Nebulized fentanyl does not improve exercise capacity or dyspnoea in fibrosing interstitial lung disease.

Exercise intolerance and exertional dyspnoea are hallmarks of fibrosing interstitial lung disease (FILD) and are associated with worse prognosis and quality of life. Activation of pulmonary vagal afferents influences the ventilatory pattern and contributes to the sensation of dyspnoea. We tested the hypothesis that nebulized fentanyl, which might attenuate aberrant pulmonary afferent activity in FILD, reduces ventilation and dyspnoea while extending exercise endurance time (EET). In this randomized, single-blind, placebo-controlled study, eight FILD patients (two males, 71 ± 6 years of age) performed incremental cardiopulmonary cycle exercise tests following nebulization of either fentanyl citrate (100 µg) or 0.9% saline. Previous work indicated that this dose was unlikely to produce central effects. Comparisons between treatment conditions at rest were undertaken using Student's paired t-test, and exercise data were evaluated with two-way ANOVA with repeated measures. Dyspnoea was assessed using the Borg dyspnoea scale. Resting respiratory variables were not different following treatment with fentanyl and saline; however, resting heart rate was lower following fentanyl (P = 0.002) and remained lower throughout exercise compared with placebo (P = 0.008). Fentanyl did not increase EET (placebo 334 ± 117 s vs. fentanyl 348 ± 126 s, P = 0.250) although overall minute ventilation was reduced slightly (mean difference: -0.97 L/min, P = 0.022). There were no differences in ratings of dyspnoea intensity or unpleasantness between the conditions either at rest or at end-exercise. Nebulized fentanyl did not improve EET or exercise dyspnoea but did decrease minute ventilation during exercise, although the extent of this reduction appears clinically insignificant. These findings suggest that nebulized fentanyl is unlikely to offer significant benefits for enhancing exercise capacity in FILD.

Cardiorespiratory responses to muscle metaboreflex activation in fibrosing interstitial lung disease.

NEW FINDINGS: What is the central question of this study? We determined whether sensory feedback from metabolically sensitive skeletal muscle afferents (metaboreflex) causes a greater ventilatory response and higher dyspnoea ratings in fibrosing interstitial lung disease (FILD). What is the main finding and its importance? Ventilatory responses and dyspnoea ratings during handgrip exercise and metaboreflex isolation were not different in FILD and control groups. Blood pressure and heart rate responses to handgrip were attenuated in FILD but not different to controls during metaboreflex isolation. These findings suggest that the muscle metaboreflex contribution to the respiratory response to exercise is not altered in FILD. ABSTRACT: Exercise limitation and dyspnoea are hallmarks of fibrosing interstitial lung disease (FILD); however, the physiological mechanisms are poorly understood. In other respiratory diseases, there is evidence that an augmented muscle metaboreflex may be implicated. We hypothesized that metaboreflex activation in FILD would result in elevated ventilation and dyspnoea ratings compared to healthy controls, due to augmented muscle metaboreflex. Sixteen FILD patients (three women, 69±14 years; mean±SD) and 16 age-matched controls (four women, 67±7 years) were recruited. In a randomized cross-over design, participants completed two min of rhythmic handgrip followed by either (i) two min of post-exercise circulatory occlusion (PECO trial) to isolate muscle metaboreflex activation, or (ii) rested for four min (Control trial). Minute ventilation ( V̇E$\dot{V}_E$ ; pneumotachometer), dyspnoea ratings (0-10 Borg scale), mean arterial pressure (MAP; finger photoplethysmography) and heart rate (HR; electrocardiogram) were measured. V̇E$\dot{V}_E$ was higher in the FILD group at baseline and exercise increased V̇E$\dot{V}_E$ similarly in both groups. V̇E$\dot{V}_E$ remained elevated during PECO, but there was no between-group difference in the magnitude of this response (Δ V̇E$\dot{V}_E$ FILD 4.2 ± 2.5 L·min-1  vs. controls 3.6 ± 2.4 L·min-1 , P = 0.596). At the end of PECO, dyspnoea ratings in FILD were similar to controls (1.0 ± 1.3 units vs. 0.5 ± 1.1 units). Exercise increased MAP and HR (P < 0.05) in both groups; however, responses were lower in FILD. Collectively, these findings suggest that there is not an augmented effect of the muscle metaboreflex on breathing and dyspnoea in FILD, but haemodynamic responses to handgrip are reduced relative to controls.

