one to a minimal one with minimum possible number of interactions. The minimal satisfiable subproblems will directly provide the solutions of the original problem.

Biased random satisfiability problems: from easy to hard instances.

In this paper we study biased random K -satisfiability ( K -SAT) problems in which each logical variable is negated with probability p . This generalization provides us a crossover from easy to hard problems and would help us in a better understanding of the typical complexity of random K -SAT problems. The exact solution of 1-SAT case is given. The critical point of K -SAT problems and results of replica method are derived in the replica symmetry framework. It is found that in this approximation alpha(c) proportional p(-(K-1)) for p --> 0. Solving numerically the survey propagation equations for K = 3 we find that for p < p* approximately 0.17 there is no replica symmetry breaking and still the SAT-UNSAT transition is discontinuous.

Laser mass spectrometry of oligonucleotides with isomer matrices.

Various isomer matrices were used for laser-desorption ionization of mixtures of oligomers. It was found that the efficiency of production of oligomer ions changed drastically when different isomers were used as matrices. For selected matrix materials, parent oligomer ions with sizes up to 64 bases were observed.

A novel family of progesterone-induced, retinol-binding proteins from uterine secretions of the pig.

Two-dimensional polyacrylamide gel electrophoresis has revealed the presence of a group of relatively acidic proteins of molecular weight about 22,000 in the uterine flushings of pseudopregnant pigs. The proteins have been purified by a combination of gel filtration chromatography and high performance anion-exchange chromatography and shown to bind both [3H] retinol and [3H]retinoic acid. At least four protein peaks that bound retinoids could be detected in the uterine secretions of a single pig. The ion-exchange procedure also allowed the retinol-free apoproteins to be separated from the holoforms that had associated ligand. Amino acid sequencing of the NH2 termini of polypeptides within three of the peaks revealed the presence of proteins with some degree of sequence identity to serum retinol-binding proteins (RBP). The most basic polypeptides showed the least similarity (about 30% identity), while the most acidic isoform analyzed shared about 70% sequence identity with the NH2 terminus of human serum RBP. Western blotting procedures employing an antiserum raised against the most basic isoforms showed that the amount of retinol-binding protein in uterine secretions increased markedly in ovariectomized animals in response to long term progesterone treatment. These proteins appear to form part of the uterine histotroph thought to be essential for nourishment of the conceptuses during pregnancy. A simple three-step procedure for purifying retinol-binding protein from pig serum is also described. The NH2-terminal sequence of this RBP is similar to that of human RBP but different from those of the uterine forms. The study suggests that a family of RBP, distinct from the serum form, is secreted by the uterine endometrium of the pig in response to progesterone.

Effects of cyclosporine on magnesium metabolism in rats.

Earlier studies have revealed hypomagnesemia with cyclosporine treatment in renal and bone marrow transplant recipients. The present study was designed to investigate the possible effect of cyclosporine on Mg metabolism in normal rats. Sprague-Dawley rats were randomized into the cyclosporine group, which was given 15 mg/kg/day cyclosporine by gastric gavage, and the control group, which received the vehicle alone. Food intake, body weight, serum concentration, urinary excretion, fecal excretion, and tissue content of Mg were determined weekly for 3 weeks. In addition, intestinal absorption of Mg was determined by using in vivo perfusion. Serum Mg concentration fell significantly after 1 week of cyclosporine treatment and remained low throughout the observation period. This was associated with reduced food intake and renal Mg conservation during the first week but normal food intake and severe renal Mg wasting thereafter. In vivo perfusion studies performed at 1 and 3 weeks showed no significant difference in intestinal absorption of Mg between the two groups, thereby excluding intestinal malabsorption as a possible culprit. Likewise, fecal Mg excretion showed no significant difference in the two groups. It was surprising that tissue Mg content (in muscle, liver, and kidney) was increased in the cyclosporine-treated group at 3 weeks. We conclude that cyclosporine administration in rats leads to a fall in serum Mg concentration primarily as a result of renal Mg wasting and possibly as a result of a shift of Mg to the tissue compartments with no discernible effect on gastrointestinal handling of Mg.