Early diagnosis of oesophageal cancer.

Squamous cell carcinoma and adenocarcinoma of the oesophagus are cancers that develop from distinct epithelial sub-types; however, they are both related to chronic inflammation of differing aetiologies. Inflammation leads to somatically inherited genetic mutations altering control of the cell cycle, DNA replication and apoptosis, which together result in autonomous and uncontrolled proliferation. These cancers have often metastasised to lymph nodes and distant organs before symptomatic presentation and therefore carry a poor prognosis. It is therefore vital to diagnose oesophageal cancer at an early stage, before the development of symptoms, when treatment can dramatically improve prognosis. Understanding the pathogenesis of these cancers is vital to guide early diagnostic strategies

Prolastin, a pharmaceutical preparation of purified human α1-antitrypsin, blocks endotoxin-mediated cytokine release

BACKGROUND: α1-antitrypsin (AAT) serves primarily as an inhibitor of the elastin degrading proteases, neutrophil elastase and proteinase 3. There is ample clinical evidence that inherited severe AAT deficiency predisposes to chronic obstructive pulmonary disease. Augmentation therapy for AAT deficiency has been available for many years, but to date no sufficient data exist to demonstrate its efficacy. There is increasing evidence that AAT is able to exert effects other than protease inhibition. We investigated whether Prolastin, a preparation of purified pooled human AAT used for augmentation therapy, exhibits anti-bacterial effects. METHODS: Human monocytes and neutrophils were isolated from buffy coats or whole peripheral blood by the Ficoll-Hypaque procedure. Cells were stimulated with lipopolysaccharide (LPS) or zymosan, either alone or in combination with Prolastin, native AAT or polymerised AAT for 18 h, and analysed to determine the release of TNFα, IL-1β and IL-8. At 2-week intervals, seven subjects were submitted to a nasal challenge with sterile saline, LPS (25 μg) and LPS-Prolastin combination. The concentration of IL-8 was analysed in nasal lavages performed before, and 2, 6 and 24 h after the challenge. RESULTS: In vitro, Prolastin showed a concentration-dependent (0.5 to 16 mg/ml) inhibition of endotoxin-stimulated TNFα and IL-1β release from monocytes and IL-8 release from neutrophils. At 8 and 16 mg/ml the inhibitory effects of Prolastin appeared to be maximal for neutrophil IL-8 release (5.3-fold, p < 0.001 compared to zymosan treated cells) and monocyte TNFα and IL-1β release (10.7- and 7.3-fold, p < 0.001, respectively, compared to LPS treated cells). Furthermore, Prolastin (2.5 mg per nostril) significantly inhibited nasal IL-8 release in response to pure LPS challenge. CONCLUSION: Our data demonstrate for the first time that Prolastin inhibits bacterial endotoxin-induced pro-inflammatory responses in vitro and in vivo, and provide scientific bases to explore new Prolastin-based therapies for individuals with inherited AAT deficiency, but also for other clinical conditions

Social Network Characteristics and Psychological Well-Being: A Replication and Extension

This article represents a replication and extension of a previous study by Israel and her colleagues that investigated the relationship between psychological well-being and social network characteristics. The present research included both a comparable sample of white women (N=104) between the ages of 60 and 68 (as in the original study), and a more extensive adult population of men and women (N=718) between the ages of 50 and 95. The network characteristics examined are categorized along three broad dimensions: Structure—linkages in the overall network (size and density); interaction-nature of the linkages themselves (frequency, geographic dispersion, and reciprocity); and functions that networks provide (affective support and instrumental support). The results indicate a predominance of comparable findings for both the replication and extension studies. Of the eight network characteristics examined, the results of five of the regression analyses were the same across all three studies. The network characteristics of size, density, geographic dispersion, reciprocal instrumental support, and instrumental support did not make a significant contribution to the variance in psychological well-being. Of the other three network characteristics, the effect of frequency of interaction varied across the studies, and a pattern of significant results was found for affective support and reciprocal affective support. A discussion of this evidence in light of current literature and implications for practice and research is included.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67842/2/10.1177_109019818701400406.pd

