Size and proximity of micro-scale hard-inclusions increase the risk of rupture in fibroatheroma-like laboratory models.

Increased mechanical stresses of the fibroatheroma cap tissue is a crucial risk factor on the pathogenesis of asymptomatic coronary artery disease events. Moreover, both numerical and analytical studies have shown that microcalcifications (µCalcs) located in the fibrous cap can multiply the cap tissue stress by a factor of 2-7. This stress amplification depends on the ratio of the gap between particles (h) and their diameter (D) when they are aligned along the tensile axis. However, the synergistic effect of cap stiffness and uCalcs on the ultimate stress and rupture risk of the atheroma cap has not been fully investigated. In this context, we studied the impact of micro-beads (µBeads) of varying diameters and concentration on the rupture of silicone-based laboratory models mimicking human fibroatheroma caps of different stiffness (shear moduli µsoft = 40 kPa, µstiff = 400 kPa) and thickness (650 µm and 100 µm). A total of 145 samples were tested under uniaxial tension up to failure and the true stress and strain response of each model was derived by means of Digital Image Correlation (DIC). Before testing, samples were scanned using high-resolution Micro-CT, to perform morphometry analyses of the embedded micro-beads and determine the number of closely spaced particles (h/D<0.5). The micro-beads structural and spatial features were then compared to the case of 29 non-ruptured human atheroma fibrous caps presenting µCalcs. Samples with and without µBeads exhibited a distinct hyperelastic behavior typical of arterial tissues. Regardless of the sample stiffness, large µBeads (>80 µm) significantly reduced the ultimate tensile stress (UTS) of the thick cap models with the effect being more pronounced as the particle diameter increases. Stiff models experienced early rupture in the presence of µBeads with 40 µm diameter. Smaller µBeads of 6 µm and 20 µm didn't affect the ultimate strength of the thick cap models. However, when 6 µm µBeads where introduced in thinner cap models, we observed more than 20% drop in UTS. Increasing the µBeads concentration was also positively correlated with lower stresses at rupture as more clusters formed resulting in lower values of h/D. Morphometry analyses of cap models and human atheroma show that the 6 µm µBeads groups present very similar size distributions to µCalcs and that human µCalcs occupy an average volume ratio of 0.79 ± 0.85%. Our results clearly capture the influence of µBeads on the rupture threshold of a vascular tissue mimicking material. This effect appears to be dependent on the µBeads-to-cap thickness size ratio as well as their proximity. These findings support previous numerical and analytical studies suggesting that µCalcs located within the fibroatheroma cap may be responsible for significantly increasing the risk of cap rupture that precedes myocardial infarction and sudden death.

Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing.

Attempts to minimize scarring remain among the most difficult challenges facing surgeons, despite the use of optimal wound closure techniques. Previously, we reported improved healing of dermal excisional wounds in circadian clock neuronal PAS domain 2 (Npas2)-null mice. In this study, we performed high-throughput drug screening to identify a compound that downregulates Npas2 activity. The hit compound (Dwn1) suppressed circadian Npas2 expression, increased murine dermal fibroblast cell migration, and decreased collagen synthesis in vitro. Based on the in vitro results, Dwn1 was topically applied to iatrogenic full-thickness dorsal cutaneous wounds in a murine model. The Dwn1-treated dermal wounds healed faster with favorable mechanical strength and developed less granulation tissue than the controls. The expression of type I collagen, Tgfß1, and α-smooth muscle actin was significantly decreased in Dwn1-treated wounds, suggesting that hypertrophic scarring and myofibroblast differentiation are attenuated by Dwn1 treatment. NPAS2 may represent an important target for therapeutic approaches to optimal surgical wound management.

A Chemotactic Functional Scaffold with VEGF-Releasing Peptide Amphiphiles Facilitates Bone Regeneration by BMP-2 in a Large-Scale Rodent Cranial Defect Model.