Self-sorting in supramolecular assemblies.

Supramolecular self-assembly enables living organisms to form highly functional hierarchical structures with individual components self-organized across multiple length scales. This has inspired work on multicomponent supramolecular materials to understand factors behind co-assembly versus self-sorting of molecules. We report here on a supramolecular system comprised of negatively charged peptide amphiphile (PA) molecules, in which only a tiny fraction of the molecules (0.7 mol%) were covalently conjugated to one of two different fluorophores, half to fluorescein isothiocyanate (FTIC) and the other half to tetramethylrhodamine (TAMRA). Confocal microscopy of the system revealed self-sorting of the two different fluorescent PA molecules, where TAMRA PA is concentrated in micron-scale domains while FITC PA remains dispersed throughout the sample. From Förster resonance energy transfer and fluorescence recovery experiments, we conclude that conjugation of the negatively charged FITC to PA significantly disrupts its co-assembly with the 99.3 mol% of unlabeled molecules, which are responsible for formation of micron-scale domains. Conversely, conjugation of the zwitterionic TAMRA causes no such disruption. Interestingly, this dissimilar behavior between FITC and TAMRA PA causes them to self-sort at large length scales in the supramolecular system, mediated not by specific interactions among the individual fluorophores but instead by their different propensities to co-assemble with the majority component. We also found that greater ionic strength in the aqueous environment of the system promotes mixing by lowering the electrostatic barriers involved in self-sorting. Our results demonstrate great thermodynamic subtlety in the driving forces that mediate self-sorting versus co-assembly in supramolecular peptide assemblies.

Surgical treatment of non-small-cell lung cancer in octogenarians: a single-centre retrospective study.

Lung resection in patients aged ≥80 years is considered high risk and contributes to the low rates of resection in this population. This review of 79 octogenarians who underwent curative surgery for non-small-cell lung cancer demonstrated no intraoperative mortality, 30-day mortality of 1.3% and 12-month mortality of 10%. In this selected cohort of octogenarians, surgery resulted in acceptable short- to medium-term outcomes.

Injectable biomimetic liquid crystalline scaffolds enhance muscle stem cell transplantation.

Muscle stem cells are a potent cell population dedicated to efficacious skeletal muscle regeneration, but their therapeutic utility is currently limited by mode of delivery. We developed a cell delivery strategy based on a supramolecular liquid crystal formed by peptide amphiphiles (PAs) that encapsulates cells and growth factors within a muscle-like unidirectionally ordered environment of nanofibers. The stiffness of the PA scaffolds, dependent on amino acid sequence, was found to determine the macroscopic degree of cell alignment templated by the nanofibers in vitro. Furthermore, these PA scaffolds support myogenic progenitor cell survival and proliferation and they can be optimized to induce cell differentiation and maturation. We engineered an in vivo delivery system to assemble scaffolds by injection of a PA solution that enabled coalignment of scaffold nanofibers with endogenous myofibers. These scaffolds locally retained growth factors, displayed degradation rates matching the time course of muscle tissue regeneration, and markedly enhanced the engraftment of muscle stem cells in injured and noninjured muscles in mice.

Self-Repair of Structure and Bioactivity in a Supramolecular Nanostructure.

