Is the quality of occlusal contacts comparable after aligner and fixed orthodontic therapy? A non-randomized cohort comparison using computerized occlusal analysis during 6 months of retention.

OBJECTIVE: Less than ideal contacts have been reported following aligner therapy, but it is considered a transitory problem, spontaneously resolving with the phenomenon of settling. Methods: Thirty-nine orthodontic patients (14 treated with aligners; 25 with fixed appliances) were evaluated with a digital occlusal analysis system (T-scan™10), assessing Maximum Intercuspation contact simultaneity, symmetry, and relative force distribution at treatment completion and after 3 and 6 months. RESULTS: No significant differences in occlusal contact quality were found between groups at treatment completion or follow-up. The center of force moved posteriorly and remained stable after 3 months but was located more anteriorly in females (p = 0.01). One-third of patients (both groups combined) had marked contact force asymmetry even after 6 months' retention. Conclusion: Occlusal contacts were comparable at completion of treatment with aligners or brackets and after 3-6 months of retention. Settling did not improve marked asymmetry in all patients.

Home Exercises Versus On-Site Rehabilitation in the Management of Lateral Elbow Tendinopathy: A Critically Appraised Topic.

Clinical Scenario: Lateral elbow tendinopathy (LE) is a common musculoskeletal condition that often results in pain and disability. An array of conservative interventions have been shown to improve patient outcomes in outpatient rehabilitation clinics. However, with the rise in health care costs, patients and rehabilitation specialists have opted to reduce the number of in-house visits and focus on home exercise programs (HEPs). As a result, many rehabilitation specialists and patients now depend on HEPs as the primary intervention to treat LE. Focused Clinical Question: For individuals with LE, is there evidence to suggest that HEPs are as effective as traditional on-site rehabilitation for reducing pain and disability? Summary of Search, Best Evidence Appraised, and Key Findings: The literature was searched for studies comparing HEP to on-site rehabilitation in the management of LE. Two clinical controlled trials (CCTs) were included. No studies suggested that HEPs demonstrated equal or improved outcomes in pain or disability. Both studies concluded that on-site rehabilitation services were more effective at reducing pain and disability in the short term. More research is needed to compare the cost effectiveness of both HEP and on-site rehabilitation. Clinical Bottom Line: Based on 2 CCTs, it can be concluded that there is moderate evidence to suggest that patients with LE experience decreased pain and disability scores with on-site rehabilitation compared to a guided HEP in the short term. The authors could not draw a conclusion regarding long-term effects of treatments or cost effectiveness of the 2 approaches. Strength of Recommendation: Based on the Centre for Evidence Based Medicine, there is level B evidence that a HEP only was not as effective as on-site rehabilitation services in patients with LE.

Potential protective role of IL15Rα during inflammation.

We have shown that TNFα specifically activates the interleukin-15 (IL15) system in cerebral endothelial cells composing the blood-brain barrier. To determine the functions of cerebral IL15 signaling in inflammation, we first treated mice with lipopolysaccharide (LPS) and determined the expression of the three receptor subtypes of IL15. Robust time-dependent upregulation occurred in all subunits. We then tested whether IL15Rα knockout (KO) affected the maintenance of body temperature and activity level after a single dose of LPS. Circadian telemetry data were analyzed by the cosinor method. Both wild-type and KO mice had clear 24-h rhythms of basal temperature and activity. KO mice had a significantly higher midline estimating statistic of rhythm (MESOR; approximating 24 h mean) of temperature and delayed 24-h acrophase (peak) of activity than the wild-type mice. LPS disrupted the circadian rhythm of activity more severely in the KO group. Besides a decrease in MESOR and 24-h amplitude of activity after LPS, the KO mice showed a significant reduction of MESOR, amplitude, and changed acrophase for temperature on the second of 2 days. The disrupted circadian rhythm of temperature and activity in the KO mice after LPS suggests that upregulated IL15 receptors may serve a beneficial role to counteract the consequences of neuroinflammation.

IL-15 receptor deletion results in circadian changes of locomotor and metabolic activity.

