Genetic background of cholesterol gallstone disease

AbstractCholesterol gallstone formation is a multifactorial process involving a multitude of metabolic pathways. The primary pathogenic factor is hypersecretion of free cholesterol into bile. For people living in the Western Hemisphere, this is almost a normal condition, certainly in the elderly, which explains the very high incidence of gallstone disease. It is probably because the multifactorial background genes responsible for the high incidence have not yet been identified, despite the fact that genetic factors clearly play a role. Analysis of the many pathways involved in biliary cholesterol secretion reveals many potential candidates and considering the progress in unraveling the regulatory mechanisms of the responsible genes, identification of the primary gallstone genes will be successful in the near future

First steps towards deriving rock magnetic and paleomagnetic data from subsets of magnetic grains in lavas using Micromagnetic Tomography

Our understanding of the behavior of the geomagnetic field arises from magnetic signals stored in geological materials, e.g. lavas. Almost all experiments to determine the past state of the Earth's magnetic field use bulk samples (typically 1 - 10 cc) and measure their magnetic moment after series of laboratory treatments. Lavas, however, consist of mixtures of different iron-oxide grains that vary in size, shape, and chemistry. Some of these grains are good recorders of the Earth's magnetic field; others are not. Only a small amount of adverse behaved magnetic grains in a sample already hampers all classical experiments to obtain paleointensities; success rates as low as 10-20% are common, i.e. for 80-90% of all lavas vital information on paleointensities is lost before it can be uncovered.Recently, we showed that it is possible to determine the magnetization of individual grains inside a synthetic sample using a new technique: Micromagnetic Tomography. The individual magnetizations of grains are determined by inverting scanning magnetometry data from the surface on the sample onto the known locations, sizes and shapes of the magnetic grains that are obtained from a microCT scan of the sample. The synthetic sample used for our proof-of-concept, however, was optimized for success: the dispersion of magnetic markers was low, and the magnetite grains had a well-defined grain size range. Furthermore, the scanning SQUID microscope used requires the sample to be at 4 K, below the Verweij transition of the magnetite grains.Here we present the first Micromagnetic Tomography results from natural samples. We used two magnetic scanning techniques that operate at room temperature, a Magnetic Tunneling Junction set-up and a Quantum Diamond Magnetometer, to acquire the magnetic surface scans from a Hawaiian lava and calculated magnetic moments of individual grains present. We show that it is possible to acquire rock magnetic information as function of grain size from these natural samples and reveal the first results of interpreting a paleomagnetic direction from selected subsets of grains in our samples. These are the first steps towards deriving rock magnetic and paleomagnetic information from subsets of known good recorders inside lava samples, a technique that will re

A mouse model of sitosterolemia: absence of Abcg8/sterolin-2 results in failure to secrete biliary cholesterol

BACKGROUND: Mutations in either of two genes comprising the STSL locus, ATP-binding cassette (ABC)-transporters ABCG5 (encoding sterolin-1) and ABCG8 (encoding sterolin-2), result in sitosterolemia, a rare autosomal recessive disorder of sterol trafficking characterized by increased plasma plant sterol levels. Based upon the genetics of sitosterolemia, ABCG5/sterolin-1 and ABCG8/sterolin-2 are hypothesized to function as obligate heterodimers. No phenotypic difference has yet been described in humans with complete defects in either ABCG5 or ABCG8. These proteins, based upon the defects in humans, are responsible for regulating dietary sterol entry and biliary sterol secretion. METHODS: In order to mimic the human disease, we created, by a targeted disruption, a mouse model of sitosterolemia resulting in Abcg8/sterolin-2 deficiency alone. Homozygous knockout mice are viable and exhibit sitosterolemia. RESULTS: Mice deficient in Abcg8 have significantly increased plasma and tissue plant sterol levels (sitosterol and campesterol) consistent with sitosterolemia. Interestingly, Abcg5/sterolin-1 was expressed in both liver and intestine in Abcg8/sterolin-2 deficient mice and continued to show an apical expression. Remarkably, Abcg8 deficient mice had an impaired ability to secrete cholesterol into bile, but still maintained the ability to secrete sitosterol. We also report an intermediate phenotype in the heterozygous Abcg8+/- mice that are not sitosterolemic, but have a decreased level of biliary sterol secretion relative to wild-type mice. CONCLUSION: These data indicate that Abcg8/sterolin-2 is necessary for biliary sterol secretion and that loss of Abcg8/sterolin-2 has a more profound effect upon biliary cholesterol secretion than sitosterol. Since biliary sitosterol secretion is preserved, although not elevated in the sitosterolemic mice, this observation suggests that mechanisms other than by Abcg8/sterolin-2 may be responsible for its secretion into bile

Micromagnetic Tomography for paleomagnetism and rock-magnetism

Our understanding of the past behavior of the geomagnetic field arises from magnetic signals stored in geological materials, e.g. (volcanic) rocks. Bulk rock samples, however, often contain magnetic grains that differ in chemistry, size and shape; some of them record the Earth’s magnetic field well, others are unreliable. The presence of a small amount of adverse behaved magnetic grains in a sample may already obscure important information on the past state of the geomagnetic field. Recently it was shown that it is possible to determine magnetizations of individual grains in a sample by combining X-ray computed tomography and magnetic surface scanning measurements. Here we establish this new Micromagnetic Tomography (MMT) technique and make it suitable for use with different magnetic scanning techniques, and for both synthetic and natural samples. We acquired reliable magnetic directions by selecting subsets of grains in a synthetic sample, and we obtained rock-magnetic information of individual grains in a volcanic sample. This illustrates that MMT opens up entirely new venues of paleomagnetic and rock-magnetic research. MMT’s unique ability to determine the magnetization of individual grains in a nondestructive way allows for a systematic analysis of how geological materials record and retain information on the past state of the Earth’s magnetic field. Moreover, by interpreting only the contributions of known magnetically well-behaved grains in a sample MMT has the potential to unlock paleomagnetic i

