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Schamanismus wird abwechselnd verstanden als religiöse Praxis archaischer oder indigener Gesellschaften, als Verfahren zur Heilung psychischer oder physischer Probleme, als rechtliches Mediationsverfahren, zuweilen auch als künstlerische Performance, die dem besseren Verständnis der Welt oder der eigenen Person oder auch nur zur Unterhaltung dienen soll. Alle diese Ansichten treffen insofern zu, als sie einen der Aspekte hervorheben, die in ihrer Gesamtheit das schamanische Ritual charakterisieren. Immer handelt es sich bei diesen Ritualen um multi-sensuelle Spektakel. Die verschiedenen Aspekte der in schamanischen Ritualen behandelten Krankheiten sind in ihrem Verständnis, ihrer Gewichtung und ihrer Konfiguration stets kulturell und historisch geprägt, und dies lässt sich am besten erkennen, wenn der konkrete Ablauf dieser Rituale durch teilnehmende Beobachtung verfolgt und in seinem weiteren ethnografischen Kontext studiert wird. Eine derartige Analyse des schamanischen Rituals bildet einen Schlüssel zum Verständnis der jeweiligen Krankheitskonzepte. In diesem Aufsatz soll ausgehend vom Fallbeispiel einer ethnischen Gruppe in Ost-Nepal, bei der sich der Autor während 30 Jahren mit Schamanismus beschäftigt hat, gezeigt werden, was die jeweilige rituelle Praxis in ihrem weiteren Kontext über das Verständnis von Krankheit aussagt und was daran kulturspezifisch und was von allgemeiner Bedeutung ist.

Extracellular enzymes are master recyclers of organic matter, and to predict their functional lifetime, we need to understand their environmental transformation processes. In surface waters, direct and indirect photochemical transformation is a known driver of inactivation. We investigated molecular changes that occur along with inactivation in aminopeptidase, an abundant class of extracellular enzymes. We studied the inactivation kinetics and localized oxidation caused by singlet oxygen, 1O2, a major photochemically derived oxidant toward amino acids. Aminopeptidase showed second-order inactivation rate constants with 1O2 comparable to those of free amino acids. We then visualized site-specific oxidation kinetics within the three-dimensional protein and demonstrated that fastest oxidation occurred around the active site and at other reactive amino acids. However, second-order oxidation rate constants did not correlate strictly with the 1O2-accessible surface areas of those amino acids. We inspected site-specific processes by a comprehensive suspect screening for 723,288 possible transformation products. We concluded that histidine involved in zinc coordination at the active site reacted slower than what was expected by its accessibility, and we differentiated between two competing reaction pathways of 1O2 with tryptophan residues. This systematic analysis can be directly applied to other proteins and transformation reactions. ISSN:0013-936X ISSN:1520-5851

There are two main models of criminal prosecution in the western world. One tasks an independent magistrate (the examining judge) with the duty of conducting the investigation of a given case and transferring all evidence collected to the parties and the trial court. The other vests the prosecution with the task of conducting the investigation before representing the accusation in court. In 2011, a new code of criminal procedure entered into force in Switzerland, forcing most Swiss cantons to transition from the first model to the second. We investigate whether the change in the person conducting the investigation (from examining judge to prosecutor) could introduce or exacerbate bias against or in favor of the defendant. Through an empirical study carried out with students, we tried to determine whether this change might affect the fairness of the proceedings. We contend that the rights of the defense are better safeguarded in the first model than in the second, even if the contrast is not as stark as was initially predicted.

Harmful cyanobacterial blooms in freshwater ecosystems produce bioactive secondary metabolites including cyanopeptides that pose ecological and human health risks. Only adverse effects of one class of cyanopeptides, microcystins, have been studied extensively and have consequently been included in water quality assessments. Inhibition is a commonly observed effect for enzymes exposed to cyanopeptides and has mostly been investigated for human biologically relevant model enzymes. Here, we investigated the inhibition of ubiquitous aquatic enzymes by cyanobacterial metabolites. Hydrolytic enzymes are utilized in the metabolism of aquatic organisms and extracellularly by heterotrophic bacteria to obtain assimilable substrates. The ubiquitous occurrence of hydrolytic enzymes leads to the co-occurrence with cyanopeptides especially during cyanobacterial blooms. Bacterial leucine aminopeptidase and alkaline phosphatase were exposed to cyanopeptide extracts of different cyanobacterial strains ( Microcystis aeruginosa wild type and microcystin-free mutant, Planktothrix rubescens) and purified cyanopeptides. We observed inhibition of aminopeptidase and phosphatase upon exposure, especially to the apolar fractions of the cyanobacterial extracts. Exposure to the dominant cyanopeptides in these extracts confirmed that purified microcystins, aerucyclamide A and cyanopeptolin A inhibit the aminopeptidase in the low mg L–1 range while the phosphatase was less affected. Inhibition of aquatic enzymes can reduce the turnover of nutrients and carbon substrates and may also impair metabolic functions of grazing organisms.

