AP-1 Expression and its Clinical Relevance in Immune Disorders and Cancer

The inflammatory response is known to have a significant role in certain autoimmune diseases and malignancies. We review current knowledge regarding the functions of activator protein 1 (AP-1) as an important modulator in several immune disorders and carcinomas. AP-1 is overexpressed in rheumatoid arthritis and in long-term allogeneic hematopoietic stem cell transplantation survivors; however, decreased expression of AP-1 has been observed in psoriasis, systematic lupus erythematosus and in patients who do not survive after hematopoietic stem cell transplantation. AP-1 also is implicated in the control of various cancer cells. Higher levels of AP-1 components are present in breast and endometrial carcinomas, colorectal cancer and in acute myeloid leukemia, Hodgkin?s lymphoma and anaplastic large cell lymphoma, with downregulation in ovarian and gastric carcinomas and in patients with chronic myelogenous leukemia. AP-1 may enable the development of helpful markers to identify early-stage disease or to predict severity.     

Suicide risk among recently released prisoners in New South Wales, Australia

OBJECTIVE: To determine the risk of suicide and drug overdose death among recently released prisoners. DESIGN, SETTING AND PARTICIPANTS: Retrospective cohort study of 85 203 adult offenders who had spent some time in full-time custody in prisons in New South Wales between 1 January 1988 and 31 December 2002. MAIN OUTCOME MEASURES: Association between time after release and risk of suicide and overdose death. RESULTS: Of 844 suicides (795 men, 49 women), 724 (86%) occurred after release. Men had a higher rate of suicide than women both in prison (129 v 56 per 100,000 person-years) and after release (135 v 82 per 100,000 person-years). The suicide rate in men in the 2 weeks after release was 3.87 (95% CI, 2.26-6.65) times higher than the rate after 6 months. Male prisoners admitted to the prison psychiatric hospital had a threefold higher risk than non-admitted men both in prison and after release. No suicides among women were observed in the 2 weeks after release. No increased risk of suicide was observed among Aboriginal Australians in the first 2 weeks after release. Of 1674 deaths due to overdose, 1627 (97%) occurred after release. Drug-related mortality in men was 9.30 (95% CI, 7.80-11.10) times higher, and in women was 6.42 (95% CI, 3.88-10.62) times higher, in the 2 weeks after release than after 6 months. CONCLUSIONS: Prisoners are at a heightened risk of suicide and overdose death in the immediate post-release period. After 6 months post-release, the suicide rate approaches the rate observed in custody.     

Ex vivo antioxidant preconditioning improves the survival rate of bone marrow stem cells in the presence of wound fluid

The advancement of autologous mesenchymal stem cell (MSC) therapy for the treatment of non‐healing diabetic wounds is hampered by endogenous MSC dysfunction and limited viability of cells post‐transplantation into the pathological wound environment. The development of effective strategies to restore the functional capabilities of these impaired MSCs prior to transplantation may be a key to their ultimate success as wound repair mediators. The current study therefore investigated whether antioxidant preconditioning [7.5 mM N‐acetylcysteine (NAC) + 0.6 mM ascorbic 2‐phosphate (AAP)] could restore the growth rate, migration ability and viability of impaired MSCs and whether this restored state is maintained in the presence of diabetic wound fluid (DWF). Healthy control (source: wild type, C57BL/6J mice) (n = 12) and impaired/diabetic MSCs (source: obese prediabetic, B6.Cg‐Lepob/J mice) (n = 12) were isolated from the bone marrow of mice. Treatment groups post‐isolation were as follow: (a) No treatment (baseline phenotype): MSCs expanded in standard growth media (SGM) (±8 days) and only exposed to growth media. (b) DWF (baseline response): MSCs expanded in SGM (±8 days) followed by exposure to DWF (24 hours, 48 hours, 96 hours). (c) Antioxidant preconditioning (preconditioned phenotype): MSCs expanded in the presence of NAC/AAP (±8 days). (d) Antioxidant preconditioning + DWF (preconditioned response): MSCs expanded in the presence of NAC/AAP (±8 days) followed by exposure to DWF (24 hours, 48 hours, 96 hours). The results demonstrated that expansion of MSCs (both healthy control and impaired diabetic) in the presence of combined NAC/AAP treatment improved ex vivo MSC viability and protected MSCs in the presence of DWF. Despite improved viability, AAP/NAC could however not rescue the reduced proliferation and migration capacity of impaired diabetic MSCs. The protective effect of NAC/AAP preconditioning against the toxicity of DWF could however be a potential strategy to improve cell number post‐transplantation.     

The Spectrum of Renal Involvement in Patients With Inflammatory Myopathies

Data regarding the incidence and outcome of renal involvement in patients with inflammatory myopathies (IM) remain scarce. We assessed the incidence and causes of acute kidney injury (AKI) and chronic kidney disease (CKD) in 150 patients with dermatomyositis, polymyositis, and antisynthetase syndrome followed in 3 French referral centers. Renal involvement occurred in 35 (23.3%) patients: AKI in 16 (10.7%), and CKD in 31 (20.7%) patients. The main cause of AKI was drug or myoglobinuria-induced acute tubular necrosis. Male sex, cardiovascular risk factors, cardiac involvement, and initial proteinuria >0.3 g/d were associated with the occurrence of AKI. The outcome of patients with AKI was poor: 13 (81%) progressed to CKD and 2 (12.5%) reached end-stage renal disease. In multivariate survival analysis, age at IM onset, male sex, a history of cardiovascular events, and a previous episode of AKI were associated with the risk of CKD. We also identified 14 IM patients who underwent a kidney biopsy in 10 nephrology centers. Renal pathology disclosed a wide range of renal disorders, mainly immune-complex glomerulonephritis. We identified in 5 patients a peculiar pattern of severe acute renal vascular damage consisting mainly of edematous thickening of the intima of arterioles.We found that AKI and CKD are frequent in patients with IM. Prevention of AKI is crucial in these patients, as AKI is a major contributor to their relatively high risk of CKD. A peculiar pattern of acute vascular damage is part of the spectrum of renal diseases associated with IM.