Harmonized outcome measures for use in degenerative lumbar spondylolisthesis patient registries and clinical practice.

OBJECTIVE: The development of new treatment approaches for degenerative lumbar spondylolisthesis (DLS) has introduced many questions about comparative effectiveness and long-term outcomes. Patient registries collect robust, longitudinal data that could be combined or aggregated to form a national and potentially international research data infrastructure to address these and other research questions. However, linking data across registries is challenging because registries typically define and capture different outcome measures. Variation in outcome measures occurs in clinical practice and other types of research studies as well, limiting the utility of existing data sources for addressing new research questions. The purpose of this project was to develop a minimum set of patient- and clinician-relevant standardized outcome measures that are feasible for collection in DLS registries and clinical practice. METHODS: Nineteen DLS registries, observational studies, and quality improvement efforts were invited to participate and submit outcome measures. A stakeholder panel was organized that included representatives from medical specialty societies, health systems, government agencies, payers, industries, health information technology organizations, and patient advocacy groups. The panel categorized the measures using the Agency for Healthcare Research and Quality's Outcome Measures Framework (OMF), identified a minimum set of outcome measures, and developed standardized definitions through a consensus-based process. RESULTS: The panel identified and harmonized 57 outcome measures into a minimum set of 10 core outcome measure areas and 6 supplemental outcome measure areas. The measures are organized into the OMF categories of survival, clinical response, events of interest, patient-reported outcomes, and resource utilization. CONCLUSIONS: This effort identified a minimum set of standardized measures that are relevant to patients and clinicians and appropriate for use in DLS registries, other research efforts, and clinical practice. Collection of these measures across registries and clinical practice is an important step for building research data infrastructure, creating learning healthcare systems, and improving patient management and outcomes in DLS.

Internalization of LDL-receptor superfamily yolk-protein receptors during mosquito oogenesis involves transcriptional regulation of PTB-domain adaptors.

In the anautogenous disease vector mosquitoes Anopheles gambiae and Aedes aegypti, egg development is nutritionally controlled. A blood meal permits further maturation of developmentally repressed previtellogenic egg chambers. This entails massive storage of extraovarian yolk precursors by the oocyte, which occurs through a burst of clathrin-mediated endocytosis. Yolk precursors are concentrated at clathrin-coated structures on the oolemma by two endocytic receptors, the vitellogenin and lipophorin receptors. Both these mosquito receptors are members of the low-density-lipoprotein-receptor superfamily that contain FxNPxY-type internalization signals. In mammals, this tyrosine-based signal is not decoded by the endocytic AP-2 adaptor complex directly. Instead, two functionally redundant phosphotyrosine-binding domain adaptors, Disabled 2 and the autosomal recessive hypercholesterolemia protein (ARH) manage the internalization of the FxNPxY sorting signal. Here, we report that a mosquito ARH-like protein, which we designate trephin, possess similar functional properties to the orthologous vertebrate proteins despite engaging AP-2 in an atypical manner, and that mRNA expression in the egg chamber is strongly upregulated shortly following a blood meal. Temporally regulated trephin transcription and translation suggests a mechanism for controlling yolk uptake when vitellogenin and lipophorin receptors are expressed and clathrin coats operate in previtellogenic ovaries.

Neuronal control of myogenic regulatory factor accumulation in fetal muscle.

The lumbosacral spinal cords of 14.5-day gestation mice (E14.5) were ablated. The number of molecules of each of the four myogenic regulatory factor (MRF) mRNAs per nanogram of total RNA were evaluated in innervated and aneural fetal crural muscles. Accumulation of all four MRF mRNAs was affected in aneural muscle, but was never more than threefold different than in innervated muscles, considerably less than after adult denervation. The effect of the nerve varied with the MRF, the fetal age, and with the muscle (extensor digitorum longus muscle [EDL] vs. soleus muscle), with the nerve having multiple effects including down-regulation of certain MRF genes at specific periods (e.g., myoD and myogenin [E16.5-E18.5] and MRF4 in the EDL only [E18.5-E19.5]); limiting the up-regulation of certain genes, which occurred in the absence of innervation (e.g., myf-5 [E18.5-E19.5] and myogenin [E14.5-E16.5]); and even enhancing the accumulation of MRF4 mRNA (E14.5-E16.5). We hypothesize that factors other than nerve contribute to the down-regulation of myf-5 and myogenin mRNAs to adult levels. Innervation was required for the emergence of the slow, but not the fast, MRF mRNA profile at birth. MyoD, found in both the nuclear and cytoplasmic protein extracts of innervated fetal muscle, increased by approximately 5-fold in the nuclear extracts (approximately 2.5-fold in the cytoplasmic) of E19.5 aneural muscles, significantly less than the 12-fold increase found in the nuclear extract of 4-day denervated adult muscle. This increase in aneural fetal muscle was due primarily to an increased concentration of myoD in muscle lineage nuclei, rather than to the presence of additional myoD(+) muscle lineage nuclei.