Extracellular enzymes are major drivers of biogeochemical nutrient and carbon cycling in surface water. While photoinactivation is regarded as a major inactivation process of these enzymes, the underlying molecular changes have received little attention. This study demonstrates how light exposure leads to a rapid loss of phosphatase, aminopeptidase, and glucosidase activities of biofilm samples and model enzymes. Here, an optimized proteomics approach allowed simultaneous observation of inactivation and molecular changes. Site-specific fingerprints of degradation kinetics have been generated and visualized in the three-dimensional proteins. Oxidation of tryptophan, the chromophoric target, initiated secondary reactions. Evidence was obtained that tyrosine residues act as intramolecular antioxidants, reflected in decelerated decay of tryptophan-containing peptides and enhanced decay of tyrosine-containing peptides. In addition, subsequent methionine oxidation and disulfide reduction contribute to heterogeneous photodamage. The proximity to tryptophan residues explains >95% of the photodamage across the protein structures. The presence of redox active organic matter or a model antioxidant in solution quenched not only photoinactivation and tryptophan oxidation but also all subsequent damage. The developed analytical approach can be applied to other research questions in environmental sciences where site-specific damage in a protein is essential., Environmental Science & Technology, 52 (14), ISSN:0013-936X, ISSN:1520-5851

Üblicherweise wird angenommen, daß die Bildung von Kaolinit in Böden, ausschließlich an das Vorherrschen warmfeuchter Klimabedingungen sowie einer intensiven Perkolation des Bodens gebunden sein muß. Die von uns durchgeführten Untersuchungen an ausgewählten Bodenprofilen im schweizerischen Mittelland, im Jura und in den Alpen belegen, daß Kaolinit in einigen Fällen nachgewiesen werden kann und dies auch unter temperierten bis subalpinen Klimabedingungen sowie in vergleichsweise jungen Böden. Entscheidend für eine rezente Kaolinitbildung scheint jeweils der Wasserhaushalt des Bodens zu sein: unsere Ergebnisse erlauben die Hypothese, daß eine gehemmte Perkolation oder der Einfluß des Grundwassers die Kristallisation von Kaolinit begünstigen.

DNA lesions that elude repair may undergo translesion synthesis catalyzed by Y-family DNA polymerases. O4-Alkylthymidines, persistent adducts that can result from carcinogenic agents, may be encountered by DNA polymerases. The influence of lesion orientation around the C4-O4 bond on processing by human DNA polymerase η (hPol η) was studied for oligonucleotides containing O4-methylthymidine, O4-ethylthymidine, and analogs restricting the O4-methylene group in an anti-orientation. Primer extension assays revealed that the O4-alkyl orientation influences hPol η bypass. Crystal structures of hPol η•DNA•dNTP ternary complexes with O4-methyl- or O4-ethylthymidine in the template strand showed the nucleobase of the former lodged near the ceiling of the active site, with the syn-O4-methyl group engaged in extensive hydrophobic interactions. This unique arrangement for O4-methylthymidine with hPol η, inaccessible for the other analogs due to steric/conformational restriction, is consistent with differences observed for nucleotide incorporation and supports the concept that lesion conformation influences extension across DNA damage. Together, these results provide mechanistic insights on the mutagenicity of O4MedT and O4EtdT when acted upon by hPol η.

