A multicenter study to evaluate pain characteristics in osteogenesis imperfecta.

The objective was to describe pain characteristics and treatments used in individuals with varying severity of osteogenesis imperfecta (OI) and investigate pain-associated variables. This work was derived from a multicenter, longitudinal, observational, natural history study of OI conducted at 12 clinical sites of the NIH Rare Diseases Clinical Research Network's Brittle Bone Disorders Consortium. Children and adults with a clinical, biochemical, or molecular diagnosis of OI were enrolled in the study. We did a cross-sectional analysis of chronic pain prevalence, characteristics, and treatments used for pain relief and longitudinal analysis to find the predictors of chronic pain. We included 861 individuals with OI, in 41.8% chronic pain was present, with similar frequency across OI types. Back pain was the most frequent location. Nonsteroidal anti-inflammatory drugs followed by bisphosphonates were the most common treatment used. Participants with chronic pain missed more days from school or work/year and performed worse in all mobility metrics than participants without chronic pain. The variables more significantly associated with chronic pain were age, sex, positive history of rodding surgery, scoliosis, other medical problems, assistive devices, lower standardized height, and higher body mass index. The predictors of chronic pain for all OI types were age, use of a wheelchair, and the number of fractures/year. Chronic pain is prevalent in OI across all OI types, affects mobility, and interferes with participation. Multiple covariates were associated with chronic pain.

What are the long-term outcomes of lateral column lengthening for pes planovalgus in cerebral palsy?

BACKGROUND: Lateral column lengthening (LCL) is commonly performed on children and adolescents with cerebral palsy (CP) for correction of pes planovalgus (PPV). There are limited reports of the long-term outcomes of this procedure. The purpose of this study was to examine the long-term results of LCL for correction of PPV in individuals with CP by evaluating subjects when they had transitioned to adulthood and were entering the workforce. METHODS: Clinical assessments, quantitative gait analysis including the Milwaukee Foot Model (MFM) for segmental foot kinematics, and patient reported outcomes were collected from 13 participants with CP treated with LCL for PPV in childhood (average age 24.4 ± 5.7 years, average 15.3 ± 8.5 years since LCL). Additionally, 27 healthy adults average age 24.5 ± 3.6 years functioned as controls. RESULTS: Strength and joint range of motion were reduced in the PPV group (p < 0.05). Sixty nine percent showed operative correction of PPV based on radiologic criteria. Gait analysis showed reduced walking speed and stride length, as well as midfoot break and residual forefoot abduction. Patient reported outcomes indicated that foot pain was not the only factor that caused limited activity and participation. LCL surgery for PPV in childhood resulted in long-term operative correction. Decreased ankle passive range of motion and strength, subtalar joint arthritic changes, inefficient and less stable ambulation, and problems with participation (difficulties in physical function, education, and employment) were observed in the long-term. CONCLUSION: This study identified postoperative impairments and limitations to guide future clinical decision-making. These results provide clinicians and researchers the common residual and recurrent issues for these individuals as they age. The inclusion of contextual factors that influence the disease and impairments can equip these individuals with enhanced skills they need as they transition into adulthood.

Potent Killing of Pseudomonas aeruginosa by an Antibody-Antibiotic Conjugate.