Supramolecular nanostructures formed through self-assembly can have energy landscapes, which determine their structures and functions depending on the pathways selected for their synthesis and processing and on the conditions they are exposed to after their initial formation. We report here on the structural damage that occurs in supramolecular peptide amphiphile nanostructures, during freezing in aqueous media, and the self-repair pathways that restore their functions. We found that freezing converts long supramolecular nanofibers into shorter ones, compromising their ability to support cell adhesion, but a single heating and cooling cycle reverses the damage and rescues their bioactivity. Thermal energy in this cycle enables noncovalent interactions to reconfigure the nanostructures into the thermodynamically preferred long nanofibers, a repair process that is impeded by kinetic traps. In addition, we found that nanofibers disrupted during freeze-drying also exhibit the ability to undergo thermal self-repair and recovery of their bioactivity, despite the extra disruption caused by the dehydration step. Following both freezing and freeze-drying, which shorten the 1D nanostructures, their self-repair capacity through thermally driven elongation is inhibited by kinetically trapped states, which contain highly stable noncovalent interactions that are difficult to rearrange. These states decrease the extent of thermal nanostructure repair, an observation we hypothesize applies to supramolecular systems in general and is mechanistically linked to suppressed molecular exchange dynamics.

Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells.

The inhibition of bone healing in humans is a well-established effect associated with cigarette smoking, but the underlying mechanisms are still unclear. Recent work using animal cell lines have implicated the aryl hydrocarbon receptor (AhR) as a mediator of the anti-osteogenic effects of cigarette smoke, but the complexity of cigarette smoke mixtures makes understanding the mechanisms of action a major challenge. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a high-affinity AhR ligand that is frequently used to investigate biological processes impacted by AhR activation. Since there are dozens of AhR ligands present in cigarette smoke, we utilized dioxin as a prototype ligand to activate the receptor and explore its effects on pro-osteogenic biomarkers and other factors critical to osteogenesis using a human osteoblast-like cell line. We also explored the capacity for AhR antagonists to protect against dioxin action in this context. We found dioxin to inhibit osteogenic differentiation, whereas co-treatment with various AhR antagonists protected against dioxin action. Dioxin also negatively impacted cell adhesion with a corresponding reduction in the expression of integrin and cadherin proteins, which are known to be involved in this process. Similarly, the dioxin-mediated inhibition of cell migration correlated with reduced expression of the chemokine receptor CXCR4 and its ligand, CXCL12, and co-treatment with antagonists restored migratory capacity. Our results suggest that AhR activation may play a role in the bone regenerative response in humans exposed to AhR activators, such as those present in cigarette smoke. Given the similarity of our results using a human cell line to previous work done in murine cells, animal models may yield data relevant to the human setting. In addition, the AhR may represent a potential therapeutic target for orthopedic patients who smoke cigarettes, or those who are exposed to secondhand smoke or other environmental sources of aryl hydrocarbons.

Clinical utility of the Borg dyspnoea score in 6-minute walk tests in interstitial lung disease: A systematic review.

BACKGROUND: Exertional dyspnoea, a cardinal symptom in interstitial lung disease (ILD), can be objectively measured during a 6-min walk test (6MWT) using the Borg Dyspnoea Score (BDS). However, the clinical utility of this measurement is unclear. The purpose of this systematic review was to determine the association between 6MWT BDS and prognosis (mortality and lung transplantation), other 6MWT variables and measures of pulmonary function. METHODS: MEDLINE, EMBASE, Cochrane and SCOPUS databases were used to identify studies reporting an association between post-6MWT BDS and the relevant outcomes in adults with ILD. Language was limited to English. Study quality was assessed using the Quality in Prognosis Study risk of bias tool. A narrative synthesis for each outcome was performed. RESULTS: Ten full-text studies (n = 518) were included. Four studies had high overall risk of bias. Two studies (n = 127) reported prognosis and both found that higher 6MWT BDS was associated with increased all-cause mortality. However, the certainty of evidence was very low due to study design and likely publication bias. Higher post-6MWT BDS may be associated with shorter, or no effect on 6MWD; and lower pulmonary function. There was insufficient evidence that BDS correlated with 6MWT oxygen saturation. CONCLUSIONS: Post-6MWT BDS has a potential role as a predictor of all-cause mortality in ILD, 6MWD and lower pulmonary function. Larger studies designed to confirm these relationships and assess the independent association between the 6MWT BDS and clinical outcomes are required.

