Law, Liberty and the Rule of Law (in a Constitutional Democracy)

In the hunt for a better--and more substantial--awareness of the “law,” The author intends to analyze the different notions related to the “rule of law” and to criticize the conceptions that equate it either to the sum of “law” and “rule” or to the formal assertion that “law rules,” regardless of its relationship to certain principles, including both “negative” and “positive” liberties. Instead, he pretends to scrutinize the principles of the “rule of law,” in general, and in a “constitutional democracy,” in particular, to conclude that the tendency to reduce the “democratic principle” to the “majority rule” (or “majority principle”), i.e. to whatever pleases the majority, as part of the “positive liberty,” is contrary both to the “negative liberty” and to the “rule of law” itself

Early Life Socioeconomic Circumstance and Late Life Brain Hyperintensities : A Population Based Cohort Study

Funding: Image acquisition and image analysis for this study was funded by the Alzheimer's Research Trust (now Alzheimer's Research UK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments The authors would like to thank the participants of the Aberdeen 1936 Birth Cohort (ABC36), without whom this research would not have been possible.Peer reviewedPublisher PD

A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis

<p>Abstract</p> <p>Background</p> <p>Long-term immunosuppression is often required in myasthenia gravis (MG). There are no published trials using methotrexate (MTX) in MG. The steroid-sparing efficacy of azathioprine (AZA) has been demonstrated after 18-months of starting therapy. However, AZA is considered expensive in Africa. We evaluated the steroid-sparing efficacy of MTX (17.5 mg weekly) compared with AZA (2.5 mg/kg daily) in subjects recently diagnosed with generalized MG by assessing their average monthly prednisone requirements.</p> <p>Methods</p> <p>The primary outcome was the average daily prednisone requirement by month between the two groups. Prednisone was given at the lowest dose to manage MG symptoms and adjusted as required according to protocol. Single-blinded assessments were performed 3-monthly for 2-years to determine the quantitative MG score and the MG activities of daily living score in order to determine those with minimal manifestations of MG.</p> <p>Results</p> <p>Thirty-one subjects (AZA n = 15; MTX n = 16) satisfied the inclusion criteria but only 24 were randomized. Baseline characteristics were similar. There was no difference between the AZA- and MTX-groups in respect of prednisone dosing (apart from months 10 and 12), in quantitative MG Score improvement, proportions in sustained remission, frequencies of MG relapses, or adverse reactions and/or withdrawals. The MTX-group received lower prednisone doses between month 10 (p = 0.047) and month 12 (p = 0.039). At month 12 the prednisone dose per kilogram bodyweight in the MTX-group (0.15 mg/kg) was half that of the AZA-group (0.31 mg/kg)(p = 0.019).</p> <p>Conclusions</p> <p>This study provides evidence that in patients with generalized MG methotrexate is an effective steroid-sparing agent 10 months after treatment initiation. Our data suggests that in generalized MG methotrexate has similar efficacy and tolerability to azathioprine and may be the drug of choice in financially constrained health systems.</p> <p>Trial registration</p> <p>SANCTR:DOH-27-0411-2436</p

Immune Evasion by Yersinia enterocolitica: Differential Targeting of Dendritic Cell Subpopulations In Vivo