Pseudomonas aeruginosa causes life-threatening infections that are associated with antibiotic failure. Previously, we identified the antibiotic G2637, an analog of arylomycin, targeting bacterial type I signal peptidase, which has moderate potency against P. aeruginosa. We hypothesized that an antibody-antibiotic conjugate (AAC) could increase its activity by colocalizing P. aeruginosa bacteria with high local concentrations of G2637 antibiotic in the intracellular environment of phagocytes. Using a novel technology of screening for hybridomas recognizing intact bacteria, we identified monoclonal antibody 26F8, which binds to lipopolysaccharide O antigen on the surface of P. aeruginosa bacteria. This antibody was engineered to contain 6 cysteines and was conjugated to the G2637 antibiotic via a lysosomal cathepsin-cleavable linker, yielding a drug-to-antibody ratio of approximately 6. The resulting AAC delivered a high intracellular concentration of free G2637 upon phagocytosis of AAC-bound P. aeruginosa by macrophages, and potently cleared viable P. aeruginosa bacteria intracellularly. The molar concentration of AAC-associated G2637 antibiotic that resulted in elimination of bacteria inside macrophages was approximately 2 orders of magnitude lower than the concentration of free G2637 required to eliminate extracellular bacteria. This study demonstrates that an anti-P. aeruginosa AAC can locally concentrate antibiotic and kill P. aeruginosa inside phagocytes, providing additional therapeutic options for antibiotics that are moderately active or have an unfavorable pharmacokinetics or toxicity profile. IMPORTANCE Antibiotic treatment of life-threatening P. aeruginosa infections is associated with low clinical success, despite the availability of antibiotics that are active in standard microbiological in vitro assays, affirming the need for new therapeutic approaches. Antibiotics often fail in the preclinical stage due to insufficient efficacy against P. aeruginosa. One potential strategy is to enhance the local concentration of antibiotics with limited inherent anti-P. aeruginosa activity. This study presents proof of concept for an antibody-antibiotic conjugate, which releases a high local antibiotic concentration inside macrophages upon phagocytosis, resulting in potent intracellular killing of phagocytosed P. aeruginosa bacteria. This approach may provide new therapeutic options for antibiotics that are dose limited.

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets.

The persistence of increased excitability and spontaneous activity in injured peripheral neurons is imperative for the development and persistence of many forms of neuropathic pain. This aberrant activity involves increased activity and/or expression of voltage-gated Na+ and Ca2+ channels and hyperpolarization activated cyclic nucleotide gated (HCN) channels as well as decreased function of K+ channels. Because they display limited central side effects, peripherally restricted Na+ and Ca2+ channel blockers and K+ channel activators offer potential therapeutic approaches to pain management. This review outlines the current status and future therapeutic promise of peripherally acting channel modulators. Selective blockers of Nav1.3, Nav1.7, Nav1.8, Cav3.2, and HCN2 and activators of Kv7.2 abrogate signs of neuropathic pain in animal models. Unfortunately, their performance in the clinic has been disappointing; some substances fail to meet therapeutic end points whereas others produce dose-limiting side effects. Despite this, peripheral voltage-gated cation channels retain their promise as therapeutic targets. The way forward may include (i) further structural refinement of K+ channel activators such as retigabine and ASP0819 to improve selectivity and limit toxicity; use or modification of Na+ channel blockers such as vixotrigine, PF-05089771, A803467, PF-01247324, VX-150 or arachnid toxins such as Tap1a; the use of Ca2+ channel blockers such as TTA-P2, TTA-A2, Z 944, ACT709478, and CNCB-2; (ii) improving methods for assessing "pain" as opposed to nociception in rodent models; (iii) recognizing sex differences in pain etiology; (iv) tailoring of therapeutic approaches to meet the symptoms and etiology of pain in individual patients via quantitative sensory testing and other personalized medicine approaches; (v) targeting genetic and biochemical mechanisms controlling channel expression using anti-NGF antibodies such as tanezumab or re-purposed drugs such as vorinostat, a histone methyltransferase inhibitor used in the management of T-cell lymphoma, or cercosporamide a MNK 1/2 inhibitor used in treatment of rheumatoid arthritis; (vi) combination therapy using drugs that are selective for different channel types or regulatory processes; (vii) directing preclinical validation work toward the use of human or human-derived tissue samples; and (viii) application of molecular biological approaches such as clustered regularly interspaced short palindromic repeats (CRISPR) technology.

Mediators of Neuropathic Pain; Focus on Spinal Microglia, CSF-1, BDNF, CCL21, TNF-α, Wnt Ligands, and Interleukin 1ß.