The number of civil and criminal trials in which there is presented at least one piece of scientific evidence—by which we mean the analysis and interpretation of physical evidence derived from the so-called hard sciences (thus excluding the fields of psychology, psychiatry, and the social and behavioral sciences)—is constantly increasing. Yet the fact finders, be they judges or juries or the attorneys arguing the cases, have limited scientific education. In this context, the way scientific experts express the results of analyses and interpretations carried out, as well as the way the members of the court understand the content of their message, is of utmost importance. Misunderstandings do happen and have dramatic consequences, as an abundant literature on wrongful convictions now well illustrates. It is thus urgent that forensic scientists learn to write more transparent statements. This requirement is also set out in a landmark report published in 2009 by the National Research Council. Following this trend, the forensic community has started developing guidelines concerning statement writing, and a structured approach to communication of expert opinion in court is now emerging. However, empirical results as to what constitutes good practice in the expression of results, and particularly the uncertainty attached to scientific results, are not abundant. Indeed, while guidelines exist, the improvement in mutual understanding is not evident. This quest for mutual understanding, in particular in the expression of evidential value, is the subject of this article. Joëlle Vuille wishes to thank the Swiss National Science Foundation for their financial support (grant PP00P1_176720).

The societal burden created by alcohol and drug use disorders is estimated to be on the order of hundreds of billions of dollars, creating a need for effective medications to reduce use and prevent relapse. While there are FDA-approved medications to facilitate abstinence and prevent relapse for some indications including, alcohol, tobacco, and opiate use disorders, there are no approved treatments for other abused substances, including cocaine, methamphetamine, and cannabis, leaving these critical medical needs unmet. The development of such medications has fallen largely to the government with efforts spearheaded by the National Institute on Drug Abuse and the National Institute on Alcoholism and Alcohol Abuse. Both agencies have medication development programs with preclinical components that include the standardized evaluation of compounds using animal models. This chapter describes the rationale and considerations involved in the use of such models, including reinstatement of drug self-administration.

Der diabetische Fuss bleibt eine häufige Diabeteskomplikation mit potenziell schwerwiegenden Folgen, wird jedoch häufig vernachlässigt. Seine systematische Früherkennung bezweckt zunächst die Einschätzung des Risikogrades für Läsionen. Diese beruht auf der klinischen Untersuchung hinsichtlich des Schweregrades einer Neuropathie, sowie deren Folgeerscheinungen und einer eventuell assoziierten Arteriopathie. Die Präventivmassnahmen werden durch den Risikograd bestimmt. Sie verlangen immer ein erhebliches Engagement sowohl des Patienten, als auch der zuständigen Medizinalfachpersonen im Bereiche der Schulung und des psychosozialen Supports, unter Berücksichtigung seiner individuellen Ressourcen und Hindernisse. Die diagnostischen und therapeutischen Problemstellungen bei einer aktiven Läsion erfordern in der Regel für eine effiziente Betreuung das Zusammenspiel mehrerer Vertreter verschiedener Fachgebiete.

Background/aims The classic Goldmann applanation tonometer (GAT) has been further developed by Haag-Streit International. The applanation principle has been retained, while the internal force transmission and the pressure gauging have been optimised, the display of results digitised. The authors compared the GAT standard with the new GAT digital. Methods Four fixed tonometer pairs were used. The protocol included: non-contact pachymetry, slit-lamp examination, three consecutive measurements with each tonometer with a 5 min interval in between, check for side effects in 15 min. Three groups (intraocular pressure (IOP) levels) were defined: (1) IOP≤16; (2) IOP>16 and Results 125 Patients (250 eyes) were evaluated. IOP (mm Hg), GAT standard versus GAT digital, for the rights eyes was: Group 1: 12.94±0.55 versus 13.11±0.53, p=0.71. Group 2: 18.26±0.59 versus 18.03±0.52, p=0.53; Group 3: 30.28±0.48 versus 30.42±0.41, p=0.97; all right eyes: 17.48±7.48 versus 17.73±7.4, p=0.99. For the left eyes, there was no significant difference, either. The correlation was very good and was not influenced by the IOP level. The Pearson coefficient for the right eye was 0.985, and for the left eye 0.994. In the Bland–Altman analysis, although there were two single readings that differed by as much as 5 mm Hg, GAT digital measures showed almost no skew, and the mean difference was 0.03±1.23 mm Hg (n=250). A multiple regression analysis showed no influence of order of measurement, eyeside or pachymetry. Conclusions The new GAT digital is as reliable and safe as GAT standard. IOP values correlate well. It offers a digitised display and a wireless transfer of data. The display of values up to the first decimal digit is not necessarily associated with a more precise measurement, but may offer an additional comfort compared with the 2 mm Hg scale of the classic GAT.

