The Breton case for regional autonomy: Centuries of struggle in Brittany, France

My first encounter with Brittany, France, came in 1973 when I was bicycling through the Breton countryside with a group of Concordia College students. I befriended a Breton activist named Sylvain Phlipponneau, then twenty-one years of age, who made what I found to be an intriguing parallel between the plight of the American Indian and that of the outlying regions of France. He criticized the French government as over-bearing, excessively centralized, and with what he called a reckless disregard for the cultural integrity of the provinces. I was then seventeen, anxious to experience some of the residual youthful activism of the previous decade. I attended a few of the meetings of the Front de la Liberation de la Bretagne, (FLB), at the time the most radical of French autonomist groups. Often speakers at FLB meeting would break into Breton phrases, however, so as to keep French gems d\u27arnes uninformed of their activities. Unfamiliar with this dialect, I ws not as aware as I might otherwise have been as to the operations of the FLB during its heyday..

The Effect of Olanzapine on Craving and Alcohol Consumption

Previous studies have indicated that olanzapine decreases craving after a priming dose of alcohol, that craving after a priming dose of alcohol is greater among individuals with the seven-repeat allele of the DRD4 variable number of tandem repeats (VNTR) polymorphism, and that the effect of olanzapine (a D2/D4 antagonist) is more pronounced among individuals with this allele. The present study tested the hypothesis that olanzapine may be differentially effective at reducing cue-elicited craving and differentially effective as a treatment for alcohol dependence over the course of a 12-week, randomized, placebo-controlled trial among individuals with and without the seven-repeat allele. Participants who met DSM IV criteria for alcohol dependence were randomly assigned to receive olanzapine (5 mg) or a placebo over the course of the trial. After 2 weeks of treatment, participants completed a cue reactivity assessment. The results suggested that participants who were homozygous or heterozygous for the seven (or longer)-repeat allele of the DRD4 VNTR responded to olanzapine with reductions in cue-elicited craving as well as reductions in alcohol consumption over the course of the 12-week trial, whereas individuals with the shorter alleles did not respond favorably to olanzapine

Health System Innovations: Adapting to Rapid Change

This paper introduces the Thematic Issue on Innovation in Health Systems in Low- and Middle-Income Countries

Quantitative Proteomics of Hepatic Drug-Metabolizing Enzymes and Transporters in Patients With Colorectal Cancer Metastasis

The impact of liver cancer metastasis on protein abundance of 22 drug-metabolizing enzymes (DMEs) and 25 transporters was investigated using liquid chromatography-tandem accurate mass spectrometry targeted proteomics. Microsomes were prepared from liver tissue taken from 15 healthy individuals and 18 patients with cancer (2 primary and 16 metastatic). Patient samples included tumors and matching histologically normal tissue. The levels of cytochrome P450 (CYPs 2B6, 2D6, 2E1, 3A4, and 3A5) and uridine 5′-diphospho-glucuronosyltransferases (UGTs 1A1, 1A6, 1A9, 2B15, 2B4, and 2B7) were lower in histologically normal tissue from patients relative to healthy controls (up to 6.6-fold) and decreased further in tumors (up to 21-fold for CYPs and 58-fold for UGTs). BSEP and MRPs were also suppressed in histologically normal (up to 3.1-fold) and tumorous tissue (up to 6.3-fold) relative to healthy individuals. Abundance of OCT3, OAT2, OAT7, and OATPs followed similar trends (up to 2.9-fold lower in histologically normal tissue and up to 16-fold lower in tumors). Abundance of NTCP and OCT1 was also lower (up to 9-fold). Interestingly, monocarboxylate transporter MCT1 was more abundant (3.3-fold) in tumors, the only protein target to show this pattern. These perturbations could be attributed to inflammation. Interindividual variability was substantially higher in patients with cancer. Proteomics-informed physiologically-based pharmacokinetic (PBPK) models of 50 drugs with different attributes and hepatic extraction ratios (Simcyp) showed substantially lower drug clearance with cancer-specific parameters compared with default parameters. In conclusion, this study provides values for decreased abundance of DMEs and transporters in liver cancer, which enables using population-specific abundance for these patients in PBPK modeling

Proteomics of Colorectal Cancer Liver Metastasis: a Quantitative Focus on Drug Elimination and Pharmacodynamics Effects

AIMS: This study aims to quantify drug‐metabolising enzymes, transporters, receptor tyrosine kinases (RTKs) and protein markers (involved in pathways affected in cancer) in pooled healthy, histologically normal and matched cancerous liver microsomes from colorectal cancer liver metastasis (CRLM) patients. METHODS: Microsomal fractionation was performed and pooled microsomes were prepared. Global and accurate mass and retention time liquid chromatography–mass spectrometry proteomics were used to quantify proteins. A QconCAT (KinCAT) for the quantification of RTKs was designed and applied for the first time. Physiologically based pharmacokinetic (PBPK) simulations were performed to assess the contribution of altered abundance of drug‐metabolising enzymes and transporters to changes in pharmacokinetics. RESULTS: Most CYPs and UGTs were downregulated in histologically normal relative to healthy samples, and were further reduced in cancer samples (up to 54‐fold). The transporters, MRP2/3, OAT2/7 and OATP2B1/1B3/1B1 were downregulated in CRLM. Application of abundance data in PBPK models for substrates with different attributes indicated substantially lower (up to 13‐fold) drug clearance when using cancer‐specific instead of default parameters in cancer population. Liver function markers were downregulated, while inflammation proteins were upregulated (by up to 76‐fold) in cancer samples. Various pharmacodynamics markers (e.g. RTKs) were altered in CRLM. Using global proteomics, we examined proteins in pathways relevant to cancer (such as metastasis and desmoplasia), including caveolins and collagen chains, and confirmed general over‐expression of such pathways. CONCLUSION: This study highlights impaired drug metabolism, perturbed drug transport and altered abundance of cancer markers in CRLM, demonstrating the importance of population‐specific abundance data in PBPK models for cancer

