Severe Gait Abnormalities Research Articles

Artemisinin Ameliorates the Neurotoxic Effect of 3-Nitropropionic Acid: A Possible Involvement of the ERK/BDNF/Nrf2/HO-1 Signaling Pathway.

Neurodegenerative disorders like Huntington's disease (HD) are a major threat to human health, with severe gait abnormalities and pathological changes (oxidative stress, neuroinflammation, and apoptosis) playing important roles in their development. The effects of artemisinin (ART) alone and in combination with the ERK antagonist PD98059 against 3-nitropropionic acid (3-NPA)-induced cell death and oxidative stress in SH-SY5Y cells were determined using the MTT and DCFH-DA assays, as well as RT-qPCR assays. In vivo, possible neuroprotective effects of ART (10, 20, and 40mg/kg i.p.) against the neurotoxicity generated by 21-day 3-NPA (10mg/kg i.p.) treatment was evaluated in rats by assessing behavioral parameters on days 1, 14, and 21. Further, various biochemical, inflammatory, apoptotic markers, histopathological changes, and protein expression were assessed using brain striatal samples. ART significantly mitigated the neurotoxic effect of 3-NPA in SH-SY5Y cells by regulating the mRNA expression of ERK, Bax, Bcl2, and cytochrome C. However, ART's neuroprotective activity was reduced in the presence of PD98059. Also, ART treatment for 21days substantially alleviated the behavioral impairments associated with 3-NPA toxicity. It reduced the oxidative stress induced by 3-NPA, as evidenced by the lower levels of MDA, nitrite, and improved catalase, SOD activity, and GSH levels. ART treatment restored 3-NPA-induced histopathological alterations in the striatal area. ART effectively suppressed neuroinflammatory (IL-6) and apoptotic markers (caspase 3 and 9), increasing BDNF levels and restoring the p-ERK1/2, Nrf2, and HO-1 expression. ART could exert its neuroprotective effect via antioxidant, anti-inflammatory, and antiapoptotic properties with a possible involvement of the ERK/BDNF/Nrf2/HO-1 pathway.

Serum bicarbonate levels and gait abnormalities in older adults: a cross-sectional study

Metabolic acidosis is associated with impaired physical function in patients with chronic kidney disease (CKD) and older adults. However, whether acidosis is associated with gait abnormalities has received little attention. In a cohort of 323 community-dwelling adults ≥ 65 years old who underwent quantitative gait analysis, we examined associations of serum bicarbonate with eight individual gait variables. After multivariable adjustment, participants in the lowest bicarbonate tertile (< 25 mEq/L) had 8.6 cm/s slower speed (95% confidence interval [CI] 3.2–13.9), 7.9 cm shorter stride length (95% CI 3.5–12.2), and 0.03 s longer double support time (95% CI 0.002–0.1) compared with those in the middle tertile (25–27 mEq/L). Furthermore, lower bicarbonate levels were associated with more severe gait abnormalities in a graded manner. After further adjustment for possible mediating factors, associations were attenuated but remained significant. Among participants with CKD, associations were of similar or greater magnitude compared with those without CKD. Factor analysis was performed to synthesize the individual gait variables into unifying domains: among the pace, rhythm, and variability domains, lower serum bicarbonate was associated with worse performance in pace. In sum, lower serum bicarbonate was independently associated with worse performance on several quantitative measures of gait among older adults.

Smartphone-based inertial sensors technology – Validation of a new application to measure spatiotemporal gait metrics

BackgroundSmartphones are increasingly recognized as the future technology for clinical gait assessment.ResearchQuestion: To determine the concurrent validity of gait parameters obtained using the smartphone technology and application in a group of patients with musculoskeletal pathologies. MethodsPatients with knee, lower back, hip, or ankle pain were included in the study (n = 72). Spatiotemporal outcomes were derived from the walkway and the smartphone simultaneously. Pearson’s correlations and limits of agreement (LoA) determined the association between the two methods. ResultsCadence and gait cycle time showed excellent correlation and agreement between the smartphone and the walkway (cadence: r = 0.997, LoA=1.4%, gait cycle time: r = 0.996, LoA = 1.6%). Gait speed, double-limb support and left and right step length demonstrated strong correlations and moderate agreement between methods (gait speed: r = 0.914, LoA=15.4%, left step length: r = 0.842, LoA = 17.0%, right step length: r = 0.800, LoA=16.4%). The left and right measures of single-limb support and stance percent showed a consistent 4% bias across instruments, yielding moderate correlation and very good agreement between the smartphone and the walkway (r = 0.532, LoA = 9% and r = 0.460, LoA=9.8% for left and right single-limb support; r = 0.463, LoA = 5.1% and r = 0.533, LoA = 4.4% for left and right stance).Significance: The examined application appears to be a valid tool for gait analysis, providing clinically significant metrics for the assessment of patients with musculoskeletal pathologies. However, additional studies should examine the technology amongst patients with severe gait abnormalities.

Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated Cardiomyopathy.

The ubiquitously expressed adaptor protein Shc exists in three isoforms p46Shc, p52Shc, and p66Shc, which execute distinctly different actions in cells. The role of p46Shc is insufficiently studied, and the purpose of this study was to further investigate its functional significance. We developed unique rat mutants lacking p52Shc and p46Shc isoforms (p52Shc/46Shc-KO) and carried out histological analysis of skeletal and cardiac muscle of parental and genetically modified rats with impaired gait. p52Shc/46Shc-KO rats demonstrate severe functional abnormalities associated with impaired gait. Our analysis of p52Shc/46Shc-KO rat axons and myelin sheets in cross-sections of the sciatic nerve revealed the presence of significant anomalies. Based on the lack of skeletal muscle fiber atrophy and the presence of sciatic nerve abnormalities, we suggest that the impaired gait in p52Shc/46Shc-KO rats might be due to the sensory feedback from active muscle to the brain locomotor centers. The lack of dystrophin in some heart muscle fibers reflects damage due to dilated cardiomyopathy. Since rats with only p52Shc knockout do not display the phenotype of p52Shc/p46Shc-KO, abnormal locomotion is likely to be caused by p46Shc deletion. Our data suggest a previously unknown role of 46Shc actions and signaling in regulation of gait.

Functional assessment of outcome of surgery to correct patellofemoral instability in human patients

A case-control study with 6 months of patient follow up. This study sought to determine if surgery followed by rehabilitation for patellar instability could restore normal gait function. A previous study has established abnormalities in gait pattern and joint congruence in patients with a history of patellar instability. We hypothesised that surgery for patellofemoral instability would improve knee function. Eight human patients (mean age 29, range 17-42) who were awaiting patella stabilisation surgery (5 tibial tuberosity osteotomy, 2 medial patellofemoral ligament reconstruction, 1 trochleoplasty) were compared against eight normal Controls (mean age 28, range 19-31). Patients were assessed pre-operatively and six months after surgery by biomechanical gait analysis. Gait trials involved simultaneous collection of kinematic and force data. Patients were grouped into two subgroups pre-operatively based on knee joint net moment during stance, and their joint moments during stance pre- and post-operatively were compared against the Control subjects. In pre-operative gait analysis, four patients (P1) produced some extensor moment in early stance and four (P2) demonstrated a severe gait deficiency with failure to generate a knee extensor moment during stance. Normalisation in gait pattern was observed in all patients post-operatively. Those who had the most severe gait abnormality (P2) demonstrated the most improvement in their knee joint moments. Improvements were observed in the milder (P1) cases, but these were less dramatic. Patella stabilisation by surgery can restore normal gait function. Normalising the anatomy of the knee extensor mechanism is the objective of surgery. Normal anatomy facilitates the rehabilitation objectives of optimising extensor function during the weight-bearing phase of gait.

A 3-Year Physiotherapy Management of a Case of Spinal Poliomyelitis Referred at Three Months Post Paralysis

