Ciclesonide activates glucocorticoid signaling in neonatal rat lung but does not trigger adverse effects in the cortex and cerebellum.

Synthetic glucocorticoids (sGCs) such as dexamethasone (DEX), while used to mitigate inflammation and disease progression in premature infants with severe bronchopulmonary dysplasia (BPD), are also associated with significant adverse neurologic effects such as reductions in myelination and abnormalities in neuroanatomical development. Ciclesonide (CIC) is a sGC prodrug approved for asthma treatment that exhibits limited systemic side effects. Carboxylesterases enriched in the lower airways convert CIC to the glucocorticoid receptor (GR) agonist des-CIC. We therefore examined whether CIC would likewise activate GR in neonatal lung but have limited adverse extra-pulmonary effects, particularly in the developing brain. Neonatal rats were administered subcutaneous injections of CIC, DEX or vehicle from postnatal days 1-5 (PND1-PND5). Systemic effects linked to DEX exposure, including reduced body and brain weight, were not observed in CIC treated neonates. Furthermore, CIC did not trigger the long-lasting reduction in myelin basic protein expression in the cerebral cortex nor cerebellar size caused by neonatal DEX exposure. Conversely, DEX and CIC were both effective at inducing the expression of select GR target genes in neonatal lung, including those implicated in lung-protective and anti-inflammatory effects. Thus, CIC is a promising, novel candidate drug to treat or prevent BPD in neonates given its activation of GR in neonatal lung and limited adverse neurodevelopmental effects. Furthermore, since sGCs such as DEX administered to pregnant women in pre-term labor can adversely affect fetal brain development, the neurological-sparing properties of CIC, make it an attractive alternative for DEX to treat pregnant women severely ill with respiratory illness, such as with asthma exacerbations or COVID-19 infections.

Glucocorticoid signalling drives reduced versican levels in the fetal mouse lung.

Glucocorticoid (GC) signaling via the glucocorticoid receptor (GR) is essential for lung maturation in mammals. Previous studies using global or conditional mouse model knockouts of the GR gene have established that GR-mediated signaling in the interstitial mesenchyme of the fetal lung is critical for normal lung development. Screens for downstream GC-targets in conditional mesenchymal GR deficient mouse lung (GRmesKO) identified Versican (Vcan), an important extracellular matrix component and cell proliferation regulator, as a potential GR-regulated target. We show that, of the five major VCAN isoforms, the VCAN-V1 isoform containing the GAGß domain is the predominant VCAN isoform in the fetal mouse lung distal mesenchyme at both E16.5 and E18.5, whereas the GAGα-specific VCAN-V2 isoform was only localized to the smooth muscle surrounding proximal airways. Both Vcan-V1 mRNA and protein levels were strongly overexpressed in the GRmesKO lung at E18.5. Finally, we investigated the GC regulation of the ECM protease ADAMTS 12 and showed that Adamts 12 mRNA levels were markedly reduced at E18.5 in GRmesKO fetal mouse lung and were strongly induced by both cortisol and betamethasone in cultures of primary rat fetal lung fibroblasts. ADAMTS12 protein immunoreactivity was also strongly increased in the distal lung at E18.5, after dexamethasone treatment in utero. In summary, glucocorticoid signaling via GR represses GAGß domain-containing VCAN isoforms in distal lung mesenchyme in vivo by repressing Vcan gene expression and, in part, by inducing the ECM protease ADAMTS12, thereby contributing to the control of ECM remodelling and lung cell proliferation prior to birth.

The science of steroids.

Steroids are complex lipophilic molecules that have many actions in the body to regulate cellular, tissue and organ functions across the life-span. Steroid hormones such as cortisol, aldosterone, estradiol and testosterone are synthesised from cholesterol in specialised endocrine cells in the adrenal gland, ovary and testis, and released into the circulation when required. Steroid hormones move freely into cells to activate intracellular nuclear receptors that function as multi-domain ligand-dependent transcriptional regulators in the cell nucleus. Activated nuclear receptors modify expression of hundreds to thousands of specific target genes in the genome. Steroid hormone actions in the fetus include developmental roles in the respiratory system, brain, and cardiovascular system. The synthetic glucocorticoid steroid betamethasone is used antenatally to reduce the complications of preterm birth. Development of novel selective partial glucocorticoid receptor agonists may provide improved therapies to treat the respiratory complications of preterm birth and spare the deleterious effects of postnatal glucocorticoids in other organs.

Identification of Betamethasone-Regulated Target Genes and Cell Pathways in Fetal Rat Lung Mesenchymal Fibroblasts.