BACKGROUND: Current common techniques for repairing calvarial defects by autologous bone grafting and alloplastic implants have significant limitations. In this study, the authors investigated a novel alternative approach to bone repair based on peptide amphiphile nanofiber gels that are engineered to control the release of vascular endothelial growth factor (VEGF) to recruit circulating stem cells to a site of bone regeneration and facilitate bone healing by bone morphogenetic protein-2 (BMP-2). METHODS: VEGF release kinetics from peptide amphiphile gels were evaluated. Chemotactic functional scaffolds were fabricated by combining collagen sponges with peptide amphiphile gels containing VEGF. The in vitro and in vivo chemotactic activities of the scaffolds were evaluated by measuring mesenchymal stem cell migration, and angiogenic capability of the scaffolds was also evaluated. Large-scale rodent cranial bone defects were created to evaluate bone regeneration after implanting the scaffolds and other control materials. RESULTS: VEGF was released from peptide amphiphile in a controlled-release manner. In vitro migration of mesenchymal stem cells was significantly greater when exposed to chemotactic functional scaffolds compared to control scaffolds. In vivo chemotaxis was evidenced by migration of tracer-labeled mesenchymal stem cells to the chemotactic functional scaffolds. Chemotactic functional scaffolds showed significantly increased angiogenesis in vivo. Successful bone regeneration was noted in the defects treated with chemotactic functional scaffolds and BMP-2. CONCLUSIONS: The authors' observations suggest that this bioengineered construct successfully acts as a chemoattractant for circulating mesenchymal stem cells because of controlled release of VEGF from the peptide amphiphile gels. The chemotactic functional scaffolds may play a role in the future design of clinically relevant bone graft substitutes for large-scale bone defects.

Mycobacterium avium-intracellulare otomastoiditis in a young AIDS patient: case report and review of the literature.

Mycobacterium avium-intracellulare (MAI) complex is a common opportunistic infection that generally occurs in patients with a CD4 cell count less than 75. Current recommendations for prophylaxis include using a macrolide once a week, while treatment usually requires a multidrug regimen. Disseminated MAI infections often occur in patients who are not compliant with prophylaxis or their highly active antiretroviral therapy (HAART). Many manifestations of MAI infection are well documented in human immunodeficiency virus (HIV) patients, including pulmonary and cutaneous manifestations, but other unusual manifestations such as pericarditis, pleurisy, peritonitis, brain abscess, otitis media, and mastoiditis are sporadically reported in the infectious diseases literature. This case report is of a 22-year-old female who contracted HIV at a young age and who was subsequently noncompliant with HAART, MAI prophylaxis, and prior treatment for disseminated MAI infection. Unsurprisingly, the patient developed recurrent disseminated MAI infection. The patient's presentation was atypical, as she developed severe otomastoiditis and posterior reversible encephalopathy syndrome. The posterior reversible encephalopathy syndrome was thought to be due to the disseminated MAI infection or to immune reconstitution inflammatory syndrome. The infection was confirmed to be secondary to MAI by culture of the mastoid bone. Microbiological analysis of the MAI strain cultured showed resistance to several first-line antibiotics used for prophylaxis against and treatment of MAI. This was likely due to the patient's chronic noncompliance. Otomastoiditis secondary to MAI is predominantly a pediatric disease and a rare entity in general. It has been reported in three case reports and one case series in pediatric patients, and now in this case report of an adult patient with HIV [corrected]. Improved clinician education in the diagnosis, treatment, and, most important, prevention of MAI and other opportunistic infections is needed. Greater HIV screening, appropriate HAART medication administration, and availability of infectious disease specialists is needed in at-risk populations to help prevent such serious infections. Patient education and greater access to care should serve to prevent medication nonadherence and to enhance affordability of HAART and prophylactic antibiotics.

Successful treatment of stent knot in the proximal ureter using ureteroscopy and holmium laser.

Knotted ureteral stent is rare yet tedious complication that might represent a treatment challenge to the endourologist. Only twelve cases of knotted stent have been reported. Different management options have been reported, including simple traction, ureteroscopy, percutaneous removal, and open surgery. In this paper, we present the successful untying of the knot using ureteroscopy with holmium laser.