Prolactin and oxytocin are important reproductive hormones implicated in several common adaptive functions during pregnancy, pseudopregnancy and lactation. Recently, extracellular recordings of supraoptic neurones have shown that prolactin may modulate the electrical activity of oxytocinergic neurones. However, no study has been conducted aiming to establish whether prolactin directly influences this activity in oxytocinergic paraventricular neurones. In the present study, we addressed this question by studying the effects of prolactin on the electrical activity and voltage-current relationship of identified paraventricular neurones in rat brain slices. Whole-cell recordings were obtained and neurones were classified on the basis of their morphological and electrophysiological fingerprint (i.e. magnocellular or parvicellular) and neuropeptide phenotype (i.e. oxytocinergic or non-oxytocinergic). We report that prolactin elicited a hyperpolarising current in 37% of the neurones in this nucleus, of which the majority (67%) were identified as putative magnocellular oxytocin neurones and the reminder (33%) were regarded as oxytocin-negative, parvicellular neuroendocrine neurones. Our results suggest that, in addition to the well-established negative feedback loop between prolactin-secreting lactotrophs and dopaminergic neurones in the arcuate nucleus, an inhibitory feedback loop also exists between lactotrophs and oxytocinergic paraventricular neurones.

The societal burden created by alcohol and drug use disorders is estimated to be on the order of hundreds of billions of dollars, creating a need for effective medications to reduce use and prevent relapse. While there are FDA-approved medications to facilitate abstinence and prevent relapse for some indications including, alcohol, tobacco, and opiate use disorders, there are no approved treatments for other abused substances, including cocaine, methamphetamine, and cannabis, leaving these critical medical needs unmet. The development of such medications has fallen largely to the government with efforts spearheaded by the National Institute on Drug Abuse and the National Institute on Alcoholism and Alcohol Abuse. Both agencies have medication development programs with preclinical components that include the standardized evaluation of compounds using animal models. This chapter describes the rationale and considerations involved in the use of such models, including reinstatement of drug self-administration.

The value of olfactory enrichment for captive-housed animals is now well recognised. Large cats have been shown to benefit from the introduction of odours to their captive environment, but to date the effect of odour introduction on the behaviour of small cats remains unknown. This study investigated the behaviour of six zoo-housed black-footed cats, Felis nigripes, in response to four odours (no odour [control], nutmeg, catnip and body odour of prey) introduced individually on cloths into the animals’ pens over a period of 5 days. It was hypothesised that the cats’ behaviour would differ significantly between the control and experimental odours and that interest in the experimental odours would wane over time. All of the experimental odours influenced the cats’ behaviour, resulting in an increase in the amount of time that the animals spent in active behaviours, i.e. moving (average increase of 8.3%), grooming (average increase of 5.9%), exploring the cloth (average increase of 10.9%) and exploring the pen (average increase of 9.2%). The experimental odours also resulted in a decrease in the amount of time that the cats spent in sedentary behaviours, i.e. standing (average decrease of 2.8%), sitting (average decrease of 5.2%) and resting (average decrease of 25.9%). Nutmeg exerted less of an effect on the cats’ behaviour than catnip or odour of prey. The cats’ response to all of the experimental odours waned over the course of the 5-day observation period, suggesting that the animals habituated to the stimuli. The results highlight the potential for odour to be employed as a method of environmental enrichment for small captive-housed felids, if presented in an appropriate manner.

Dieser Beitrag handelt von den Ahnen und dem Personenbegriff der Sunuwār, einer ethnischen Gruppe in Ostnepal. Wie in vielen Kulturen bilden Ahnengeister auch fur die Sunuwār ein Bindeglied zum mythischen Ursprung. Die zu Ahnen gewordenen Seelen Verstorbener verkorpern die Normen der Sunuwār-Gesellschaft in ihrer Ursprunglichkeit, und in Tranceritualen wird mindestens einmal im Jahr und zusatzlich in Krankheitsfallen die Vereinigung mit ihnen gesucht. Dies stellt fur die Sunuwār, wie auch fur den ausenstehenden Ethnographen, vordergrundig eine demonstrative Unterwerfung unter die sozialen Normen und in diesem Sinne eine Fremdkontrolle des Einzelnen durch das Kollektiv dar, wie sie in vergleichbarer Weise in komplexen westlichen Gesellschaften unbekannt ist.