The epidemiology of pertussis in Germany: past and present

<p>Abstract</p> <p>Background</p> <p>Current and past pertussis epidemiology in the two parts of Germany is compared in the context of different histories of vaccination recommendations and coverage to better understand patterns of disease transmission.</p> <p>Methods</p> <p>Available regional pertussis surveillance and vaccination coverage data, supplemented by a literature search for published surveys as well as official national hospital and mortality statistics, were analyzed in the context of respective vaccination recommendations from 1964 onwards.</p> <p>Results</p> <p>Routine childhood pertussis vaccination was recommended in the German Democratic Republic (GDR) from 1964 and in former West German states (FWG) from 1969, but withdrawn from 1974–1991 in FWG. Pertussis incidence declined to <1 case/100.000 inhabitants in GDR prior to reunification in 1991, while in FWG, where pertussis was not notifiable after 1961, incidence was estimated at 160–180 cases/100.000 inhabitants in the 1970s-1980s. Despite recommendations for universal childhood immunization in 1991, vaccination coverage decreased in former East German States (FEG) and increased only slowly in FWG. After introduction of acellular pertussis vaccines in 1995, vaccination coverage increased markedly among younger children, but remains low in adolescents, especially in FWG, despite introduction of a booster vaccination for 9–17 year olds in 2000. Reported pertussis incidence increased in FEG to 39.3 cases/100.000 inhabitants in 2007, with the proportion of adults increasing from 20% in 1995 to 68% in 2007. From 2004–2007, incidence was highest among 5–14 year-old children, with a high proportion fully vaccinated according to official recommendations, which did not include a preschool booster until 2006. Hospital discharge statistics revealed a ~2-fold higher pertussis morbidity among infants in FWG than FEG.</p> <p>Conclusion</p> <p>The shift in pertussis morbidity to older age groups observed in FEG is similar to reports from other countries with longstanding vaccination programs and suggests that additional booster vaccination may be necessary beyond adolescence. The high proportion of fully vaccinated cases in older children in FEG suggests waning immunity 5–10 years after primary immunisation in infancy. The higher incidence of pertussis hospitalisations in infants suggests a stronger force of infection in FWG than FEG. Nationwide pertussis reporting is required for better evaluation of transmission patterns and vaccination policy in both parts of Germany.</p

The Role of Transporters in the Pharmacokinetics of Orally Administered Drugs

Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux transporters in organs responsible for drug biotransformation and excretion gives transporter proteins a unique gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. This review seeks to discuss the influence intestinal and hepatic drug transporters have on pharmacokinetic parameters, including bioavailability, exposure, clearance, volume of distribution, and half-life, for orally dosed drugs. This review also describes in detail the Biopharmaceutics Drug Disposition Classification System (BDDCS) and explains how many of the effects drug transporters exert on oral drug pharmacokinetic parameters can be predicted by this classification scheme

Long-term effectiveness of Self-Help Plus in refugees and asylum seekers resettled in Western Europe: 12-month outcomes of a randomised controlled trial

AimsAs refugees and asylum seekers are at high risk of developing mental disorders, we assessed the effectiveness of Self-Help Plus (SH + ), a psychological intervention developed by the World Health Organization, in reducing the risk of developing any mental disorders at 12-month follow-up in refugees and asylum seekers resettled in Western Europe.MethodsRefugees and asylum seekers with psychological distress (General Health Questionnaire-12 ⩾ 3) but without a mental disorder according to the Mini International Neuropsychiatric Interview (M.I.N.I.) were randomised to either SH + or enhanced treatment as usual (ETAU). The frequency of mental disorders at 12 months was measured with the M.I.N.I., while secondary outcomes included self-identified problems, psychological symptoms and other outcomes.ResultsOf 459 participants randomly assigned to SH + or ETAU, 246 accepted to be interviewed at 12 months. No difference in the frequency of any mental disorders was found (relative risk [RR] = 0.841; 95% confidence interval [CI] 0.389–1.819; p-value = 0.659). In the per protocol (PP) population, that is in participants attending at least three group-based sessions, SH + almost halved the frequency of mental disorders at 12 months compared to ETAU, however so few participants and events contributed to this analysis that it yielded a non-significant result (RR = 0.528; 95% CI 0.180–1.544; p-value = 0.230). SH + was associated with improvements at 12 months in psychological distress (p-value = 0.004), depressive symptoms (p-value = 0.011) and wellbeing (p-value = 0.001).ConclusionsThe present study failed to show any long-term preventative effect of SH + in refugees and asylum seekers resettled in Western European countries. Analysis of the PP population and of secondary outcomes provided signals of a potential effect of SH + in the long-term, which would suggest the value of exploring the effects of booster sessions and strategies to increase SH + adherence.</p