BackgroundLow back pain exerts a tremendous burden on individual patients and society due to its prevalence and ability to cause long-term disability. Contemporary treatment and prevention efforts are stymied by the absence of a confirmed cause for the majority of low back pain patients.MethodsA system dynamics approach is used to build a physiologically-based model investigating the relationship between disc degeneration and low back pain. The model’s predictions are evaluated under two different types of study designs and compared with established observations on low back pain.ResultsA three-compartment model (no disc degeneration, disc degeneration with pain remission, disc degeneration with pain recurrence) accurately predicts the age-specific prevalence observed in one of the largest population-based surveys (R2 = 0.998). The estimated transition age at which intervertebral discs lose the growth potential and begin degenerating is 13.3 years. The estimated disc degeneration rate is 0.0344/year. Without any additional change being made to parameter’s values, the model also fully accounts for the age-specific prevalence of disc degeneration detected with a lumbar MRI among asymptomatic individuals (R2 = 0.978).ConclusionsDual testing of the proposed mechanistic model with two independent data sources (one with lumbar MRI and the other without) confirm that disc degeneration is the driving force behind and cause of age dependence in low back pain. Observed complexity of low back pain epidemiology arises from the slow dynamics of disc degeneration coupled with the fast dynamics of disease recurrence.
Previously proposed mechanisms for Down syndrome (trisomy 21) have generally invoked a progressive increase in meiotic nondisjunction to explain maternal-age dependence, but models of this sort have failed to predict the observed patterns of marker segregation. Here we propose instead that age-dependent trisomy 21 results primarily from a mechanism that favors maturation and utilization of euploid oocytes in preference to the pre-existing aneuploid products of mitotic (premeiotic) nondisjunction. The increased utilization of aneuploid oocytes at later stages of maternal life would result from their increased proportion following many progressive cycles of selection against their maturation in earlier stages. Derivation of a quantitative model and evaluation of existing data indicate that the pattern of marker segregation associated with age-dependent trisomy 21 supports the proposed mechanism.
is defined to quantify the curvilinearity phenomenon. We used statistics software to determine the k max of spirometry data from 67 sequential patients, and to determine the relationship of k max to FEV 1 . RESULTS: Individual k max estimates appeared to correspond well with the degree of curvilinearity observed and were related in an exponential manner to FEV 1 . CONCLUSIONS: We defined a curvature index to quantify the curvilinearity phenomenon observed in the expiratory limb of flow-volume loops from patients with obstructive lung disease. This index uses data from a major segment of the flow-volume curve, and our preliminary data indicate an exponential relationship with FEV 1 . This new index allows the putative association between curvilinearity and obstructive lung disease to be examined quantitatively in clinical practice and future studies.
Recent findings indicate that tandemly repeated triplet sequences in certain disease-causing human genes may render these genes highly unstable not only in meiosis but also in mitosis. Typically, a dominant mutation arises upon expansion in the number of these repeated elements. We have considered how mitotic instability of this sort might affect both phenotypic expression and allele transmission. A model based on these considerations leads to the following predictions: (i) Phenotypic severity among individuals who inherit an unstable allele should be highly variable due to stochastic variation in the stage of its earliest mutagenic expansion. (ii) Strikingly increased severity or decreased age of onset in some offspring should arise because of parental germ-line mosaicism for an expanded or mutant allele. (iit) The magnitude of genetic anticipation should be more strongly correlated with paternal than with maternal age at the time of conception. (iv) Given a child born with a severe phenotype, the recurrence risk for a second severely affected child should be significantly elevated. (v) The severity of phenotype in a child should be positively correlated with that in a parent. Available data on fragile X syndrome, Huntington disease, and myotonic dystrophy are shown to be consistent with the model, and implications for an understanding of achondroplasia and other dominant disorders are discussed.
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