Limited bedding and nesting increases ethanol drinking in female rats.

Prenatal opioid exposure (POE) and postnatal adverse experiences are early life adversities (ELA) that often co-occur and increase problematic alcohol (EtOH) drinking during adolescence. We investigated the relationship between POE, postnatal adversity, and adolescent EtOH drinking in rats. We also sought to determine whether ELAs affect alpha-adrenoceptor density in the brain because the noradrenergic system is involved in problematic alcohol drinking and its treatment. We hypothesized that the combination of POE and postnatal adversity will increase alcohol drinking in rats compared to rats with exposure to either adversity alone or to control. We also predicted that POE and postnatal adversity would increase α1-adrenoceptor density and decrease α2-adrenoceptor density in brain to confer a stress-responsive phenotype. Pregnant rats received morphine (15 mg/kg/day) or saline via subcutaneous minipumps from gestational day 9 until birth. Limited bedding and nesting (LBN) procedures were introduced from postnatal day (PD) 3-11 to mimic early life adversity-scarcity. Offspring rats (PD 31-33) were given opportunities to drink EtOH (20 %, v/v) using intermittent-access, two-bottle choice (with water) procedures. Rats given access to EtOH were assigned into sub-groups that were injected with either yohimbine (1 mg/kg, ip) or vehicle (2 % DMSO, ip) 30 min prior to each EtOH access session to determine the effects of α2-adrenoceptor inhibition on alcohol drinking. We harvested cortices, brainstems, and hypothalami from EtOH-naïve littermates on either PD 30 or PD 70 and conducted radioligand receptor binding assays to quantify α1- and α2-adrenoceptor densities. Contrary to our hypothesis, only LBN alone increased EtOH intake in female adolescent rats compared to female rats with POE. Neither POE nor LBN affected α1- or α2-adrenoceptor densities in the cortex, brainstem, or hypothalamus of early- or late-aged adolescent rats. These results suggest a complex interaction between ELA type and sex on alcohol drinking.

Significant differences among physician specialties in management recommendations of BRCA1 mutation carriers.

The National Comprehensive Cancer Network (NCCN) has published guidelines for hereditary breast and ovarian cancer syndrome (HBOCS) management. Little data exist on compliance with these guidelines among different physician specialties. We performed an on-line case-based survey by randomly sampling physicians from five specialties, Family Medicine (FM), Obstetrics and Gynecology (OG), General Surgery (GS), Internal Medicine (IM), and Hematology and Oncology (HO). The physicians (n = 225) were asked to provide HBOCS management of healthy women ages 40-42 in the presence of a familial BRCA1 mutation. For women negative for the BRCA1 mutation, 59% of the physicians recommended appropriate surveillance although with significant differences among specialties; P = 0.01. Using an aggregate screening intensity score, physicians clearly recommended more intense screening for mutation positive than negative women (P < 0.0001), but only 16% of physicians followed NCCN guidelines for BRCA1-positive women. Seventy-six percent of all physicians recommended breast MRI with significant variation among specialties ranging from 62% of FM to 89% of OG (P = 0.0020). Similarly, 63% of physicians recommended prophylactic oophorectomy, with 76 and 78% of GS and OG compared to 38% of IM (P < 0.0001) and 57% recommended prophylactic mastectomy ranging from 84% of HO to 32% of FM (P < 0.0001). Independent of specialty, respondents with BRCA testing experience recommended more intense management than those without; P = 0.021. Management recommendations of BRCA1 mutation carriers are not consistent with NCCN guidelines and vary by medical specialty and genetic testing experience. Targeted education of physicians by specialty is needed, so that optimal management is offered to these high-risk women.

Phytochromes: photosensory perception and signal transduction.

The phytochrome family of photoreceptors monitors the light environment and dictates patterns of gene expression that enable the plant to optimize growth and development in accordance with prevailing conditions. The enduring challenge is to define the biochemical mechanism of phytochrome action and to dissect the signaling circuitry by which the photoreceptor molecules relay sensory information to the genes they regulate. Evidence indicates that individual phytochromes have specialized photosensory functions. The amino-terminal domain of the molecule determines this photosensory specificity, whereas a short segment in the carboxyl-terminal domain is critical for signal transfer to downstream components. Heterotrimeric GTP-binding proteins, calcium-calmodulin, cyclic guanosine 5'-phosphate, and the COP-DET-FUS class of master regulators are implicated as signaling intermediates in phototransduction.

