Factors affecting the severity of central centrifugal cicatricial alopecia.

BACKGROUND: Central centrifugal cicatricial alopecia (CCCA) is a type of scarring hair loss primarily seen in African-American women. The risk factors that affect the severity of disease remain unclear. OBJECTIVES: This study was designed to elucidate risk factors that may be associated with severity of CCCA. METHODS: A cross-sectional survey study was conducted. Women with biopsy-confirmed CCCA responded to a questionnaire and were grouped according to a photographic scale of central scalp alopecia. The severity of disease was considered: grade 1 and 2 disease was interpreted as early-stage CCCA, and grade 3-5 disease was interpreted as advanced-stage CCCA. Data from the questionnaire were compared with levels of severity to determine the strength of associations with severity of disease. RESULTS: A total of 38 women with biopsy-confirmed CCCA were recruited to participate in this study. Early-stage CCCA was seen in 22 subjects (57.9%), and advanced-stage CCCA was noted in 16 subjects (42.1%). The average duration of hair loss was 5.7 years in early-stage disease and 10.1 years in advanced-stage disease. There was a positive correlation between duration of hair loss and degree of hair loss (Spearman's correlation 0.471, P = 0.003). CONCLUSIONS: This study reports on data sourced from patients with biopsy-confirmed CCCA and examines the relationships between various factors and severity of CCCA. The findings demonstrate that duration of hair loss is positively associated with severity of disease and that androgen-related conditions are prevalent in those affected with CCCA.

Identification of a circadian output circuit for rest:activity rhythms in Drosophila.

Though much is known about the cellular and molecular components of the circadian clock, output pathways that couple clock cells to overt behaviors have not been identified. We conducted a screen for circadian-relevant neurons in the Drosophila brain and report here that cells of the pars intercerebralis (PI), a functional homolog of the mammalian hypothalamus, comprise an important component of the circadian output pathway for rest:activity rhythms. GFP reconstitution across synaptic partners (GRASP) analysis demonstrates that PI cells are connected to the clock through a polysynaptic circuit extending from pacemaker cells to PI neurons. Molecular profiling of relevant PI cells identified the corticotropin-releasing factor (CRF) homolog, DH44, as a circadian output molecule that is specifically expressed by PI neurons and is required for normal rest:activity rhythms. Notably, selective activation or ablation of just six DH44+ PI cells causes arrhythmicity. These findings delineate a circuit through which clock cells can modulate locomotor rhythms.

Altered metabolism and persistent starvation behaviors caused by reduced AMPK function in Drosophila.

Organisms must utilize multiple mechanisms to maintain energetic homeostasis in the face of limited nutrient availability. One mechanism involves activation of the heterotrimeric AMP-activated protein kinase (AMPK), a cell-autonomous sensor to energetic changes regulated by ATP to AMP ratios. We examined the phenotypic consequences of reduced AMPK function, both through RNAi knockdown of the gamma subunit (AMPKγ) and through expression of a dominant negative alpha (AMPKα) variant in Drosophila melanogaster. Reduced AMPK signaling leads to hypersensitivity to starvation conditions as measured by lifespan and locomotor activity. Locomotor levels in flies with reduced AMPK function were lower during unstressed conditions, but starvation-induced hyperactivity, an adaptive response to encourage foraging, was significantly higher than in wild type. Unexpectedly, total dietary intake was greater in animals with reduced AMPK function yet total triglyceride levels were lower. AMPK mutant animals displayed starvation-like lipid accumulation patterns in metabolically key liver-like cells, oenocytes, even under fed conditions, consistent with a persistent starved state. Measurements of O(2) consumption reveal that metabolic rates are greater in animals with reduced AMPK function. Lastly, rapamycin treatment tempers the starvation sensitivity and lethality associated with reduced AMPK function. Collectively, these results are consistent with models that AMPK shifts energy usage away from expenditures into a conservation mode during nutrient-limited conditions at a cellular level. The highly conserved AMPK subunits throughout the Metazoa, suggest such findings may provide significant insight for pharmaceutical strategies to manipulate AMPK function in humans.

Functional differences between two CRF-related diuretic hormone receptors in Drosophila.

In Drosophila, two related G-protein-coupled receptors are members of the corticotropin releasing factor (CRF) receptor subfamily. We have previously reported that one of these receptors, encoded by CG8422 is a functional receptor for a diuretic hormone, DH(44). Here, we report that the other CRF receptor subfamily member, encoded by CG12370, is also a receptor for the DH(44) neuropeptide. The lines of evidence to support this identification include increases in cAMP levels due to CG12370 receptor activation and the recruitment of beta-arrestin-GFP to the plasma membrane in response to DH(44) application. We compared these features of the receptors DH44-R2 (encoded by CG12370) and DH44-R1 (encoded by CG8422) and found fundamental differences in signaling, association with the arrestins, and peptide sensitivity. We found that the sensitivity of DH44-R2 to the DH(44) peptide is lower than that of DH44-R1, specifically an estimated EC(50) of 7.98E-07 moll(-1) for DH(44) by DH44-R2 to an EC(50) of 5.12E-09 moll(-1) by DH44-R1 and found that previous reports on the sensitivity of the tubule to DH(44) is in agreement with our measurements of DH44-R2 sensitivity. We employed a specific RNAi construct to selectively knock-down DH44-R2 expression and this led to heightened sensitivity to osmotic challenges. The functional characterization of this diuretic hormone receptor in Drosophila demonstrates a high degree of conservation of CRF-like signaling.