This study was carried out to characterize angiotensin II (ANG II) sensitive neurons in the hypothalamic paraventricular nucleus (PVN) of the rat. An approach was chosen in which a combination of an electrophysiological, a morphological, and an immunocytochemical method was focused on one single neuron. The cell’s reaction to an application of ANG II and its specific antagonist Losartan (Dup753) was investigated using the technique of intracellular recording inside 450-μm-thick brain slices. A final injection of a fluorescent dye labelled the neurons. Optical sections were taken through the marked cells by a confocal laser-scanning microscope and made into a three-dimensional cell model on a computer. One-micrometer thin sections were cut from the thick slice at the level of the electrophysiologically characterized and marked cell body for immunocytochemical tests with different antibodies. Our results show an example of such a neuron inside the PVN excited by ANG II. It was possible to block this excitation with the specific ANG II receptor subtype 1 (AT 1 ) antagonist Losartan. The result indicated that the ANG II reaction was mediated by the AT 1 receptor subtype. Immunocytochemical studies show that this ANG II-sensitive neuron contains ANG II but no vasopressin. The combination of the results enables us to gain improved information on interactions of peptidergic systems.

The yeast TRP4 mRNA 3' end formation element is a bidirectional element which functions in both orien-tations in an artificial in vivo test system. In this study, the role of 3' end formation was analysed in the context of the entire TRP4 gene. The 3' untranslated region (3'UTR) of TRP4 was altered and changes were analysed for their influence on TRP4 gene expression. The 3'UTR in reverse orientation was fully functional and did not affect TRP4 gene expression. Exchanging the TRP4 3'UTR by the bidirectional ARO4 or the unidirectional GCN4 3' end formation element allowed efficient gene expression. Deletion of the entire TRP4 3'UTR resulted in 70% reduction of TRP4 mRNA and 50% reduced specific Trp4 enzyme activity in comparison to wild-type. A single point mutation within the TRP4 3'UTR caused the same effect on gene expression. This point mutation did not only affect the efficiency of 3' end formation, but also produced new poly(A) sites which were situated upstream of the wild-type poly(A) sites. Therefore this sequence motif in the TRP4 3'UTR acts simultaneously as both an efficiency and positioning element.

The yeast TRP4 3'-end formation signal functions in both orientations in an in vivo test system. We show here that the TRP4 3'-end formation element consists of two functionally different sequence regions. One region of approximately 70 nucleotides is located in the untranslated region between the translational stop codon and the major poly(A) site. The major poly(A) site is not part of this region and can be deleted without a decrease in TRP4 3'-end formation. 5'and 3'deletions and point mutations within this region affected 3'-end formation similarly in both orientations. In the center of this region the motif TAGT is located on the antisense strand. Point mutations within this motif resulted in a drastic reduce of 3'-end formation activity in both orientations. A second region consists of the 3'-end of the TRP4 open reading frame and is required for 3'-end formation in forward orientation. A single point mutation in a TAGT motif of the TRP4 open reading frame abolished TRP4 mRNA 3'-end formation in forward orientation and had no effect on the reverse orientation.

The influence of different NH + 4 loads on aluminium speciation in percolating water was studied on acid luvisols with similar soil-pH values but with different soil adsorption surface characteristics. All of the applied NH + 4 was nitrified and therefore led to proton production. Thus, Al displacement in the percolate was increased. The extent of this enhanced translocation was found to be chiefly a function of the amount of exchangeable base cations which buffered the protons produced by nitrification. The proportion of the different Al species in the percolate was altered at large NH + 4 loads. Very large Al 3+ concentrations eliminated Al species bound to dissolved organic matter and particles, presumably because of flocculation and precipitation of organic ligands. Furthermore, increased NO - 3 and Al 3+ concentrations enhanced the desorption of F- giving rise to an additional increase in Al displacement by the formation of Al fluoro complexes in the aqueous phase.

The diabetic foot remains a diabetes complication with potentially devastating consequences, which is initially silent and too often neglected. Its systematic screening first has to target the estimation of the risk level of foot lesions. This estimation is based on clinical examination regarding the severity of neuropathy, its consequences and of a possibly associated arterial disease. Preventive interventions are determined according to the risk level. They always rely on an important involvement of the patient, which in turn requires the healthcare professionals' engagement in individualized patient education and psychosocial support. Wound management and its diagnostic and therapeutic challenges usually calls for a collaborative approach involving several different specialists.

