Statistical shape analysis and computational modeling reveal novel relationships between tibiofemoral bony geometry and knee mechanics in young, female athletes.

Young female athletes participating in sports requiring rapid changes of direction are at heightened risk of suffering traumatic knee injury, especially noncontact rupture of the anterior cruciate ligament (ACL). Clinical studies have revealed that geometric features of the tibiofemoral joint are associated with increased risk of suffering noncontact ACL injury. However, the relationship between three-dimensional (3D) tibiofemoral geometry and knee mechanics in young female athletes is not well understood. We developed a statistically augmented computational modeling workflow to determine relationships between 3D geometry of the knee and tibiofemoral kinematics and ACL force in response to an applied loading sequence of compression, valgus, and anterior force, which is known to load the ACL. This workflow included 3D characterization of tibiofemoral bony geometry via principal component analysis and multibody dynamics models incorporating subject-specific knee geometries. A combination of geometric features of both the tibia and the femur that spanned all three anatomical planes was related to increased ACL force and to increased kinematic coupling (i.e., anterior, medial, and distal tibial translations and internal tibial rotation) in response to the applied loads. In contrast, a uniplanar measure of tibiofemoral geometry that is associated with ACL injury risk, sagittal plane slope of the lateral tibial plateau subchondral bone, was not related to ACL force. Thus, our workflow may aid in developing mechanics-based ACL injury screening tools for young, active females based on a unique combination of bony geometric features that are related to increased ACL loading.

Prediction of Model Generated Patellofemoral Joint Contact Forces Using Principal Component Prediction and Reconstruction.

It is not currently possible to directly and noninvasively measure in vivo patellofemoral joint contact force during dynamic movement; therefore, indirect methods are required. Simple models may be inaccurate because patellofemoral contact forces vary for the same knee flexion angle, and the patellofemoral joint has substantial out-of-plane motion. More sophisticated models use 3-dimensional kinematics and kinetics coupled to a subject-specific anatomical model to predict contact forces; however, these models are time consuming and expensive. We applied a principal component analysis prediction and regression method to predict patellofemoral joint contact forces derived from a robust musculoskeletal model using exclusively optical motion capture kinematics (external approach), and with both patellofemoral and optical motion capture kinematics (internal approach). We tested this on a heterogeneous population of asymptomatic subjects (n = 8) during ground-level walking (n = 12). We developed equations that successfully capture subject-specific gait characteristics with the internal approach outperforming the external. These approaches were compared with a knee-flexion based model in literature (Brechter model). Both outperformed the Brechter model in interquartile range, limits of agreement, and the coefficient of determination. The equations generated by these approaches are less computationally demanding than a musculoskeletal model and may act as an effective tool in future rapid gait analysis and biofeedback applications.

Knee extension moment arm variations relate to mechanical function in walking and running.

The patellofemoral joint plays a crucial mechanical role during walking and running. It increases the knee extensor mechanism's moment arm and reduces the knee extension muscle forces required to generate the extension moment that supports body weight, prevents knee buckling and propels the centre of mass. However, the mechanical implications of moment arm variation caused by patellofemoral and tibiofemoral motion remain unclear. We used a data-driven musculoskeletal model with a 12-degree-of-freedom knee to simulate the knee extension moment arm during walking and running. Using a geometric method to calculate the moment arm, we found smaller moment arms during running than during walking in the swing phase. Overall, knee flexion causes differences between running and walking moment arms as increased flexion causes a posterior shift in the tibiofemoral rotation axis and patella articulation with the distal femur. Moment arms were also affected by knee motion direction and best predicted by separating by direction instead of across the entire gait cycle. Furthermore, we found high inter-subject variation in the moment arm that was largely explained by out-of-plane motion. Our results are consistent with the concept that shorter moment arms increase the effective mechanical advantage of the knee and may contribute to increased running velocity.

Patella Apex Influences Patellar Ligament Forces and Ratio.

