Impact of obesity on operative treatment and inpatient outcomes of paediatric limb fractures.

AIMS: The aim of this study was to utilize a national paediatric inpatient database to determine whether obesity influences the operative management and inpatient outcomes of paediatric limb fractures. PATIENTS AND METHODS: The Kids' Inpatient Database (KID) was used to evaluate children between birth and 17 years of age, from 1997 and 2012, who had undergone open and closed treatment of humeral, radial and ulna, femoral, tibial, and ankle fractures. Demographics, hospital charges, lengths of stay (LOS), and complications were analyzed. RESULTS: Obesity was significantly associated with increased rates of open reduction and internal fixation (ORIF) for: distal humeral (odds ratio (OR) = 2.139, 95% confidence interval (CI) 1.92 to 3.44; p < 0.001); distal radius and ulna fractures (OR = 1.436, 95% CI 1.14 to 2.16; p < 0.05); distal femoral (OR = 2.051, 95% CI 1.69 to 3.60; p < 0.05); tibial and fibula shaft (OR = 2.101, 95% CI 2.10 to 3.50; p < 0.001); and ankle (OR = 1.733, 95% CI 1.70 to 2.39; p < 0.001). Older age was significantly associated with ORIF for all fractures (p < 0.05). LOS, hospital charges, and complications were significantly increased in obese patients following ORIF for upper and lower limb fractures (p < 0.05). CONCLUSION: Obese paediatric patients are more likely to undergo ORIF in both upper and lower limb fractures and have more inpatient complications. These findings may assist in informing obese paediatric fracture patients and their families regarding the increased risk for open operative fixation and associated outcomes. Cite this article: Bone Joint J 2019;101-B:491-496.

Correlation and prediction of a large blood-brain distribution data set--an LFER study.

We report linear free energy relation (LFER) models of the equilibrium distribution of molecules between blood and brain, as log BB values. This method relates log BB values to fundamental molecular properties, such as hydrogen bonding capability, polarity/polarisability and size. Our best model of this form covers 148 compounds, the largest set of log BB data yet used in such a model, resulting in R(2)=0.745 and e.s.d.=0.343 after inclusion of an indicator variable for carboxylic acids. This represents rather better accuracy than a number of previously reported models based on subsets of our data. The model also reveals the factors that affect log BB: molecular size and dispersion effects increase brain uptake, while polarity/polarisability and hydrogen-bond acidity and basicity decrease it. By splitting the full data set into several randomly selected training and test sets, we conclude that such a model can predict log BB values with an accuracy of less than 0.35 log units. The method is very rapid-log BB can be calculated from structure at a rate of 700 molecules per minute on a silicon graphics O(2).

Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure-activity relationship (QSAR) with the Abraham descriptors.

The human intestinal absorption of 241 drugs was evaluated. Three main methods were used to determine the human intestinal absorption: bioavailability, percentage of urinary excretion of drug-related material following oral administration, and the ratio of cumulative urinary excretion of drug-related material following oral and intravenous administration. The general solvation equation developed by Abraham's group was used to model the human intestinal absorption data of 169 drugs we considered to have reliable data. The model contains five Abraham descriptors calculated by the ABSOLV program. The results show that Abraham descriptors can successfully predict human intestinal absorption if the human absorption data is carefully classified based on solubility and administration dose to humans.

Estimation of molecular linear free energy relationship descriptors. 4. Correlation and prediction of cell permeation.

PURPOSE: The passage of molecules across cell membranes is a crucial step in many physiological processes. We therefore seek physical models of this process, in order to predict permeation for new molecules, and to better understand the important interactions which determine the rate of permeation. METHODS: Several sets of cell permeation data reported by Collander have been correlated against calculated Linear Free Energy Relation (LFER) descriptors. These descriptors, taken as the sum of fragmental contributions, cover the size, polarity, polarizabilty, and hydrogen bonding capacity of each molecule. RESULTS: For 36 values of permeation into Chara ceratophylla cells, a model (sd = 0.24) dominated by hydrogen bond acidity is found, while for 63 rates of permeation values into Nitella cells a very similar model yields sd = 0.46. Comparisons between the two cell types are made directly for 17 compounds in both data sets, indicate differences of a similar magnitude to the standard deviations of the above models. The two data sets can be combined to yield a generic model of rates of permeation into cells, resulting in an sd value of 0.46 for a total of 100 data points. CONCLUSIONS: Models allowing accurate prediction of cell permeation have been constructed using 100 experimental data. We demonstrate that hydrogen bond acidity is the dominating factor in determining cell permeation for two distinct species of algal cell.