Preterm birth is characterized by severe lung immaturity that is frequently treated antenatally or postnatally with the synthetic steroid betamethasone. The underlying cellular targets and pathways stimulated by betamethasone in the fetal lung are poorly defined. In this study, betamethasone was compared with corticosterone in steroid-treated primary cultures of fetal rat lung fibroblasts stimulated for 6 hours and analyzed by whole-cell transcriptome sequencing and glucocorticoid (GC) receptor (GR) chromatin immunoprecipitation sequencing (ChIP-Seq) analysis. Strikingly, betamethasone stimulated a much stronger transcriptional response compared with corticosterone for both induced and repressed genes. A total of 483 genes were significantly stimulated by betamethasone or corticosterone, with 476 stimulated by both steroids, indicating a strong overlap in regulation. Changes in mRNA levels were confirmed by quantitative PCR for eight induced and repressed target genes. Pathway analysis identified cell proliferation and cytoskeletal/cell matrix remodeling pathways as key processes regulated by both steroids. One target, transglutaminase 2 (Tgm2), was localized to fetal lung mesenchymal cells. Tgm2 mRNA and protein levels were strongly increased in fibroblasts by both steroids. Whole-genome GR ChIP-Seq analysis with betamethasone identified GC response element-binding sites close to the previously characterized GR target genes Per1, Dusp1, Fkbp5, and Sgk1 and near the genes identified by transcriptome sequencing encoding Crispld2, Tgm2, Hif3α, and Kdr, defining direct genomic induction of expression in fetal lung fibroblasts via the GR. These results demonstrate that betamethasone stimulates specific genes and cellular pathways controlling cell proliferation and extracellular matrix remodeling in lung mesenchymal fibroblasts, providing a basis for betamethasone's treatment efficacy in preterm birth.

Outcome of Lateral Transfer of the FHL or FDL for Concomitant Peroneal Tendon Tears.

BACKGROUND: Concomitant tears of the peroneus longus and brevis tendons are rare injuries, with literature limited to case reports and small patient series. Only 1 recent study directly compared the results of single-stage lateral deep flexor transfer, and no previous series objectively evaluated power and balance following transfer. The purpose of this study was to evaluate clinical outcomes, patient satisfaction, and objective power and balance data following single-stage flexor hallucis longus (FHL) and flexor digitorum longus (FDL) tendon transfers for treatment of concomitant peroneus longus and brevis tears. METHODS: Over an 8-year period (2005-2012), 9 patients underwent lateral transfer of the FHL or FDL tendon for treatment of concomitant peroneus longus and brevis tears. All but 1 patient underwent additional procedures to address hindfoot malalignment or other contributing deformity at the time of surgery. Mean age was 56.9 years, and average body mass index was 27.9. Lateral transfer of the FHL was performed in 5 patients, and FDL transfer performed in 4 with mean follow-up 35.7 months (range: 11-94). Eight of 9 patients completed SF-12 and Foot Function Index (FFI) scores, and 7 returned for range of motion (ROM) and manual strength testing of the involved and normal extremities. These 7 patients also completed force plate balance tests, in addition to peak force and power testing on a PrimusRS machine with a certified physical therapist. RESULTS: All patients were satisfied with the results of the procedure. Mean SF-12 physical and mental scores were 32 and 55, respectively; mean FFI total score was 56.7. No postoperative infections were noted. Two patients continued to utilize orthotics or braces, and 2 patients reported occasional pain with weightbearing activity. Three patients noted mild paresthesias in the distribution of the sural nerve and 2 demonstrated tibial neuritis. All patients demonstrated 4/5 eversion strength in the involved extremity. Average loss of inversion and eversion ROM were 24.7% and 27.2% of normal, respectively. Mean postoperative eversion peak force and power were decreased greater than 55% relative to the normal extremity. Patients demonstrated nearly 50% increases in both center-of-pressure tracing length and velocity during balance testing. There were no statistically significant differences between the FHL and FDL transfer groups with regards to clinical examination or objective power and balance tests. CONCLUSION: The FHL and FDL tendons were both successful options for lateral transfer in cases of concomitant peroneus longus and brevis tears. Objective measurements of strength and balance demonstrated significant deficits in the operative extremity, even years following the procedure. These differences, however, did not appear to alter or inhibit patient activity levels or high satisfaction rates with the procedure. Although anatomic studies have demonstrated benefits of FHL transfer over the FDL tendon, further studies with increased patient numbers are needed to determine if these differences are clinically significant. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Temperature mediates the effect of humidity on the viscoelasticity of glycoprotein glue within the droplets of an orb-weaving spider's prey capture threads.