An artificial messenger RNA containing a derivative of a tobacco ringspot virus ribozyme was expressed in the bakers' yeast Saccharomyces cerevisiae. This mRNA was able to cleave itself efficiently in vivo. Using this system, the two steps of mRNA 3' processing, i.e. cleavage and the addition of a poly(A) tail, can be separated in yeast in vivo. The ribozyme-cleaved transcript was shown to be polyadenylated. The poly(A) tail length was similar to the poly(A) tail length of an endogenous yeast mRNA. Therefore, cleavage of the precursor RNA at the polyadenylation site and the addition of adenosine residues to the 5' product require independent cellular machineries in yeast and can be separately analyzed. This is in contrast to higher eukaryotes where both processes are coupled.

Transplantation of human fetal ventral mesencephalon (VM) to Parkinsonian patients has shown beneficial effects in several clinical trials. However, further improvements in the transplantation technique are needed. Delayed surgery, i.e., the in vitro maintenance of the tissue prior to transplantation would present several advantages. The roller tube technique as initially described by Gähwiler (1981) was modified in several aspects for the long-term maintenance of dopaminergic neurones of human fetal VM. Tissue cultures were maintained free-floating in the medium for up to 42 days. The human fetal material was obtained from legal induced suction abortions. The embryonic age ranged from 5 to 12 weeks post-conception. Identification of VM was possible in 43% of the cases. Neurones in cultures were demonstrated by means of immunohistochemistry for tyrosine hydroxylase (TH) and gamma-amino butyric acid (GABA), by electron microscopy and by hybridisation histochemistry using a TH-mRNA-sensitive probe. A high variability in the number of TH-positive cells in individual cultures derived from the same embryo was observed. In 20 microns frozen sections of such tissue cultures the mean +/- SEM of TH-positive cells was 6.5 +/- 1.2/0.1 mm2 (n = 79; range: 0-73). The technique described insures the growth of long-term cultures of human fetal VM.

During an acute hospital stay, unpredictable glycemic changes related to the combined effects of multiple factors always ask for an increased attention to diabetes management. Initially an insulin treatment which has to be adjusted individually based on continuous glycemic follow-up is usually inevitable. This requires adequate coordination between the various health-care professionals who are simultaneously and successively involved in patient care. A proper discharge plan including reassessment of treatment, developed in consultation with the practicioners in charge of outpatient follow-up is a key component of this process. As in other complex conditions, deficiencies in this field are associated with increased errors and costs, which can be improved through interventions targeting inpatient to outpatient transition.

The new antiepileptic drug zonisamide was evaluated in a European multicenter parallel-group double-blind trial as add-on treatment for 139 patients with refractory partial epilepsy. During treatment with zonisamide complex partial seizures decreased by 27.7% compared to placebo (P < 0.05) and the median rate dropped from 12/month to 7.1/month with no changes in the placebo group (P < 0.007). During the 12-week double-blind phase a 50% reduction of all seizures was recorded in 29.9% of the patients treated with zonisamide vs. 9.4% during placebo. Complete remission was observed during treatment with zonisamide in 6.2%. The plasma concentrations of the concomitant antiepileptic drugs did not change markedly when zonisamide was added. Adverse events, mostly fatigue, somnolence, dizziness and ataxia, occurred in 59.2% of the patients compared to 27.9% during placebo. Zonisamide was withdrawn in two patients due to adverse events. Kidney stones were not observed nor any relevant clinical chemistry or hematological changes. Zonisamide is an effective antiepileptic drug for add-on treatment of refractory partial epilepsy.

In 2009 a novel screening strategy for diabetes based on the level of glycated hemoglobin has been proposed by the main international organizations, with a diagnostic threshold of 6.5%. The preventive efficacy of multiple risk factor control in type 2 diabetes reflected by the low rate of cardiac events in the DIAD 2 study calls for a revision of the current recommendations for coronary disease screening. In gestational diabetes, the linear correlation between degree of hyperglycemia and risk of associated complications in the HAPO study strenghtens the therapeutic targets for this frequent condition, which identifies women at high future risk of diabetes. No conclusive evidence for an increased risk of cancer associated with insulin glargin remains when taking into account all the data currently available on this topic.

