From the vendor in the hemp shop to the dealer in the alleyway? A comparison of the sources of supply of cannabis in a time of 'de-normalising' cannabis use.

Objectives: After several years of increasing 'normalisation' of cannabis use in Switzerland at the beginning of the new millennium, a reversed tendency, marked among others by a more stringent law-enforcement, set in. The presentation examines the question of where adolescents and young adults obtained cannabis, within the context of this societal change. In addition, it compares the sources of supply for cannabis with those found in studies of other European countries. Methods: Analyses are based on data from the Swiss Cannabis Monitoring Study. As part of this longitudinal, representative population survey, more than 5000 adolescents and young adults were interviewed by telephone on the topic of cannabis. Within the total sample, 593 (2004) or 554 (2007) respectively, current cannabis users replied to the questions on sources of supply. Changes in law-enforcement and societal climate concerning cannabis are assessed based on relevant literature, media reports and parliamentary discussions. Results: Whereas 22% of cannabis users stated in 2004 that they bought their cannabis from vendors in hemp shops, this proportion drastically decreased to 6% three years later. At the same time, cannabis was obtained increasingly from friends, while the proportion of users who purchased cannabis from dealers in the alleyway, more than doubled from 6% (2004) to 13% (2007). It was male cannabis users, and in particular, young adult and frequent users, who have moved into the alleyways. Generally, users who buy cannabis in the alleyway show more cannabis-related problems than those who mainly name other sources of supply, even when adjusted for sex, age and frequency of cannabis use. Discussion: Possible consequences of these changes in cannabis supply, like the risk of merging a previously cannabis-only market with other 'harder' drugs markets, are discussed.

SOCS-1 protein prevents Janus Kinase/STAT-dependent inhibition of beta cell insulin gene transcription and secretion in response to interferon-gamma.

In the pathogenesis of type I diabetes mellitus, activated leukocytes infiltrate pancreatic islets and induce beta cell dysfunction and destruction. Interferon (IFN)-gamma, tumor necrosis factor-alpha and interleukin (IL)-1 beta play important, although not completely defined, roles in these mechanisms. Here, using the highly differentiated beta Tc-Tet insulin-secreting cell line, we showed that IFN-gamma dose- and time-dependently suppressed insulin synthesis and glucose-stimulated secretion. As described previously IFN-gamma, in combination with IL-1 beta, also induces inducible NO synthase expression and apoptosis (Dupraz, P., Cottet, S., Hamburger, F., Dolci, W., Felley-Bosco, E., and Thorens, B. (2000) J. Biol. Chem. 275, 37672--37678). To assess the role of the Janus kinase/signal transducer and activator of transcription (STAT) pathway in IFN-gamma intracellular signaling, we stably overexpressed SOCS-1 (suppressor of cytokine signaling-1) in the beta cell line. We demonstrated that SOCS-1 suppressed cytokine-induced STAT-1 phosphorylation and increased cellular accumulation. This was accompanied by a suppression of the effect of IFN-gamma on: (i) reduction in insulin promoter-luciferase reporter gene transcription, (ii) decrease in insulin mRNA and peptide content, and (iii) suppression of glucose-stimulated insulin secretion. Furthermore, SOCS-1 also suppressed the cellular effects that require the combined presence of IL-1 beta and IFN-gamma: induction of nitric oxide production and apoptosis. Together our data demonstrate that IFN-gamma is responsible for the cytokine-induced defect in insulin gene expression and secretion and that this effect can be completely blocked by constitutive inhibition of the Janus kinase/STAT pathway.

A gamma camera count rate saturation correction method for whole-body planar imaging.

