Effect of cyclosporine on hepatic cytosolic estrogen and androgen receptor levels before and after partial hepatectomy

Estrogen and androgen receptors within the liver have been reported to modulate the hepatic regenerative response to partial hepatectomy. Moreover, cyclosporine has several untoward effects that might occur as a consequence of alterations in sex hormone activity. To evaluate these questions the following experiments were performed. Estrogen and androgen receptors in cytosol were quantitated in livers of rats treated with cyclosporine or olive oil vehicle before and after partial hepatectomy or a sham operation. Ornithine decarboxylase activity and thymidine kinase activity were assessed as indices of hepatic regeneration. Preoperative levels of estrogen receptor activity in the hepatic cytosol were significantly greater in rats treated with cyclosporine as compared to vehicle treated controls (P<0.01). In contrast, preoperative levels of androgen receptor activity in the cyclosporine-treated and vehicle-treated animals were similar. Following partial hepatectomy, a reduction in the activity of both sex hormone receptors in the hepatic cytosol was observed and was compatible with results described previously in normal animals. Unexpectedly the preoperative levels of ornithine decarboxylase (P<0.01) and thymidine kinase activity (P<0.01) were significantly greater in the rats treated with cyclosporine as compared to the vehicle treated controls. As expected, ornithine decarboxylase activity (at 6 hr) and thymidine kinase activity (at 24 hr) rose and peaked in response to a partial hepatectomy but were significantly greater (P<0.05) in the rats treated with cyclosporine as compared to the vehicle. These results show that cyclosporine treatment causes an increase in the hepatic content of estrogen receptor activity that is associated with an enhanced potential for a regenerative response. These effects of cyclosporine treatment on the sex hormone receptor levels in liver may explain the mechanisms responsible for some of the untoward effects of treatment with this agent. © 1990 Plenum Publishing Corporation

Age, time living with diagnosed HIV infection, and self-rated health.

OBJECTIVES: An increasing proportion of people living with HIV are older adults, who may require specialized care. Adverse physical and psychological effects of HIV infection may be greatest among older people or those who have lived longer with HIV. METHODS: The ASTRA study is a cross-sectional questionnaire study of 3258 HIV-diagnosed adults (2248 men who have sex with men, 373 heterosexual men and 637 women) recruited from UK clinics in 2011-2012. Associations of age group with physical symptom distress (significant distress for at least one of 26 symptoms), depression and anxiety symptoms (scores ≥ 10 on PHQ-9 and GAD-7, respectively), and health-related functional problems (problems on at least one of three domains of the Euroqol 5D-3L)) were assessed, adjusting for time with diagnosed HIV infection, gender/sexual orientation and ethnicity. RESULTS: The age distribution of participants was: < 30 years, 5%; 30-39 years, 23%; 40-49 years, 43%; 50-59 years, 22%; and ≥ 60 years, 7%. Overall prevalences were: physical symptom distress, 56%; depression symptoms, 27%; anxiety symptoms, 22%; functional problems, 38%. No trend was found in the prevalence of physical symptom distress with age [adjusted odds ratio (OR) for trend across age groups, 0.96; 95% confidence interval (CI) 0.89, 1.04; P = 0.36]. The prevalence of depression and anxiety symptoms decreased with age [adjusted OR 0.86 (95% CI 0.79, 0.94; P = 0.001) and adjusted OR 0.85 (95% CI 0.77, 0.94; P = 0.001), respectively], while that of functional problems increased (adjusted OR 1.28; 95% CI 1.17, 1.39; P < 0.001). In contrast, a longer time with diagnosed HIV infection was strongly and independently associated with a higher prevalence of symptom distress, depression symptoms, anxiety symptoms, and functional problems (P < 0.001 for trends, adjusted analysis). CONCLUSIONS: Among people living with HIV, although health-related functional problems were more common with older age, physical symptom distress was not, and mental health was more favourable. These results suggest that a longer time with diagnosed HIV infection, rather than age, is the dominating factor contributing to psychological morbidity and lower quality of life

Effects of age on symptom burden, mental health and quality of life amongst people with HIV in the UK.