Intractable neuropathic pain is a frequent consequence of nerve injury or disease. When peripheral nerves are injured, damaged axons undergo Wallerian degeneration. Schwann cells, mast cells, fibroblasts, keratinocytes and epithelial cells are activated leading to the generation of an "inflammatory soup" containing cytokines, chemokines and growth factors. These primary mediators sensitize sensory nerve endings, attract macrophages, neutrophils and lymphocytes, alter gene expression, promote post-translational modification of proteins, and alter ion channel function in primary afferent neurons. This leads to increased excitability and spontaneous activity and the generation of secondary mediators including colony stimulating factor 1 (CSF-1), chemokine C-C motif ligand 21 (CCL-21), Wnt3a, and Wnt5a. Release of these mediators from primary afferent neurons alters the properties of spinal microglial cells causing them to release tertiary mediators, in many situations via ATP-dependent mechanisms. Tertiary mediators such as BDNF, tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and other Wnt ligands facilitate the generation and transmission of nociceptive information by increasing excitatory glutamatergic transmission and attenuating inhibitory GABA and glycinergic transmission in the spinal dorsal horn. This review focusses on activation of microglia by secondary mediators, release of tertiary mediators from microglia and a description of their actions in the spinal dorsal horn. Attention is drawn to the substantial differences in the precise roles of various mediators in males compared to females. At least 25 different mediators have been identified but the similarity of their actions at sensory nerve endings, in the dorsal root ganglia and in the spinal cord means there is considerable redundancy in the available mechanisms. Despite this, behavioral studies show that interruption of the actions of any single mediator can relieve signs of pain in experimental animals. We draw attention this paradox. It is difficult to explain how inactivation of one mediator can relieve pain when so many parallel pathways are available.

Do Bisphosphonates Alleviate Pain in Children? A Systematic Review.

PURPOSE OF REVIEW: The goal of this systematic review is to analyze the effectiveness of bisphosphonates (BPs) to treat bone pain in children and adolescents who have diseases with skeletal involvement. RECENT FINDINGS: We included 24 studies (2 randomized controlled trials, 3 non-randomized controlled trials, 10 non-randomized open-label uncontrolled studies, 8 retrospective studies, and 1 study with design not specified). The majority of included studies assessed pain from a unidimensional approach, with pain intensity the most frequently evaluated dimension. Only 38% of studies used validated tools; visual analogue scale was the most frequently employed. BPs were used to alleviate bone pain in a wide variety of pediatrics conditions such as osteogenesis imperfecta, secondary osteoporosis, osteonecrosis related to chemotherapy, chronic non-bacterial osteitis, idiopathic juvenile osteoporosis, unresectable benign bone tumor, and cancer-related pain. Twenty of the 24 studies reported a positive effect of BPs for alleviating pain in different pathologies, but 58% of the studies were categorized as having high risk of bias. Intravenous BPs are helpful in alleviating bone pain in children and adolescents. It is advised that our results be interpreted with caution due to the heterogeneity of the doses used, duration of treatments, and types of pathologies included. In addition, this review shows the paucity of high-quality evidence in the available literature and further research is needed. TRIAL REGISTRATION: Before the completion of this review, the protocol was registered to PROSPERO (International prospective register of systematic reviews), PROSPERO 2020 ID # CRD42020158316. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020158316.

Time Course of Inflammation in Dorsal Root Ganglia Correlates with Differential Reversibility of Mechanical Allodynia.