Phytochrome-Deficient hy1 and hy2 Long Hypocotyl Mutants of Arabidopsis Are Defective in Phytochrome Chromophore Biosynthesis.

The hy1 and hy2 long hypocotyl mutants of Arabidopsis contain normal levels of immunochemically detectable phytochrome A, but the molecule is photochemically nonfunctional. We have investigated the biochemical basis for this lack of function. When the hy1 and hy2 mutants were grown in white light on a medium containing biliverdin IX[alpha], a direct precursor to phytochromobilin, the phytochrome chromophore, the seedlings developed with a morphological phenotype indistinguishable from the light-grown wild-type control. Restoration of a light-grown phenotype in the hy1 mutant was also accomplished by using phycocyanobilin, a tetrapyrrole analog of phytochromobilin. Spectrophotometric and immunochemical analyses of the rescued hy1 and hy2 mutants demonstrated that they possessed wild-type levels of photochemically functional phytochrome that displayed light-induced conformational changes in the holoprotein indistinguishable from the wild type. Moreover, phytochrome A levels declined in vivo in response to white light in rescued hy1 and hy2 seedlings, indicative of biliverdin-dependent formation of photochemically functional phytochrome A that was then subject to normal selective turnover in the far-red-light-absorbing form. Combined, these data suggest that the hy1 and hy2 mutants are inhibited in chromophore biosynthesis at steps prior to the formation of biliverdin IX[alpha], thus potentially causing a global functional deficiency in all members of the phytochrome photoreceptor family.

Photocontrol of stem growth.

Rapid and measurable growth rate changes that occur in seedling stems upon illumination serve as an excellent means to analyze signal transduction. Growth kinetic studies have shown how red, far-red and blue light signals are transduced via the solitary and/or coordinated action of known plant photoreceptors. These reports are consistent with current findings describing light-induced photoreceptor interaction and compartmentation.

A knotless bidirectional-barbed tendon repair is inferior to conventional 4-strand repairs in cyclic loading.

UNLABELLED: We divided 21 flexor digitorum profundus tendons in the index, middle and ring fingers in seven cadaver hands into three groups. The tendons were cut in zone 2 and repaired using a 4-strand cruciate core suture repair with one of the following three materials in each group: (1) a knotless repair with a 2-0 bidirectional-barbed suture, which has similar tensile strength as a 4-0 non-barbed suture used in the other two groups; (2) a knotted locking repair with a non-barbed 4-0 conventional suture; and (3) a non-locking repair with a non-barbed 4-0 knotless suture. The repaired fingers were cyclically loaded through a simulated active range of motion to a 5 N load. We monitored and recorded the gap sizes at regular intervals during the test. The 2-0 bidirectional-barbed suture group and non-barbed suture groups developed gaps of 2.2 mm after 10 cycles and 2.4 mm after 20 cycles, respectively. Over 1000 cycles, the mean gaps were 3.2 mm in the 4-0 conventional suture group and 9.1 mm in the 2-0 bidirectional-barbed group. The tendons in the 2-0 bidirectional-barbed group gapped earlier, with statistically significant differences compared with those in the locking repair with a non-barbed 4-0 knotless suture group. The repair strength of the barbed suture technique was inferior to the cruciate repairs using a conventional 4-0 non-barbed suture tested in this cyclic-loading model. LEVEL OF EVIDENCE: Level V.

Decipher correlation patterns post prostatectomy: initial experience from 2 342 prospective patients.