Background: Poliomyelitis is known to bring about huge complications that foist debilitating disabilities on a patient with poliomyelitis. Most post-polio survivors live with disabilities throughout a lifetime with an attendant social and economic consequence.&#x0D; Objective: Based on the findings from subjective assessment and physical examination, the objective of the current study focused on early physiotherapy intervention measures for preventing complications such as contracture, joint stiffness, muscle wasting, severe gait abnormality, vertebral mal-alignment, and unusual pain.&#x0D; Case Description: A 4-month-old patient referred for physiotherapy evaluation following an inability to functionally move the two lower limbs and lifting of the left upper limb. There was no history of previous treatment before referral to physiotherapy management. The physical therapists reviewed the available literature, consulted with medical and physical therapist experts and the patient, and elected to use an approach combining the use of low intensity, short duration, and intermittent activity or exercise performed within patient’s limit of fatigue, weakness, and pain.&#x0D; Intervention: The child was on low-intensity exercises, electrical muscle stimulation and heat therapy 3 times per week for 12 months, 2 times per week for12 months, once a week, and once in two weeks for 6 months.&#x0D; Outcomes: Patient was able to achieve one-minute ambulation without walking aid in 33 months. Significantly, patient attained 5-minute ambulation in 36 months’ time. Also, ranges of motion were intact with no records of contracture in any tendon.&#x0D; Discussion: The outcome of this study demonstrated that early physiotherapy intervention and long-term follow-up are beneficial in preventing/reducing complications, thereby regaining of millstones and achieving functional independence in patients with acute flaccid paralysis such as polio.

Outcomes of Bilateral vs Unilateral Ankle Arthrodesis.

While ankle arthrodesis is a common treatment for severe ankle osteoarthritis, performing bilateral ankle arthrodesis is controversial because of associated problems, such as severe gait abnormality and bilateral loss of talocrural joint motion. Furthermore, few reports exist regarding the detailed outcomes of bilateral ankle arthrodesis. Therefore, we aimed to compare the outcomes of bilateral ankle arthrodesis with those of unilateral ankle arthrodesis, using both subjective and objective assessments. The data from 20 patients (10 each in the bilateral and unilateral groups), who underwent arthrodesis between 2005 and 2015, were retrospectively reviewed. The minimum follow-up duration was 2 years. Radiographic outcomes were assessed using radiographs and computed tomography. Clinical outcomes were assessed using the Japanese Society for Surgery of the Foot (JSSF) scale and the Self-Administered Foot Evaluation Questionnaire (SAFE-Q). With the numbers available, no significant group differences were observed for any of the patient characteristics or postoperative range of motion. Mean JSSF scale scores significantly improved in both groups ( P < .001); however, scores on the SAFE-Q subscale for "social functioning" were significantly lower in the bilateral group compared to the unilateral group ( P = .049). Within the limitations of the current study design, bilateral ankle arthrodesis did not appear to be inferior to unilateral ankle arthrodesis, with the possible exception of social functioning ability. Thus, bilateral ankle arthrodesis can be considered a viable treatment option. Level III, retrospective cohort study.

Crocin reduced acrylamide-induced neurotoxicity in Wistar rat through inhibition of oxidative stress.

Acrylamide (ACR) has many applications in different industries. ACR damages the central and the peripheral nervous system in human and animals. Importance of ACR-induced neurotoxicity encouraged researchers to find both different mechanisms involved in ACR neurotoxicity and potent neuroprotective agents. Therefore, this study was designed to investigate the protective effect of crocin, an active constituent of Crocus sativus L. (saffron) on ACR-induced neurotoxicity in Wistar rats. Animals were treated with ACR (50 mg/kg, IP) 11 days for induction neurotoxicity. Crocin (12.5, 25 and 50 mg/kg, IP) were used during treatment with ACR. At the end of treatment, gait score examination was performed. Then, rats were sacrificed and the severity of damage in brain tissue was determined using pathological tests. The level of malondialdehyde (MDA) and glutathione (GSH) content were evaluated in cerebral cortex and cerebellum to determine the role of oxidative stress in this model. Exposure to ACR induced severe gait abnormalities and pathological changes, but administration of crocin markedly improved behavioral index and histopathological damages. The elevation of lipid peroxidation parallel with reduction of GSH level was observed in cerebral cortex and cerebellum following exposure to ACR. Treatment with crocin markedly decreased MDA level, while elevated GSH content in nervous system as compared to ACR-treated animals. The administration of crocin markedly improved behavioral and histopathological damages in Wistar rats exposed to ACR. Reduction of oxidative stress can be considered as an important mechanism of neuroprotective effects of crocin against ACR-induced toxicity.