Some individuals recover from the pain of nerve trauma within 12 months or less whereas others experience life-long intractable pain. This transition between reversible pain and the establishment of chronic neuropathic pain is poorly understood. We examined the role of persistent inflammation in the dorsal root ganglia (DRG) in the long-term maintenance of mechanical allodynia; an index of neuropathic pain. Male Sprague-Dawley rats underwent chronic constriction injury (CCI), spared nerve injury (SNI) or sham surgery. Both CCI and SNI animals displayed robust mechanical allodynia in the ipsilateral paw at 7 d post-surgery; however, only SNI animals maintained mechanical allodynia at 42 d post-surgery. DRGs were extracted at 7 d or 42 d post-surgery to assess inflammation via rt-qPCR or immunohistochemistry to measure colony stimulating factor 1 (CSF1) expression, satellite glial cell (SGC) activation, presence of Iba1 positive macrophages and interleukin1 ß (IL-1ß) mRNA levels. Whereas DRGs from SNI animals continued to display inflammatory markers at 42 d, those from CCI animals did not. Moreover, the level of allodynia displayed by each individual animal correlated with the extent of DRG inflammation. These data support the hypothesis that the amount of CSF1 immunoreactivity and the persistence of inflammation in ipsilateral DRGs contribute to the difference between transient and persistent mechanical allodynia observed in the CCI and SNI models. We also suggest that feedback loops involving cytokines and neurotransmitters may contribute to increased DRG activity in chronic neuropathic pain. Consequently, targeting persistent CSF1 production and peripheral neuroinflammation may be an effective approach to the management of chronic neuropathic pain.

A Long-term Follow-up of Young Adults With Idiopathic Clubfoot: Does Foot Morphology Relate to Pain?

BACKGROUND: Individuals with clubfoot, treated in infancy with either the Ponseti method or comprehensive clubfoot release, often encounter pain as adults. Multiple studies have characterized residual deformity after Ponseti or surgical correction using physical exam, radiographs and pedobarography; however, the relationship between residual foot deformity and pain is not well defined. The purpose of the current study was 2-fold: (1) to evaluate the relationship between foot morphology and pain for young adults treated as infants for idiopathic clubfoot and (2) to describe and compare pedobarographic measures and outcome measures of pain and morphology among surgically treated, Ponseti treated, and typically developing feet. METHODS: We performed a case-control study of individuals treated for clubfoot at 2 separate institutions with either the Ponseti method or comprehensive clubfoot release between 1983 and 1987. All subjects (24 treated with comprehensive clubfoot release, 18 with Ponseti method, and 48 controls) were evaluated using the International Clubfoot Study Group (ICFSG) morphology scoring, dynamic pedobarography, and foot function index surveys. During pedobarography, we collected the subarch angle and arch index as well as the center of pressure progression (COPP) on all subjects. RESULTS: Foot morphology (ICFSG) scores were highly correlated with foot function index pain scores (r=0.43; P<0.001), although the difference in pain scores between the surgical and Ponseti group did not reach significance. The surgical group exhibited greater subarch angle and arch indexes than the Ponseti group, demonstrating a significant difference in morphology, a flatter foot. Finally, we found more abnormalities in foot progression, decreased COPP in the forefoot and increased COPP in the midfoot and hindfoot, in the surgical group compared with controls. CONCLUSIONS: Measures of foot morphology were correlated with pain among all treated for clubfoot. Compared with Ponseti method, comprehensive surgical release lead to greater long-term foot deformity, flatter feet and greater hindfoot loading time. LEVEL OF EVIDENCE: Level III-Therapeutic.

Long-term actions of interleukin-1ß on K+, Na+ and Ca2+ channel currents in small, IB4-positive dorsal root ganglion neurons; possible relevance to the etiology of neuropathic pain.

Excitation of dorsal root ganglion (DRG) neurons by interleukin 1ß (IL-1ß) is implicated in the onset of neuropathic pain. To understand its mechanism of action, isolectin B4 positive (IB4+) DRG neurons were exposed to 100pM IL-1ß for 5-6d. A reversible increase in action potential (AP) amplitude reflected increased TTX-sensitive sodium current (TTX-S INa). An irreversible increase in AP duration reflected decreased Ca2+- sensitive K+ conductance (BK(Ca) channels). Different processes thus underlie regulation of the two channel types. Since changes in AP shape facilitated Ca2+ influx, this explains how IL-1ß facilitates synaptic transmission in the dorsal horn; thereby provoking pain.

