Cohesive Polydensified Matrix Hyaluronic Acid for the Treatment of Etched-In Fine Facial Lines: A 6-Month, Open-Label Clinical Trial.

BACKGROUND: Available hyaluronic acid dermal fillers have unique biophysical properties that influence their clinical utility, longevity, and aesthetic outcomes. OBJECTIVE: To evaluate the effectiveness and durability of a cohesive polydensified matrix hyaluronic acid dermal filler (CPM-HA) for the treatment of etched-in fine facial lines. MATERIALS AND METHODS: Subjects with etched-in fine lines of the forehead, cutaneous lip, melolabial folds, nasolabial folds, and/or radial cheek received treatment with CPM-HA mixed with lidocaine and epinephrine, with an optional touch-up treatment at Week 2, if deemed necessary. Response to treatment (as measured by the Merz Aesthetics Scales, Lemperle Facial Wrinkle Scales, and subject self-assessment) and safety/tolerability were monitored over the course of 26 weeks. RESULTS: Thirty-one subjects received treatment with CPM-HA to 1 or more facial areas. All 5 treatment areas showed clinically meaningful and statistically significant improvements in average clinician rating scale scores at all study visits (p < .001 vs baseline). Most subjects reported maintained improvement from baseline of 50% or more throughout the 26-week study. Injection site reactions were mild and resolved without intervention. CONCLUSION: Cohesive polydensified matrix hyaluronic acid dermal filler treatment was well tolerated and provided consistent and durable improvement in the appearance of a diverse range of etched-in fine facial lines.

A genetic study of the suppressors of the Engrailed-1 cerebellar phenotype.

The mouse Engrailed genes, En1 and En2, play an important role in the development of the cerebellum from its inception at the mid/hindbrain boundary in early embryonic development through cell type specification events and beyond. In the absence of En1, the cerebellum and caudal midbrain fail to develop normally--a phenotype that we have previously reported to be strain dependent. On the 129/S1 strain background, En1 null alleles lead to mid/hindbrain failure, whereas on the C57BL/6 background, En1 deficiency is compatible with near normal cerebellar development. We have pursued this dramatic effect of genetic background by performing a genetic modifier screen through F1 backcross and F1 intercross matings. The backcross has yielded two strong candidate intervals with suggestive linkage to a third region. Moreover, variations in rescue frequency among subgroups within the backcross indicate gender and parent of origin influences on rescue penetrance. The intercross data reveal locus heterogeneity of the En1 modifiers, with more than one compliment of C57BL/6 and 129/S1 alleles capable of mediating the rescue phenotype. These findings highlight the complexity and plasticity of gene networks involved in brain development.

Factors in the genetic background suppress the engrailed-1 cerebellar phenotype.

The mouse homeodomain protein, Engrailed-1, is generally viewed as an essential player in the early establishment and maintenance of the midbrain/hindbrain region that gives rise to the cerebellum and midbrain. In keeping with this, engineered null mutations at this locus have been reported to lead to perinatal lethality accompanied by near-total absence of cerebellar and caudal midbrain structures. We report here that these cerebellar phenotypes are nearly completely suppressed on a C57BL/6J genetic background. All cell types are present and arranged properly in both the cortex and the deep nuclei, and cell counts reveal no significant absence of cerebellar Purkinje cells. Folial patterns are nearly normal, although an apparent fusion of lobules IV and V is consistently noted. Significantly, no change in the Engrailed-2 mutant phenotype occurs after a similar background switch, and whole-mount in situ hybridization reveals identical En2 expression patterns in wild-type C57BL/6J and 129/Sv mice. One likely mechanism for the En1-/- phenotype suppression is a temporal and/or spatial change in the pattern of Engrailed-2 expression apparent only in the absence of Engrailed-1. In support of this, C57BL/6-En1-/- embryos that are also En2+/- lack a cerebellum and caudal midbrain: a phenotype identical to 129/Sv-En1-/- mice.

A question of balance: a proposal for new mouse models of autism.

Autism spectrum disorder (ASD) represents a major mental health problem with estimates of prevalence ranging from 1/500 to 1/2000. While generally recognized as developmental in origin, little to nothing is certain about its etiology. Currently, diagnosis is made on the basis of a variety of early developmental delays and/or regressions in behavior. There are no universally agreed upon changes in brain structure or cell composition. No biomarkers of any type are available to aid or confirm the clinical diagnosis. In addition, while estimates of the heritability of the condition range from 60 to 90%, as of this writing no disease gene has been unequivocally identified. The prevalence of autism is three- to four-fold higher in males than in females, but the reason for this sexual dimorphism is unknown. In light of all of these ambiguities, a proposal to discuss potential animal models may seem the heart of madness. However, parsing autism into its individual genetic, behavioral, and neurobiological components has already facilitated a 'conversation' between the human disease and the neuropathology and biochemistry underlying the disorder. Building on these results, it should be possible to not just replicate one aspect of autism but to connect the developmental abnormalities underlying the ultimate behavioral phenotype. A reciprocal conversation such as this, wherein the human disease informs on how to make a better animal model and the animal model teaches of the biology causal to autism, would be highly beneficial.

Dissecting complex genetic interactions that influence the Engrailed-1 limb phenotype.

Engrailed-1, a homeobox containing transcriptional repressor, is known to play an important role in the development of the vertebrate limb. In its absence, mouse limbs develop with improper specification of dorsal identity and digit abnormalities. We report here that specific malformations in the mutant limb are dependent on strain background. We have subdivided these defects on the basis of morphology to define five independent traits. Each of these shows marked differences in prevalence among the 129/S1 and C57BL/6J strains carrying the En1(hd) mutation. In a genome-wide scan using SSLP markers, we have determined the location of one significant modifier and several additional suggestive loci responsible for these traits, each a facet of the En1(-/-) phenotype. We propose this type of sensitized genetic screen as a model approach for the discovery and mapping of quantitative loci that affect the subtle details of limb pattern formation.