Incidence of Amblyopia and Its Risk Factors in Children With Isolated Metopic Craniosynostosis.

OBJECTIVE: Ophthalmic abnormalities in children with syndromic craniosynostosis have been reported previously, and referral of these children to a pediatric ophthalmologist is recommended. However, it is not as clear whether a child with nonsyndromic synostosis needs to be referred to a pediatric ophthalmologist. The aim of this study is to report the incidence of amblyopia and its risk factors in children with isolated metopic craniosynostosis. DESIGN: An institutional review board-approved, retrospective review was performed on 91 children diagnosed with isolated metopic craniosynostosis. Ophthalmologic records were reviewed for diagnoses of amblyopia, strabismus, and refractive error. RESULTS: Of the 91 children, 19 (20.9%) had astigmatism, eight (8.8%) had amblyopia, eight (8.8%) had strabismus, five had myopia (5.5%), five had hyperopia (5.5%), and five had anisometropia (5.5%). The incidence of amblyopia and its risk factors found in our study are higher than the rate found in the clinically normal pediatric population. CONCLUSIONS: In our patient population, children with isolated metopic craniosynostosis demonstrate an increased rate of amblyopia and its risk factors. Amblyopia is best treated early in life to achieve a successful outcome. A referral to a pediatric ophthalmologist for a formal eye exam and potential treatment is therefore recommended for children with isolated metopic craniosynostosis.

Does the use of particulate bone graft increase the incidence of postoperative infection in surgery for craniosynostosis?

OBJECTIVE: The use of particulate bone graft (PBG) has become an accepted technique for filling cranial defects created during cranial vault expansion for craniosynostosis. However, the use of PBG may be a risk factor for postoperative infection. The aim of this study was to compare the rate of postoperative infection in patients who received particulate bone graft (PBG+) with that in patients who did not (PBG-). DESIGN: An Institutional Review Board-approved, retrospective, cohort study of consecutive patients was performed. Twenty-seven consecutive patients in the PBG- group were compared with 21 consecutive patients in the PBG+ group. The two cohorts were assessed for incidence of surgical-site infection. RESULTS: Statistical analysis was performed using the Fisher exact probability test. Surgical site infection occurred in none of the PBG- patients (0%) versus one of the PBG+ patients (4.76%). This difference in infection rates between the two cohorts was not statistically significant (P = .4375). CONCLUSIONS: Although there may be concern that PBG could serve as a facilitative medium for bacterial growth, this study demonstrates no statistically significant increase in infection rates with its use. Particulate bone grafting of cranial defects resulting from cranial vault expansion in craniosynostosis remains a useful and valuable technique.

Incidence of Amblyopia and Its Risk Factors in Children With Isolated Metopic Craniosynostosis.

OBJECTIVE: Ophthalmic abnormalities in children with syndromic craniosynostosis have been reported previously, and referral of these children to a pediatric ophthalmologist is recommended. However, it is not as clear whether a child with nonsyndromic synostosis needs to be referred to a pediatric ophthalmologist. The aim of this study is to report the incidence of amblyopia and its risk factors in children with isolated metopic craniosynostosis. DESIGN: An institutional review board-approved, retrospective review was performed on 91 children diagnosed with isolated metopic craniosynostosis. Ophthalmologic records were reviewed for diagnoses of amblyopia, strabismus, and refractive error. RESULTS: Of the 91 children, 19 (20.9%) had astigmatism, eight (8.8 %) had amblyopia, eight (8.8%) had strabismus, five had myopia (5.5%), five had hyperopia (5.5%), and five had anisometropia (5.5%). The incidence of amblyopia and its risk factors found in our study are higher than the rate found in the clinically normal pediatric population. CONCLUSIONS: In our patient population, children with isolated metopic craniosynostosis demonstrate an increased rate of amblyopia and its risk factors. Amblyopia is best treated early in life to achieve a successful outcome. A referral to a pediatric ophthalmologist for a formal eye exam and potential treatment is therefore recommended for children with isolated metopic craniosynostosis.

Controlling plasma protein binding: structural correlates of interactions of hydrophobic polyamine endotoxin sequestrants with human serum albumin.

Hydrophobically substituted polyamine compounds, particularly N-acyl or N-alkyl derivatives of homospermine, are potent endotoxin (lipopolysaccharide) sequestrants. Despite their polycationic nature, the aqueous solubilites are limited owing to the considerable overall hydrophobicity contributed by the long-chain aliphatic substituent, but solubilization is readily achieved in the presence of human serum albumin (HSA). We desired first to delineate the structural basis of lipopolyamine-albumin interactions and, second, to explore possible structure-activity correlates in a well-defined, congeneric series of N-alkyl and -acyl homospermine lead compounds. Fluorescence spectroscopic and isothermal titration calorimetry (ITC) results indicate that these compounds appear to bind to HSA via occupancy of the fatty-acid binding sites on the protein. The acyl and carbamate compounds bind HSA the strongest; the ureido and N-alkyl analogues are significantly weaker, and the branched alkyl compound is weaker still. ITC-derived dissociation constants are weighted almost in their entirety by enthalpic deltaH terms, which is suggestive that the polarizability of the carbonyl groups facilitate, at least in large part, their interactions with HSA. The relative affinities of these lipopolyamines toward HSA is reflected in discernible differences in apparent potencies of LPS-sequestering activity under experimental conditions requiring physiological concentrations of HSA, and also of in vivo pharmacodynamic behavior. These results are likely to be useful in designing analogues with varying pharmacokinetic profiles.

Bound to shock: protection from lethal endotoxemic shock by a novel, nontoxic, alkylpolyamine lipopolysaccharide sequestrant.