Whole-body (WB) planar imaging has long been one of the staple methods of dosimetry, and its quantification has been formalized by the MIRD Committee in pamphlet no 16. One of the issues not specifically addressed in the formalism occurs when the count rates reaching the detector are sufficiently high to result in camera count saturation. Camera dead-time effects have been extensively studied, but all of the developed correction methods assume static acquisitions. However, during WB planar (sweep) imaging, a variable amount of imaged activity exists in the detector's field of view as a function of time and therefore the camera saturation is time dependent. A new time-dependent algorithm was developed to correct for dead-time effects during WB planar acquisitions that accounts for relative motion between detector heads and imaged object. Static camera dead-time parameters were acquired by imaging decaying activity in a phantom and obtaining a saturation curve. Using these parameters, an iterative algorithm akin to Newton's method was developed, which takes into account the variable count rate seen by the detector as a function of time. The algorithm was tested on simulated data as well as on a whole-body scan of high activity Samarium-153 in an ellipsoid phantom. A complete set of parameters from unsaturated phantom data necessary for count rate to activity conversion was also obtained, including build-up and attenuation coefficients, in order to convert corrected count rate values to activity. The algorithm proved successful in accounting for motion- and time-dependent saturation effects in both the simulated and measured data and converged to any desired degree of precision. The clearance half-life calculated from the ellipsoid phantom data was calculated to be 45.1 h after dead-time correction and 51.4 h with no correction; the physical decay half-life of Samarium-153 is 46.3 h. Accurate WB planar dosimetry of high activities relies on successfully compensating for camera saturation which takes into account the variable activity in the field of view, i.e. time-dependent dead-time effects. The algorithm presented here accomplishes this task.

The IFN gamma receptor: a paradigm for cytokine receptor signaling.

During the last several years, the mechanism of IFN gamma-dependent signal transduction has been the focus of intense investigation. This research has recently culminated in the elucidation of a comprehensive molecular understanding of the events that underlie IFN gamma-induced cellular responses. The structure and function of the IFN gamma receptor have been defined. The mechanism of IFN gamma signal transduction has been largely elucidated, and the physiologic relevance of this process validated. Most recently, the molecular events that link receptor ligation to signal transduction have been established. Together these insights have produced a model of IFN gamma signaling that is nearly complete and that serves as a paradigm for signaling by other members of the cytokine receptor superfamily.

Gamma Knife, CyberKnife, TomoTherapy: gadgets or useful tools?

Purpose of reviewThis review provides information and an update on stereotactic radiosurgery (SRS) equipment, with a focus on intracranial lesions and brain neoplasms.Recent findingsGamma Knife radiosurgery represents the gold standard for intracranial radiosurgery, using a dedicated equipment, and has recently evolved with a newly designed technology, Leksell Gamma Knife Perfexion. Linear accelerator-based radiosurgery is more recent, and originally based on existing systems, either adapted or dedicated to radiosurgery. Equipment incorporating specific technologies, such as the robotic CyberKnife system, has been developed. Novel concepts in radiation therapy delivery techniques, such as intensity-modulated radiotherapy, were also developed; their integration with computed tomography imaging and helical delivery has led to the TomoTherapy system. Recent data on the management of intracranial tumors with radiosurgery illustrate the trend toward a larger use and acceptance of this therapeutic modality.SummarySRS has become an important alternative treatment for a variety of lesions. Each radiosurgery system has its advantages and limitations. The 'perfect' and ubiquitous system does not exist. The choice of a radiosurgery system may vary with the strategy and needs of specific radiosurgery programs. No center can afford to acquire every technology, and strategic choices have to be made. Institutions with large neurosurgery and radiation oncology programs usually have more than one system, allowing optimization of the management of patients with a choice of open neurosurgery, radiosurgery, and radiotherapy. Given its minimally invasive nature and increasing clinical acceptance, SRS will continue to progress and offer new advances as a therapeutic tool in neurosurgery and radiotherapy.

Targetting of the ventro-intermediate nucleus using ultra-high field (7T) MRI for gamma knife surgery purposes: A pilot in vivo study on healthy subjects.