Sticky viscous prey capture threads retain insects that strike araneoid orb-webs. The threads' two axial fibers support a series of glue droplets, each featuring a core of adhesive viscoelastic glycoprotein covered by an aqueous solution. After sticking, the glue extends, summing the adhesion of multiple droplets, and dissipates some of the energy of a struggling prey. As a day progresses, threads experience a drop in humidity and an increase in temperature, environmental variables that have the potential to alter thread and web function. We hypothesize that thread droplets respond to these opposing environmental changes in a manner that stabilizes their performance, and test this by examining threads spun by Argiope aurantia, a species that occupies exposed, weedy habitats. We confirmed that decreased humidity increases glycoprotein viscosity and found that increased temperature had the opposite effect. To evaluate the combined effect of temperature and humidity on a droplet's ability to transfer adhesive force and dissipate energy, we extended a droplet and measured both the deflection of the axial line supporting the droplet and the duration of its tensive load. The cumulative product of these two indices, which reflects the energy required to extend a droplet, was greatest under afternoon (hot and dry) conditions, less under morning (cool and humid) conditions, and least under hot and humid afternoon conditions. Although the opposing effects of temperature and humidity tend to stabilize glycoprotein performance, A. aurantia thread droplets appear to function optimally during the afternoon, equipping this species to capture large orthopterans, which are most active at this time.

Efficacy of a new pressure-sensitive alarm for clinical use in orthopaedics.

The current study evaluated a new pressure alarm and compared the ability of subjects to limit weightbearing to 20 lb with and without the alarm. The 28 subjects were divided into four groups (Group 1, n = 7, mean age, 33 years, with normal sensation; Group 2, n = 7, mean age, 59 years, with normal sensation; Group 3, n = 6, mean age, 56 years, without protective lower limb sensation, and Group 4, n = 8, mean age, 39 years, with transtibial amputation). All subjects were instructed in partial weightbearing ambulation and then practiced weight shifting onto a scale set at 20 lb for 2 minutes. Average peak force was measured using the F-scan in-shoe sensor while subjects ambulated in two trials: one with a deactivated pressure alarm and the other with an activated alarm. Data were analyzed using two-tailed t tests. In Groups 1, 2, and 4, significantly lower average peak force with the activated alarm versus deactivated alarm occurred in 43%, 86%, and 100% of subjects, respectively. Weightbearing was limited to less than 20 lb with the activated alarm in 86%, 57%, 33%, and 38% of subjects versus 71%, 14%, 0%, and 0% of subjects with the deactivated alarm, respectively.

Relationship between loss of pedal sensibility, balance, and falls in patients with peripheral neuropathy.

: The purpose of this study was to describe the relationship between balance and foot sensibility in a population of patients with impaired lower extremity sensation. The hypothesis was that increasing impairment of sensation correlates with impaired balance. To date, no report has investigated the relationship between loss of balance with the degree of sensibility in the foot in a population with neuropathy. Ten control subjects and 35 patients with sensory abnormalities and balance problems related to a neuropathy were evaluated. The MatScan Measurement System was used to measure their ability to stand still, maintaining their balance with their eyes open and then with their eyes shut. The degree to which the person moves while attempting to stand still is defined as "sway," which was recorded for normal and neuropathy patients. Sensibility of the foot was measured with the Pressure-Specified Sensory Device, which is noninvasive and nonpainful. The 1- and 2-point static touch thresholds are measured for the pulp of the big toe, medial heel, and the dorsum of the foot. Loss of 2- or 1-point sensation was recorded as sensibility score and compared with controls. Statistical analysis of data and their comparisons for the 2 groups was completed. There were 55% females in control and 64% in neuropathy patients, whereas average age was 50 and 62 years, respectively. Neuropathy was the result of diabetes in 64.5%, hypothyroidism in 19.3%, their combination in 13%, and of unknown etiology in the remaining 19% of patients. Controls had significantly lower mean sway than neuropathy patients (22.9 +/- 9% vs. 189.5 +/- 180%, P = 0.006). Likewise, sensibility score for normal and neuropathy patients was also significantly different (31.4 +/- 9% vs. 232.8 +/- 59%, P <0.0001). When compared with the controls, 99% upper limit of confidence, sensibility in the neuropathy group at the hallux pulp was abnormal at a level consistent with axonal loss in 52% and was completely absent in the remaining 48%. Similarly, at the heel, sensibility was normal in 6.5%, abnormal at a level consistent with axonal loss in 71%, and absent in the remaining 22.5%. The correlation coefficient between sway and sensibility score was 0.36. The results of this investigation for the first time document the intuitive relationship between increasing loss of foot sensibility and increasing loss of balance. These measurements can now be used prospectively to evaluate whether restoration of sensation to patients with neuropathy, through peripheral nerve decompression, can improve balance and reduce falls/fractures in this patient population.

Benefits of early prosthetic management of transtibial amputees: a prospective clinical study of a prefabricated prosthesis.

To evaluate the use of an immediate postoperative prosthesis (IPOP) for transtibial amputees, we compared patient outcomes from a prospective clinical study of 19 patients managed with an IPOP with those of a retrospective review of a matched historic control group of 23 patients managed with standard soft dressings. Data were analyzed with the Student's t-test, and significance was set at P = 0.05. The IPOP patients had no surgical revisions, whereas the patients with standard soft dressings had 11. This was a significant difference. IPOP patients also had significantly fewer postoperative complications and shorter times to custom prosthesis than did controls.