Etiology and Pharmacology of Neuropathic Pain.

Injury to or disease of the nervous system can invoke chronic and sometimes intractable neuropathic pain. Many parallel, interdependent, and time-dependent processes, including neuroimmune interactions at the peripheral, supraspinal, and spinal levels, contribute to the etiology of this "disease of pain." Recent work emphasizes the roles of colony-stimulating factor 1, ATP, and brain-derived neurotrophic factor. Excitatory processes are enhanced, and inhibitory processes are attenuated in the spinal dorsal horn and throughout the somatosensory system. This leads to central sensitization and aberrant processing such that tactile and innocuous thermal information is perceived as pain (allodynia). Processes involved in the onset of neuropathic pain differ from those involved in its long-term maintenance. Opioids display limited effectiveness, and less than 35% of patients derive meaningful benefit from other therapeutic approaches. We thus review promising therapeutic targets that have emerged over the last 20 years, including Na+, K+, Ca2+, hyperpolarization-activated cyclic nucleotide-gated channels, transient receptor potential channel type V1 channels, and adenosine A3 receptors. Despite this progress, the gabapentinoids retain their status as first-line treatments, yet their mechanism of action is poorly understood. We outline recent progress in understanding the etiology of neuropathic pain and show how this has provided insights into the cellular actions of pregabalin and gabapentin. Interactions of gabapentinoids with the α2δ-1 subunit of voltage-gated Ca2+ channels produce multiple and neuron type-specific actions in spinal cord and higher centers. We suggest that drugs that affect multiple processes, rather than a single specific target, show the greatest promise for future therapeutic development.

Peripheral nerve injury increases contribution of L-type calcium channels to synaptic transmission in spinal lamina II: Role of α2δ-1 subunits.

Background Following peripheral nerve chronic constriction injury, the accumulation of the α2δ-1 auxiliary subunit of voltage-gated Ca2+ channels in primary afferent terminals contributes to the onset of neuropathic pain. Overexpression of α2δ-1 in Xenopus oocytes increases the opening properties of Cav1.2 L-type channels and allows Ca2+ influx at physiological membrane potentials. We therefore posited that L-type channels play a role in neurotransmitter release in the superficial dorsal horn in the chronic constriction injury model of neuropathic pain. Results Whole-cell recording from lamina II neurons from rats, subject to sciatic chronic constriction injury, showed that the L-type Ca2+ channel blocker, nitrendipine (2 µM) reduced the frequency of spontaneous excitatory postsynaptic currents. Nitrendipine had little or no effect on spontaneous excitatory postsynaptic current frequency in neurons from sham-operated animals. To determine whether α2δ-1 is involved in upregulating function of Cav1.2 L-type channels, we tested the effect of the α2δ-1 ligand, gabapentin (100 µM) on currents recorded from HEK293F cells expressing Cav1.2/ß4/α2δ-1 channels and found a significant decrease in peak amplitude with no effect on control Cav1.2/ß4/α2δ-3 expressing cells. In PC-12 cells, gabapentin also significantly reduced the endogenous dihydropyridine-sensitive calcium current. In lamina II, gabapentin reduced spontaneous excitatory postsynaptic current frequency in neurons from animals subject to chronic constriction injury but not in those from sham-operated animals. Intraperitoneal injection of 5 mg/kg nitrendipine increased paw withdrawal threshold in animals subject to chronic constriction injury. Conclusion We suggest that L-type channels show an increased contribution to synaptic transmission in lamina II dorsal horn following peripheral nerve injury. The effect of gabapentin on Cav1.2 via α2δ-1 may contribute to its anti-allodynic action.

Segmental kinematic analysis of planovalgus feet during walking in children with cerebral palsy.

