Skin-specific knockdown of hyaluronan in mice by an optimized topical 4-methylumbelliferone formulation

Hyaluronan (HA) is abundant in the skin; while HA can be synthesized by the synthases (HAS1-3), HAS2 is the leading contributor. Dysregulation and accumulation of HA is implicated in the pathogenesis of diseases such as keloid scarring, lymphedema and metastatic melanoma. To understand how HA synthesis contributes to skin physiology, and pathologic and fibrotic disorders, we propose the development of skin-specific HA inhibition model, which tests an optimal delivery system of topical 4-methylumbelliferone (4-MU).A design-of-experiments (DOE) approach was employed to develop an optimal 4-MU skin-delivery formulation comprising propylene glycol, ethanol, and water, topically applied to dorsal skin in male and female C57BL/6J wildtype mice to determine the effect on HAS gene expression and HA inhibition. Serum and skin samples were analyzed for HA content along with analysis of expression of HAS1-3, hyaluronidases (HYAL 1-2), and KIAA1199.Using results from DOE and response surface methodology with genetic algorithm optimization, we developed an optimal topical 4-MU formulation to result in ∼70% reduction of HA in dorsal skin, with validation demonstrating ∼50% reduction in HA in dorsal skin. 4-MU topical application resulted in significant decrease in skin HAS2 expression in female mice only. Histology showed thicker dermis in male mice, whereas female mice had thinner dermal layer with more adiposity; and staining for HA-binding protein showed that topical 4-MU resulted in breakdown in HA.Our data suggest a topical 4-MU formulation-based dermal HA inhibition model that would enable elucidating the skin-specific effects of HA in normal and pathologic states.     

Barriers to and Facilitators of Stocking Healthy Food Options: Viewpoints of Baltimore City Small Storeowners

Receptivity to strategies to improve the food environment by increasing access to healthier foods in small food stores is underexplored. We conducted 20 in-depth interviews with small storeowners of different ethnic backgrounds as part of a small-store intervention trial. Store owners perceived barriers and facilitators to purchase, stock, and promote healthy foods. Barriers mentioned included customer preferences for higher fat and sweeter taste and for lower prices; lower wholesaler availability of healthy food; and customers’ lack of interest in health. Most store owners thought positively of taste tests, free samples, and communication interventions. However, they varied in terms of their expectations of the effect of these strategies on customers’ healthy food purchases. The findings reported add to the limited data on motivating and working with small-store owners in low-income urban settings.     

Effect of Formulation Variables on the Stability of a Live,Rotavirus (RV3-BB) Vaccine Candidate using in vitro Gastric Digestion Models to Mimic Oral Delivery

In this work, two different in vitro gastric digestion models were used to evaluate the stability of a live attenuated rotavirus vaccine candidate (RV3-BB) under conditions designed to mimic oral delivery in infants. First, a forced-degradation model was established at low pH to assess the buffering capacity of formulation excipients and to screen for RV3-BB stabilizers. Second, a sequential-addition model was implemented to examine RV3-BB stability under conditions more representative of oral administration to infants. RV3-BB rapidly inactivated at < pH 5.0 (37 °C, 1 h) as measured by an infectivity RT-qPCR assay. Pre-neutralization with varying volumes of infant formula (Enfamil®) or antacid (Mylanta®) conferred partial to full protection of RV3-BB. Excipients with sufficient buffering capacity to minimize acidic pH inactivation of RV3-BB were identified (e.g., succinate, acetate, adipate), however, they concomitantly destabilized RV3-BB in accelerated storage stability studies. Both effects were concentration dependent, thus excipient optimization was required to design candidate RV3-BB formulations which minimize acid-induced viral inactivation during oral delivery while not destabilizing the vaccine during long-term 2–8 °C storage. Finally, a statistical Design -of-Experiments (DOE) study examining RV3-BB stability in the in vitro sequential-addition model identified key formulation parameters likely affecting RV3-BB stability during in vivo oral delivery.     

Clinicopathological profile of orbital exenteration: 14 years of experience from a tertiary eye care center in South India

This study aims to describe the clinicopathological features and outcomes of patients who underwent orbital exenteration at a tertiary eye care center in south India. Retrospective chart reviews were performed on all patients undergoing orbital exenteration from January 1999 to December 2012. Parameters recorded include demographic data, clinical presentations, past medical or surgical interventions, exenteration notes, histopathological diagnosis, adjunctive treatment, follow-up examination findings, recurrences, complications, and their management. Orbital exenteration was performed on 119 orbits of 119 patients over a 14-year period. The mean age was 48.9 years (range 1–82 years). The indications were malignancies in 90.7 % (108/119), while 9.3 % (11/119) of cases were exenterated for non-malignant indications. Among the malignancies, the commonest tissue of origin was conjunctiva, noted in 45.4 % (49/108), followed by eyelids (25.9 %, 28/108), orbit (19.4 %, 21/108), and intraocular tissues (9.3 %, 10/108). The commonest malignancies noted in this series were an extensive ocular surface squamous neoplasia (OSSN) (44.4 %, 48/108) and sebaceous gland carcinoma of eyelids with an orbital involvement (18.5 %, 20/108). Extensive fungal granuloma (mucormycosis-4, aspergillosis-4) was the commonest (81.8 %, 9/11) indication among the non-malignant group. All complications were wound related, and none had a recurrence at a mean follow-up of 12.8 months. Extensive orbital involvement with OSSN and SGC were the commonest indications for exenteration. There is a need of creating awareness among general ophthalmologists in specific geographical regions regarding early diagnosis, standardized protocols of management, and appropriate referral.     

Fever without apparent source on clinical examination

PURPOSE OF REVIEW: Routine immunization of children with the heptavalent pneumococcal conjugate (PCV7) vaccine and rapid tests for identification of viruses since the last review in 2002 make this review timely and relevant. RECENT FINDINGS: Since the introduction of the PCV7 vaccine, the incidence of true bacteremia has decreased to 1% and has impacted the epidemiology of fever in the under-3-year-old population, making urinary tract infection the most common cause. Polymerase chain reaction testing for viruses helps in early diagnosis and serves to decrease the unnecessary use of antibiotics. Serious infections are dependent not only on the virulence of the agent, but also on host susceptibility, which has been getting more attention recently. Kawasaki disease in the very young infant is also discussed and awareness is increasing among physicians. SUMMARY: The decrease in the rate of bacteremia since the PCV7 vaccine was introduced means that the management guidelines for fever in the under-3-year-old population need to be reviewed. In addition, better markers are required to predict serious bacterial infection in this population. Further research into the understanding of the host immune response is also needed.