INTRODUCTION: The evolving HIV epidemic, coupled with advances in HIV treatment, has resulted in an ageing HIV-diagnosed population. It has been suggested that adverse physical and psychological effects of HIV may be higher among older people. However, few studies have examined the effect of older age on well-being for people with HIV. MATERIALS AND METHODS: The ASTRA study included 3258 HIV-diagnosed individuals (2248 MSM; 373 heterosexual men; 637 women) recruited from eight UK clinics in 2011-12 (64% response rate). Participants completed a questionnaire that included standard inventories on symptoms and health-related quality of life (HrQoL). Associations of age group with: physical symptom distress (reporting significant distress for ≥1 of 26 symptoms), depression and anxiety (score ≥10 on PHQ-9 and GAD-7, respectively) and HrQoL problem (reporting problems on ≥1 of 5 Eurqol-5D domains) were assessed; adjustment was made for gender/sexuality and time with diagnosed HIV. RESULTS: Of all participants, 87% were taking ART, 76% had VL ≤50c/mL and 19% had CD4 <350/mm(3). Mean age was 45 years (range 18-88) with 5% <30, 23% 30-39, 43% 40-49, 22% 50-59 and 7% ≥60 years. The most prevalent distressing physical symptoms were: lack of energy/tiredness (26%), difficulty sleeping (24%), muscle-ache/joint pain (21%) and pain (18%). With older age, there was no clear trend in prevalence of physical symptom distress, but prevalence of depression and anxiety decreased, while prevalence of HrQoL problems increased. This pattern remained after adjustment for gender/sexuality and time diagnosed with HIV. The increase with age in overall prevalence of HrQoL problem was due to increased problems for "mobility," "self-care" and "performing usual activities" domains, not an increase in "depression/anxiety." Longer time with diagnosed HIV was strongly associated with higher prevalence of all symptoms measures and HrQoL problem (p<0.001 for trend, adjusted models). CONCLUSIONS: Physical and psychological symptoms are common among people living with HIV, but the burden of these symptoms is not highest among the older age group. While HrQoL tended to worsen with older age, physical symptom distress did not, and mental health improved. This may reflect greater resilience in older adults, or the potential for "successful ageing": maintaining mental health despite age-related health losses

The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection—evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology

Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury

Cross-Sectional Analysis of Late HAART Initiation in Latin America and the Caribbean: Late Testers and Late Presenters

Background: Starting HAART in a very advanced stage of disease is assumed to be the most prevalent form of initiation in HIV-infected subjects in developing countries. Data from Latin America and the Caribbean is still lacking. Our main objective was to determine the frequency, risk factors and trends in time for being late HAART initiator (LHI) in this region. Methodology: Cross-sectional analysis from 9817 HIV-infected treatment-naive patients initiating HAART at 6 sites (Argentina, Chile, Haiti, Honduras, Peru and Mexico) from October 1999 to July 2010. LHI had CD4$^+$ count $\leq$200cells/mm$^3$ prior to HAART. Late testers (LT) were those LHI who initiated HAART within 6 months of HIV diagnosis. Late presenters (LP) initiated after 6 months of diagnosis. Prevalence, risk factors and trends over time were analyzed. Principal Findings: Among subjects starting HAART (n = 9817) who had baseline CD4$^+$ available (n = 8515), 76% were LHI: Argentina (56%[95%CI:52–59]), Chile (80%[95%CI:77–82]), Haiti (76%[95%CI:74–77]), Honduras (91%[95%CI:87–94]), Mexico (79%[95%CI:75–83]), Peru (86%[95%CI:84–88]). The proportion of LHI statistically changed over time (except in Honduras) ($p\leq0.02$; Honduras p = 0.7), with a tendency towards lower rates in recent years. Males had increased risk of LHI in Chile, Haiti, Peru, and in the combined site analyses (CSA). Older patients were more likely LHI in Argentina and Peru (OR 1.21 per +10-year of age, 95%CI:1.02–1.45; OR 1.20, 95%CI:1.02–1.43; respectively), but not in CSA (OR 1.07, 95%CI:0.94–1.21). Higher education was associated with decreased risk for LHI in Chile (OR 0.92 per +1-year of education, 95%CI:0.87–0.98) (similar trends in Mexico, Peru, and CSA). LHI with date of HIV-diagnosis available, 55% were LT and 45% LP. Conclusion: LHI was highly prevalent in CCASAnet sites, mostly due to LT; the main risk factors associated were being male and older age. Earlier HIV-diagnosis and earlier treatment initiation are needed to maximize benefits from HAART in the region