We show that the polyadenylation site derived from the plant cauliflower mosaic virus (CaMV) is specifically functional in the yeast Saccharomyces cerevisiae. The mRNA 3' endpoints were mapped at the same position in yeast cells as in plants, and the CaMV polyadenylation site was recognized in an orientation-dependent manner. Mutational analysis of the CaMV 3'-end-formation signal revealed that multiple elements are essential for proper activity in yeast cells, including two upstream elements that are situated more than 100 and 43 to 51 nucleotides upstream of the poly(A) addition site and the sequences at or near the poly(A) addition site. A comparison of the sequence elements that are essential for proper function of the CaMV signal in yeast cells and plants showed that both organisms require a distal and a proximal upstream element but that these sequence elements are not identical in yeast cells and plants. The key element for functioning of the CaMV signal in yeast cells is the sequence TAGTATGTA, which is similar to a sequence previously proposed to act in yeast cells as a bipartite signal, namely, TAG ... TATGTA. Deletion of this sequence in the CaMV polyadenylation signal abolished 3'-end formation in yeast cells, and a single point mutation in this motif reduced the activity of the CaMV signal to below 15%. These results indicate that the bipartite sequence element acts as a signal for 3'-end formation in yeast cells but only together with other cis-acting elements.

In Saccharomyces cerevisiae, two differently regulated 3-deoxy-D-arabino-heptulosonate-7-phosphate (DAHP) synthase (DAHPS; EC 4.1.2.15) isoenzymes carry out the first step in the shikimate pathway. Mutations in both genes are necessary to cause aromatic amino acid (aa) auxotrophy, since one isoenzyme alone is sufficient to produce enough DAHP for normal growth of the cells. The phenylalanine-inhibited DAHPS is encoded by the previously isolated and characterized ARO3 gene. Here, we report the cloning and characterization of the ARO4 gene, encoding the second DAHPS, which is inhibited by tyrosine. The aa sequence of the ARO4 gene product reveals 76% similarity to the ARO3-encoded isoenzyme and 66 and 73% to the three DAHPS isoenzymes from Escherichia coli. ARO4 gene expression is regulated by the general control system of aa biosynthesis. As in the case of the ARO3 gene, a single GCN4-recognition element in the promoter is responsible for derepression of the ARO4 gene under aa starvation conditions. However, in contrast to the situation in the isogene, ARO3, GCN4 does not contribute to the basal level of ARO4 transcription under nonderepressing conditions.

We show that the single intron of the actin gene of the yeast Saccharomyces cerevisiae contains a cryptic promoter for transcription of the second exon. This promoter is inactive in the normal actin gene, but can be activated when the actin gene promoter is deleted. An identical activation was induced by placing efficient transcriptional terminators at position 61 of the 309 bp intron. In all cases transcripts with identical 5' ends close to the boundary of the intron and the second exon were produced. These results indicate that the cryptic promoter in the actin intron is occluded in the normal actin gene by transcriptional interference with the actin gene promoter. Transcription initiation near the intron/exon 2 boundary is enabled by protection from traversing polymerases, that initiated transcription at the upstream located actin gene promoter. A partial promoter protection using leaky terminators resulted in small amounts of transcripts initiated from the cryptic promoter. Although we do not know any function of the cryptic promoter in actin gene expression, it is tentative to speculate that the cryptic intron promoter might be a relict of a promoter that was functional earlier in evolution.

This report provides an analysis of the function of polyadenylation sites from six different genes of the yeast Saccharomyces cerevisiae. These sites were tested for their ability to turn off read-through transcription into the URA3 gene in vivo when inserted into an ACT-URA3 fusion gene. The 3' ends of all polyadenylation sites inserted into the test system in their natural configuration are identical to the 3' ends of the chromosomal genes. We identified two classes of polyadenylation sites: (i) efficient sites (originating from the genes GCN4 and PHO5) that were functional in a strict orientation-dependent manner and (ii) bidirectional sites (derived from ARO4, TRP1, and TRP4) that had a distinctly reduced efficiency. The ADH1 polyadenylation site was efficient and bidirectional and was shown to be a combination of two polyadenylation sites of two convergently transcribed genes. Sequence comparison revealed that all efficient unidirectional polyadenylation sites contain the sequence TTTTTAT, whereas all bidirectional sites have the tripartite sequence TAG...TA (T)GT...TTT. Both sequence elements have previously been proposed to be involved in 3' end formation. Site-directed point mutagenesis of the TTTTTAT sequence had no effect, whereas mutations within the tripartite sequence caused a reduced efficiency for 3' end formation. The tripartite sequence alone, however, is not sufficient for 3' end formation, but it might be part of a signal sequence in the bidirectional class of yeast polyadenylation sites. Our findings support the assumption that there are at least two different mechanisms with different sequence elements directing 3' end formation in yeast.

