C/EBP�� and G-CSF receptor signals cooperate to induce the myeloperoxidase and neutrophil elastase genes

To assess cooperation between G-CSF signals and C/EBP, we characterized Ba/F3 pro-B cell lines expressing C/EBPWT-ER and the G-CSF receptor (GCSFR). In these lines, GCSFR signals can be evaluated independent of their effect on C/EBP levels. G-CSF alone did not induce the MPO, NE, LF, or PU.1 RNAs, and C/EBPWT-ER alone stimulated low-level MPO and high-level PU.1 expression. Simultaneous activation of the GCSFR and C/EBPWT-ER markedly increased MPO and NE induction at 24 h, and LF mRNA was detected at 48 h. G-CSF did not increase endogenous GCSFR, endogenous C/EBP or exogenous C/EBPWT-ER levels, and C/EBPWT-ER did not induce endogenous or exogenous GCSFR. Several GCSFR mutants were also co-expressed with C/EBPWT-ER. Mutation of all four cytoplasmic tyrosines prevented NE induction but enhanced MPO induction. Mutation of Y704 was required for increased MPO induction. Consistent with this finding, removing IL-3 without G-CSF addition enabled MPO, but not NE, induction by C/EBPWT-ER. GCSFR signals or related signals from other receptors may cooperate with C/EBP to direct differentiation of normal myeloid stem cells.

Association of high-sensitivity C-reactive protein with de novo major depression

<b>Background:</b> Although there is cross-sectional evidence that changes in the immune system contribute to the pathophysiology of depression, longitudinal data capable of elucidating cause and effect relationships are lacking. <br /><br /><b>Aims: </b>We aimed to determine whether subclinical systemic inflammation, as measured by serum high-sensitivity C-reactive protein (hsCRP) concentration, is associated with an increased risk of de novo major depressive disorder. <br /><br /><b>Method:</b> Major depressive disorder was diagnosed using a clinical interview (SCID-I/NP). This is a retrospective cohort study; from a population-based sample of 1494 randomly selected women recruited at baseline during the period 1994-7, 822 were followed for a decade and provided measures of both exposure and outcome. Of these women, 644 (aged 20-84 years) had no prior history of depression at baseline and were eligible for analysis. <br /><br /><b>Results:</b> During 5827 person-years of follow-up, 48 cases of de novo major depressive disorder were identified. The hazard ratio (HR) for depression increased by 44% for each standard deviation increase in log-transformed hsCRP (ln-hsCRP) (HR = 1.44, 95% CI 1.04-1.99), after adjusting for weight, smoking and use of non-steroidal anti-inflammatory drugs. Further adjustment for other lifestyle factors, medications and comorbidity failed to explain the observed increased risk for depression. <br /><br /><b>Conclusions:</b> Serum hsCRP is an independent risk marker for de novo major depressive disorder in women. This supports an aetiological role for inflammatory activity in the pathophysiology of depression.

Effect of naloxone-precipitated morphine withdrawal on c-fos expression in rat corticotropin-releasing hormone neurons in the paraventricular hypothalamus and extended amygdala

Morphine withdrawal is characterized by physical symptoms and a negative affective state. The 41 amino acid polypeptide corticotropin-releasing hormone (CRH) is hypothesized to mediate, in part, both the negative affective state and the physical withdrawal syndrome. Here, by means of dual-immunohistochemical methodology, we examined the co-expression of the c-Fos protein and CRH following naloxone-precipitated morphine withdrawal. Rats were treated with slow-release morphine 50 mg/kg (subcutaneous, s.c.) or vehicle every 48 h for 5 days, then withdrawn with naloxone 5 mg/kg (s.c.) or saline 48 h after the final morphine injection. Two hours after withdrawal rats were perfused transcardially and their brains were removed and processed for immunohistochemistry. We found that naloxone-precipitated withdrawal of morphine-dependent rats increased c-Fos immunoreactivity (IR) in CRH positive neurons in the paraventricular hypothalamus. Withdrawal of morphine-dependent rats also increased c-Fos-IR in the central amygdala and bed nucleus of the stria terminalis, however these were in CRH negative neurons.<br />

Use of ultraviolet C (UVC) radiation to inactivate infectious hematopoietic necrosis virus (IHNV) and viral haemorrhagic septicaemia virus (VHSV) in fish processing plant effluent

We determined the stability of infectious hematopoietic necrosis virus (IHNV) and viral hemorrhagic septicemia virus (VHSV) suspended in either fish processing plant effluent blood water (EBW) or culture media and examined the effectiveness of UVC radiation to inactivate IHNV and VHSV suspended in both solutions. Without exposure to UVC, IHNV and VHSV were maintained in 4&deg;C blood water for up to 48 hours without significant reduction in virus titer. However when exposed to UVC radiation using a low pressure mercury vapour lamp collimated beam, IHNV and VHSV were inactivated, and the efficacy of UVC radiation was dependent upon the solution and virus type being treated. A 3-log reduction for VHSV and IHNV in culture media was achieved at 3.28 and 3.84 mJ cm-2, respectively. The UV dose needed for a 3-log reduction of VHSV in EBW was 3.82 mJ cm-2. However, exposure of IHNV in EBW to the maximum UVC dose tested (4.0 mJ cm-2) only led to a 2.26-log-reduction. Factors such as particle size, and possible association of viruses with suspended EBW particulate, were not investigated in this study, but may have contributed to the difference in UVC effectiveness. Future work should emphasize improved filtration methods prior to UV treatment of processing plant EBW at an industrial scale.<br />

Hepatitis C virus treatment in the 'real-world': how well do 'real' patients respond?

Background: Published clinical trials of the treatment of HCV are largely multicentre prospective pharmaceutical trials. Patients in clinical trials tend to have more favorable outcomes than patients in the 'real-world', due to strict patient selection and differences in treatment conditions and available resources. Objectives: To assess the outcomes of Hepatitis C infected patients treated at the Barwon Health Liver Clinic with combination Pegylated interferon (PEG-IFN) and Ribavirin (RBV) therapy and to determine factors associated with a treatment response. Methods: Retrospective review of patients who received treatment for Hepatitis C at our institution's Liver Clinic from January 2001-September 2011. Patient demographics, comorbidities, treatment-related parameters and side effects were extracted from medical records and analyzed. Results: A total of 190 patients (120 male, 70 female) with a mean age of 42.8 years (range 20-68 years) commenced treatment. The most common genotype was genotype 3 (48.9%), followed by genotype 1 (42.6%). 150 of 190 patients (78.9%) completed treatment and had end of treatment data available. 107 of 182 patients, (58.8%) for whom sustained virologic response (SVR) rate data was available achieved an SVR. Overall response rates were; 46.9%, 68.8% and 62.4% in genotypes 1, 2 and 3 respectively. The response rate was significantly lower in 29 patients with documented cirrhosis (20.7%). Age, diabetes and alcohol abuse did not predict treatment response in our cohort. Side effects reported in 81.6% of patients included general malaise, hematological disturbance and psychiatric issues, and necessitated cessation of therapy in 16 patients (8.4%) and dose reduction in 26 patients (13.7%). Conclusions: Response rates to combination PEG-IFN and RBV therapy at our institution are comparable to other 'real-world' and pharmaceutical registration trials. Side effects of combination therapy were prominent but resulted in fewer discontinuations of therapy compared to pharmaceutical trials.