Rise in morning saliva cortisol is associated with abdominal obesity in men: a preliminary report

An abnormal regulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with risk factors for cardiovascular disease and Type 2 diabetes mellitus. The objective of this study was to examine if morning saliva cortisols show similar associations. Twenty-eight men, all 53 yr of age, delivered during an ordinary working day saliva cortisol samples immediately upon awakening and 15 min thereafter as well as at different times during the day, including after a standardized lunch. Dexamethasone (0.5 mg) suppression of cortisol was also measured. The rise of morning cortisol values was positively associated with body mass index (r: 0.45, p=0.016), waist/hip ratio (r: 0.54, p=0.003), abdominal sagittal diameter (r: 0.54, p=0.003), glucose (r: 0.54, p=0.003), insulin (r: 0.57, p=0.002) and triglycerides (r: 0.46, p=0.014). The morning rise also correlated positively with the elevation of cortisol following lunch (r: 0.45, p=0.043) but not with other cortisol measurements or dexamethasone suppression. Elevation of cortisol immediately after awakening has previously been found to provide a simple indicator of HPA axis regulation, as suggested also by the results of this study, and an elevated rise has been reported after exposure to frequent or chronic perceived stress. The rise of cortisol immediately after awakening might be an indicator of an increased risk of developing serious, prevalent diseases via the metabolic syndrome.     

Modulation of anti-idiotypic immune response by immunization with the autologous M-component protein in multiple myeloma patients

Multiple myeloma is characterized by a proliferation of clonal B lymphocytes and plasma cells. The idiotypic structure of clonal immunoglobulin (Ig) expressed on the tumour B-cell surface can be regarded as a tumour-specific antigen and, as such, a potential target for anti-idiotypic T and B cells in an immune regulation of the tumour-cell clone. Active immunization using the autologous monoclonal Ig as a 'vaccine' was shown to induce tumour-specific immunity in murine B-cell tumours and in human B-cell lymphoma. With the aim to induce or amplify an anti-idiotypic response in multiple myeloma, five stage I–III patients were repeatedly immunized with the autologous monoclonal IgG. Induction of idiotype-specific cellular immunity was analysed in vitro by an enzyme-linked immunospot assay (interferon-γ and interleukin-4 secreting cells). B cells secreting anti-idiotypic IgM antibodies were also analysed. An anti-idiotypic T-cell response was amplified 1.9–5-fold in three of the five patients during immunization. The number of B cells secreting anti-idiotypic antibodies also increased in these three patients. In two of the patients induction of idiotype-specific immunity was associated with a gradual decrease of blood CD19⁺ B cells. The induced T-cell response was eliminated during repeated immunization. Further studies are warranted to optimize the immunization schedule in order to achieve a long-lasting T-cell immunity against idiotypic determinants on the tumour clone. A role for immunity in controlling the tumour clone remains to be established.     

In Vitro Activity and Resistance Profile of Dasabuvir,a Nonnucleoside Hepatitis C Virus Polymerase Inhibitor

Dasabuvir (ABT-333) is a nonnucleoside inhibitor of the RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene. Dasabuvir inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates, with 50% inhibitory concentration (IC₅₀) values between 2.2 and 10.7 nM, and was at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. In the HCV subgenomic replicon system, dasabuvir inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concentration (EC₅₀) values of 7.7 and 1.8 nM, respectively, with a 13-fold decrease in inhibitory activity in the presence of 40% human plasma. This level of activity was retained against a panel of chimeric subgenomic replicons that contained HCV NS5B genes from 22 genotype 1 clinical isolates from treatment-naive patients, with EC₅₀s ranging between 0.15 and 8.57 nM. Maintenance of replicon-containing cells in medium containing dasabuvir at concentrations 10-fold or 100-fold greater than the EC₅₀ resulted in selection of resistant replicon clones. Sequencing of the NS5B coding regions from these clones revealed the presence of variants, including C316Y, M414T, Y448C, Y448H, and S556G, that are consistent with binding to the palm I site of HCV polymerase. Consequently, dasabuvir retained full activity against replicons known to confer resistance to other polymerase inhibitors, including the S282T variant in the nucleoside binding site and the M423T, P495A, P495S, and V499A single variants in the thumb domain. The use of dasabuvir in combination with inhibitors targeting HCV NS3/NS4A protease (ABT-450 with ritonavir) and NS5A (ombitasvir) is in development for the treatment of HCV genotype 1 infections.