CD4+ T cells are essential for the control of Yersinia enterocolitica (Ye) infection in mice. Ye can inhibit dendritic cell (DC) antigen uptake and degradation, maturation and subsequently T-cell activation in vitro. Here we investigated the effects of Ye infection on splenic DCs and T-cell proliferation in an experimental mouse infection model. We found that OVA-specific CD4+ T cells had a reduced potential to proliferate when stimulated with OVA after infection with Ye compared to control mice. Additionally, proliferation of OVA-specific CD4+ T cells was markedly reduced when cultured with splenic CD8α+ DCs from Ye infected mice in the presence of OVA. In contrast, T-cell proliferation was not impaired in cultures with CD4+ or CD4−CD8α− DCs isolated from Ye infected mice. However, OVA uptake and degradation as well as cytokine production were impaired in CD8α+ DCs, but not in CD4+ and CD4−CD8α− DCs after Ye infection. Pathogenicity factors (Yops) from Ye were most frequently injected into CD8α+ DCs, resulting in less MHC class II and CD86 expression than on non-injected CD8α+ DCs. Three days post infection with Ye the number of splenic CD8α+ and CD4+ DCs was reduced by 50% and 90%, respectively. The decreased number of DC subsets, which was dependent on TLR4 and TRIF signaling, was the result of a faster proliferation and suppressed de novo DC generation. Together, we show that Ye infection negatively regulates the stimulatory capacity of some but not all splenic DC subpopulations in vivo. This leads to differential antigen uptake and degradation, cytokine production, cell loss, and cell death rates in various DC subpopulations. The data suggest that these effects might be caused directly by injection of Yops into DCs and indirectly by affecting the homeostasis of CD4+ and CD8α+ DCs. These events may contribute to reduced T-cell proliferation and immune evasion of Ye

Potential role of p53 on metallothionein induction in human epithelial breast cancer cells

The expression and induction of metallothionein has been associated with protection against oxidative stress and apoptosis. This study examines the effect of tumour suppressor protein p53 on metallothionein expression following CdCl2 treatment in eight human epithelial breast cancer cell lines differing in p53 and oestrogen-receptor status. Cells were treated with 10 μM CdCl2 for 24 h and metallothionein protein levels were measured by cadmium binding assay. MCF7 cells which are p53-positive (p53+) and oestrogen-receptor-positive showed a large induction in metallothionein synthesis by 10.79±1.36-fold. Other breast cancer cell lines which are p53-negative (p53−) and oestrogen-receptor-negative or weakly oestrogen-receptor-positive showed a small induction ranging from 1.40±0.10 to 3.65±0.30-fold. RT–PCR analysis showed an induction of metallothionein mRNA in MCF7 cells by about 1.61±0.08-fold, while in HCC1806 cells (p53−, oestrogen-receptor-negative) by 1.11±0.13-fold, and in MDA-MB-231 (p53−, oestrogen-receptor-negative) by 1.25±0.06-fold. Metallothionein localisation was determined by immunohistochemical staining. Prior to metal treatment, metallothionein was localised mainly in the cytoplasm of MCF7 and MDA-MB-231 cells. After treatment with 10 μM CdCl2 for 24 h, MCF7 cells showed intense nuclear and cytoplasmic staining for metallothionein, while MDA-MB-231 cells showed staining in the cytoplasm with weak nuclear staining. Apoptosis induced by 10–40 μM CdCl2 at time points between 4 and 48 h was examined with TUNEL assay. In MCF7 cells, apoptosis increased with higher concentrations of CdCl2, it peaked at 6–8 h and appeared again at 48 h for all concentrations of CdCl2 tested. In MDA-MB-231 cells, apoptosis remained at low levels for 10–40 μM CdCl2 at all time points. Studies on cadmium uptake showed similar uptake and accumulation of cadmium at 8 and 24 h in all the cell lines. The data demonstrate that treatment of epithelial breast cancer cells with 10 μM CdCl2 for 24 h caused a greater induction of metallothionein protein and mRNA expression in p53+ and oestrogen-receptor-positive cells as compared to p53− and oestrogen-receptor-negative or weakly oestrogen-receptor-positive cells. This effect may be associated with the occurrence of apoptosis and suggests a role for p53 and oestrogen-receptor on the expression and induction of metallothionein in epithelial cells

Metformin as an Adjunctive Therapy for Pancreatic Cancer: A Review of the Literature on Its Potential Therapeutic Use

