Endogenous peroxidase in the nuclear envelope and endoplasmic reticulum of human monocytes in vitro: association with arachidonic acid metabolism

The development of peroxidase (PO) reaction in the nuclear envelope (NE) and endoplasmic reticulum (ER) of monocytes differentiating in vitro and its relationship with arachidonic acid metabolism were studied. The PO, as visualized by the diaminobenzidine (DAB) technique, appeared in the NE and ER of the majority of monocytes within 24 hours of culture, with a substantial decrease thereafter. The influence of three major groups of agents--inhibitors of PO, of prostanoids, and of protein biosynthesis--upon the development of the PO reaction was examined. When aminotriazole, a PO inhibitor, was added to the culture medium, the appearance of PO was suppressed in the monocytes. The cyclooxygenase blocker, indomethacin, however, did not influence the development of PO. Also the blockers of protein synthesis, puromycin, cycloheximide, and actinomycin D, did not affect the appearance of PO. The prostanoids released from the monocytes, ie, prostaglandin E and thromboxane B2, were determined by radioimmunoassay and showed a time sequence of secretion that corresponded to the appearance of PO in the cells: a marked increase within the first 24 hours with a substantial decrease thereafter. The presence of the PO inhibitors aminotriazole and sodium azide in the culture medium produced a suppression of prostanoid release from the monocytes comparable with that of indomethacin. The data suggest that the PO in the NE and ER of differentiating monocytes in vitro (1) is associated with arachidonic acid metabolism, and (2) is not formed by de novo protein synthesis but rather by an activation process.     

A 1-Year Randomized Controlled Study of Everolimus Versus Mycophenolate Mofetil With Reduced-Dose Cyclosporine in Maintenance Heart Transplant Recipients

Background

The aim of this study was to demonstrate noninferiority of everolimus with reduced cyclosporine (CsA) vs mycophenolate mofetil (MMF) with reduced CsA in improving renal function.

Methods

In this 1-year randomized, open-label, noninferiority study in maintenance heart transplant recipients with impaired renal function 70 patients received everolimus (n = 36) or MMF (n = 34) in combination with reduced CsA. The planned sample size was not reached as the study was prematurely discontinued due to slow recruitment.

Results

Noninferiority of the everolimus regimen could not be shown: In the total population MMF seemed to be favorable on renal function assessed by serum creatinine and filtration rates, but not in the subset of patients who reached the intended reduced CsA level. Incidence rates of rejection episodes were significantly higher under MMF at month 6 (P = .0332).

Conclusions

Overall, the results of this trial using reduced CsA in combination with either everolimus or MMF show that there is evidence to reduce the CsA level when everolimus is given concomitantly and that the benefit of MMF with reduced CsA levels is limited due to insufficient immunosuppression.     

Everolimus immunosuppression in de novo heart transplant recipients: What does the evidence tell us now?

The efficacy of everolimus with reduced cyclosporine in de novo heart transplant patients has been demonstrated convincingly in randomized studies. Moreover, everolimus-based immunosuppression in de novo heart transplant recipients has been shown in two randomized trials to reduce the increase in maximal intimal thickness based on intravascular ultrasound, indicating attenuation of cardiac allograft vasculopathy (CAV). Randomized trials of everolimus in de novo heart transplantation have also consistently shown reduced cytomegalovirus infection versus antimetabolite therapy. In maintenance heart transplantation, conversion from calcineurin inhibitors to everolimus has demonstrated a sustained improvement in renal function. In de novo patients, a renal benefit may only be achieved if there is an adequate reduction in exposure to calcineurin inhibitor therapy. Delayed introduction of everolimus may be appropriate in patients at high risk of wound healing complications, e.g. diabetic patients or patients with ventricular assist device. The current evidence base suggests that the most convincing reasons for use of everolimus from the time of heart transplantation are to slow the progression of CAV and to lower the risk of cytomegalovirus infection. A regimen of everolimus with reduced-exposure calcineurin inhibitor and steroids in de novo heart transplant patients represents a welcome addition to the therapeutic armamentarium.     

Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy

TRACK‐HD is a multicentre longitudinal observational study investigating the use of clinical assessments and 3‐Tesla magnetic resonance imaging as potential biomarkers for future therapeutic trials in Huntington's disease (HD). The cross‐sectional data from this large well‐characterized dataset provide the opportunity to improve our knowledge of how the underlying neuropathology of HD may contribute to the clinical manifestations of the disease across the spectrum of premanifest (PreHD) and early HD. Two hundred and thirty nine gene‐positive subjects (120 PreHD and 119 early HD) from the TRACK‐HD study were included. Using voxel‐based morphometry (VBM), grey and white matter volumes were correlated with performance in four domains: quantitative motor (tongue force, metronome tapping, and gait); oculomotor [anti‐saccade error rate (ASE)]; cognition (negative emotion recognition, spot the change and the University of Pennsylvania smell identification test) and neuropsychiatric measures (apathy, affect and irritability). After adjusting for estimated disease severity, regionally specific associations between structural loss and task performance were found (familywise error corrected, P < 0.05); impairment in tongue force, metronome tapping and ASE were all associated with striatal loss. Additionally, tongue force deficits and ASE were associated with volume reduction in the occipital lobe. Impaired recognition of negative emotions was associated with volumetric reductions in the precuneus and cuneus. Our study reveals specific associations between atrophy and decline in a range of clinical modalities, demonstrating the utility of VBM correlation analysis for investigating these relationships in HD. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Maternal administration of granulocyte colony-stimulating factor improves neonatal rat survival after a lethal group B streptococcal infection

Maternally administered recombinant human granulocyte colony- stimulating factor (rhG-CSF) has been shown to cross the placenta and induce a peripheral neutrophilia and increases in the marrow and spleen neutrophil storage pools in fetal and newborn rats. In the present study, we have used this model system to investigate the efficacy of prenatally administered rhG-CSF on neonatal defense to a lethal challenge with Group B-beta hemolytic Streptococcus (GBS). Pregnant rats were injected with rhG-CSF twice daily beginning 6 days before parturition. At birth, all pups were infected with a dose of GBS that is lethal for 90% of infected pups (LD90). Survival was monitored daily for 5 days. Survival of infected pups from saline-treated mothers beyond 60 hours after infection was 10%. No difference in survival was observed among pups from mothers treated 2 and 4 days before parturition. In contrast, we determined that survival was 82.5% among infected pups from mothers treated for 6 days before parturition with rhG-CSF. Our results demonstrate that maternal administration of rhG- CSF augments neonatal defenses against a lethal bacterial challenge.     

Impact of gender and age on risk factor distribution and health perception: evaluation in a prospective population with heart disease

Aim

Several large surveys have highlighted the inadequate risk factor control in populations at elevated cardiovascular risk. These populations would substantially benefit from risk reduction and could demonstrate increased awareness for risk factor control. Risk factor segregation by gender has been previously described, yet its analysis in the medical field frequently omits sociodemographic variables, which could act as potential confounders.

Subject and methods

We analyzed risk factor prevalence in a population of 1,559 patients with severe coronary heart disease prior to a coronary bypass graft (CABG) surgery. Univariate correlations between risk factor type and frequency and gender were explored. Following, multivariable models were fitted to account for sociodemographic aspects associated with gender. Interaction terms were incorporated as fit. Lastly, the correlation between gender-specific risk factor profiles and their association with self-perceived health status was assessed.

Results

Our study identified gender as the main segregating variable for risk factors after multiple adjustments and inclusion of interaction terms. Obesity and hypertension displayed a significant association with the female population (OR?=?1.598, p?=?0.047 and OR?=?3.737, p?=?0.006, respectively), while smoking and elevated alcohol consumption prevailed in males (OR?=?1.77, p?=?0.038 and OR?=?2.768, p?=?0.013, respectively). Additionally, gender-specific analysis of health perception according to risk factor loads revealed that male patients rate their health in overall better terms regardless of their risk profile.

Conclusions

Our study confirmed the role of gender as the primary risk profile segregator after multiple adjustments for potential sociodemographic confounders, even in a population at elevated cardiovascular risk. Subjective health perception, which displayed marked gender differences, should be further investigated as a potential adherence and outcome modulator.