Dynamic clonal equilibrium and predetermined cancer risk in Barrett's oesophagus

abstract: Surveillance of Barrett’s oesophagus allows us to study the evolutionary dynamics of a human neoplasm over time. Here we use multicolour fluorescence in situ hybridization on brush cytology specimens, from two time points with a median interval of 37 months in 195 non-dysplastic Barrett's patients, and a third time point in a subset of 90 patients at a median interval of 36 months, to study clonal evolution at single-cell resolution. Baseline genetic diversity predicts progression and remains in a stable dynamic equilibrium over time. Clonal expansions are rare, being detected once every 36.8 patient years, and growing at an average rate of 1.58 cm[superscript 2] (95% CI: 0.09–4.06) per year, often involving the p16 locus. This suggests a lack of strong clonal selection in Barrett’s and that the malignant potential of ‘benign’ Barrett’s lesions is predetermined, with important implications for surveillance programs.The final version of this article, as published in Nature Communications, can be viewed online at: https://www.nature.com/articles/ncomms1215

EEG alterations during treatment with olanzapine

The aim of this naturalistic observational study was to investigate EEG alterations in patients under olanzapine treatment with a special regard to olanzapine dose and plasma concentration. Twenty-two in-patients of a psychiatric university ward with the monodiagnosis of paranoid schizophrenia (ICD-10: F20.0), who received a monotherapy of olanzapine were included in this study. All patients had a normal alpha-EEG before drug therapy, and did not suffer from brain-organic dysfunctions, as verified by clinical examination and cMRI scans. EEG and olanzapine plasma levels were determined under steady-state conditions (between 18 and 22 days after begin of treatment). In 9 patients (40.9%), pathological EEG changes (one with spike-waves) consecutive to olanzapine treatment were observed. The dose of olanzapine was significantly higher in patients with changes of the EEG than in patients without changes (24.4 mg/day (SD: 8.1) vs. 12.7 mg/day (SD: 4.8); T = −4.3, df = 21, P < 0.001). In patients with EEG changes, the blood plasma concentration of olanzapine (45.6 μg/l (SD: 30.9) vs. 26.3 μg/l (SD: 21.6) tended to be also higher. The sensitivity of olanzapine dosage to predict EEG changes was 66.7%, the specificity 100% (Youden-index: 0.67). EEG abnormalities during olanzapine treatment are common. These are significantly dose dependent. Thus, EEG control recordings should be mandatory during olanzapine treatment with special emphasis on dosages exceeding 20 mg per day, although keeping in mind that EEGs have only a limited predictive power regarding future epileptic seizures

Euphol, a tetracyclic triterpene, from Euphorbia tirucalli induces autophagy and sensitizes temozolomide cytotoxicity on glioblastoma cells

Glioblastoma (GBM) is the most frequent and aggressive type of brain tumor. There are limited therapeutic options for GBM so that new and effective agents are urgently needed. Euphol is a tetracyclic triterpene alcohol, and it is the main constituent of the sap of the medicinal plant Euphorbia tirucalli. We previously identified anti-cancer activity in euphol based on the cytotoxicity screening of 73 human cancer cells. We now expand the toxicological screening of the inhibitory effect and bioactivity of euphol using two additional glioma primary cultures. Euphol exposure showed similar cytotoxicity against primary glioma cultures compared to commercial glioma cells. Euphol has concentration-dependent cytotoxic effects on cancer cell lines, with more than a five-fold difference in the IC50 values in some cell lines. Euphol treatment had a higher selective cytotoxicity index (0.64-3.36) than temozolomide (0.11-1.13) and reduced both proliferation and cell motility. However, no effect was found on cell cycle distribution, invasion and colony formation. Importantly, the expression of the autophagy-associated protein LC3-II and acidic vesicular organelle formation were markedly increased, with Bafilomycin A1 potentiating cytotoxicity. Finally, euphol also exhibited antitumoral and antiangiogenic activity in vivo, using the chicken chorioallantoic membrane assay, with synergistic temozolomide interactions in most cell lines. In conclusion, euphol exerted in vitro and in vivo cytotoxicity against glioma cells, through several cancer pathways, including the activation of autophagy-associated cell death. These findings provide experimental support for further development of euphol as a novel therapeutic agent for GBM, either alone or in combination chemotherapy.The work was supported by the Amazonia Fitomedicamentos (FITO05/2012) Ltda. and Barretos Cancer Hospital, all from Brazil