Aberrant development of motor axons and neuromuscular synapses in MyoD-null mice.

Myogenic regulatory factors (MRFs), muscle-specific transcription factors, are implicated in the activity-dependent regulation of nicotinic acetylcholine receptor (AChR) subunit genes. Here we show, with immunohistochemistry, Western blotting, and electron microscopy that MyoD, a member of the MRF family, also plays a role in fetal synapse formation. In the diaphragm of 14.5 d gestation (E14.5) wild-type and MyoD-/- mice, AChR clusters (the formation of which is under a muscle intrinsic program) are confined to a centrally located endplate zone. This distribution persists in wild-type adult muscles. However, beginning at E15.5 and extending to the adult, innervated AChR clusters are distributed all over the diaphragm of MyoD-/- mice, extending as far as the insertion of the diaphragm into the ribs. In wild-type muscle, motor axons terminate on clusters adjacent to the main intramuscular nerve; in MyoD-/- muscle, axonal bundles form extensive secondary branches that terminate on the widely distributed clusters. The number of AChR clusters on adult MyoD-/- and wild-type diaphram muscles is similar. Junctional fold density is reduced at MyoD-/- endplates, and the transition from the fetal (alpha, beta, gamma, delta) to adult-type (alpha, beta, delta, epsilon) AChRs is markedly delayed. However, MyoD-/- mice assemble a complex postsynaptic apparatus that includes muscle-specific kinase (MuSK), rapsyn, erbB, and utrophin.

Effects of vitamin D metabolites on axolotl limb regeneration.

Vitamin D is essential for normal metabolism of phosphorus and calcium, and differentiation of skeletal elements. 1,25 dihydroxyvitamin-D3 , the biologically active metabolite, acts as an induction/proliferation switch in various cell types and promotes chondrogenesis of chick limb bud mesenchymal cells. The function of vitamin D is mediated through its nuclear receptor, the vitamin D receptor (VDR). The proliferative actions of 1,25(OH)2 -D3 on limb bud mesenchymal cells are similar to the ones produced by retinoids, such as all-trans retinoic acid (RA) or 9-cis retinoic acid (9-cis). The retinoids have been shown to be compounds of extreme importance in the field of limb development and regeneration. In order to examine possible roles of vitamin D metabolites on limb regeneration, the effects of 1,25(OH)2 -D3 , 24,25(OH)2 -D3 and KH1060 (a more potent metabolite) alone or in conjunction with all-trans RA or 9-cis RA on the regenerating axolotl limb. Vitamin D affects limb morphogenesis by generating abnormalities in skeletal elements. Synergism of vitamin D with retinoic acid in affecting pattern formation is suggested by the results.

Morphogenetic effects of 9-cis-retinoic acid on the regenerating limbs of the axolotl.

9-cis-retinoic acid has recently been found to be a high affinity ligand for the retinoic X receptor (RXR). RXRs are believed to be involved in metabolic activities rather than in morphogenetic ones. Interestingly, RXR has been found to form heterodimers involving other receptors from the steroid family, such as the thyroid hormone receptor, vitamin D receptor or retinoic acid receptors (RARs). In this paper we examined whether or not 9-cis-retinoic acid had any morphogenetic properties on the regenerating axolotl limb. It is shown that 9-cis-retinoic acid proximalized regenerating limbs and was somewhat more potent in this action than all-trans-retinoic acid. Based on these observations, the possible roles of other receptors during pattern formation is discussed.

Variable manifestations in the short toes (s) mutation of the axolotl.

We describe a detailed histological analysis of the affected organs in the Short toes (s) mutation of the Mexican axolotl, Ambystoma mexicanum. The s mutant animals displayed a variation in the response to the mutation such as the time of death and the degree of abnormalities of the affected organs (limbs, kidney, ducts, and reproductive structures). In addition to the numerous histological abnormalities characterized here, we also examined the presence of laminin-related molecules in s mutant kidney tissues to elucidate further the nature of the renal aplasia these animals encounter as a result of this recessive lethal mutation. Our data suggest that there may be a disruption in tissue interactions necessary for proper development and functioning of the affected tissues. © 1993 Wiley-Liss, Inc.