INTRODUCTION: Gamma Knife surgery (GKS) is a non-invasive neurosurgical stereotactic procedure, increasingly used as an alternative to open functional procedures. This includes targeting of the ventro-intermediate nucleus of the thalamus (e.g. Vim) for tremor. We currently perform an indirect targeting, as the Vim is not visible on current 3Tesla MRI acquisitions. Our objective was to enhance anatomic imaging (aiming at refining the precision of anatomic target selection by direct visualisation) in patients treated for tremor with Vim GKS, by using high field 7T MRI. MATERIALS AND METHODSH: Five young healthy subjects were scanned on 3 (T1-w and diffusion tensor imaging) and 7T (high-resolution susceptibility weighted images (SWI)) MRI in Lausanne. All images were further integrated for the first time into the Gamma Plan Software(®) (Elekta Instruments, AB, Sweden) and co-registered (with T1 was a reference). A simulation of targeting of the Vim was done using various methods on the 3T images. Furthermore, a correlation with the position of the found target with the 7T SWI was performed. The atlas of Morel et al. (Zurich, CH) was used to confirm the findings on a detailed analysis inside/outside the Gamma Plan. RESULTS: The use of SWI provided us with a superior resolution and an improved image contrast within the basal ganglia. This allowed visualization and direct delineation of some subgroups of thalamic nuclei in vivo, including the Vim. The position of the target, as assessed on 3T, perfectly matched with the supposed one of the Vim on the SWI. Furthermore, a 3-dimensional model of the Vim-target area was created on the basis of the obtained images. CONCLUSION: This is the first report of the integration of SWI high field MRI into the LGP, aiming at the improvement of targeting validation of the Vim in tremor. The anatomical correlation between the direct visualization on 7T and the current targeting methods on 3T (e.g. quadrilatere of Guyot, histological atlases) seems to show a very good anatomical matching. Further studies are needed to validate this technique, both by improving the accuracy of the targeting of the Vim (potentially also other thalamic nuclei) and to perform clinical assessment.

Central and peripheral metabolic changes induced by gamma-hydroxybutyrate.

STUDY OBJECTIVES: Gamma-hydroxybutyrate (GHB) was originally introduced as an anesthetic but was first abused by bodybuilders and then became a recreational or club drug.1 Sodium salt of GHB is currently used for the treatment of cataplexy in patients with narcolepsy. The mode of action and metabolism of GHB is not well understood. GHB stimulates growth hormone release in humans and induces weight loss in treated patients, suggesting an unexplored metabolic effect. In different experiments the effect of GHB administration on central (cerebral cortex) and peripheral (liver) biochemical processes involved in the metabolism of the drug, as well as the effects of the drug on metabolism, were evaluated in mice. DESIGN: C57BL/6J, gamma-aminobutyric acid B (GABAB) knockout and obese (ob/ob) mice were acutely or chronically treated with GHB at 300 mg/kg. MEASUREMENTS AND RESULTS: Respiratory ratio decreased under GHB treatment, independent of food intake, suggesting a shift in energy substrate from carbohydrates to lipids. GHB-treated C57BL/6J and GABAB null mice but not ob/ob mice gained less weight than matched controls. GHB dramatically increased the corticosterone level but did not affect growth hormone or prolactin. Metabolome profiling showed that an acute high dose of GHB did not increase the brain GABA level. In the brain and the liver, GHB was metabolized into succinic semialdehyde by hydroxyacid-oxoacid transhydrogenase. Chronic administration decreased glutamate, s-adenosylhomocysteine, and oxidized gluthathione, and increased omega-3 fatty acids. CONCLUSIONS: Our findings indicate large central and peripheral metabolic changes induced by GHB with important relevance to its therapeutic use.

Carbon isotopic ratio analysis by gas chromatography/combustion/isotope ratio mass spectrometry for the detection of gamma-hydroxybutyric acid (GHB) administration to humans.

