Neck and waist circumference biomarkers of cardiovascular risk in a cohort of predominantly African-American college students: a preliminary study.

Receiver operating characteristic curves were constructed to assess the value of measuring neck and waist circumference and waist-to-hip ratio (WHR) as biomarkers of metabolic syndrome in college students (18 to 25 years of age). Participants (n=109) were 92% black, 62.4% female, 45.9% overweight or obese, and 20.2% prehypertensive or hypertensive. Overall, 41 (37.6%) students had one or more risk factors for metabolic syndrome. Percent body fat, assessed using whole-body air-displacement plethysmography, was positively correlated (P<0.0001) with neck and waist circumference (as measured at the midpoint between the right lower rib and suprailiac crest; hereafter "midpoint"). Neck circumference correlated with low-density lipoprotein cholesterol (P ≤ 0.02) and both neck circumference and waist circumference-midpoint correlated with insulin (P ≤ 0.001) and triglycerides (P ≤ 0.002). The best-fit cutoffs were ≥ 83 cm waist circumference-midpoint and ≥ 88 cm waist circumference measured at the suprailiac crest for percent body fat in men and ≥ 75 cm waist circumference-midpoint for metabolic syndrome in women. The proportion of overweight and prehypertensive individuals among self-described healthy students underscores the need for screening tools that identify those who might benefit most from health interventions. Waist circumference-midpoint provides a simple yet sensitive method for the estimation of percent body fat and metabolic syndrome risk in primarily African-American college students. The novel use of neck circumference should be further investigated.

Effect of the SORT1 low-density lipoprotein cholesterol locus is sex-specific in a fit, Canadian young-adult population.

The SORT1 locus was originally identified by genome-wide association studies of low-density lipoprotein cholesterol (LDL-C) in adults. Although the effect sizes of this locus are relatively small, we hypothesized that a younger population would show a greater genetic effect because of fewer confounding variables. As such, we investigated the association between the SORT1 locus and LDL-C in a group of healthy young adults. Subjects (n = 122, mean age = 23.2 years) were recruited from the University of Calgary. Lipid measures and genomic DNA were collected from peripheral blood after an overnight fast. Blood pressure, percent body fat (%BF), and maximal oxygen consumption were also measured. Associations between genotype and LDL-C were investigated using linear regression. Nearly one half (42.9%) of the female and 21.7% of the male subjects had a %BF that was above a healthy range. More than one quarter of the subjects had LDL-C values that were considered nonoptimal. Although the association was not significant when both sexes were combined, a significant association was observed between the SORT1 locus (GG: 2.46 ± 0.11 mmol·L(-1) vs. GT-TT: 2.06 ± 0.12 mmol·L(-1), p = 0.016) and LDL-C in male subjects, with genotype explaining 3.0% of the variability in LDL-C. A high prevalence of nonoptimal LDL-C exists in this young population even though it is otherwise fit and healthy. A significant association was found between LDL-C and the minor SORT1 allele in male subjects, with an effect size larger than previously reported in older populations. SORT1 is a valuable target for identifying individuals who would most benefit from early interventions to prevent cardiovascular disease.

Targeting the calcineurin pathway enhances ergosterol biosynthesis inhibitors against Trichophyton mentagrophytes in vitro and in a human skin infection model.

Fluconazole-FK506 or fluconazole-cyclosporine drug combinations were tested in an ex vivo Trichophyton mentagrophytes human skin infection model. Conidia colonization was monitored by scanning electron microscopy over a 7-day treatment period. The fluconazole-FK506 combination demonstrated the most obvious advantage over single-drug therapy by clearing conidia and protecting skin from damage at low drug concentrations.

Calcineurin promotes infection of the cornea by Candida albicans and can be targeted to enhance fluconazole therapy.

In an established Candida albicans murine keratitis model, combination therapy with ophthalmic preparations of fluconazole and cyclosporine A (CsA) demonstrated in vivo drug synergy and effectively resolved wild-type C. albicans infection more rapidly than monotherapy with either drug. Calcineurin, the target of CsA, was also found to contribute to pathogenicity.

The calcineurin target, Crz1, functions in azole tolerance but is not required for virulence of Candida albicans.

In Candida albicans, calcineurin is essential for virulence and survival during membrane perturbation by azoles. Crz1 is a proposed downstream target of calcineurin based on studies of Saccharomyces cerevisiae. However, the in vitro phenotypes of C. albicans crz1/crz1 and calcineurin mutants differ and Crz1 is not required for virulence.

In vitro interactions between antifungals and immunosuppressants against Aspergillus fumigatus.

The optimal treatment for invasive aspergillosis remains elusive, despite the increased efficacy of newer agents. The immunosuppressants cyclosporine (CY), tacrolimus (FK506), and sirolimus (formerly called rapamycin) exhibit in vitro and in vivo activity against Candida albicans, Cryptococcus neoformans, and Saccharomyces cerevisiae, including fungicidal synergy with azole antifungals. We report here that both FK506 and CY exhibit a clear in vitro positive interaction with caspofungin against Aspergillus fumigatus by disk diffusion, microdilution checkerboard, and gross and microscopic morphological analyses. Microscopic morphological analyses indicate that the calcineurin inhibitors delay filamentation, and in combination with caspofungin there is a positive interaction. Our findings suggest a potential role for combination therapy with calcineurin pathway inhibitors and existing antifungal agents to augment activity against A. fumigatus.

Ergosterol biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors against Candida albicans, Candida glabrata, and Candida krusei.

Azoles target the ergosterol biosynthetic enzyme lanosterol 14alpha-demethylase and are a widely applied class of antifungal agents because of their broad therapeutic window, wide spectrum of activity, and low toxicity. Unfortunately, azoles are generally fungistatic and resistance to fluconazole is emerging in several fungal pathogens. We recently established that the protein phosphatase calcineurin allows survival of Candida albicans during the membrane stress exerted by azoles. The calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506) are dramatically synergistic with azoles, resulting in potent fungicidal activity, and mutant strains lacking calcineurin are markedly hypersensitive to azoles. Here we establish that drugs targeting other enzymes in the ergosterol biosynthetic pathway (terbinafine and fenpropimorph) also exhibit dramatic synergistic antifungal activity against wild-type C. albicans when used in conjunction with CsA and FK506. Similarly, C. albicans mutant strains lacking calcineurin B are markedly hypersensitive to terbinafine and fenpropimorph. The FK506 binding protein FKBP12 is required for FK506 synergism with ergosterol biosynthesis inhibitors, and a calcineurin mutation that confers FK506 resistance abolishes drug synergism. Additionally, we provide evidence of drug synergy between the nonimmunosuppressive FK506 analog L-685,818 and fenpropimorph or terbinafine against wild-type C. albicans. These drug combinations also exert synergistic effects against two other Candida species, C. glabrata and C. krusei, which are known for intrinsic or rapidly acquired resistance to azoles. These studies demonstrate that the activity of non-azole antifungal agents that target ergosterol biosynthesis can be enhanced by inhibition of the calcineurin signaling pathway, extending their spectrum of action and providing an alternative approach by which to overcome antifungal drug resistance.