Pes planovalgus (flatfoot) is a common deformity among children with cerebral palsy. The Milwaukee Foot Model (MFM), a multi-segmental kinematic foot model, which uses radiography to align the underlying bony anatomy with reflective surface markers, was used to evaluate 20 pediatric participants (30feet) with planovalgus secondary to cerebral palsy prior to surgery. Three-dimensional kinematics of the tibia, hindfoot, forefoot, and hallux segments are reported and compared to an age-matched control set of typically-developing children. Most results were consistent with known characteristics of the deformity and showed decreased plantar flexion of the forefoot relative to hindfoot, increased forefoot abduction, and decreased ranges of motion during push-off in the planovalgus group. Interestingly, while forefoot characteristics were uniformly distributed in a common direction in the transverse plane, there was marked variability of forefoot and hindfoot coronal plane and hindfoot transverse plane positioning. The key finding of these data was the radiographic indexing of the MFM was able to show flat feet in cerebral palsy do not always demonstrate more hindfoot eversion than the typically-developing hindfoot. The coronal plane kinematics of the hindfoot show cases planovalgus feet with the hindfoot in inversion, eversion, and neutral. Along with other metrics, the MFM can be a valuable tool for monitoring kinematic deformity, facilitating clinical decision making, and providing a quantitative analysis of surgical effects on the planovalgus foot.

Non-Lethal Type VIII Osteogenesis Imperfecta Has Elevated Bone Matrix Mineralization.

CONTEXT: Type VIII osteogenesis imperfecta (OI; OMIM 601915) is a recessive form of lethal or severe OI caused by null mutations in P3H1, which encodes prolyl 3-hydroxylase 1. OBJECTIVES: Clinical and bone material description of non-lethal type VIII OI. DESIGN: Natural history study of type VIII OI. SETTING: Pediatric academic research centers. PATIENTS: Five patients with non-lethal type VIII OI, and one patient with lethal type VIII OI. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Clinical examinations included bone mineral density, radiographs, and serum and urinary metabolites. Bone biopsy samples were analyzed for histomorphometry and bone mineral density distribution by quantitative backscattered electron imaging microscopy. Collagen biochemistry was examined by mass spectrometry, and collagen fibrils were examined by transmission electron microscopy. RESULTS: Type VIII OI patients have extreme growth deficiency, an L1-L4 areal bone mineral density Z-score of -5 to -6, and normal bone formation markers. Collagen from bone and skin tissue and cultured osteoblasts and fibroblasts have nearly absent 3-hydroxylation (1-4%). Collagen fibrils showed abnormal diameters and irregular borders. Bone histomorphometry revealed decreased cortical width and very thin trabeculae with patches of increased osteoid, although the overall osteoid surface was normal. Quantitative backscattered electron imaging showed increased matrix mineralization of cortical and trabecular bone, typical of other OI types. However, the proportion of bone with low mineralization was increased in type VIII OI bone, compared to type VII OI. CONCLUSIONS: P3H1 is the unique enzyme responsible for collagen 3-hydroxylation in skin and bone. Bone from non-lethal type VIII OI children is similar to type VII, especially bone matrix hypermineralization, but it has distinctive features including extremely thin trabeculae, focal osteoid accumulation, and an increased proportion of low mineralized bone.

Reprogramming of HUVECs into induced pluripotent stem cells (HiPSCs), generation and characterization of HiPSC-derived neurons and astrocytes.