Protective Effect of Green Tea Aqueous Extract on Acrylamide Induced Neurotoxicity

Background: Acrylamide (ACR) monomer is an effective neurotoxicant, which damages the central and peripheral nervous systems in humans and animals. Green tea, an infusion from the leaves of Camellia sinensis Theaceae, is a known antioxidant traditional medicine. Objectives: In this study, the protective effect of green tea aqueous extract (GTAE) was evaluated on ACR induced neurotoxicity. Materials and Methods: In our in vitro study, the effect of different concentrations of GTAE on ACR toxicity (IC50) in PC12 cells was evaluated using MTT assay. Moreover in another experiment, the effect of GTAE on neural toxicity induced by ACR was evaluated in rats. Results: Treatment with ACR (50 mg/kg via intraperitoneal injection for 11 days), induced severe gait abnormalities and significantly decreased body weight at the end of 11 days. Treatment with GTAE (6.25, 12.5, 25 and 50 mg/kg) reduced ACR-induced neurotoxicity, but the effect was only significant in a group which received GTAE at a dose of 12.5 mg/kg and ACR (P < 0.01). ACR decreased cell viability in PC12 cells used as an in vitro model. Pretreatment with GTAE (7.8 - 62.5 µg/mL) decreased ACR-induced cytotoxicity (P < 0.01 and P < 0.001, respectively). Conclusions: As green tea is an essential source of antioxidants such as flavonoids, suppression of reactive oxygen species (ROS) generation may be in part considered as the neuroprotective mechanism on ACR induced neurotoxicity.

Neuroprotective effect of thymoquinone in acrylamide-induced neurotoxicity in Wistar rats.

Acrylamide (ACR) has broad applications in different industries. It also forms in food during heating process. Oxidative stress has a critical role in ACR-induced neurotoxicity in both in vitro and in vivo models; therefore, the aim of the current study was the evaluation of effects of thymoquinone, the main constituent of volatile oil from Nigella sativa seeds in ACR-induced neurotoxicity. Male Wistar rats were treated with ACR (50 mg/kg IP) alone or with thymoquinone (TQ) (2.5, 5, 10 mg/kg IP) for 11 days. Two protocols were used in this study, A: in this one TQ and ACR were used simultaneously, B: Administration of TQ was started 1 week before ACR treatment and continued during exposure to ACR. At the end of the treatment, behavioral index (gait score) was examined for rats. After that, rats were sacrificed and molondialdehyde (MDA) as a marker of lipid peroxidation and glutathione (GSH) content were determined in cerebral cortex. Exposure to ACR led to severe gait abnormalities and treatment with TQ significantly decreased abnormalities. Level of MDA was elevated in cerebral cortex after exposure to ACR while TQ treatment significantly and in a dose-dependent manner reduced lipid peroxidation. Results clearly showed that there is no significant difference between two protocols of administration of TQ. It suggests the neuroprotective effect of TQ in this model in part, may be because of due the antioxidant activity of this natural compound.

Linalool as a neuroprotective agent against acrylamide-induced neurotoxicity in Wistar rats

Acrylamide (ACR) is a water-soluble monomer which has broad application in different industries and also can form in food during heating process. This monomer is a potent neurotoxic and damages the central and the peripheral nervous system in human and animals. Oxidative stress has been mentioned as an important pathway in ACR neurotoxicity, therefore the purpose of the current study was evaluation of possible effects of linalool which is a naturally enantiomer monoterpene compound. Linalool has shown antioxidant properties in several studies. Male Wistar rats were treated with ACR (50 mg/kg ip) alone or with linalool (12.5, 25, 50 and 100 mg/kg ip) for 11 days. In another 2 groups rats were treated with linalool (12.5 mg/kg ip) 3 days after and before ACR administration. Then behavior index (gait score) was examined for rats. After that, rats were sacrified and molondialdehyde (MDA) as a marker of lipid peroxidation and glutathione (GSH) content were determined in brain tissue. Exposure to ACR led to severe gait abnormalities and treatment with linalool significantly reduced abnormalities. ACR reduced GSH content and increased level of MDA in cerebral cortex. Linalool increased GSH content while decreased ACR-induced lipid peroxidation in rat brain tissue and the best protocols were initiation of supplementation before or simultaneous with ACR administration.

Chrysin reduced acrylamide-induced neurotoxicity in both in vitro and in vivo assessments.