Text messaging to enhance glucose monitoring and self-care in teens with type 1 diabetes: Teens' perceptions predict outcomes.

AIMS: We assessed association between how teens with type 1 diabetes (T1D) perceived a text-messaging (TM) reminder system to check glucose levels and how their perceptions related to their responsiveness to TM reminders to check glucose levels. METHODS: Teens received TM reminders 1-4 times daily to check glucose levels and to reply with the result. Qualitative assessments were performed quarterly. Teens were categorized by perceptions expressed at the majority of the visits and their TM responsiveness over 18 months. RESULTS: There were 135 teens (51 % male), with a mean age of 14.8 ± 1.2 years, receiving TM reminders. Distribution of participants' perceptions was 37 % positive (POS), 35 % neutral (with both positive and negative responses (POS/NEG)), and 28 % negative (NEG). Teens with POS perceptions about TM reminders were more likely to respond with a glucose value to the TM reminders than teens with NEG or POS/NEG perceptions (p = 0.002). Youth with POS perceptions and TM responsiveness on ≥ 50 % of days had an 0.81 % improvement in their HbA1c (p = 0.004) over 18 months. CONCLUSIONS: Teens with POS perceptions to TM reminders were likely to respond and their responsiveness yielded glycemic benefit, suggesting need to consider opinions of teens with T1D to maximize their intervention engagement and resulting benefits.

Optimisation of a primary human CAR-NK cell manufacturing pipeline.

Objectives: Autologous chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies achieves long-term disease remission in a high fraction of patients and has triggered intense research into translating this successful approach into additional cancer types. However, the complex logistics involved in autologous CAR-T manufacturing, the compromised fitness of patient-derived T cells, the high rates of serious toxicities and the overall cost involved with product manufacturing and hospitalisation have driven innovation to overcome such hurdles. One alternative approach is the use of allogeneic natural killer (NK) cells as a source for CAR-NK cell therapy. However, this source has traditionally faced numerous manufacturing challenges. Methods: To address this, we have developed an optimised expansion and transduction protocol for primary human NK cells primed for manufacturing scaling and clinical evaluation. We have performed an in-depth comparison of primary human NK cell sources as a starting material by characterising their phenotype, functionality, expansion potential and transduction efficiency at crucial timepoints of our CAR-NK manufacturing pipeline. Results: We identified adult peripheral blood-derived NK cells to be the superior source for generating a CAR-NK cell product because of a higher maximum yield of CAR-expressing NK cells combined with potent natural, as well as CAR-mediated anti-tumor effector functions. Conclusions: Our optimised manufacturing pipeline dramatically improves lentiviral transduction efficiency of primary human NK cells. We conclude that the exponential expansion pre- and post-transduction and high on-target cytotoxicity make peripheral blood-derived NK cells a feasible and attractive CAR-NK cell product for clinical utility.

Updated Psychosocial Surveys With Continuous Glucose Monitoring Items for Youth With Type 1 Diabetes and Their Caregivers.

AIM: We added items relevant to continuous glucose monitoring (CGM) to the Diabetes Family Conflict Scale (DFC), Diabetes Family Responsibility Questionnaire (DFR), and Blood Glucose Monitoring Communication Questionnaire (GMC) and evaluated the psychometric properties of the updated surveys. RESEARCH DESIGN AND METHODS: Youth with type 1 diabetes who recently started CGM and their parents completed the updated surveys and additional psychosocial surveys. Medical data were collected from self-reports and review of the medical record. RESULTS: Youth (N = 114, 49% adolescent girls) were aged 13.3 ± 2.7 years and had mean glycated hemoglobin (HbA1c) 7.9 ± 0.9%; 87% of them used pump therapy. The updated surveys demonstrated high internal consistency (DFC youth: α = .91, parent: α = .81; DFR youth: α = .88, parent: α = .93; and GMC youth: α = .88, parent: α = .86). Higher youth and parent DFC scores (more diabetes-specific family conflict) and GMC scores (more negative affect related to glucose monitoring) were associated with more youth and parent depressive symptoms (r = 0.28-0.60, P ≤ .003), more diabetes burden (r = 0.31-0.71, P ≤ .0009), more state anxiety (r = 0.24 to r = 0.46, P ≤ .01), and lower youth quality of life (r = -0.29 to -0.50, P ≤ .002). Higher youth and parent DFR scores (more parent involvement in diabetes management) were associated with younger youth age (youth: r = -0.76, P < .0001; parent: r = -0.81, P < .0001) and more frequent blood glucose monitoring (youth: r = 0.27, P = .003; parent: r = 0.35, P = .0002). CONCLUSIONS: The updated DFC, DFR, and GMC surveys maintain good psychometric properties. The addition of CGM items expands the relevance of these surveys for youth with type 1 diabetes who are using CGM and other diabetes technologies.