Interleukin-15 (IL-15) is a cytokine produced in the normal brain that acts on its specific receptor IL-15Ralpha and co-receptors IL-2Rbeta and IL-2Rgamma in neuronal cells. The functions of the cerebral IL-15 system, however, are not yet clear. To test the hypothesis that IL-15Ralpha regulates metabolic activity and body temperature, we quantified the specific metabolic phenotype of IL-15Ralpha knockout mice. These normal-appearing mice were leaner with lower fat composition. During the entire circadian cycle, the knockout mice had a significantly higher acrophase in locomotor activity and heat dissipation. During the light phase, there was significantly greater food intake, oxygen consumption, and carbon dioxide production. The difference in the dark and light phases suggests that IL-15Ralpha participates in circadian rhythm regulation. The higher oxygen consumption in the light phase indicates adaptive thermogenesis in the knockout mice. The body temperature of the receptor knockout mice was significantly higher than the control in the light phase, and this was mainly caused by a large difference occurring between 0600 and 0900 h. In addition to the metabolic chamber studies and circadian rhythm analyses, qPCR of hypothalamic homogenates indicated higher mRNA expression of orexin and transient receptor potential vanilloid 4 cation channels. Consistent with a direct role of IL-15Ralpha in the hypothalamus, IL-15 treatment of the wild-type mice induced c-Fos expression in the preoptic area. We conclude that activation of hypothalamic neurons by IL-15 in mice contributes to thermoregulation and modifies the metabolic phenotype.

Partial rescue of glomerular laminin alpha5 mutations by wild-type endothelia produce hybrid glomeruli.

Both endothelial cells and podocytes are sources for laminin alpha1 at the inception of glomerulogenesis and then for laminin alpha5 during glomerular maturation. Why glomerular basement membranes (GBM) undergo laminin transitions is unknown, but this may dictate glomerular morphogenesis. In mice that genetically lack laminin alpha5, laminin alpha5beta2gamma1 is not assembled, vascularized glomeruli fail to form, and animals die at midgestation with neural tube closure and placental deficits. It was previously shown that renal cortices of newborn mice contain endothelial progenitors (angioblasts) and that when embryonic day 12 kidneys are transplanted into newborn kidney, hybrid glomeruli (host-derived endothelium and donor-derived podocytes) result. Reasoning that host endothelium may correct the glomerular phenotype that is seen in laminin alpha5 mutants, alpha5 null embryonic day 12 metanephroi were grafted into wild-type newborn kidney. Hybrid glomeruli were identified in grafts by expression of a host-specific LacZ lineage marker. Labeling of glomerular hybrid GBM with chain-specific antibodies showed a markedly stratified distribution of laminins: alpha5 was found only on the inner endothelial half of GBM, whereas alpha1 located to outer layers beneath mutant podocytes. For measurement of the contribution of host endothelium to hybrid GBM, immunofluorescent signals for laminin alpha5 were quantified: Hybrid GBM contained approximately 50% the normal alpha5 complement as wild-type GBM. Electron microscopy of glomerular hybrids showed vascularization, but podocyte foot processes were absent. It was concluded that (1) endothelial and podocyte-derived laminins remain tethered to their cellular origin, (2) developing endothelial cells contribute large amounts of GBM laminins, and (3) podocyte foot process differentiation may require direct exposure to laminin alpha5.

Peritoneal changes after exposure to sterile solutions by catheter.

Most current animal models that are used to study effects of long-term peritoneal exposure to dialysis solutions use an indwelling catheter for daily injections. It was hypothesized that the presence of a foreign body in the peritoneal cavity (PC) might alter the inflammatory response to the solutions and that the response would depend on exposure duration. For addressing these, long-term injections were carried out for 2 to 8 wk in 90 Sprague-Dawley rats: 40 via a subcutaneous port connected to a silicone catheter tunneled to the PC, 40 via direct needle injection, and 10 noninjected, age-control rats. Daily volumes were 30 to 40 ml of filter-sterilized, bicarbonate-buffered solutions that contained 4% dextrose. After 2, 4, 6, and 8 wk, anesthetized rats underwent transport experiments with a chamber affixed to the abdominal wall to determine mass transfer coefficients of mannitol (MTC(mannitol)) and albumin (MTC(BSA)), osmotic filtration flux (J(osm)), and hydrostatic pressure-driven flux. After the rats were killed, tissues were collected for measurement of peritoneal thickness, vascular density, and immunohistochemical staining. ANOVA demonstrated significant (P < 0.01) differences in thickness, vessel density, MTC(mannitol), and MTC(BSA) among the groups at the various time intervals and in overall means. Differences among the groups were less pronounced for hydrostatic pressure-driven flux and J(osm). Vessel density, MTC(mannitol), MTC(BSA), and J(osm) were dependent on injection duration (P < 0.01). There were marked differences between the needle injection and catheter injection groups at various intervals in the expression of three cytokines. It is concluded that the histologic and functional response depends on the duration of injection with animals that are exposed for as little as 2 wk demonstrating alterations. These findings confirm the hypothesis that the presence of a PC catheter increases inflammatory response to sterile solutions as evidenced by the structural and functional changes in the peritoneal barrier.