Acrylamide (ACR) is a well-known industrial toxic chemical that produces neurotoxicity, which is characterized by progressive central and peripheral neuronal degeneration. Chrysin is a natural, biologically active flavonoid compound, which is commonly found in many plants. The antioxidant and neuroprotective properties of chrysin have been demonstrated. In this study, the possible effect of chrysin on ACR-induced toxicity was evaluated in both in vitro and in vivo experiments. PC12 cells were used as a suitable in vitro model. Cells were exposed to chrysin (0.5-5 µM) for 12 and 24 h, and then ACR in IC50 concentration was added to the cells. Finally, cell viability was determined using (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay. For in vivo assay, Wistar rats were treated with ACR (50 mg/kg i.p. for 11 days) alone or in combination with chrysin (12.5, 25, and 50 mg/kg). At the end of treatment, behavioral index was evaluated. ACR decreased cell viability and pre-treatment with chrysin (0.5-5 µM) significantly decreased ACR-induced cytotoxicity in the time- and dose-dependent manner. In Wistar rats, exposure to ACR significantly induced severe gait abnormalities, but treatment with chrysin (50 mg/kg) reduced ACR-induced neurotoxicity in animals. In the current study, chrysin exhibited neuroprotective effect on PC12 cells as an in vitro model and also on Wistar rats.

Sagittal plane hip motion reversals during walking are associated with disease severity and poorer function in subjects with hip osteoarthritis

A midstance reversal of sagittal plane hip motion during walking, or motion discontinuity (MD), has previously been observed in subjects with endstage hip osteoarthritis (OA) and in patients with femoroacetabular impingement. The goal of the present study was to evaluate whether this gait pattern is a marker of OA presence or radiographic severity by analyzing a large IRB approved motion analysis data repository. We also hypothesized that subjects with the MD would show more substantial gait impairments than those with normal hip motion. We identified 150 subjects with symptomatic unilateral hip OA and Kellgren–Lawrence OA severity data on file, and a control group of 159 asymptomatic subjects whose ages fell within 2 standard deviations of the mean OA group age. From the gait data, the MD was defined as a reversal in the slope of the hip flexion angle curve during midstance. Logistic regressions and general linear models were used to test the association between the MD and OA presence, OA severity and, other gait variables. 53% of OA subjects compared to 7.5% of controls had the MD (p<0.001); occurrence of the MD was associated with OA severity (p=0.009). Within the OA subject group, subjects with the MD had reduced dynamic range of motion, peak, extension, and internal rotation moments compared to those who did not (MANCOVA p≤0.042) after controlling for walking speed. We concluded that sagittal plane motion reversals are indeed associated with OA presence and severity, and with more severe gait abnormalities in subjects with hip OA.

Training Conditions Influence Walking Kinematics and Self-Selected Walking Speed in Patients with Neurological Impairments

Gait training is a major focus of rehabilitation for many people with neurological disorders, yet systematic reviews have failed to identify the most effective form of gait training. The main objective of this study was to compare conditions for gait training for people with acquired brain injury (ABI). Seventeen people who had sustained an ABI and were unable to walk without assistance were recruited as a sample. Each participant was exposed to seven alternative gait training conditions in a randomized order. These were: (1) therapist manual facilitation; (2) the use of a gait-assistive device; (3) unsupported treadmill walking; and (4) four variations of body weight support treadmill training (BWSTT). Quantitative gait analysis was performed and Gait Profile Scores (GPS) were generated for each participant to determine which condition most closely resembled normal walking. BWSTT without additional therapist or self-support of the upper limbs was associated with more severe gait abnormality [Wilks' lambda = 0.20, F(6, 6) = 3.99, p = 0.047]. With the exception of therapist facilitation, the gait training conditions that achieved the closest approximation of normal walking required self-support of the upper limbs. When participants held on to a stable handrail, self-selected gait speeds were up to three times higher than the speeds obtained for over-ground walking [Wilks' lambda = 0.17, F(6, 7) = 5.85, p < 0.05]. The provision of stable upper-limb support was associated with high self-selected gait speeds that were not sustained when walking over ground. BWSTT protocols may need to prioritize reduction in self-support of the upper limbs, instead of increasing treadmill speed and reducing body weight support, in order to improve training outcomes.