Lipopolysaccharide (LPS), or endotoxin, a structural component of gram-negative bacterial outer membranes, plays a key role in the pathogenesis of septic shock, a syndrome of severe systemic inflammation which leads to multiple-system organ failure. Despite advances in antimicrobial chemotherapy, sepsis continues to be the commonest cause of death in the critically ill patient. This is attributable to the lack of therapeutic options that aim at limiting the exposure to the toxin and the prevention of subsequent downstream inflammatory processes. Polymyxin B (PMB), a peptide antibiotic, is a prototype small molecule that binds and neutralizes LPS toxicity. However, the antibiotic is too toxic for systemic use as an LPS sequestrant. Based on a nuclear magnetic resonance-derived model of polymyxin B-LPS complex, we had earlier identified the pharmacophore necessary for optimal recognition and neutralization of the toxin. Iterative cycles of pharmacophore-based ligand design and evaluation have yielded a synthetically easily accessible N(1),mono-alkyl-mono-homologated spermine derivative, DS-96. We have found that DS-96 binds LPS and neutralizes its toxicity with a potency indistinguishable from that of PMB in a wide range of in vitro assays, affords complete protection in a murine model of LPS-induced lethality, and is apparently nontoxic in vertebrate animal models.

Protection from endotoxic shock by EVK-203, a novel alkylpolyamine sequestrant of lipopolysaccharide.

Lipopolysaccharides (LPS) play a key role in the pathogenesis of septic shock, a major cause of mortality in the critically ill patient. The only therapeutic option aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide is Toraymyxin, an extracorporeal hemoperfusion device using solid phase-immobilized polymyxin B (PMB). While PMB is known to effectively sequester LPS, its severe systemic toxicity proscribes its parenteral use, and hemoperfusion may not be feasible in patients in shock. In our continuing efforts to develop small-molecule mimics which display the LPS-sequestering properties, but not the toxicity of PMB, a series of mono- and bis-substituted dialkylpolyamines were synthesized and evaluated. We show that EVK-203, an alkylpolyamine compound, specifically binds to and neutralizes the activity of LPS, and affords complete protection in a murine model of endotoxic shock. EVK-203 is without any apparent toxicity when administered to mice at multiples of therapeutic doses for several days. The specific endotoxin-sequestering property along with a very favorable therapeutic index renders this compound an ideal candidate for preclinical development.

Polycationic sulfonamides for the sequestration of endotoxin.

Lipopolysaccharides (LPS) play a key role in the pathogenesis of septic shock, a major cause of mortality in the critically ill patient. We had previously shown that monoacylated polyamine compounds specifically bind to and neutralize the activity of LPS with high in vitro potency and afford complete protection in a murine model of endotoxic shock. Fatty acid amides of polyamines may be rapidly cleared from systemic circulation due to their susceptibility to nonspecific serum amidases and, thus, would be predicted to have a short duration of action. In a systematic effort to increase the likelihood of better bioavailability properties together with structural modifications that may result in gains in activity, we now report structure-activity relationships pertaining to endotoxin-binding and -neutralizing activities of homologated polyamine sulfonamides.

Structural correlation between lipophilicity and lipopolysaccharide-sequestering activity in spermine-sulfonamide analogs.

Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are outer-membrane constituents of Gram-negative bacteria, and play a key role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient. We had previously defined the pharmacophore necessary for small molecules to specifically bind and neutralize this complex carbohydrate. A series of aryl and aliphatic spermine-sulfonamide analogs were synthesized and tested in a series of binding and cell-based assays in order to probe the effect of lipophilicity on sequestration ability. A strong correlation was indeed found, supporting the hypothesis that endotoxin-neutralizing ability involves a lipophilic or membrane attachment event. The research discussed herein may be useful for the design of additional carbohydrate recognizing molecules and endotoxin-neutralizing drugs.

Structural correlates of antibacterial and membrane-permeabilizing activities in acylpolyamines.

A homologous series of mono- and bis-acyl polyamines with varying acyl chain lengths originally synthesized for the purpose of sequestering lipopolysaccharide were evaluated for antimicrobial activity to test the hypothesis that these bis-cationic amphipathic compounds may also bind to and permeabilize intact gram-negative bacterial membranes. Some compounds were found to possess significant antimicrobial activity, mediated via permeabilization of bacterial membranes. Structure-activity relationship studies revealed a strong dependence of the acyl chain length on antimicrobial potency and permeabilization activity. Homologated spermine, bis-acylated with C8 or C9 chains, was found to profoundly sensitize Escherichia coli to hydrophobic antibiotics such as rifampin. Nonspecific cytotoxicity is a potential drawback of these membranophilic compounds. However, the surface activity of these cationic amphipaths is strongly attenuated under physiological conditions via binding to serum albumin. Significant antibacterial activity is still retained in the presence of physiological concentrations of human serum albumin, suggesting that these compounds may serve as leads in the development of novel adjuncts to conventional antimicrobial chemotherapy.

Novel endotoxin-sequestering compounds with terephthalaldehyde-bis-guanylhydrazone scaffolds.

We have shown that lipopolyamines bind to the lipid A moiety of lipopolysaccharide, a constituent of Gram-negative bacterial membranes, and neutralize its toxicity in animal models of endotoxic shock. In an effort to identify non-polyamine scaffolds with similar endotoxin-recognizing features, we had observed an unusually high frequency of hits containing guanylhydrazone scaffolds in high-throughput screens. We now describe the syntheses and preliminary structure-activity relationships in a homologous series of bis-guanylhydrazone compounds decorated with hydrophobic functionalities. These first-generation compounds bind and neutralize lipopolysaccharide with a potency comparable to that of polymyxin B, a peptide antibiotic known to sequester LPS.