Observed Characteristics Associated with Diabetes Device Use Among Teens with Type 1 Diabetes.

BACKGROUND: Despite advancements in diabetes technologies, disparities remain with respect to diabetes device use in youth with type 1 diabetes (T1D). We compared sociodemographic, diabetes, and psychosocial characteristics associated with device (pump and continuous glucose monitor [CGM]) use in 13- to 17-year-old teens with T1D. MATERIALS/METHODS: Data were derived from a multicenter clinical trial to optimize self-care and glycemic control in teens with T1D. We categorized teens as pump users versus non-users and CGM users versus non-users based on their diabetes device usage. Chi-square and t-tests compared characteristics according to device use. RESULTS: The sample comprised 301 teens (50% female) with baseline mean ± SD age 15.0 ± 1.3 years, T1D duration 6.5 ± 3.7 years, and HbA1c 8.5 ± 1.1% (69 ± 12 mmol/mol). Two-thirds (65%) were pump users, and 27% were CGM users. Pump users and CGM users (vs. non-users) were more likely to have a family annual household income ≥$150,000, private health insurance, and a parent with a college education (all P < .001). Pump users and CGM users (vs. non-users) also performed more frequent daily blood glucose (BG) checks (both P < .001) and reported more diabetes self-care behaviors (both P < .05). Pump users were less likely to have baseline HbA1c ≥9% (75 mmol/mol) (P = .005) and to report fewer depressive symptoms (P = .02) than pump non-users. Parents of both CGM and pump users reported a higher quality of life in their youth (P < .05). CONCLUSION: There were many sociodemographic, diabetes-specific, and psychosocial factors associated with device use. Modifiable factors can serve as the target for clinical interventions; youth with non-modifiable factors can receive extra support to overcome potential barriers to device use.

Optimization of peptide amphiphile-lipid raft interaction by changing peptide amphiphile lipophilicity.

Various peptide amphiphile (PA) molecules have been developed to promote bone regeneration. Previously we discovered that a peptide amphiphile with a palmitic acid tail (C16) attenuates the signaling threshold of leucine-rich amelogenin peptide (LRAP)-mediated Wnt activation by increasing membrane lipid raft mobility. In the current study, we found that treatment of murine ST2 cells with an inhibitor (Nystatin) or Caveolin-1-specific siRNA abolishes the effect of C16 PA, indicating that Caveolin-mediated endocytosis is required. To determine whether hydrophobicity of the PA tail plays a role in its signaling effect, we modified the length of the tail (C12, C16 and C22) or composition (cholesterol). While shortening the tail (C12) decreased the signaling effect, lengthening the tail (C22) had no prominent effect. On the other hand, the cholesterol PA displayed a similar function as the C16 PA at the same concentration of 0.001% w/v. Interestingly, a higher concentration of C16 PA (0.005%) is cytotoxic while cholesterol PA at the higher concentration (0.005%) is well-tolerated by cells. Use of the cholesterol PA at 0.005% enabled a further reduction of the signaling threshold of LRAP to 0.20 nM, compared to 0.25 nM at 0.001%. Caveolin-mediated endocytosis is also required for cholesterol PA, as evidenced by Caveolin-1 siRNA knockdown experiments. We further demonstrated that the noted effects of cholesterol PA are also observed in human bone marrow mesenchymal stem cells (BMMSCs). Taken together, these results indicate that the cholesterol PA modulates lipid raft/caveolar dynamics, thereby increasing receptor sensitivity for activation of canonical Wnt signaling. STATEMENT OF SIGNIFICANCE: Cell signaling involves not only the binding of growth factors (or other cytokines) and cognate receptors, but also their clustering on the cell membrane. However, little or no work has been directed thus far toward investigating how biomaterials can serve to enhance growth factor or peptide signaling by increasing diffusion of cell surface receptors within membrane lipid rafts. Therefore, a better understanding of the cellular and molecular mechanism(s) operating at the material-cell membrane interface during cell signaling has the potential to change the paradigm in designing future biomaterials and regenerative medicine therapeutics. In this study, we designed a peptide amphiphile (PA) with a cholesterol tail to enhance canonical Wnt signaling by modulating lipid raft/caveolar dynamics.