Effect of tamoxifen on hepatic regeneration in male rats

A number of metabolic changes within the liver occur concurrent with hepatic regeneration. These processes suggest that the administration of an antiestrogen might alter the rate of hepatic regeneration. To examine this question, male Wistar rats were treated with tamoxifen (0.1 mg/rat/day or 1.0 mg/rat/day) or vehicle for three days prior to and after partial hepatectomy, and the anatomic and biochemical process of hepatic regeneration was assessed. Tamoxifen administration caused a dose-dependent decrease in the hepatic cytosolic estrogen receptor activity and, conversely, a dose-dependent increase in cytosolic androgen receptor activity. Despite these changes in baseline hepatic sex steroid receptor status, all receptor activities were comparable between the three groups within 24 hr of partial hepatectomy. Moreover, no differences in any of the the parameters assessing hepatic regeneration following partial hepatectomy were evident: liver-body ratio, ornithine decarboxylase activity, and thymidine kinase activity. This lack of effect of tamoxifen treatment on hepatic regeneration suggests either that estrogens do not play a role in the modulation of liver growth after partial hepatectomy or that, once initiated, the regenerative process per se determines a series of events that regulate hepatocellular sex hormone receptor status independent of extrahepatic stimuli. © 1989 Plenum Publishing Corporation

Effect of partial portal vein ligation on hepatic regeneration

To evaluate the effect of portal hypertension and diminished portal venous blood flow to the liver on hepatic regeneration, male rats were subjected to partial portal vein ligation and subsequently to a two-thirds partial hepatectomy. The levels of ornithine decarboxylase activity at 6 h after partial hepatectomy were greater (p > 0.001) in the rats with prior partial portal vein ligation than in those without portal hypertension. The rats with prior partial portal vein ligation also had greater (p > 0.005) levels of thymidine kinase activity at 48 h after partial hepatectomy than did those without portal hypertension. Hepatic sex hormone receptor activity was not affected by prior partial portal vein ligation either before or after partial hepatectomy. The reductions in both estrogen and androgen receptor activity observed in the hepatic cytosol after partial hepatectomy were similar to those observed in control animals. These data indicate that animals with portal hypertension having a diminished hepatic portal blood flow have a normal capacity to regenerate hepatic mass following a hepatic resection © 1988 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted

Biological effects of cobalt-chromium nanoparticles and ions on dural fibroblasts and dural epithelial cells.

The introduction of metal-on-metal total disc replacements motivated studies to evaluate the effects of cobalt-chromium (CoCr) nanoparticles on cells of the dura mater. Porcine fibroblasts and epithelial cells isolated from the dura mater were cultured with clinically-relevant CoCr nanoparticles and the ions, generated by the particles over 24 h, at doses up to 121 μm(3)per cell. Cell viability and production of proinflammatory cytokines was assessed over 4 days. The capacity of the particles to induce oxidative stress in the cells was evaluated at 24 h. The CoCr particles and their ions significantly reduced the viability of the dural epithelial cells in a dose-dependent manner but not the fibroblasts. Both cell types secreted IL-8 in response to particle exposure at doses of 60.5 μm(3) (epithelial cells) and 121 μm(3) (fibroblasts, epithelial cells) per cell. No significant release of IL-6 was observed in both cell types at any dose. Reactive oxygen species were induced in both cell types at 50 μm(3) per cell after 24 h exposure. The data suggested novel differences in the resistance of the dural epithelial cells and fibroblasts to CoCr nanoparticle/ion toxicity and demonstrated the inflammatory potential of the particles. The data contributes to a greater understanding of the potential biological consequences of the use of metal-on-metal total disc prostheses