BACKGROUND: Currently, there are multiple commercially available RNA-based biomarkers that are Medicare approved and suggested for use by the National Comprehensive Cancer Network guidelines. There is uncertainty as to which patients benefit from genomic testing and for whom these tests should be ordered. Here, we examined the correlation patterns of Decipher assay to understand the relationship between the Decipher and patient tumor characteristics. METHODS: De-identified Decipher test results (including Decipher risk scores and clinicopathologic data) from 2 342 consecutive radical prostatectomy (RP) patients tested between January and September 2015 were analyzed. For clinical testing, tumor specimen from the highest Gleason grade was sampled using a 1.5 mm tissue punch. Decipher scores were calculated based on a previously locked model. Correlations between Decipher score and clinicopathologic variables were computed using Spearman's rank correlation. Mixed-effect linear models were used to study the association of practice type and Decipher score. The significance level was 0.05 for all tests. RESULTS: Decipher score had a positive correlation with pathologic Gleason score (PGS; r=0.37, 95% confidence interval (CI) 0.34-0.41), pathologic T-stage (r=0.31, 95% CI 0.28-0.35), CAPRA-S (r=0.32, 95% CI 0.28-0.37) and patient age (r=0.09, 95% CI 0.05-0.13). Decipher reclassified 52%, 76% and 40% of patients in CAPRA-S low-, intermediate- and high-risk groups, respectively. We detected a 28% incidence of high-risk disease through the Decipher score in pT2 patients and 7% low risk in pT3b/pT4, PGS 8-10 patients. There was no significant difference in the Decipher score between patients from community centers and those from academic centers (P=0.82). CONCLUSIONS: Although Decipher correlated with baseline tumor characteristics for over 2 000 patients, there was significant reclassification of tumor aggressiveness as compared to clinical parameters alone. Utilization of the Decipher genomic classifier can have major implications in assessment of postoperative risk that may impact physician-patient decision making and ultimately patient management.

The safety, tolerability, and pharmacokinetics of fosphenytoin after intramuscular and intravenous administration in neurosurgery patients.

STUDY OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetic profile of fosphenytoin, a water-soluble phenytoin prodrug, after intramuscular and intravenous administration. DESIGN: Open-label study of intramuscular administration, and double-blind, randomized study of intravenous administration. SETTING: Six and ten hospitals throughout the United States for the intramuscular and intravenous multicenter studies, respectively. PATIENTS: Neurosurgical patients who required anticonvulsant prophylaxis or treatment. INTERVENTIONS: In the intramuscular study, 118 patients received loading doses ranging from 480-1500 mg phenytoin equivalents (PE) and daily maintenance doses ranging from 130-1250 mg PE for 3-14 days. In the intravenous study, 88 patients received fosphenytoin and 28 received phenytoin sodium for 3-14 days. Mean +/- SD loading doses and maintenance doses of intravenous fosphenytoin and phenytoin were 1082 +/- 299 mg PE and 411 +/- 221 mg PE, and 1082 +/- 299 mg and 422 +/- 197 mg, respectively. Trough phenytoin concentrations were measured daily in all patients. MEASUREMENTS AND MAIN RESULTS: Intramuscular fosphenytoin was safe and well tolerated, with no irritation found for 99% of all injection site evaluations. Adverse events associated with the drug occurred in 9% of patients, commonly those typical of the parent drug. For intravenous treatment, the frequency of mild irritation at the infusion site was significantly lower in the fosphenytoin group (6%) than in the phenytoin group (25%, p < 0.05). Reductions in infusion rates were required in 17% and 36% of fosphenytoin and phenytoin recipients, respectively. No significant difference was observed relative to adverse events or seizure frequency between the groups. Trough plasma phenytoin concentrations were approximately 10 micrograms/ml or greater in patients receiving at least 3 days of intramuscular and intravenous fosphenytoin. Trough phenytoin concentrations were similar between patients receiving intravenous phenytoin and fosphenytoin on all study days. CONCLUSION: Fosphenytoin can be administered intramuscularly and intravenously in neurosurgical patients to achieve and maintain therapeutic phenytoin concentrations for up to 14 days. Both routes are safe and well tolerated. Intravenous fosphenytoin is significantly better tolerated than intravenous phenytoin sodium in this patient subset.

Response covariation on self-stimulatory behaviors during sensory extinction procedures.

The effects of sensory extinction procedures on nontargeted self-stimulatory behaviors of two autistic boys were assessed. In Experiment 1, the frequencies of two topographically similar behaviors of one child and two topographically dissimilar behaviors of the other child were examined within a reversal design. Application of sensory extinction for target behaviors resulted in a decrease in the topographically similar behavior, but no change in the dissimilar behavior. In Experiment 2, sensory extinction procedures were applied to three behaviors of one child using a multiple-baseline design. Two of these behaviors were topographically similar and all were maintained by the same sensory modality. Suppression occurred only for the topographically similar behavior. Results are discussed in terms of their treatment implications.

Anticonvulsant blood levels: historical review with a pediatric focus.