A supramolecular polymer-collagen microparticle slurry for bone regeneration with minimal growth factor.

Recombinant bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive growth factor that can promote bone regeneration for challenging skeletal repair and even for ectopic bone formation in spinal fusion procedures. However, serious clinical side effects related to supraphysiological dosing highlight the need for advances in novel biomaterials that can significantly reduce the amount of this biologic. Novel biomaterials could not only reduce clinical side effects but also expand the indications for use of BMP-2, while at the same time lowering the cost of such procedures. To achieve this objective, we have developed a slurry containing a known supramolecular polymer that potentiates BMP-2 signaling and porous collagen microparticles. This slurry exhibits a paste-like consistency that stiffens into an elastic gel upon implantation making it ideal for minimally invasive procedures. We carried out in vivo evaluation of the novel biomaterial in the rabbit posterolateral spine fusion model, and discovered efficacy at unprecedented ultra-low BMP-2 doses (5 µg/implant). This dose reduces the growth factor requirement by more than 100-fold relative to current clinical products. This observation is significant given that spinal fusion involves ectopic bone formation and the rabbit model is known to be predictive of human efficacy. We expect the novel biomaterial can expand BMP-2 indications for difficult cases requiring large volumes of bone formation or involving patients with underlying conditions that compromise bone regeneration.

Hidden genetic diversity in the green alga Spirogyra (Zygnematophyceae, Streptophyta).

BACKGROUND: The unbranched filamentous green alga Spirogyra (Streptophyta, Zygnemataceae) is easily recognizable based on its vegetative morphology, which shows one to several spiral chloroplasts. This simple structure falsely points to a low genetic diversity: Spirogyra is commonly excluded from phylogenetic analyses because the genus is known as a long-branch taxon caused by a high evolutionary rate. RESULTS: We focused on this genetic diversity and sequenced 130 Spirogyra small subunit nuclear ribosomal DNA (SSU rDNA) strands of different origin. The resulting SSU rDNA sequences were used for phylogenetic analyses using complex evolutionary models (posterior probability, maximum likelihood, neighbor joining, and maximum parsimony methods). The sequences were between 1672 and 1779 nucleotides long. Sequence comparisons revealed 53 individual clones, but our results still support monophyly of the genus. Our data set did not contain a single slow-evolving taxon that would have been placed on a shorter branch compared to the remaining sequences. Out of 130 accessions analyzed, 72 showed a secondary loss of the 1506 group I intron, which formed a long-branched group within the genus. The phylogenetic relationship to the genus Spirotaenia was not resolved satisfactorily. The genetic distance within the genus Spirogyra exceeded the distances measured within any other genus of the remaining Zygnemataceae included in this study. CONCLUSION: Overall, we define eight distinct clades of Spirogyra, one of them including the genus Sirogonium. A large number of non-homoplasious synapomorphies (NHS; 114 NHS in total) was found for Spirogyra (41 NHS) and for each clade (totaling 73 NHS). This emphasizes the high genetic diversity of this genus and the distance to the remaining Zygnematophyceae.