'Public administration in an age of austerity' : Positive lessons from policy studies

Peer reviewedPostprin

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Determinants of participation in colonoscopic screening by siblings of colorectal cancer patients in France

International audienceBACKGROUND: Targeted colonosocopic screening is recommended for first-degree relatives of colorectal cancer patients diagnosed before the age of 60 and offers the possibility of reducing morbidity and mortality, but participation remains too low. The objective of this study was to determine in a French population the factors that affect siblings' participation in screening, notably those relating to the individuals, their medical care, their family and their social network. METHODS: A cross sectional survey was conducted in siblings of index patients having undergone surgery for colorectal cancer between 1999 and 2002 in two French counties. Siblings were contacted during 2007 and 2008 through the index patient. The factors affecting participation in colonoscopic screening were studied by logistic regression taking into account family cluster effect. RESULTS: 172 siblings of 74 index cases were included. The declared rate of undergoing at least one colonoscopy among siblings was 66%; 95%CI 59-73%. Five variables were independently associated with colonoscopic screening: perceiving fewer barriers to screening (OR = 3.2; 95%CI 1.2-8.5), having received the recommendation to undergo screening from a physician (OR = 4.9; 1.7-13.7), perceiving centres practising colonoscopy as more accessible (OR = 3.2, 1.3-7.8), having discussed screening with all siblings (OR = 3.9; 1.6-9.6) and being a member of an association (OR = 2.6; 1.0-6.6). CONCLUSIONS: The factors independently associated with participation in CRC screening by an individual at increased risk belonged to each of four dimensions relating to his individual psychosocial characteristics, to his relationship with a physician, within the family and social environment. The relevance of these results to clinical practice may help to improve compliance to recommendations in a global preventive strategy including all stages of the information pathway from the physician to the index patient and his relatives

The modulation of adult neuroplasticity is involved in the mood-improving actions of atypical antipsychotics in an animal model of depression

Depression is a prevalent psychiatric disorder with an increasing impact in global public health. However, a large proportion of patients treated with currently available antidepressant drugs fail to achieve remission. Recently, antipsychotic drugs have received approval for the treatment of antidepressant-resistant forms of major depression. The modulation of adult neuroplasticity, namely hippocampal neurogenesis and neuronal remodeling, has been considered to have a key role in the therapeutic effects of antidepressants. However, the impact of antipsychotic drugs on these neuroplastic mechanisms remains largely unexplored. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 3 weeks of stress exposure, animals were treated with two different antipsychotics: haloperidol (a classical antipsychotic) and clozapine (an atypical antipsychotic). We demonstrated that clozapine improved both measures of depressive-like behavior (behavior despair and anhedonia), whereas haloperidol aggravated learned helplessness in the forced-swimming test and behavior flexibility in a cognitive task. Importantly, an upregulation of adult neurogenesis and neuronal survival was observed in animals treated with clozapine, whereas haloperidol promoted a downregulation of these processes. Furthermore, clozapine was able to re-establish the stress-induced impairments in neuronal structure and gene expression in the hippocampus and prefrontal cortex. These results demonstrate the modulation of adult neuroplasticity by antipsychotics in an animal model of depression, revealing that the atypical antipsychotic drug clozapine reverts the behavioral effects of chronic stress by improving adult neurogenesis, cell survival and neuronal reorganization.This work was co-funded by the Life and Health Sciences Research Institute (ICVS), and Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (Projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023). This work has been also funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE) and by National funds, through the FCT, under the scope of the project POCI-01-0145-FEDER-007038. We thank Luís Martins and Ana Lima for the technical assistanceinfo:eu-repo/semantics/publishedVersio