Epilepsy is heterogeneous and its treatment is often complicated by variable drug responses. Buchtal et al reported a close correlation between serum phenytoin levels, electroencephalographic findings, and clinical status in 1960. They suggested that physicians adjust dosage to attain a "therapeutic level." The concept was enthusiastically received. "Therapeutic serum levels" were proposed for most anticonvulsant drugs, and by 1975, most authorities believed that pharmacokinetic factors explained individual differences in drug response. However, Froscher found that measuring levels did not improve patient outcome. More recently, Schumacher's double-blind study found no correlation between phenytoin levels and seizure control or adverse effects. Pharmacodynamic variables (differences in drug responsiveness) are more important than pharmacokinetic factors for many drugs, especially receptor-active drugs. Pharmacokinetic variables were studied first, and led to a simplistic model. They are less significant than pharmacodynamic factors in the case of warfarin anticoagulation. Anticonvulsant levels can reveal noncompliance and pharmacokinetic differences. They say nothing about pharmacodynamics. Reports of "subtherapeutic levels" imply a need to increase dosage, but this is not supported by outcome data. We still lack evidence that specific drug levels are a valid intermediate target 40 years after Buchtal's paper. Responses to some anticonvulsants could depend primarily on pharmacokinetic factors, while pharmacodynamic factors could be supreme for others.

Hematologic monitoring in children with epilepsy treated with carbamazepine.

One hundred seventy-six children treated with carbamazepine for epilepsy were monitored over a 12-month period to determine the effects of carbamazepine on the hematologic system. There were no significant changes within the total population in the mean hematocrit or platelet count. The white blood cell count and total neutrophil count showed declines at 1, 8, and 12 months, but the differences did not achieve statistical significance. There was no correlation between the hematologic parameters and carbamazepine blood level, age or sex, or the presence of other drugs. Pretreatment leukopenia and neutropenia were present in 2.8% and 4.0% of children, respectively. During carbamazepine therapy, 8.0% and 17.0% of the children developed leukopenia and neutropenia, respectively, and it was persistent in 1.7% and 2.8%, respectively. The changes in the white blood cell count could be attributed to the changes in the total neutrophil count.

Pediatric patients with undetectable anticonvulsant blood levels: comparison with compliant patients.

Undetectable anticonvulsant blood levels indicate sustained noncompliance (several consecutive doses missed). We compared 91 consecutive outpatients with epilepsy and undetectable anticonvulsant blood levels to 100 patients seen during the same time period, verified as compliant by acceptable serum levels. We hypothesized that pay status, application for Supplemental Security Income, patient age, history of missed appointments, and functional status would differ between compliant and noncompliant patients. We were surprised to find large differences between clinic and insurance patients and between Caucasian and non-Caucasian patients. The 100 compliant patients included 44 Caucasian and 56 non-Caucasian patients, whereas only 9 of 91 noncompliant patients were Caucasian, and only 9 had insurance, compared to 32 compliant patients. Applications for Supplemental Security Income and history of missed appointments were significantly associated with noncompliance, but patient age, seizure type, and seizure control were not. Uninsured Caucasians were more often compliant than non-Caucasians were. Many noncompliant patients had mild epilepsy, which was reportedly doing well. Race and pay status were closely correlated. Several noncompliant females became pregnant, whereas no compliant patients did. Compliant patients were much more likely to be accompanied by a parent or caretaker on clinic visits than noncompliant patients. Noncompliant patients had at least one acceptable subsequent serum level, although 2 patients with intractable epilepsy had undetectable serum levels on three or more occasions. Noncompliance may respond to discussion and advice. We reviewed 124 episodes of undetectable drug levels in the 91 noncompliant patients. Eighteen of these resulted in hospitalization, but in 25 cases, we were told that there had been no seizures since the preceding visit. Many noncompliant patients have infrequent seizures, even if they take little or no medication. Socioeconomic status influences health, life expectancy, and educational success, but it has been claimed to be irrelevant to compliance and adherence issues in epilepsy. Our data and the experience of other centers with childhood diabetes suggest that socioeconomic, racial, and family factors influence compliance or adherence to treatment for many chronic conditions. Educational efforts and support for parents at the start of anticonvulsant treatment may improve compliance. Uninsured patients missed more appointments and were much more likely to be noncompliant than insured patients. Attention to the special problems of Medicaid and minority children is needed.

