ABSTRACT
CONTEXT: The olfactory phenotype in patients with idiopathic hypogonadotropic hypogonadism (IHH) ranges from complete anosmia (Kallmann syndrome) to normosmia (normosmic IHH). However, the true prevalence of intermediary olfactory phenotypes (hyposmia) in IHH patients has not yet been assessed, and systematic correlations with anatomical and genetic abnormalities have not been reported. OBJECTIVE: The objective of this study was to evaluate olfactory function in a large IHH cohort and correlate these findings with olfactory magnetic resonance imaging (MRI) and underlying genetic etiology. DESIGN AND SETTING: We conducted a cross-sectional case-control study at an academic referral center. PATIENTS: A total of 286 IHH patients (201 males and 85 females) and 2183 healthy historic controls (1011 males and 1172 females) were studied. MAIN OUTCOME MEASURES: We measured olfactory function using the University of Pennsylvania Smell Identification Test; in 208 subjects, the genetic etiology of IHH was ascertained by DNA sequencing; in a minor subset [39 of 286 subjects (13%)], olfactory structures were determined by MRI. RESULTS: In the IHH cohort, 31.5% were anosmic, 33.6% were hyposmic, and 34.9% were normosmic. Most hyposmic (seven of 11) subjects with MRI data exhibited olfactory structure abnormalities. Of hyposmic subjects, 39.5% harbored mutations in genes involved in either GnRH neuronal migration or GnRH secretion. CONCLUSIONS: IHH subjects display a broad spectrum of olfactory function, with a significant hyposmic phenotype in nearly one third of subjects. The hyposmic subjects harbor mutations in genes affecting GnRH neuronal migration and its secretion, suggesting a pathophysiological overlap between Kallmann syndrome and normosmic IHH. Accurate olfactory phenotyping in IHH subjects will inform the pathophysiology of this condition and guide genetic testing.
Subject(s)
Hypogonadism/complications , Olfaction Disorders/classification , Olfaction Disorders/etiology , Olfaction Disorders/genetics , Adolescent , Adult , Case-Control Studies , Cohort Studies , Cross-Sectional Studies , Female , Humans , Hypogonadism/genetics , Hypogonadism/physiopathology , Kallmann Syndrome/etiology , Kallmann Syndrome/genetics , Kallmann Syndrome/physiopathology , Male , Middle Aged , Olfaction Disorders/diagnosis , Olfactory Pathways/physiopathology , Phenotype , Young AdultABSTRACT
Nanocomposites of Ethylene Vinyl Acetate (EVA 260) with Cloisite 20A organo clay and Cloisite 20A organo clay impregnated with Fe(CO)(5) were produced in a twin-screw extruder. Dynamic mechanical analysis (DMA) measurements indicated that the moduli increased monotonically for the Cloisite, up to a concentration of 10%, after which the modulus decreased. Adult human dermal fibroblasts (AHDF) were plated on these surfaces and the cell growth was found to be maximal on the nanocomposites containing 10% Cloisite. AHDFs cultured on substrates with higher Cloisite content had low surface area, poor growth curves, and misshaped actin fibers. Compounding EVA with Fe(CO)(5) soaked Cloisite did not enhance the modulus even at a loading of 10%. TEM images indicate nanoparticles form and coat the Cloisite platelet surfaces, possibly interfering with the exfoliation process. On the other hand, cell culture of MC3T3 osteoblasts proliferated on the Fe containing nanocomposites, the largest effect being observed when cultured in a constant magnetic field. These results indicate how the chemical nature of the Cloisite 20A organo clay can also play a major role. Finally, since natural ECM is fibrillar, these EVA nanocomposites were also electrospun into micron thick fibers. MC3T3s proliferated well on these fibers and the MC3T3 proliferation was maximized by culture on electrospun aligned fibers in a constant magnetic field.