Acquired Copper Deficiency: A Potentially Serious and Preventable Complication Following Gastric Bypass Surgery

Copper is an essential cofactor in many enzymatic reactions vital to the normal function of the hematologic, vascular, skeletal, antioxidant, and neurologic systems. Copper deficiency in the United States is believed to be relatively rare but has been described in the setting of zinc supplementation, myelodysplastic syndrome, use of parenteral nutrition and chronic tube feeding, and in various malabsorptive syndromes, including following gastrectomy and gastric bypass surgery. Features of copper deficiency include hematologic abnormalities (anemia, neutropenia, and leukopenia) and myeloneuropathy; the latter is a rarer and often unrecognized complication of copper deficiency. We here describe two patients who presented with severe gait abnormalities and anemia combined with neutropenia several years after roux-en-Y gastric bypass (RYGB) surgery for obesity who were found to be severely copper deficient. Intravenous copper repletion resulted in the rapid correction of hematologic indices; combined intravenous and oral copper supplementation and eventual oral copper supplements alone normalized serum copper levels in each patient, but resulted in only partial resolution of the neurologic deficits. This report serves to alert physicians of the association between RYGB procedures and subsequent copper deficiency in order to avoid diagnostic delays and to improve treatment outcomes.

Congenital Portosystemic Shunts in Five Mature Dogs With Neurological Signs

Congenital portosystemic shunts are a common cause of hepatic encephalopathy and are typically first identified when dogs are <2 years of age. This case series describes five dogs with congenital portosystemic shunts; the dogs were presented for severe encephalopathic signs during middle or old age. Three dogs had portoazygos shunts, and four dogs had multifocal and lateralizing neurological abnormalities, including severe gait abnormalities and vestibular signs. All five dogs responded to medical or surgical treatment, demonstrating that older animals can respond to treatment even after exhibiting severe neurological signs.

Epidemiology of Gait Disorders in Community‐Residing Older Adults

To study the epidemiology of gait disorders in community-residing older adults and their association with death and institutionalization. Community-based cohort study. Bronx County and the research center at Albert Einstein College of Medicine. The Einstein Aging study recruited 488 adults aged 70 to 99 between 1999 and 2001. At entry and during annual visits over 5 years, subjects received clinical evaluations to determine presence of neurological or nonneurological gait abnormalities. Prevalence and incidence of gait disorders based on clinical evaluations and time to institutionalization and death. Of 468 subjects (95.9%) with baseline gait evaluations, 168 had abnormal gaits: 70 neurological, 81 nonneurological, and 17 both. Prevalence of abnormal gait was 35.0% (95% confidence interval (CI) = 28.6-42.1). Incidence of abnormal gait was 168.6 per 1,000 person-years (95% CI = 117.4-242.0) and increased with age. Men had a higher incidence of neurological gait abnormalities, whereas women had a higher incidence of nonneurological gaits. Abnormal gaits were associated with greater risk of institutionalization and death (hazard ratio (HR) = 2.2, 95% CI =1.5-3.2). The risk was strongly related to severity of impairment; subjects with moderate to severe gait abnormalities (HR = 3.2, 95% CI = 1.9-5.2) were at higher risk than those with mild gait abnormalities (HR = 1.8, 95% CI = 1.0-2.8). The incidence and prevalence of gait disorders are high in community-residing older adults and are associated with greater risk of institutionalization and death.

A Syndrome of Joint Laxity and Impaired Tendon Integrity in Lumican- and Fibromodulin-deficient Mice

Lumican and fibromodulin regulate the assembly of collagens into higher order fibrils in connective tissues. Here, we show that mice deficient in both of these proteoglycans manifest several clinical features of Ehlers-Danlos syndrome. The Lum(-/-)Fmod(-/-) mice are smaller than their wild type littermates and display gait abnormality, joint laxity, and age-dependent osteoarthritis. Misaligned knee patella, severe knee dysmorphogenesis, and extreme tendon weakness are the likely causes for joint laxity in the double-nulls. Fibromodulin deficiency alone leads to significant reduction in tendon stiffness in the Lum(+/+)Fmod(-/-) mice, with further loss in stiffness in a Lum gene dose-dependent way. At the protein level, we show marked increase of lumican in Fmod(-/-) tendons, which may partially rescue the tendon phenotype in this genotype. These results establish fibromodulin as a key regulator and lumican as a modulator of tendon strength. A disproportionate increase in small diameter immature collagen fibrils and a lack of progression to mature, large diameter fibrils in the Fmod(-/-) background may constitute the underlying cause of tendon weakness and suggest that fibromodulin aids fibril maturation. This study demonstrates that the collagen fibril-modifying proteoglycans, lumican and fibromodulin, are candidate genes and key players in the pathogenesis of certain types of Ehlers-Danlos syndrome and other connective tissue disorders.