Sphingomyelinase inhibits in vitro Leydig cell function.

Activation of the immune system has profound effects on endocrine function which are mediated by cytokines including tumor necrosis factor-alpha (TNF alpha). In vitro, TNF alpha has been shown to directly inhibit Leydig cell testosterone (T) production, but the mechanism of this effect is still unclear. Recent studies using cultured human fibroblasts have shown that TNF alpha stimulates the activity of neutral sphingomyelinase (SMase) which hydrolyses sphingomyelin (SM) generating ceramide and changing membrane components including cholesterol. The cellular affects of increased SMase activity have been reproduced in vitro by the addition of exogenous SMase. In cultured fibroblasts, exogenous SMase decreases cholesterol synthesis. These findings led us to hypothesize that SMase might be important in the regulation of steroid hormone synthesis. To our knowledge, no previous studies have investigated this possibility. To test this hypothesis, rat Leydig cell enriched cultures were incubated in media containing SMase (0.1 to 100 mU/ml) or in control media. SMase significantly decreased basal and human chorionic gonadotropin (hCG) stimulated T production. SMase also decreased hCG binding and hCG stimulated adenosine 3':5'-cyclic monophosphate (cAMP). N-acetyl-sphingosine (0.1 to 10 microM), a water soluble ceramide, was used to determine whether or not the effects of SMase could be reproduced by ceramide addition. N-acetyl-sphingosine had only slight effects on basal T and cAMP, and no effect on hCG binding or hCG stimulated T or cAMP. These data suggest the metabolism of membrane sphingomyelin may be an important regulatory pathway in the control of Leydig cell function.

A comparison of the mechanical properties of fiberglass cast materials and their clinical relevance.

The mechanical properties of five synthetic fiberglass casting materials were evaluated and compared with the properties of plaster of Paris. Two of the tests were designed to bear clinical relevance and the third to determine intrinsic material properties. The effect of water on strength degradation was also evaluated. It was found that the synthetics as a group are far superior to plaster of Paris in all methods of testing and that, among the synthetics, KCast Tack Free, Deltalite "S", and KCast Improved were the stronger materials. Clinically, the most important results are that the synthetics attain their relatively high strength in a much shorter time frame than does plaster of Paris, and retain 70-90% of their strength after being immersed in water and allowed to dry.

Cyclic loading of rotator cuff repairs: A comparison of bioabsorbable tacks with metal suture anchors and transosseous sutures.

PURPOSE: The purposes of the study were (1) to compare rotator cuff repair strengths after cyclic loading of 2 bioabsorbable nonsuture-based tack-type anchors, transosseous sutures, and a metal suture-based anchor, and (2) to correlate bone mineral density with mode of failure and cycles to failure. We hypothesized that specimens with a lower bone density would fail through bone at a lower number of cycles independent of the method of cuff fixation. TYPE OF STUDY: Ex vivo biomechanical study. METHODS: Standardized full-thickness rotator cuff defects were created in 30 fresh-frozen cadaveric shoulders that were randomized to 1 of 4 repair groups: transosseous sutures; Mitek Super suture anchors (Mitek Surgical Products, Westwood, MA); smooth bioabsorbable 8-mm Suretacs (Acufex, Smith & Nephew Endoscopy, Mansfield, MA); or spiked bioabsorbable 8-mm Suretacs (Acufex). All repairs were cyclically loaded from 10 to 180 N; the numbers of cycles to 50% (gap, 5 mm) and 100% (gap, 10 mm) failure were recorded. RESULTS: In comparing the repair groups, we found only 1 significant difference: the number of cycles to 100% failure was significantly higher (P <.05) for the smooth bioabsorbable tack than for the transosseous suture group. There were no statistically significant (P

Sudden death due to streptococcal infection.

Sudden unexpected deaths form a large population of medical examiner caseloads. Presented are the clinical, pathologic, and virulence features of sudden death due to Group A beta-hemolytic streptococcus. Emphasis is placed on the importance of post-mortem cultures. Case histories are included to illustrate the sometimes unusual presentation of this disease. Recent publicity has led to a heightened public awareness of this unusually virulent entity.

Decay rates of human remains in an arid environment.