Estimation of molecular linear free energy relationship descriptors by a group contribution approach. 2. Prediction of partition coefficients

A previously published method for the prediction of molecular linear free energy relationship descriptors is tested against experimentally determined partition coefficients in various solvent systems. Sets of partition data between water and octanol, cyclohexane, and chloroform were taken from the literature. For each set of partition data used, r2 values ranged from 0.8 to 0.9 and RMS errors from 0.7 to 1.0 log unit, comparable to errors obtained with previously published models for octanol-water partition. Modified solvation equations for water-octanol and water-cyclohexane partition are presented, and their implications discussed. The possibility of applying the current approach to a wide range of solvation and transport properties is put forward.

X-ray crystal structure of human dopamine sulfotransferase, SULT1A3. Molecular modeling and quantitative structure-activity relationship analysis demonstrate a molecular basis for sulfotransferase substrate specificity.

Humans are one of the few species that produce large amounts of catecholamine sulfates, and they have evolved a specific sulfotransferase, SULT1A3 (M-PST), to catalyze the formation of these conjugates. An orthologous protein has yet to be found in other species. To further our understanding of the molecular basis for the unique substrate selectivity of this enzyme, we have solved the crystal structure of human SULT1A3, complexed with 3'-phosphoadenosine 5'-phosphate (PAP), at 2.5 A resolution and carried out quantitative structure-activity relationship (QSAR) analysis with a series of phenols and catechols. SULT1A3 adopts a similar fold to mouse estrogen sulfotransferase, with a central five-stranded beta-sheet surrounded by alpha-helices. SULT1A3 is a dimer in solution but crystallized with a monomer in the asymmetric unit of the cell, although dimer interfaces were formed by interaction across crystallographic 2-fold axes. QSAR analysis revealed that the enzyme is highly selective for catechols, and catecholamines in particular, and that hydrogen bonding groups and lipophilicity (cLogD) strongly influenced K(m). We also investigated further the role of Glu(146) in SULT1A3 using site-directed mutagenesis and showed that it plays a key role not only in defining selectivity for dopamine but also in preventing many phenolic xenobiotics from binding to the enzyme.

Correlation and estimation of gas-chloroform and water-chloroform partition coefficients by a linear free energy relationship method.

A linear free energy relationship, LFER, has been used to correlate 150 values of gas-chloroform partition coefficients, as log Lchl with a standard deviation, sd, of 0.23 log units, a correlation coefficient r2 of 0.985, and an F-statistic of 1919. The equation reveals that bulk chloroform is dipolar/polarizable, of little hydrogen-bond basicity, but as strong a hydrogen-bond acid as bulk methanol or bulk ethanol. However, the main influence on gaseous solubility in chloroform is due to solute-solvent London dispersion interactions. A slightly modified LFER has been used to correlate 302 values of water-chloroform partition coefficients, as log Pchl. The correlation equation predicts log Pchl for a further 34 compounds not used in the equation with sd = 0.17 log units. When the LFER is applied to all 335 log Pchl values, the resulting equation has sd = 0.25, r2 = 0.971, and F = 2218.

A quantitative structure-activity relationship approach to the minimization of albumin binding.

The binding of 2,6-disubstituted xanthones to human serum albumin (HSA) has been investigated using an ultrafiltration technique. A set of 26 compounds was chosen for study using a selection procedure aimed at minimizing the interparameter correlations, while ensuring that the physicochemical properties covered the maximum possible range of values. The magnitude of binding has been expressed as the compound concentration required to produce a specified bound concentration, in preference to equilibrium constants and number of albumin binding sites. Albumin binding was found to have a nonlinear dependence on the octanol-water partition coefficient (log P) and has been rationalized in terms of a simple binding model.

A method for the comparative assessment of antioxidants as peroxyl radical scavengers.

Antioxidants which are peroxyl radical scavengers have been compared in a model of lipid peroxidation based on the oxidation of a suspension of linoleic acid initiated by a thermolabile azo compound. By analysing the effect of antioxidant concentration on linoleic acid peroxidation we have defined the constant kAH which characterises the rate of the reaction of the antioxidant with the peroxyl radical. This allows quantitative comparison of the efficiency of different antioxidants as peroxyl radical scavengers. By using an initiation system which is not iron dependent we were able to show that the iron chelators desferrioxamine, BW A4C and U74500A are also peroxyl radical scavengers.