Pancreatic ductal adenocarcinoma has the worst prognosis of any cancer. New adjuvant chemotherapies are urgently required, which are well tolerated by patients with unresectable cancers. This paper reviews the existing proof of concept data, namely laboratory, pharmacoepidemiological, experimental medicine and clinical trial evidence for investigating metformin in patients with pancreatic ductal adenocarcinoma. Laboratory evidence shows metformin inhibits mitochondrial ATP synthesis which directly and indirectly inhibits carcinogenesis. Drug–drug interactions of metformin with proton pump inhibitors and histamine H2-receptor antagonists may be of clinical relevance and pertinent to future research of metformin in pancreatic ductal adenocarcinoma. To date, most cohort studies have demonstrated a positive association with metformin on survival in pancreatic ductal adenocarcinoma, although there are many methodological limitations with such study designs. From experimental medicine studies, there are sparse data in humans. The current trials of metformin have methodological limitations. Two small randomized controlled trials (RCTs) reported null findings, but there were potential inequalities in cancer staging between groups and poor compliance with the intervention. Proof of concept data, predominantly from laboratory work, supports assessing metformin as an adjunct for pancreatic ductal adenocarcinoma in RCTs. Ideally, more experimental medicine studies are needed for proof of concept. However, many feasibility criteria need to be answered before such trials can progress

Alcohol consumption and the risk of morbidity and mortality for different stroke types - a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Observational studies have suggested a complex relationship between alcohol consumption and stroke, dependent on sex, type of stroke and outcome (morbidity vs. mortality). We undertook a systematic review and a meta-analysis of studies assessing the association between levels of average alcohol consumption and relative risks of ischemic and hemorrhagic strokes separately by sex and outcome. This meta-analysis is the first to explicitly separate morbidity and mortality of alcohol-attributable stroke and thus has implications for public health and prevention.</p> <p>Methods</p> <p>Using Medical Subject Headings (alcohol drinking, ethanol, cerebrovascular accident, cerebrovascular disorders, and intracranial embolism and thrombosis and the key word stroke), a literature search of MEDLINE, EMBASE, CINAHL, CABS, WHOlist, SIGLE, ETOH, and Web of Science databases between 1980 to June 2009 was performed followed by manual searches of bibliographies of key retrieved articles. From twenty-six observational studies (cohort or case-control) with ischemic or hemorrhagic strokes the relative risk or odds ratios or hazard ratios of stroke associated with alcohol consumption were reported; alcohol consumption was quantified; and life time abstention (manually estimated where data for current abstainers were given) was used as the reference group. Two reviewers independently extracted the information on study design, participant characteristics, level of alcohol consumption, stroke outcome, control for potential confounding factors, risk estimates and key criteria of study quality using a standardized protocol.</p> <p>Results</p> <p>The dose-response relationship for hemorrhagic stroke had monotonically increasing risk for increasing consumption, whereas ischemic stroke showed a curvilinear relationship, with a protective effect of alcohol for low to moderate consumption, and increased risk for higher exposure. For more than 3 drinks on average/day, in general women had higher risks than men, and the risks for mortality were higher compared to the risks for morbidity.</p> <p>Conclusions</p> <p>These results indicate that heavy alcohol consumption increases the relative risk of any stroke while light or moderate alcohol consumption may be protective against ischemic stroke. Preventive measures that should be initiated are discussed.</p

Diabetes, periodontitis, and the subgingival microbiota

Both type 1 and type 2 diabetes have been associated with increased severity of periodontal disease for many years. More recently, the impact of periodontal disease on glycaemic control has been investigated. The role of the oral microbiota in this two-way relationship is at this stage unknown. Further studies, of a longitudinal nature and investigating a wider array of bacterial species, are required in order to conclusively determine if there is a difference in the oral microbiota of diabetics and non-diabetics and whether this difference accounts, on the one hand, for the increased severity of periodontal disease and on the other for the poorer glycaemic control seen in diabetics

(Putative) sex differences in neuroimmune modulation of memory

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134408/1/jnr23921.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134408/2/jnr23921_am.pd

The Tumor Microenvironment: The Making of a Paradigm

What has been will be again, what has been done will be done again; there is nothing new under the su