The relationship between three-dimensional shape and patellofemoral mechanics is complicated. The Wiberg patella classification is a method of distinguishing shape differences in the axial plane of the patella that can be used to connect shape differences to observed mechanics. This study uses the Wiberg patella classification to differentiate variance in a statistical shape model describing changes in patella morphology and height. We investigate how patella morphology influences force distribution within the patellofemoral joint. The Wiberg type I patella has a more symmetrical medial and lateral facet while the type III patella has a larger lateral facet compared to medial. The second principal component of the statistical shape model described shape variation that qualitatively resembled the different Wiberg patellas. We generated patellofemoral morphologies from the statistical shape model and integrated them into a musculoskeletal model with a twelve degrees-of-freedom knee. We simulated an overground walking trial with these morphologies and recorded patellofemoral mechanics and ligament forces. An increase in patellar ligament force corresponded with an increase in patella height. Wiberg type III patellas had a sharper patella apex which related to lower ratios of quadriceps tendon forces to patellar ligament forces. The change in pivot point of the patella affects the ratio of forces as well as the patellofemoral reaction force. This study provides a better understanding of how patella morphology affects fundamental patella mechanics which may help identify at-risk populations for pathology development.

Patellofemoral Mechanics: a Review of Pathomechanics and Research Approaches.

PURPOSE OF REVIEW: The patellofemoral joint is a complicated articulation of the patella and femur that is prone to pathologies. The purpose of this review is to report on the current methods of investigating patellofemoral mechanics, factors that affect joint function, and future directions in patellofemoral joint research with emerging technologies and techniques. RECENT FINDINGS: While previous hypotheses have suggested that the patella is only a moment arm extender, recent literature has suggested that the patella influences the control of knee moments and forces acting on the tibia as well as contributes to various aspects of patellar function with minimal neural input. With advancements in simulating a six-degrees-of-freedom patellofemoral joint, we have gained a better understanding of patella motion and have shown that geometry and muscle activations impact patella mechanics. Research into influences on patella mechanics from other joints such as the hip and foot has become more prevalent. In this review, we report current in vivo, in vitro, and in silico approaches to studying the patellofemoral joint. Kinematic and anatomical factors that affect patellofemoral joint function such as patella alta and tilt or bone morphology and ligaments are discussed. Moving forward, we suggest that advanced in vivo dynamic imaging methods coupled to musculoskeletal simulation will provide further understanding of patellofemoral pathomechanics and allow engineers and clinicians to design interventions to mitigate or prevent patellofemoral pathologies.

Tyrosinemia type II: Mutation update, 11 novel mutations and description of 5 independent subjects with a novel founder mutation.

BACKGROUND: Tyrosinemia type II, also known as Richner-Hanhart Syndrome, is an extremely rare autosomal recessive disorder, caused by mutations in the gene encoding hepatic cytosolic tyrosine aminotransferase, leading to the accumulation of tyrosine and its metabolites which cause ocular and skin lesions, that may be accompanied by neurological manifestations, mostly intellectual disability. AIMS: To update disease-causing mutations and current clinical knowledge of the disease. MATERIALS AND METHODS: Genetic and clinical information were obtained from a collection of both unreported and previously reported cases. RESULTS: We report 106 families, represented by 143 individuals, carrying a total of 36 genetic variants, 11 of them not previously known to be associated with the disease. Variants include 3 large deletions, 21 non-synonymous and 5 nonsense amino-acid changes, 5 frameshifts and 2 splice variants. We also report 5 patients from Gran Canaria, representing the largest known group of unrelated families sharing the same P406L mutation. CONCLUSIONS: Data analysis did not reveal a genotype-phenotype correlation, but stressed the need of early diagnosis: All patients improved the oculocutaneous lesions after dietary treatment but neurological symptoms prevailed. The discovery of founder mutations in isolated populations, and the benefits of early intervention, should increase diagnostic awareness in newborns.

