Late-night salivary cortisol as a screening test for Cushing's syndrome.

The clinical features of Cushing's syndrome (such as obesity, hypertension, and diabetes) are commonly encountered in clinical practice. Patients with Cushing's syndrome have been identified by an abnormal low-dose dexamethasone suppression test, elevated urine free cortisol (UFC), an absence of diurnal rhythm of plasma cortisol, or an elevated late-night plasma cortisol. Because the concentration of cortisol in the saliva is in equilibrium with the free (active) cortisol in the plasma, measurement of salivary cortisol in the evening (nadir) and morning (peak) may be a simple and convenient screening test for Cushing's syndrome. The purpose of this study was to evaluate the usefulness of the measurement of late-night and morning salivary cortisol in the diagnosis of Cushing's syndrome. We studied 73 normal subjects and 78 patients referred for the diagnosis of Cushing's syndrome. Salivary cortisol was measured at 2300 h and 0700 h using a simple, commercially-available saliva collection device and a modification of a standard cortisol RIA. In addition, 24-h UFC was measured within 1 month of saliva sampling. Patients with proven Cushing's syndrome (N = 39) had significantly elevated 2300-h salivary cortisol (24.0 +/- 4.5 nmol/L), as compared with normal subjects (1.2 +/- 0.1 nmol/L) or with patients referred with the clinical features of hypercortisolism in whom the diagnosis was excluded or not firmly established (1.6 +/- 0.2 nmol/L; N = 39). Three of 39 patients with proven Cushing's had 2300-h salivary cortisol less than the calculated upper limit of the reference range (3.6 nmol/L), yielding a sensitivity of 92%; one of these 3 patients had intermittent hypercortisolism, and one had an abnormal diurnal rhythm (salivary cortisol 0700-h to 2300-h ratio <2). An elevated 2300-h salivary cortisol and/or an elevated UFC identified all 39 patients with proven Cushing's syndrome (100% sensitivity). Salivary cortisol measured at 0700 h demonstrated significant overlap between groups, even though it was significantly elevated in patients with proven Cushing's syndrome (23.0 +/- 4.2 nmol/L), as compared with normal subjects (14.5 +/- 0.8 nmol/L) or with patients in whom Cushing's was excluded or not firmly established (15.3 +/- 1.5 nmol/L). Late-night salivary cortisol measurement is a simple and reliable screening test for spontaneous Cushing's syndrome. In addition, late-night salivary cortisol measurements may simplify the evaluation of suspected intermittent hypercortisolism, and they may facilitate the screening of large high-risk populations (e.g. patients with diabetes mellitus).

Elevated salivary cortisol in the evening in healthy elderly men and women: correlation with bone mineral density.

BACKGROUND: Aging is associated with a loss of bone mineral density (BMD) in men and women. Loss of BMD can also be caused by hypercortisolemia in men or women at any age. This study measured salivary cortisol at 2300 h and 0700 h as indices of cortisol secretory activity in 228 elderly, community-dwelling subjects. Salivary cortisol results were correlated with BMD. We hypothesized that salivary cortisol is elevated at 2300 h in elderly people, and that salivary cortisol will correlate negatively with BMD. METHODS: Saliva was sampled at 2300 h (nadir in circadian rhythm) and 0700 h (peak in circadian rhythm) in 130 men (70.7 +/- 0.4 years old) and 98 women (70.0 +/- 0.4 years old); approximately half of the women were receiving hormone replacement therapy (HRT). BMD was measured by dual energy x-ray absorptiometry. RESULTS: Salivary cortisol at 2300 h was significantly elevated in men (2.3 +/- 0.1 nmol/L) and women (2.1 +/- 0.1 nmol/L) as compared to 73 younger controls (1.2 +/- 0.1 nmol/L; 37 +/- 1 year old). Salivary cortisol at 0700 h was not different between older subjects and younger controls. There was a significant negative correlation of lumbar (L2-4) BMD and 2300 h salivary cortisol in older women (r = -0.20, p = .05; n = 98); this correlation was significant only in women not on HRT. There was a highly significant negative correlation of lumbar (L2-4) BMD and 0700 h salivary cortisol in older men (r = -0.31, p = .0003). CONCLUSIONS: Salivary cortisol is a simple, nonstressful method for assessing activity of the hypothalamic-pituitary-adrenal (HPA) axis in the elderly population. A major finding was an elevation in the late night nadir in cortisol secretion. We also suggest that elevated cortisol secretion in elderly people may contribute to the age-related loss in bone mineral density and that this effect is prevented by HRT.