The environment of southern Arizona with mild winters and hot, dry summers produces great variability in decay rates of human remains. Summer temperatures, which range well over 38 degrees C (100 degrees F), induce rapid bloating as a result of the accumulation of decompositional gases. However, in certain circumstances, the aridity can lead to extensive mummification, allowing preservation of remains for hundreds of years. A retrospective study of 189 cases, concentrating on remains found on the desert floor or in the surrounding mountains and on remains found within closed structures, outlines the time frame and sequences of the decay process. Remains can retain a fresh appearance for a considerable time in the winter, but the onset of marked decomposition is rapid in the summer months. Bloating of the body usually is present two to seven days following death. Following this, within structures, there is frequently rapid decomposition and skeletonization. With outdoor exposure, remains are more likely to pass through a long period of dehydration of outer tissues, mummification, and reduction of desiccated tissue. Exposure of large portions of the skeleton usually does not occur until four to six months after death. Bleaching and exfoliation of bone--the beginning stages of destruction of the skeletal elements--begins at about nine months' exposure. Insect activity, including that of maggot and beetle varieties, may accelerate decomposition, but this process is greatly affected by location of the body, seasonal weather, and accessibility of the soft tissues. Carnivores and other scavengers also are contributing factors, as are clothing or covering of the body, substrate, elevation, and latitude.

Biomechanical evaluation of two different screw positions for fusion of the calcaneocuboid joint.

In triple arthrodesis performed for severe deformity and neuroarthropathy in poorly compliant patients with osteoporotic bone, fixation of the arthrodesis is critical. We biomechanically tested an alternative means of stabilization for calcaneocuboid fusions. In seven matched pairs of fresh-frozen cadaver feet, we removed the soft tissue from around the calcaneocuboid joint, except for the capsule, and we did not resect the articular cartilage. One joint of each pair was fixed with an oblique standard screw, and the contralateral joint was stabilized with an axial screw placed perpendicularly to the joint surface. Testing on an MTS Mini Bionix Test Frame (MTS Systems Corp., Eden Prairie, MN) demonstrated that the axial screw provided significantly higher initial stiffness and maximum load to failure. We concluded that an axial screw provided better fixation of the calcaneocuboid joint.

Midfoot fusion technique for neuroarthropathic feet: biomechanical analysis and rationale.

To test the hypothesis that a plate applied to the plantar (tension) side of the medial midfoot provides stronger fixation than midfoot fusion with screw fixation, we biomechanically compared the two constructs for midfoot fusion. We created a model of midfoot instability in eight matched pairs of cadaver legs by section of joint capsule, ligaments, and tendons about Lisfranc's joints, and then performed a load-to-failure study to compare the fixation provided by a plantarly applied third tubular plate with that by cortical screws. After an initial load deformation curve to 1000 N was obtained, specimens were cyclically loaded at 200 to 750 N for 3000 cycles and then loaded to failure (screw pullout, fracture, or deformation >3 mm). Comparing the plantar plate and midfoot fusion with screw fixation constructs, a plate applied to the plantar (tension) aspect of the medial midfoot provides a stronger, sturdier construct than does midfoot fusion with screw fixation.

Experimental flatfoot model: the contribution of dynamic loading.

The goal of this study was to determine if the application of muscle forces (simulating the dynamic phase of the midstance part of gait) had an effect on flatfoot deformity. We created a flatfoot model in each of seven cadaver foot specimens by grasping the Achilles, peroneus longus, peroneus brevis, flexor digitorum longus, and flexor hallucis longus tendons with soft-tissue vice clamps connected via wire cables to pneumatic cylinders. The experiment included four stages: 1) initial static axial loading; 2) axial loading after 3,000 load cycles (average, 735 N; range, 70 to 1400 N); 3) axial loading after releasing the spring ligament and plantar fascia; and 4) axial loading after an additional 3,000 load cycles. At each stage, both static (with axial loading only) and dynamic (axial loading with tensioning of the tendons to simulate the muscle forces at midstance) conditions were evaluated radiographically. No change was observed between the static and dynamic conditions in the first two phases of the experiment. After the third phase, changes in the talar-first metatarsal angle and the height of the medial cuneiform were noted, particularly in the dynamic condition. These and additional radiographic changes were magnified in the fourth phase, but only in the dynamic condition. We concluded that, to create an effective flatfoot model, the medial structures, including the spring ligament and possibly the plantar fascia, must be severed. Cyclic loading of the foot further increased the arch flattening, and this effect was magnified by dynamic loading.