Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement

Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinsons disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1(-/-))] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra(-/-))] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra(-/-) mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1(-/-) mice. Casp1(-/-) mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra(-/-) mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1(-/-) mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice.Funding Agencies|John Curtin School of Medical Research, The Australian National University</p

Attenuated Inflammatory Response in Aged Mice Brains following Stroke

Background: Increased age is a major risk factor for stroke incidence, post-ischemic mortality, and severe and long-term disability. Stroke outcome is considerably influenced by post-ischemic mechanisms. We hypothesized that the inflammatory response following an ischemic injury is altered in aged organisms. Methods and Results: To that end, we analyzed the expression pattern of pro-inflammatory cytokines (TNF, IL-1a, IL-1b, IL-6), anti-inflammatory cytokines (IL-10, TGFb1), and chemokines (Mip-1a, MCP-1, RANTES) of adult (2 months) and aged (24 months) mice brains at different reperfusion times (6 h, 12 h, 24 h, 2 d, 7 d) following transient occlusion of the middle cerebral artery. The infarct size was assessed to monitor possible consequences of an altered inflammatory response in aged mice. Our data revealed an increased neuro-inflammation with age. Above all, we found profound age-related alterations in the reaction to stroke. The response of pro-inflammatory cytokines (TNF, and IL-1b) and the level of chemokines (Mip-1a, and MCP-1) were strongly diminished in the aged post-ischemic brain tissue. IL-6 showed the strongest age-dependent decrease in its post-ischemic expression profile. Anti-inflammatory cytokines (TGFb1, and IL-10) revealed no significant age dependency after ischemia. Aged mice brains tend to develop smaller infarcts. Conclusion: The attenuated inflammatory response to stroke in aged animals may contribute to their smaller infarcts. The results presented here highlight the importance of using aged animals to investigate age-associated diseases like stroke

End of life care in sub-Saharan Africa: a systematic review of the qualitative literature

<p>Abstract</p> <p>Background</p> <p>End of life (EoL) care in sub-Saharan Africa still lacks the sound evidence-base needed for the development of effective, appropriate service provision. It is essential to make evidence from all types of research available alongside clinical and health service data, to ensure that EoL care is ethical and culturally appropriate. This article aims to synthesize qualitative research on EoL care in sub-Saharan Africa to inform policy, practice and further research. It seeks to identify areas of existing research; describe findings specifically relevant to the African context; and, identify areas lacking evidence.</p> <p>Methods</p> <p>Relevant literature was identified through eight electronic databases: AMED, British Nursing Index & Archive, CINAHL, EMBASE, IBSS, MEDLINE, PsycINFO, and the Social Sciences Citation Index; and hand searches. Inclusion criteria were: published qualitative or mixed-method studies in sub-Saharan Africa, about EoL care. Study quality was assessed using a standard grading scale. Relevant data including findings and practice recommendations were extracted and compared in tabular format.</p> <p>Results</p> <p>Of the 407 articles initially identified, 51 were included in the qualitative synthesis. Nineteen came from South Africa and the majority (38) focused on HIV/AIDS. Nine dealt with multiple or unspecified conditions and four were about cancer. Study respondents included health professionals, informal carers, patients, community members and bereaved relatives. Informal carers were typically women, the elderly and children, providing total care in the home, and lacking support from professionals or the extended family. Twenty studies focused on home-based care, describing how programmes function in practice and what is needed to make them effective. Patients and carers were reported to prefer institutional care but this needs to be understood in context. Studies focusing on culture discussed good and bad death, culture-specific approaches to symptoms and illness, and the bereavement process.</p> <p>Conclusions</p> <p>The data support or complement the findings from quantitative research. The review prompts a reconsideration of the assumption that in Africa the extended family care for the sick, and that people prefer home-based care. The review identifies areas relevant for a research agenda on socio-cultural issues at the EoL in sub-Saharan Africa.</p

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9–10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13–15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Mesalazine pharmacokinetics and NAT2 phenotype

BACKGROUND: Mesalazine undergoes extensive metabolism by N-acetylation. While there is some evidence for an involvement of N-acetyltransferase (NAT) type 1, a potential role of NAT type 2 (NAT2) in vivo has not been tested. METHODS: In two studies in healthy young Caucasians, NAT2 phenotyping was carried out using a caffeine metabolic ratio in urine 4-6 h postdose. In study A, 1,000 mg mesalazine doses were given thrice daily for 5 days, and urine and blood samples were drawn during the last dosing interval. In study B, a 1,000 mg single dose was given, and samples were taken for 48 h postdose. Pharmacokinetics of mesalazine and N-acetylmesalazine (LC-MS/MS) were calculated by noncompartmental methods. RESULTS: NAT2 phenotype could be allocated unequivocally in 21 slow and 5 rapid acetylators in study A, and in 9 slow and 8 rapid acetylators in study B. Geometric mean (CV%) values in study A for slow [rapid] acetylators were as follows: mesalazine AUC 11.1 microg/mL.h (51%) [12.0 microg/mL.h (52%)], N-acetylmesalazine AUC 27.7 microg/mL.h (32%) [30.5 microg/mL.h (27%)], mesalazine Ae 8.53% (89%) [9.03% (52%)], N-acetylmesalazine Ae 31.4% (46%) [32.2 (41%)]. Values in study B were as follows: mesalazine AUC 3.45 microg/mL.h (113%) [2.36 microg/mL.h (87%)], N-acetylmesalazine AUC 21.3 microg/mL.h (29%) [18.0 microg/mL.h (39%)], mesalazine Ae 0.2% (256%) [0.1% (359%)], N-acetylmesalazine Ae 30.9% (44%) [18.1% (84%)]. Higher AUC and Ae values for mesalazine in steady state study indicate saturation of mesalazine metabolism. Statistics provided no evidence for a true difference in mesalazine pharmacokinetics between slow and rapid acetylators, and no significant correlation between NAT2 activity and any mesalazine pharmacokinetic parameter was found. CONCLUSION: NAT2 has no major role in human metabolism of mesalazine in vivo

Therapeutic targeting of C-terminal binding protein in human cancer

The CtBP transcriptional corepressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is antagonized by p14/p19ARF tumor suppressors. The CtBP dehydrogenase substrate 4-methylthio-2-oxobutyric acid (MTOB) can act as a CtBP inhibitor at high concentrations, and is cytotoxic to cancer cells. MTOB induced apoptosis was p53-independent, correlated with the derepression of the proapoptotic CtBP repression target Bik, and was rescued by CtBP overexpression or Bik silencing. MTOB did not induce apoptosis in mouse embryonic fibroblasts (MEFs), but was increasingly cytotoxic to immortalized and transformed MEFs, suggesting that CtBP inhibition may provide a suitable therapeutic index for cancer therapy. In human colon cancer cell peritoneal xenografts, MTOB treatment decreased tumor burden and induced tumor cell apoptosis. To verify the potential utility of CtBP as a therapeutic target in human cancer, the expression of CtBP and its negative regulator ARF was studied in a series of resected human colon adenocarcinomas. CtBP and ARF levels were inversely-correlated, with elevated CtBP levels (compared with adjacent normal tissue) observed in greater than 60% of specimens, with ARF absent in nearly all specimens exhibiting elevated CtBP levels. Targeting CtBP may represent a useful therapeutic strategy in human malignancies