LPIN1 deficiency with severe recurrent rhabdomyolysis and persistent elevation of creatine kinase levels due to chromosome 2 maternal isodisomy.

Fatty acid oxidation disorders and lipin-1 deficiency are the commonest genetic causes of rhabdomyolysis in children. We describe a lipin-1-deficient boy with recurrent, severe rhabdomyolytic episodes from the age of 4 years. Analysis of the LPIN1 gene that encodes lipin-1 revealed a novel homozygous frameshift mutation in exon 9, c.1381delC (p.Leu461SerfsX47), and complete uniparental isodisomy of maternal chromosome 2. This mutation is predicted to cause complete lipin-1 deficiency. The patient had six rhabdomyolytic crises, with creatine kinase (CK) levels up to 300,000 U/L (normal, 30 to 200). Plasma CK remained elevated between crises. A treatment protocol was instituted, with early aggressive monitoring, hydration, electrolyte replacement and high caloric, high carbohydrate intake. The patient received dexamethasone during two crises, which was well-tolerated and in these episodes, peak CK values were lower than in preceding episodes. Studies of anti-inflammatory therapy may be indicated in lipin-1 deficiency.

Diversity of ARSACS mutations in French-Canadians.

BACKGROUND: The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations reported worldwide has broadened the clinical phenotype of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The identification of Quebec ARSACS cases without two known SACS mutation led to the development of a multi-modal genomic strategy to uncover mutations in this large gene and explore phenotype variability. METHODS: Search for SACS mutations by combining various methods on 20 cases with a classical French-Canadian ARSACS phenotype without two mutations and a group of 104 sporadic or recessive spastic ataxia cases of unknown cause. Western blot on lymphoblast protein from cases with different genotypes was probed to establish if they still expressed sacsin. RESULTS: A total of 12 mutations, including 7 novels, were uncovered in Quebec ARSACS cases. The screening of 104 spastic ataxia cases of unknown cause for 98 SACS mutations did not uncover carriers of two mutations. Compounds heterozygotes for one missense SACS mutation were found to minimally express sacsin. CONCLUSIONS: The large number of SACS mutations present even in Quebec suggests that the size of the gene alone may explain the great genotypic diversity. This study does not support an expanding ARSACS phenotype in the French-Canadian population. Most mutations lead to loss of function, though phenotypic variability in other populations may reflect partial loss of function with preservation of some sacsin expression. Our results also highlight the challenge of SACS mutation screening and the necessity to develop new generation sequencing methods to ensure low cost complete gene sequencing.

Genetics, physiology and perinatal influences in childhood obesity: view from the Chair.

The current epidemic of childhood obesity will be a serious threat to population health for at least the next several decades. The biology of childhood obesity was the theme of an international symposium held in November 2007. Speakers discussed monogenic causes of obesity, prenatal epigenetic programming, neurobehavioral aspects of obesity, and hormonal and neuroendocrine abnormalities, and the insights provided by non-murine models for understanding the biology of early-onset obesity. Several new developments have been reported in white and brown adipose tissue biology. They are summarized briefly in this review and include observations about cell lineage of adipocytes, the renewal of adipocytes throughout life and the numerous factors that influence adipocyte fatty acid release. The biological underpinnings of childhood obesity are multiple and complex.

Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15.