Neurodegenerative diseases are characterized by chronic and progressive structural or functional loss of neurons. Limitations related to the animal models of these human diseases have impeded the development of effective drugs. This emphasizes the need to establish disease models using human-derived cells. The discovery of induced pluripotent stem cell (iPSC) technology has provided novel opportunities in disease modeling, drug development, screening, and the potential for "patient-matched" cellular therapies in neurodegenerative diseases. In this study, with the objective of establishing reliable tools to study neurodegenerative diseases, we reprogrammed human umbilical vein endothelial cells (HUVECs) into iPSCs (HiPSCs). Using a novel and direct approach, HiPSCs were differentiated into cells of central nervous system (CNS) lineage, including neuronal, astrocyte and glial cells, with high efficiency. HiPSCs expressed embryonic genes such as nanog, sox2 and Oct-3/4, and formed embryoid bodies that expressed markers of the 3 germ layers. Expression of endothelial-specific genes was not detected in HiPSCs at RNA or protein levels. HiPSC-derived neurons possess similar morphology but significantly longer neurites compared to primary human fetal neurons. These stem cell-derived neurons are susceptible to inflammatory cell-mediated neuronal injury. HiPSC-derived neurons express various amino acids that are important for normal function in the CNS. They have functional receptors for a variety of neurotransmitters such as glutamate and acetylcholine. HiPSC-derived astrocytes respond to ATP and acetylcholine by elevating cytosolic Ca2+ concentrations. In summary, this study presents a novel technique to generate differentiated and functional HiPSC-derived neurons and astrocytes. These cells are appropriate tools for studying the development of the nervous system, the pathophysiology of various neurodegenerative diseases and the development of potential drugs for their treatments.

Behavior of scoliosis during growth in children with osteogenesis imperfecta.

BACKGROUND: Spinal deformities are common in patients with osteogenesis imperfecta, a heritable disorder that causes bone fragility. The purpose of this study was to describe the behavior of spinal curvature during growth in patients with osteogenesis imperfecta and establish its relationship to disease severity and medical treatment with bisphosphonates. METHODS: The medical records and radiographs of 316 patients with osteogenesis imperfecta were retrospectively reviewed. The severity of osteogenesis imperfecta was classified with the modified Sillence classification. Serial curve measurements were recorded throughout the follow-up period for each patient with scoliosis. Regression analysis was used to determine the effect of disease severity (Sillence type), patient age, and bisphosphonate treatment on the progression of scoliosis as measured with the Cobb method. RESULTS: Of the 316 patients with osteogenesis imperfecta, 157 had associated scoliosis, a prevalence of 50%. Scoliosis prevalence (68%) and mean progression rate (6° per year) were the highest in the group of patients with the most severe osteogenesis imperfecta (modified Sillence type III). A group with intermediate osteogenesis imperfecta severity, modified Sillence type IV, demonstrated intermediate scoliosis values (54%, 4° per year). The patient group with the mildest form of osteogenesis imperfecta, modified Sillence type I, had the lowest scoliosis prevalence (39%) and rate of progression (1° per year). Early treatment-before the patient reached the age of six years-of type-III osteogenesis imperfecta with bisphosphonate therapy decreased the curve progression rate by 3.8° per year, which was a significant decrease. Bisphosphonate treatment had no demonstrated beneficial effect on curve behavior in patients with other types of osteogenesis imperfecta or in patients of older age. CONCLUSIONS: The prevalence of scoliosis in association with osteogenesis imperfecta is high. Progression rates of scoliosis in children with osteogenesis imperfecta are variable, depending on the Sillence type of osteogenesis imperfecta. High rates of scoliosis progression in type-III and type-IV osteogenesis imperfecta contrast with a benign course in type I. Bisphosphonate therapy initiated before the patient reaches the age of six years can modulate curve progression in type-III osteogenesis imperfecta.

Long-term results of comprehensive clubfoot release versus the Ponseti method: which is better?

