A mathematical model for the determination of mouse excisional wound healing parameters from photographic data.

We present a mathematical model to quantify parameters of mouse excisional wound healing from photographic data. The equation is a piecewise linear function in log scale that includes key parameters of initial wound radius (R0 ), an initial wound stasis phase (Ti ), and time to wound closure (Tc ); subsequently, these terms permit calculation of a latter active proliferative phase (Tp ), and the healing rate (HR) during this active phase. A daily photographic record of wound healing (utilizing 6 mm diameter splinted excisional wounds) permits the necessary sampling for robust parameter refinement. When implemented with an automated nonlinear fitting routine, the healing parameters are determined in an operator-independent (i.e., unbiased) manner. The model was evaluated using photographic data from a splinted excisional surgical procedure involving several different mouse cohorts. Model fitting demonstrates excellent coefficients of determination (R2 ) in each case. The model, thus, permits quantitation of key parameters of excisional wound healing, from initial wounding through to wound closure, from photographic data.

Fine-Sampled Photographic Quantitation of Dermal Wound Healing Senescence in Aged BALB/cByJ Mice and Therapeutic Intervention with Fibroblast Growth Factor-1.

Objective: To determine quantitative parameters of dermal wound healing senescence in aged BALB/cByJ mice (an important animal model of aging) and to evaluate the potential for therapeutic intervention by fibroblast growth factor-1 (FGF-1). Approach: Utilize a novel noninvasive fine-sampled photographic methodology to quantify wound healing parameters for healing phases from wounding through to wound closure. Results: Parameters associated with key healing phases were quantified and compared between nonaged and aged cohorts of both genders. The results identify a sexual dimorphism in dermal wound healing, with nonaged females exhibiting a greater overall healing efficiency than males. This enhanced healing in females, however, senesces with age such that healing parameters for aged males and females are statistically indistinguishable. Topical application of FGF-1 was identified as an effective therapeutic intervention to treat dermal healing senescence in aged females. Innovation: The FGF intervention is being analyzed using a new recently published model. This approach significantly increases the amount of preclinical animal data obtainable in wound healing studies, minimizes cohort number compared with (lethal) histological studies, and permits a direct statistical comparison between different healing studies. Conclusion: Quantitative parameters of dermal wound healing, obtained from noninvasive fine-sampled photographic data, identify topical FGF-1 as an effective therapeutic to treat the senescence of dermal healing present in aged female BALB/cByJ mice.

Pharmacokinetic properties of 2nd-generation fibroblast growth factor-1 mutants for therapeutic application.

Fibroblast growth factor-1 (FGF-1) is an angiogenic factor with therapeutic potential for the treatment of ischemic disease. FGF-1 has low intrinsic thermostability and is characteristically formulated with heparin as a stabilizing agent. Heparin, however, adds a number of undesirable properties that negatively impact safety and cost. Mutations that increase the thermostability of FGF-1 may obviate the need for heparin in formulation and may prove to be useful "2nd-generation" forms for therapeutic use. We report a pharmacokinetic (PK) study in rabbits of human FGF-1 in the presence and absence of heparin, as well as three mutant forms having differential effects upon thermostability, buried reactive thiols, and heparin affinity. The results support the hypothesis that heparan sulfate proteoglycan (HSPG) in the vasculature of liver, kidney and spleen serves as the principle peripheral compartment in the distribution kinetics. The addition of heparin to FGF-1 is shown to increase endocrine-like properties of distribution. Mutant forms of FGF-1 that enhance thermostability or eliminate buried reactive thiols demonstrate a shorter distribution half-life, a longer elimination half-life, and a longer mean residence time (MRT) in comparison to wild-type FGF-1. The results show how such mutations can produce useful 2nd-generation forms with tailored PK profiles for specific therapeutic application.

Clinical characteristics and mode of inheritance of familial focal seizures in Standard Poodles.

OBJECTIVE: To determine clinical characteristics and mode of inheritance of seizures in a family of Standard Poodles. DESIGN: Case series. ANIMALS: 90 Standard Poodles descended from the same maternal bloodline (30 with probable idiopathic epilepsy [PIE] and 60 without any history of seizures). PROCEDURES: Researchers contacted owners to determine whether dogs had ever had any seizures and, if so, the nature of any such seizures and any potential underlying causes. Dogs were considered to have PIE if they were between 6 months and 7.5 years old at the time of seizure onset and had no evidence of any underlying cause. To determine the mode of inheritance, segregation analyses were designed to allow the family to be analyzed as a whole, as opposed to as nuclear families. Competing models of inheritance were compared statistically for their ability to explain the data. RESULTS: Of the dogs with PIE, 28 (93%) had focal onset seizures with or without secondary generalization. Median age of onset was 3.7 years; 6 dogs were > 5 years old at the onset of seizures. Segregation analyses strongly suggested that PIE was inherited as a simple recessive autosomal trait with complete or almost complete penetrance. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that in this family of Standard Poodles, PIE was inherited as a simple recessive autosomal trait with complete or almost complete penetrance. Seizures often had focal, as opposed to generalized, onsets, and it was not uncommon for seizures to begin after 5 years of age.

Clinical presentations of naturally occurring canine seizures: similarities to human seizures.

The clinical presentations of 119 canine seizures from 41 Standard Poodles and 11 Dalmatians were classified according to a modified version of the International League Against Epilepsy (ILAE) seizure classification system. Standardized use of the ILAE system with dogs not only should facilitate research in veterinary medicine, which has no standard criteria for seizure classification, but also should facilitate comparisons between canine and human seizures. We found that for more than 80% of both breeds, at least some of their seizures had partial onsets. However, because it was common for partial seizures to secondarily generalize, the majority of Poodles (81%) and Dalmatians (91%) experienced at least some generalized seizures. Among partial seizures, complex partial were more frequent than simple partial. For both breeds, two thirds of those with partial onset seizures had exclusively complex partial. Among dogs with primary or secondarily generalized seizures, 80% of both breeds had tonic-clonic seizures.