BACKGROUND: Hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome (OMIM 238970) is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15. To date, 22 different mutations of the SLC25A15 gene have been described in 49 patients belonging to 31 unrelated families. OBJECTIVE: To further delineate the phenotypic spectrum of HHH syndrome from a description of a genetically homogeneous cohort of patients and identify prognostic factors based on long-term follow-up. METHODS: Sixteen French-Canadian patients were retrospectively and prospectively clinically assessed. RESULTS: Owing to a founder effect, 15 of the 16 patients were homozygous for the F188del mutation in the SLC25A15 gene. The main clinical features at presentation were liver dysfunction (6/16) and neurological disease (9/16), including chronic neurological symptoms (6/9) and acute encephalopathy (3/9). Hyperammonaemia was not constant and usually mild and uncommon after start of treatment. Long-term follow-up showed that variable intellectual impairment and lower limb spasticity often occur, together or separately, with no obvious relationship to age at diagnosis and compliance with treatment. CONCLUSION: We report the largest known cohort to date of patients with HHH syndrome. A similar range of severity occurred in the clinical course and outcome of patients homozygous for delF188 and in the 33 other reported patients compiled from the literature. The poor clinical outcome of some patients with HHH syndrome despite early treatment and repeatedly normal plasma ammonia levels emphasises the need to better understand the pathophysiology and to reconsider the therapeutic goals for HHH.

Reduced brain choline in homocystinuria due to remethylation defects.

OBJECTIVE: To investigate whether secondary impairment of the transmethylation pathway is a mechanism underlying the neurologic involvement in homocystinuria due to remethylation defects. METHODS: Twelve patients with neurologic disease due to remethylation defects were examined by brain magnetic resonance spectroscopic imaging ((1)H MRSI). Brain N-acetylaspartate, choline-containing compounds (Cho), and creatine (Cr) were quantified and compared to with controls. Metabolites of remethylation cycle and creatine biosynthesis pathway were measured in plasma and urine. RESULTS: MRSI revealed isolated Cho deficiency in all regions examined (mean concentration units +/- SD, patients vs controls): frontal white matter (0.051 +/- 0.010 vs 0.064 +/- 0.010; p = 0.001), lenticular nucleus (0.056 +/- 0.011 vs 0.069 +/- 0.009; p < 0.001), and thalamus (0.063 +/- 0.010 vs 0.071 +/- 0.007; p = 0.006). In contrast to controls, the Cho/Cr ratio decreased with age in patients in the three brain regions examined. Low creatine urinary excretion (p < 0.005), normal urine and plasma guanidinoacetate, and a paradoxical increase in plasma S-adenosylmethionine (p < 0.005) concentrations were observed. CONCLUSION: Patients with homocystinuria due to remethylation defects have an isolated brain choline deficiency, probably secondary to depletion of labile methyl groups produced by the transmethylation pathway. Although biochemical studies suggest mild peripheral creatine deficiency, brain creatine is in the reference range, indicating a possible compartmentation phenomenon. Paradoxical increase of S-adenosylmethionine suggests that secondary inhibition of methylases contributes to the transmethylation defect in these conditions.

Pyruvate dehydrogenase deficiency presenting as intermittent isolated acute ataxia.

OBJECTIVE: The aim of this study is to report and emphasize unusual presentations of pyruvate dehydrogenase (PDH) deficiency (OMIM 312170). METHODS: PDH activity and PDHA1 gene were studied in two siblings presenting with intermittent ataxia in childhood. Similar presentations in reported PDH-deficient patients were searched for using the Medline database. RESULTS: Both patients had PDH deficiency caused by a new mutation (G585C) in the PDHA1 gene, which is predicted to replace a highly conserved glycine at codon 195 by alanine. Although this mutation lies within the thiamine pyrophosphate binding domain, there was no thiamine responsiveness IN VIVO. The patients presented recurrent episodes of acute isolated ataxia in infancy. Both had normal blood and CSF lactate levels. Although symptoms initially resolved between episodes during the first decade, both patients subsequently worsened and developed progressive and severe encephalopathy, leading to death in their twenties. The spectrum of intermittent presentations in PDH deficiency includes episodic ataxia, intermittent peripheral weakness, recurrent dystonia and extrapyramidal movement disorders. CONCLUSIONS: PDH deficiency should be considered in patients with unexplained intermittent and recurrent acute neurological symptoms. Long-term prognosis and outcome remain uncertain. PDH deficiency can occur even with normal CSF lactate concentration.

Generalization mediates sensitivity to complex odor features in the honeybee.