BACKGROUND: Clubfoot can be treated nonoperatively, most commonly using a Ponseti approach, or surgically, most often with a comprehensive clubfoot release. Little is known about how these approaches compare with one another at longer term, or how patients treated with these approaches differ in terms of foot function, foot biomechanics, or quality-of-life from individuals who did not have clubfoot as a child. QUESTIONS/PURPOSES: We compared (1) focused physical and radiographic examinations, (2) gait analysis, and (3) quality-of-life measures at long-term followup between groups of adult patients with clubfoot treated either with the Ponseti method of nonsurgical management or a comprehensive surgical release through a Cincinnati incision, and compared these two groups with a control group without clubfoot. METHODS: This was a case control study of individuals treated for clubfoot at two separate institutions with different methods of treatment between 1983 to 1987. One hospital used only the Ponseti method and the other mainly used a comprehensive clubfoot release. There were 42 adults (24 treated surgically, 18 treated with Ponseti method) with isolated clubfoot along with 48 healthy control subjects who agreed to participate in a detailed analysis of physical function, foot biomechanics, and quality-of-life metrics. RESULTS: Both treatment groups had diminished strength and motion compared with the control subjects on physical examination measures; however, the Ponseti group had significantly greater ankle plantar flexion ROM (p < 0.001), greater ankle plantar flexor (p = 0.031) and evertor (p = 0.012) strength, and a decreased incidence of osteoarthritis in the ankle and foot compared with the surgical group. During gait the surgical group had reduced peak ankle plantar flexion (p = 0.002), and reduced sagittal plane hindfoot (p = 0.009) and forefoot (p = 0.008) ROM during the preswing phase compared with the Ponseti group. The surgical group had the lowest overall ankle power generation during push off compared with the control subjects (p = 0.002). Outcome tools revealed elevated pain levels in the surgical group compared with the Ponseti group (p = 0.008) and lower scores for physical function and quality-of-life for both clubfoot groups compared with age-range matched control subjects (p = 0.01). CONCLUSIONS: Although individuals in each treatment group experienced pain, weakness, and reduced ROM, they were highly functional into early adulthood. As adults the Ponseti group fared better than the surgically treated group because of advantages including increased ROM observed at the physical examination and during gait, greater strength, and less arthritis. This study supports efforts to correct clubfoot with Ponseti casting and minimizing surgery to the joints, and highlights the need to improve methods that promote ROM and strength which are important for adult function. LEVEL OF EVIDENCE: Level III, prognostic study.

An upper extremity inverse dynamics model for pediatric Lofstrand crutch-assisted gait.

The objective of this study was to develop an instrumented Lofstrand crutch system, which quantifies three-dimensional (3-D) upper extremity (UE) kinematics and kinetics using an inverse dynamics model. The model describes the dynamics of the shoulders, elbows, wrists, and crutches and is compliant with the International Society of Biomechanics (ISB) recommended standards. A custom designed Lofstrand crutch system with four, six-degree-of-freedom force transducers was implemented with the inverse dynamics model to obtain triaxial UE joint reaction forces and moments. The crutch system was validated statically and dynamically for accuracy of computing joint reaction forces and moments during gait. The root mean square (RMS) error of the system ranged from 0.84 to 5.20%. The system was demonstrated in children with diplegic cerebral palsy (CP), incomplete spinal cord injury (SCI), and type I osteogenesis imperfecta (OI). The greatest joint reaction forces were observed in the posterior direction of the wrist, while shoulder flexion moments were the greatest joint reaction moments. The subject with CP showed the highest forces and the subject with SCI demonstrated the highest moments. Dynamic quantification may help to elucidate UE joint demands in regard to pain and pathology in long-term assistive device users.

Muscle force sensitivity of a finite element fracture risk assessment model in osteogenesis imperfecta - biomed 2009.

Osteogenesis imperfecta (OI) is a heritable bone fragility disorder characterized by skeletal deformities and increased bone fragility. There is currently no established clinical method for quantifying fracture risk in OI patients. A method for developing a finite element model of the femur to assist in fracture risk assessment of a selected patient with OI type I was created. The material properties were based on nanoindentation testing of OI bone specimens collected during routine surgery. Dynamic data from clinical gait analysis was used to prescribe joint reaction forces and moments in a quasi-static model. Muscle forces were prescribed according to current literature. Von Mises stresses were analyzed across all seven phases of the gait cycle and analyzed for sensitivity to changes in muscle forces. The model showed that the patient with OI was not at current risk for fracture during normal gait. The highest stress levels occurred during mid stance and loading response. Maximum von Mises stresses were most sensitive to the gluteal muscles. Insight provided by the model may be useful for similar clinical applications, more refined model development and an improved ability for fracture prediction.