A recent meta-analysis on the rosiglitazone in the treatment of type 2 diabetes revealed a significant increased risk of myocardial infarction and a trend to a higher cardiovascular mortality. In the following month after this publication, the methodology as its conclusions were criticized. This study shows the limits of the meta-analyses to which one lends a row obviously too high in the hierarchy of the levels of evidence. The study 4T evaluated 3 insulin strategies in the treatment of the type 2 diabetes. The results at one year show that only a minority of the patients achieve the goals. Post-Steno 2 was presented at the European congress diabetes. These new data confirm that the intensified treatment of all cardiovascular factors risk allows a major reduction of cardiovascular mortality after 13.3 years.

Vigabatrin (gamma-vinyl-GABA), an irreversible inhibitor of gamma-aminobutyric acid transaminase, has been reported to be effective in the treatment of refractory epilepsies. Animal toxicology studies have shown that long-term application of vigabatrin induces intramyelinic edema and microvacuolation of the white matter in non-primate species. However, clinical and neuropathological studies of patients exposed to long-term vigabatrin treatment have, so far, provided no evidence for microvacuolation in the human brain. We report on the histopathological findings of selective amygdalohippocampectomy specimens from a 36-year-old female patient treated with vigabatrin for a period of 11.5 months, and from 2 control patients with chronic refractory temporal lobe seizures. All specimens showed changes associated with chronic epileptic seizures including focal neuronal loss and hippocampal gliosis. Microvacuoles, intramyelinic edema or other manifestations of neurotoxic damage were not observed in vigabatrin exposed tissue, supporting the view that this compound may not exert hippocampal neurotoxicity in humans.

The GLP-1 agonists and DPP-4 inhibitors are two novel drug classes in the treatment of type 2 diabetes. They increase insulin secretion and inhibit glucagon secretion without risk of hypoglycaemia. A decrease of glycated haemoglobin of about 1% can be expected with their use as monotherapy and as add-on therapy to the usual oral antidiabetics. In addition, GLP-1 agonists induce weight reduction at the price of gastro-intestinal side-effects and the need for subcutaneous administration. DPP-4 inhibitors can be taken orally, are well-tolerated, but weight-neutral. In the absence of relevant clinical studies, their long-term efficacy is currently unknown, as well as the clinical impact of other promising effects like beta-cell preservation.

Introduction Malgre un consensus sur les risques de complications du PD pouvant etre theoriquement prevenus en ameliorant la prise en charge du diabete selon le Chronic Care Model, peu d’etudes s’interessent a la perspective des patients, ce qui peut compromettre une autogestion efficace des risques. But: etablir un etat des lieux afin de comprendre les obstacles a l’autogestion pour la prevention des risques de complications du PD. Patients et methodes Analyses transversales descriptives des donnees du suivi 2013 de la cohorte CoDiab-VD incluant: 449 patients diabetiques adultes ; vivant a domicile ; residant dans le canton de Vaud (Suisse) ; sans troubles cognitifs majeurs ; comprenant le francais ecrit ; recrutes en 2011-2012 dans les pharmacies. Instrument: questionnaire postal auto-administre comprenant un « Module Pied Diabetique ». Dimensions mesurees: prise en charge du PD ; niveau d’information recu ; frequence des problemes de pieds ; connaissances/croyances sur le PD. Resultats 395 patients (participation 88 %). Âge moyen: 65,5 ans ; 85 % diabete type 2. Seuls 57,9 % ont eu un controle des pieds au cours des 12 derniers mois, le plus souvent par un medecin. Dans 60,7 % des cas, un instrument a ete utilise pour ce controle ; 43,8 % des patients n’ont pas recu d’information sur le niveau de risque du pied et 53,7 % n’ont eu aucune demonstration des gestes de soins preventifs du PD, alors que 46,2 % reportaient actuellement callosites, ulceres ou suintements. Par ailleurs, 26,3 % ne connaissaient pas la cause la plus importante des problemes du PD. Conclusion Cette etude identifie une prise en charge insuffisante, peu documen-tee du PD et des lacunes pour l’information sur le risque, les connaissances et les gestes preventifs. Ce sont autant d’obstacles au developpement, dans la relation therapeutique, d’une autogestion efficace pour la prevention des risques de complications du PD. Declaration d’interet Les auteurs declarent avoir un interet avec un organisme prive, industriel ou commercial en relation avec le sujet presente. Projet finance par Service de la Sante Publique du Canton de Vaud (Suisse) dans le cadre du programme Diabete Swiss School of Public Health + Assistant Professorship grant (I. Peytremann-Bridevaux).