Animals use odors as signals for mate, kin, and food recognition, a strategy which appears ubiquitous and successful despite the high intrinsic variability of naturally-occurring odor quantities. Stimulus generalization, or the ability to decide that two objects, though readily distinguishable, are similar enough to afford the same consequence, could help animals adjust to variation in odor signals without losing sensitivity to key inter-stimulus differences. The present study was designed to investigate whether an animal's ability to generalize learned associations to novel odors can be influenced by the nature of the associated outcome. We use a classical conditioning paradigm for studying olfactory learning in honeybees to show that honeybees conditioned on either a fixed- or variable-proportion binary odor mixture generalize learned responses to novel proportions of the same mixture even when inter-odor differences are substantial. We also show that the resulting olfactory generalization gradients depend critically on both the nature of the stimulus-reward paradigm and the intrinsic variability of the conditioned stimulus. The reward dependency we observe must be cognitive rather than perceptual in nature, and we argue that outcome-dependent generalization is necessary for maintaining sensitivity to inter-odor differences in complex olfactory scenes.

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling.

AIMS/HYPOTHESIS: The aim of this study was to determine the role of fatty acid signalling in islet beta cell compensation for insulin resistance in the Zucker fatty fa/fa (ZF) rat, a genetic model of severe obesity, hyperlipidaemia and insulin resistance that does not develop diabetes. MATERIALS AND METHODS: NEFA augmentation of insulin secretion and fatty acid metabolism were studied in isolated islets from ZF and Zucker lean (ZL) control rats. RESULTS: Exogenous palmitate markedly potentiated glucose-stimulated insulin secretion (GSIS) in ZF islets, allowing robust secretion at physiological glucose levels (5-8 mmol/l). Exogenous palmitate also synergised with glucagon-like peptide-1 and the cyclic AMP-raising agent forskolin to enhance GSIS in ZF islets only. In assessing islet fatty acid metabolism, we found increased glucose-responsive palmitate esterification and lipolysis processes in ZF islets, suggestive of enhanced triglyceride-fatty acid cycling. Interruption of glucose-stimulated lipolysis by the lipase inhibitor Orlistat (tetrahydrolipstatin) blunted palmitate-augmented GSIS in ZF islets. Fatty acid oxidation was also higher at intermediate glucose levels in ZF islets and steatotic triglyceride accumulation was absent. CONCLUSIONS/INTERPRETATION: The results highlight the potential importance of NEFA and glucoincretin enhancement of insulin secretion in beta cell compensation for insulin resistance. We propose that coordinated glucose-responsive fatty acid esterification and lipolysis processes, suggestive of triglyceride-fatty acid cycling, play a role in the coupling mechanisms of glucose-induced insulin secretion as well as in beta cell compensation and the hypersecretion of insulin in obesity.

Odour concentration affects odour identity in honeybees.

The fact that most types of sensory stimuli occur naturally over a large range of intensities is a challenge to early sensory processing. Sensory mechanisms appear to be optimized to extract perceptually significant stimulus fluctuations that can be analysed in a manner largely independent of the absolute stimulus intensity. This general principle may not, however, extend to olfaction; many studies have suggested that olfactory stimuli are not perceptually invariant with respect to odour intensity. For many animals, absolute odour intensity may be a feature in itself, such that it forms a part of odour identity and thus plays an important role in discrimination alongside other odour properties such as the molecular identity of the odorant. The experiments with honeybees reported here show a departure from odour-concentration invariance and are consistent with a lower-concentration regime in which odour concentration contributes to overall odour identity and a higher-concentration regime in which it may not. We argue that this could be a natural consequence of odour coding and suggest how an 'intensity feature' might be useful to the honeybee in natural odour detection and discrimination.

Population history and its impact on medical genetics in Quebec.