Since GHB (gamma-hydroxybutyric acid) is naturally produced in the human body, clinical and forensic toxicologists must be able to discriminate between endogenous levels and a concentration resulting from exposure. To suggest an alternative to the use of interpretative concentration cut-offs, the detection of exogenous GHB in urine specimens was investigated by means of gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS). GHB was isolated from urinary matrix by successive purification on Oasis MCX and Bond Elute SAX solid-phase extraction (SPE) cartridges prior to high-performance liquid chromatography (HPLC) fractioning using an Atlantis dC18 column eluted with a mixture of formic acid and methanol. Subsequent intramolecular esterification of GHB leading to the formation of gamma-butyrolactone (GBL) was carried out to avoid introduction of additional carbon atoms for carbon isotopic ratio analysis. A precision of 0.3 per thousand was determined using this IRMS method for samples at GHB concentrations of 10 mg/L. The (13)C/(12)C ratios of GHB in samples of subjects exposed to the drug ranged from -32.1 to -42.1 per thousand, whereas the results obtained for samples containing GHB of endogenous origin at concentration levels less than 10 mg/L were in the range -23.5 to -27.0 per thousand. Therefore, these preliminary results show that a possible discrimination between endogenous and exogenous GHB can be made using carbon isotopic ratio analyses.

Effects of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals.

Aims/Hypothesis: Glitazones are powerful insulin sensitisers prescribed for the treatment of type 2 diabetes. Their use is, however, associated with fluid retention and an increased risk of congestive heart failure. We previously demonstrated that pioglitazone increases proximal sodium reabsorption in healthy volunteers. This study examines the effects of pioglitazone on renal sodium handling in individuals prone to insulin resistance, i.e. those with diabetes and/or hypertension. Methods: In this double-blind randomised placebo-controlled four-way crossover study, we examined the effects of pioglitazone (45 mg daily during 6 weeks) or placebo on renal, systemic and hormonal responses to changes in sodium intake in 16 individuals, eight with type 2 diabetes and eight with hypertension. Results: Pioglitazone was associated with a rapid increase in body weight and an increase in diurnal proximal sodium reabsorption, without any change in renal haemodynamics or in the modulation of the renin-angiotensin aldosterone system to changes in salt intake. A compensatory increase in brain natriuretic peptide levels was observed. In spite of sodium retention, pioglitazone dissociated the blood-pressure response to salt and abolished salt sensitivity in salt-sensitive individuals. Conclusions/Interpretation: Pioglitazone increases diurnal proximal sodium retention in diabetic and hypertensive individuals. These effects cause fluid retention and may contribute to the increased incidence of congestive heart failure with glitazones.

Quantifying network properties in multi-electrode recordings: spatiotemporal characterization and inter-trial variation of evoked gamma oscillations in mouse somatosensory cortex in vitro.

Linking the structural connectivity of brain circuits to their cooperative dynamics and emergent functions is a central aim of neuroscience research. Graph theory has recently been applied to study the structure-function relationship of networks, where dynamical similarity of different nodes has been turned into a "static" functional connection. However, the capability of the brain to adapt, learn and process external stimuli requires a constant dynamical functional rewiring between circuitries and cell assemblies. Hence, we must capture the changes of network functional connectivity over time. Multi-electrode array data present a unique challenge within this framework. We study the dynamics of gamma oscillations in acute slices of the somatosensory cortex from juvenile mice recorded by planar multi-electrode arrays. Bursts of gamma oscillatory activity lasting a few hundred milliseconds could be initiated only by brief trains of electrical stimulations applied at the deepest cortical layers and simultaneously delivered at multiple locations. Local field potentials were used to study the spatio-temporal properties and the instantaneous synchronization profile of the gamma oscillatory activity, combined with current source density (CSD) analysis. Pair-wise differences in the oscillation phase were used to determine the presence of instantaneous synchronization between the different sites of the circuitry during the oscillatory period. Despite variation in the duration of the oscillatory response over successive trials, they showed a constant average power, suggesting that the rate of expenditure of energy during the gamma bursts is consistent across repeated stimulations. Within each gamma burst, the functional connectivity map reflected the columnar organization of the neocortex. Over successive trials, an apparently random rearrangement of the functional connectivity was observed, with a more stable columnar than horizontal organization. This work reveals new features of evoked gamma oscillations in developing cortex.