Toddler With New Onset Diabetes and Atypical Hemolytic-Uremic Syndrome in the Setting of COVID-19.

This is a novel case of a 16-month-old boy with a history of prematurity with intrauterine growth restriction, severe failure to thrive, microcephaly, pachygyria, agenesis of the corpus callosum, and postnatal embolic stroke, who presented with new-onset diabetes mellitus with diabetic ketoacidosis in the setting of severe acute respiratory syndrome coronavirus 2 infection, with a course complicated by atypical hemolytic syndrome (aHUS). This patient demonstrated remarkable insulin resistance in the period before aHUS diagnosis, which resolved with the first dose of eculizumab therapy. There is increasing evidence that COVID-19 is associated with thrombotic disorders and that microangiopathic processes and complement-mediated inflammation may be implicated. In this case report, we describe a pediatric patient with COVID-19 and a new complement-mediated microangiopathic thrombotic disease. Because whole-exome sequencing and extensive workup returned without a clear etiology for aHUS, this is likely a COVID-19 triggered case of aHUS versus an idiopathic case that was unmasked by the infection.

Supramolecular self-assembling peptides to deliver bone morphogenetic proteins for skeletal regeneration.

Recombinant human bone morphogenetic proteins (BMPs) have shown clinical success in promoting bone healing, but they are also associated with unwanted side effects. The development of improved BMP carriers that can retain BMP at the defect site and maximize its efficacy would decrease the therapeutic BMP dose and thus improve its safety profile. In this review, we discuss the advantages of using self-assembling peptides, a class of synthetic supramolecular biomaterials, to deliver recombinant BMPs. Peptide amphiphiles (PAs) are a broad class of self-assembling peptides, and the use of PAs for BMP delivery and bone regeneration has been explored extensively over the past decade. Like many self-assembling peptide systems, PAs can be designed to form nanofibrous supramolecular biomaterials in which molecules are held together by non-covalent bonds. Chemical and biological functionality can be added to PA nanofibers, through conjugation of chemical moieties or biological epitopes to PA molecules. For example, PA nanofibers have been designed to bind heparan sulfate, a natural polysaccharide that is known to bind BMPs and potentiate their signal. Alternatively, PA nanofibers have been designed to synthetically mimic the structure and function of heparan sulfate, or to directly bind BMP specifically. In small animal models, these bio-inspired PA materials have shown the capacity to promote bone regeneration using BMP at doses 10-100 times lower than established therapeutic doses. These promising results have motivated further evaluation of PAs in large animal models, where their safety and efficacy must be established before clinical translation. We conclude with a discussion on the possiblity of combining PAs with other materials used in orthopaedic surgery to maximize their utility for clinical translation.

Biliary Tract Abnormalities as a Cause of Distal Bowel Gas in Neonatal Duodenal Atresia.

BACKGROUND: The presence of distal bowel gas in an infant does not exclude the diagnosis of duodenal atresia. CASE PRESENTATION: We report a term neonate with Down syndrome. The infant developed vomiting and cyanosis with each feeding soon after birth. Plain film abdominal X-rays showed a nonspecific gas-filled stomach and small bowel. Duodenal atresia and an anomalous common bile were noted on an upper GI study and exploratory laparotomy. CONCLUSION: In the absence of a "double bubble" appearance and intestinal gas distally on a plain radiograph, one must not exclude duodenal atresia as the differential diagnosis.

Ventriculomegaly and cerebellar hypoplasia in a neonate with interstitial 11q 24 deletion in Jacobsen syndrome region.

Jacobsen syndrome (JS) is a rare contiguous gene disorder caused by partial deletion of the distal part of the long arm of chromosome 11 ranging in size from 7 to 20 Mb. We report a term male neonate with an interstitial deletion of about 12.3 megabase (Mb) of chromosome 11q24.1qter. Our case is the first reported newborn patient with 11q24 deletion.