Knowledge of the genetic demography of Quebec is useful for gene mapping, diagnosis, treatment, community genetics and public health. The French-Canadian population of Quebec, currently about 6 million people, descends from about 8500 French settlers who arrived in Nouvelle-France between 1608 and 1759. The migrations of those settlers and their descendants led to a series of regional founder effects, reflected in the geographical distribution of genetic diseases in Quebec. This review describes elements of population history and clinical genetics pertinent to the treatment of French Canadians and other population groups from Quebec and summarizes the cardinal features of over 30 conditions reported in French Canadians. Some were discovered in French Canadians, such as autosomal recessive ataxia of the Charlevoix-Saguenay (MIM 270550), agenesis of corpus callosum and peripheral neuropathy (MIM 218000) and French-Canadian-type Leigh syndrome (MIM 220111). Other conditions are particularly frequent or have special genetic characteristics in French Canadians, including oculopharyngeal muscular dystrophy, hepatorenal tyrosinaemia, cystic fibrosis, Leber hereditary optic neuropathy and familial hypercholesterolaemia. Three genetic diseases of Quebec First Nations children are also discussed: Cree encephalitis (MIM 608505), Cree leukoencephalopathy (MIM 603896) and North American Indian childhood cirrhosis (MIM 604901).

The Delta>15 Kb deletion French Canadian founder mutation in familial hypercholesterolemia: rapid polymerase chain reaction-based diagnostic assay and prevalence in Quebec.

Approximately one in 500 individuals in Western population has autosomal dominant familial hypercholesterolemia due to mutations in the low-density lipoprotein receptor (LDLR) gene. Screening for these mutations is hampered by their large number, except in founder populations. We identified the breakpoint of the >15 kb deletion involving the LDLR gene promoter and exon 1, responsible for more than 60% of French Canadian hypercholesterolemia cases, as well as the breakpoint of the 5 kb deletion of exons 2 and 3 that accounts for an additional 5% of cases. Both deletions appear to be because of homologous recombination by unequal crossing-over between the left arms of Alu repeats. Using RepeatMasker, we determined that 55% of the LDLR gene is composed of Alu elements; thus, it is not surprising that most LDLR rearrangements involve at least one Alu. Furthermore, we developed a rapid polymerase chain reaction-based assay for the French Canadian-1 (>15 kb) and French Canadian-5 (5 kb) hypercholesterolemia alleles. Screening a representative population sample of 943 French Canadian youths whose LDL cholesterol levels were above the 50th percentile allowed us to estimate the prevalence of the >15 kb allele as 0.11% (95% confidence interval, 0.03-0.38).

Carnitine transport by organic cation transporters and systemic carnitine deficiency.

The intracellular homeostasis is controlled by different membrane transporters. Organic cation transporters function primarily in the elimination of cationic drugs, endogenous amines, and other xenobiotics in tissues such as the kidney, intestine, and liver. Among these molecules, carnitine is an endogenous amine which is an essential cofactor for mitochondrial beta-oxidation. Recently, a new family of transporters, named OCT (organic cation transporters) has been described. In this minireview, we present the recent knowledge about OCT and focus on carnitine transport, more particularly by the OCTN2. The importance of this sodium-dependent carnitine cotransporter, OCTN2, comes from various recently reported mutations in the gene which give rise to the primary systemic carnitine deficiency (SCD; OMIM 212140). The SCD is an autosomal recessive disorder of fatty acid oxidation characterized by skeletal myopathy, progressive cardiomyopathy, hypoglycemia and hyperammonemia. Most of the OCTN2 mutations identified in humans with SCD result in loss of carnitine transport function. Identifying these mutations will allow an easy targeting of the SCD syndrome. The characteristics of the juvenile visceral steatosis (jvs) mouse, an animal model of SCD showing similar symptoms as humans having this genetic disorder, are also described. These mice have a mutation in the gene encoding the mouse carnitine transporter octn2. Although various OCTN carnitine transporters have been identified and functionally characterized, their membrane localization and regulation are still unknown and must be investigated. This knowledge will also help in designing new drugs that regulate carnitine transport activity.