Oxidised- and total non-protein bound glutathione and related thiols in gallbladder bile of patients with various gastrointestinal disorders

BACKGROUND: Glutathione is a tripeptide composed of glutamate, cysteine and glycine, accomplishing a broad range of vital functions. Synthesis of glutathione and cysteine is performed mainly in the liver, whereas most other tissues are supplied with these thiols via sinusoidal efflux into the blood. Since canalicular efflux also occurs, thiols may be present in human bile. However, thiol composition of human gallbladder bile is largely unknown, which makes it difficult to speculate on the exact function of thiols in bile. In this study we report on the levels of non-protein bound thiols in gallbladder bile of patients with various gastrointestinal disorders. METHODS: Gallbladder bile was obtained after cholecystectomy from 30 patients who were operated for pancreatic cancer, duodenal cancer, chronic pancreatitis or cholecystolithiasis. Bile was analysed for non-protein bound total- and oxidised glutathione and related thiols, by high performance liquid chromatography. RESULTS: A more than 100-fold inter-individual variation in non-protein bound thiol levels was found in human gallbladder bile of patients with a variety of gastrointestinal disorders. Bile did contain high amounts of cysteine, whereas much lower levels of glutathione, cysteinylglycine and homocysteine were detected. Most thiols were present in their oxidised forms. CONCLUSION: Thiols are present in considerable amounts in human gallbladder bile of patients with various gastrointestinal disorders, levels of cysteine being much higher than those of glutathione and other thiols. Most thiols were in their oxidised forms, which may indicate the presence of considerable chemical- or oxidative stress in the patients studied here

Proteomics of colorectal cancer liver metastasis: A quantitative focus on drug elimination and pharmacodynamics effects

From Wiley via Jisc Publications RouterHistory: received 2021-07-22, rev-recd 2021-09-14, accepted 2021-09-16, pub-electronic 2021-12-03Article version: VoRPublication status: PublishedFunder: Merck KGaA; Id: http://dx.doi.org/10.13039/100009945Aims: This study aims to quantify drug‐metabolising enzymes, transporters, receptor tyrosine kinases (RTKs) and protein markers (involved in pathways affected in cancer) in pooled healthy, histologically normal and matched cancerous liver microsomes from colorectal cancer liver metastasis (CRLM) patients. Methods: Microsomal fractionation was performed and pooled microsomes were prepared. Global and accurate mass and retention time liquid chromatography–mass spectrometry proteomics were used to quantify proteins. A QconCAT (KinCAT) for the quantification of RTKs was designed and applied for the first time. Physiologically based pharmacokinetic (PBPK) simulations were performed to assess the contribution of altered abundance of drug‐metabolising enzymes and transporters to changes in pharmacokinetics. Results: Most CYPs and UGTs were downregulated in histologically normal relative to healthy samples, and were further reduced in cancer samples (up to 54‐fold). The transporters, MRP2/3, OAT2/7 and OATP2B1/1B3/1B1 were downregulated in CRLM. Application of abundance data in PBPK models for substrates with different attributes indicated substantially lower (up to 13‐fold) drug clearance when using cancer‐specific instead of default parameters in cancer population. Liver function markers were downregulated, while inflammation proteins were upregulated (by up to 76‐fold) in cancer samples. Various pharmacodynamics markers (e.g. RTKs) were altered in CRLM. Using global proteomics, we examined proteins in pathways relevant to cancer (such as metastasis and desmoplasia), including caveolins and collagen chains, and confirmed general over‐expression of such pathways. Conclusion: This study highlights impaired drug metabolism, perturbed drug transport and altered abundance of cancer markers in CRLM, demonstrating the importance of population‐specific abundance data in PBPK models for cancer

Sustainable drainage systems: Helping people live with water

Sustainable drainage systems or ‘Suds’ are increasingly accepted as an effective means of ‘making space for water’, adapting to possible climate change and helping communities become more flood and drought resilient. This study explores potential shifts in perception and attitude through Suds installation, development and habituation. Attitudes and awareness in communities in the USA and UK, where Suds have been in place for some time, were compared and contrasted, examining any evolution of beliefs and practices and wider community resilience. The principal finding was that there existed a lack of understanding about the existence and function of Suds. The paper concludes that consultation regarding solutions during Suds planning and installation, and ongoing dialogue afterwards, could usefully be explored as a means to improve local awareness of and satisfaction with Suds and promote greater understanding of their function. This may in turn encourage behaviour change to improve longer-term functionality of Suds and increase community resilience to flooding and drought

A TALEN Genome-Editing System for Generating Human Stem Cell-Based Disease Models

SummaryTranscription activator-like effector nucleases (TALENs) are a new class of engineered nucleases that are easier to design to cleave at desired sites in a genome than previous types of nucleases. We report here the use of TALENs to rapidly and efficiently generate mutant alleles of 15 genes in cultured somatic cells or human pluripotent stem cells, the latter for which we differentiated both the targeted lines and isogenic control lines into various metabolic cell types. We demonstrate cell-autonomous phenotypes directly linked to disease—dyslipidemia, insulin resistance, hypoglycemia, lipodystrophy, motor-neuron death, and hepatitis C infection. We found little evidence of TALEN off-target effects, but each clonal line nevertheless harbors a significant number of unique mutations. Given the speed and ease with which we were able to derive and characterize these cell lines, we anticipate TALEN-mediated genome editing of human cells becoming a mainstay for the investigation of human biology and disease