Derivation and differentiation of glomerular endothelial cells.

Data on the embryonic derivation of metanephric endothelial cells are reviewed, paying particular attention to results obtained from anterior chamber and intrarenal grafts of embryonic kidneys. Most of the evidence supports an intrinsic origin of the endothelium, which probably differentiates from metanephric mesenchyme. The roles of several growth factor receptor/ligand systems are also discussed, with an emphasis on the VEGF receptors, Flk1 and neuropilin-1.

Laminin-1 reexpression in Alport mouse glomerular basement membranes.

BACKGROUND: Alport disease is a heritable basement membrane disorder caused by mutations in genes encoding the alpha3, alpha4, or alpha5 chains of type IV collagen, which normally comprise the collagenous network of mature glomerular basement membranes (GBMs). In Alport disease, the alpha3(IV), alpha4(IV), alpha5(IV) collagen network is absent and substituted for by alpha1(IV), and alpha2(IV) collagen, which normally is present only in developing, immature GBMs. The disease is marked by progressive GBM thickening and delamination, proteinuria, and renal failure. In addition to collagen IV dysregulation, abnormal GBM laminins also occur and may contribute to the pathogenesis of Alport glomerulopathy. METHODS: To investigate laminin dysregulation in a mouse model of Alport disease, we used antibodies specific for laminin-alpha1 and -beta1 chains (to recognize laminin-1), and -alpha5 chain (to recognize laminin-11), and evaluated their distribution during glomerular development in alpha3(IV) collagen-deficient mice. RESULTS: Developing glomeruli of infant alpha3(IV) collagen knockout mice underwent normal down-regulation of laminin-1, but laminin-1 chains were then reexpressed in maturing glomeruli, becoming concentrated in the subepithelial GBM projections typical of Alport disease. Immunoelectron microscopy showed that laminin-1 reexpression took place in both glomerular endothelial cells and podocytes. CONCLUSIONS: The absence of a alpha3(IV), alpha4(IV), alpha5(IV) network may stimulate reexpression of laminin-1 by Alport mouse endothelial cells and podocytes. This abnormal GBM, which is more characteristic of immature glomeruli, may promote podocyte foot process effacement and reversion to a less differentiated state.

Podocyte expression of hypoxia-inducible factor (HIF)-1 and HIF-2 during glomerular development.

The heterodimeric transcription factors, hypoxia-inducible factor (HIF)-1 and HIF-2, are essential for the maintenance of cellular oxygen homeostasis. In response to hypoxia, stabilized HIF-1alpha and HIF-2alpha proteins bind HIF-1beta and initiate expression of genes that alleviate hypoxic stress, including those promoting neovascularization. Both HIF-1 and HIF-2 stimulate transcription of vascular endothelial growth factor (VEGF), a crucial regulator of vascular development. Because VEGF is highly expressed by metanephric podocytes and collecting ducts, developing mouse kidney was examined for the presence and distribution of HIF-1alpha, HIF-2alpha, and HIF-1beta. The expression of HIF-1alpha and HIF-2alpha mRNAs in newborn mouse kidney was confirmed by RT-PCR and Northern blot analysis. By in situ hybridization, HIF-1alpha and HIF-2alpha mRNAs were highly expressed in the nephrogenic zone of newborn kidney cortex and in the medulla. Particularly intense hybridization was found in podocytes of developing glomeruli and in medullary collecting ducts. Both HIF-1 and HIF-2 heterodimers were identified in newborn kidney lysates by immunoprecipitation with HIF-1alpha, HIF-2alpha, and HIF-1beta antibodies and Western blots. Immunofluorescence analysis of the hypoxia marker, pimonidazole, showed that collecting ducts and many developing tubules undergo severe hypoxia in developing kidney. Immunohistochemistry of newborn kidney demonstrated widespread expression of HIF-1beta protein in nuclei of glomeruli and all tubular segments, whereas HIF-2alpha protein expression was more restricted and localized chiefly to podocytes of developing glomeruli and developing tubules. HIF-1alpha and HIF-2alpha protein and VEGF mRNA were all strongly induced in embryonic kidneys maintained in hypoxic organ cultures. Collectively, these data suggest that HIF stabilization, by hypoxia and/or by other means, may be critical for VEGF production and kidney vascular development.