The TACC domain identifies a family of centrosomal proteins that can interact with microtubules.

We recently showed that the Drosophila transforming acidic coiled-coil (D-TACC) protein is located in the centrosome, interacts with microtubules, and is required for mitosis in the Drosophila embryo. There are three known human TACC proteins that share a conserved, C-terminal, coiled-coil region with D-TACC. These proteins have all been implicated in cancer, but their normal functions are unknown. We show that all three human TACC proteins are concentrated at centrosomes, but with very different characteristics: TACC1 is weakly concentrated at centrosomes during mitosis; TACC2 is strongly concentrated at centrosomes throughout the cell cycle; and TACC3 is strongly concentrated in a more diffuse region around centrosomes during mitosis. When the C-terminal TACC domain is overexpressed in HeLa cells, it forms large polymers in the cytoplasm that can interact with both microtubules and tubulin. The full-length TACC proteins form similar polymers when overexpressed, but their interaction with microtubules and tubulin is regulated during the cell cycle. At least one of the human TACC proteins appears to increase the number and/or stability of centrosomal microtubules when overexpressed during mitosis. Thus, the TACC domain identifies a family of centrosomal proteins that can interact with microtubules. This may explain the link between the TACC genes and cancer.

Polyanionic (i.e., polysulfonate) dendrimers can inhibit the replication of human immunodeficiency virus by interfering with both virus adsorption and later steps (reverse transcriptase/integrase) in the virus replicative cycle.

Polyanionic dendrimers were synthesized and evaluated for their antiviral effects. Phenyldicarboxylic acid (BRI6195) and naphthyldisulfonic acid (BRI2923) dendrimers were found to inhibit the replication of human immunodeficiency virus type 1 (HIV-1; strain III(B)) in MT-4 cells at a EC(50) of 0.1 and 0.3 microg/ml, respectively. The dendrimers were not toxic to MT-4 cells up to the highest concentrations tested (250 microg/ml). These compounds were also effective against various other HIV-1 strains, including clinical isolates, HIV-2 strains, simian immunodeficiency virus (SIV, strain MAC(251)), and HIV-1 strains that were resistant to reverse transcriptase inhibitors. HIV strains containing mutations in the envelope glycoprotein gp120 (engendering resistance to known adsorption inhibitors) displayed reduced sensitivity to the dendrimers. The compounds inhibited the binding of wild-type virus and recombinant virus (containing wild-type gp120) to MT-4 cells at concentrations comparable to those that inhibited the replication of HIV-1(III(B)) in these cells. Cellular uptake studies indicated that BRI2923, but not BRI6195, permeates into MT-4 and CEM cells. Accordingly, the naphtyldisulfonic acid dendrimer (BRI2923) proved able to inhibit later steps of the replication cycle of HIV, i.e., reverse transcriptase and integrase. NL4.3 strains resistant to BRI2923 were selected after passage of the virus in the presence of increasing concentrations of BRI2923. The virus mutants showed 15-fold reduced sensitivity to BRI2923 and cross-resistance to known adsorption inhibitors. However, these virus mutants were not cross-resistant to reverse transcriptase inhibitors or protease inhibitors. We identified several mutations in the envelope glycoprotein gp120 gene (i.e., V2, V3, and C3, V4, and C4 regions) of the BRI2923-resistant NL4.3 strains that were not present in the wild-type NL4.3 strain, whereas no mutations were found in the reverse transcriptase or integrase genes.