Does intravenous Δ9-tetrahydrocannabinol increase dopamine release? A SPET study

Intravenous (IV) Δ9-tetrahydrocannabinol (THC) induces transient psychotic symptoms in healthy subjects and in schizophrenic patients, but the psychotomimetic mechanism is unknown. One possibility is that THC stimulates dopamine (DA) release in the striatum. In this study we tested whether IV THC led to an increase in striatal DA release compared to placebo. We also investigated whether DA release and positive psychotic symptoms were related. Eleven healthy male volunteers completed two 123I-iodobenzamide ([123I]IBZM) single photon emission tomography (SPET) sessions and received IV THC (2.5 mg) or placebo in a randomized counterbalanced order, under double-blind conditions. Analysable data were obtained from nine participants. The Positive and Negative Syndrome Scale (PANSS) was used to rate psychotomimetic effects. Striatal binding index values were calculated using the occipital cortex as a reference region. Both the PANSS positive and general symptoms increased significantly at 30 min following IV THC. There were no significant differences in binding index in the caudate or putamen under THC compared to placebo conditions. Positive psychotic symptoms and DA release were unrelated. THC did not lead to a significant increase in DA release even though the dose was sufficient for participants to have psychotic symptoms. These findings do not support a central role for striatal DA in THC-elicited psychosis.

Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment

Community-based studies suggest that cannabis products that are high in Δ⁹-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600 mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥ 3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ²=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6 ± 18.9%) compared with the CBD group (-0.4% ± 9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.

Consensus statement for inert gas washout measurement using multiple- and single- breath tests

Inert gas washout tests, performed using the single- or multiple-breath washout technique, were first described over 60 years ago. As measures of ventilation distribution inhomogeneity, they offer complementary information to standard lung function tests, such as spirometry, as well as improved feasibility across wider age ranges and improved sensitivity in the detection of early lung damage. These benefits have led to a resurgence of interest in these techniques from manufacturers, clinicians and researchers, yet detailed guidelines for washout equipment specifications, test performance and analysis are lacking. This manuscript provides recommendations about these aspects, applicable to both the paediatric and adult testing environment, whilst outlining the important principles that are essential for the reader to understand. These recommendations are evidence based, where possible, but in many places represent expert opinion from a working group with a large collective experience in the techniques discussed. Finally, the important issues that remain unanswered are highlighted. By addressing these important issues and directing future research, the hope is to facilitate the incorporation of these promising tests into routine clinical practice.

Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women

Intravenous bisphosphonates reduce fracture risk but have been associated in rare cases with deteriorating renal-function in cancer patients. The renal effects of zoledronic acid were assessed in osteoporotic postmenopausal women from 27 countries who received three annual infusions of zoledronic acid or a placebo in a randomized, double-blind trial. Serum creatinine, estimated creatinine clearance and urinary protein were measured before and after at least one infusion in a predefined renal safety cohort of 5035 equally divided patients. This group was compared to 7714 patients whose parameters were measured annually. Significantly more transient pre- to post-infusion increases in serum creatinine occurred in zoledronic acid than placebo-treated patients with significant elevations, relative to pre-infusion, only in the second year. All 31 zoledronic acid and 8 of 10 patients on placebo recovered their pre-infusion serum creatinine value within 12 months. No differences in mean changes in serum creatinine, estimated creatinine clearance or adverse renal events were found. We found that transient changes in renal function can occur following an annual zoledronic acid infusion but, in the long term, renal function was not different from control patients.

CCN2/CTGF is required for matrix organization and to protect growth plate chondrocytes from cellular stress

CCN2 (connective tissue growth factor (CTGF/CCN2)) is a matricellular protein that utilizes integrins to regulate cell proliferation, migration and survival. The loss of CCN2 leads to perinatal lethality resulting from a severe chondrodysplasia. Upon closer inspection of Ccn2 mutant mice, we observed defects in extracellular matrix (ECM) organization and hypothesized that the severe chondrodysplasia caused by loss of CCN2 might be associated with defective chondrocyte survival. Ccn2 mutant growth plate chondrocytes exhibited enlarged endoplasmic reticula (ER), suggesting cellular stress. Immunofluorescence analysis confirmed elevated stress in Ccn2 mutants, with reduced stress observed in Ccn2 overexpressing transgenic mice. In vitro studies revealed that Ccn2 is a stress responsive gene in chondrocytes. The elevated stress observed in Ccn2-/- chondrocytes is direct and mediated in part through integrin α5. The expression of the survival marker NFκB and components of the autophagy pathway were decreased in Ccn2 mutant growth plates, suggesting that CCN2 may be involved in mediating chondrocyte survival. These data demonstrate that absence of a matricellular protein can result in increased cellular stress and highlight a novel protective role for CCN2 in chondrocyte survival. The severe chondrodysplasia caused by the loss of CCN2 may be due to increased chondrocyte stress and defective activation of autophagy pathways, leading to decreased cellular survival. These effects may be mediated through nuclear factor κB (NFκB) as part of a CCN2/integrin/NFκB signaling cascade.

Differences in primary sites of infection between zoonotic and human tuberculosis: results from a worldwide systematic review.

Tuberculosis (TB) is one of the most devastating infectious diseases worldwide. Whilst global burden estimates for M. tuberculosis infection (MtTB) are well established, accurate data on the contribution of zoonotic TB (zTB) caused by M. bovis or M. caprae to human TB are scarce. The association of M. bovis infection with extrapulmonary tuberculosis has been suggested repeatedly, though there is little scientific evidence available to support this relationship. The present study aimed to determine globally the occurrence of extrapulmonary TB and the primary site (i.e. primary body location affected) of zTB in comparison with MtTB, based on previously published reports. A systematic literature review was conducted in 32 different bibliographic databases, selecting reports on zTB written in English, French, German, Spanish or Portuguese. Data from 27 reports from Africa, America, Europe and the Western Pacific Region were extracted for analyses. Low income countries, in Africa and South-East Asia, were highly underrepresented in the dataset. The median proportion of extrapulmonary TB cases was significantly increased among zTB in comparison with data from registries of Europe and USA, reporting mainly MtTB cases (47% versus 22% in Europe, 73% versus 30% in the USA). These findings were confirmed by analyses of eight studies reporting on the proportions of extrapulmonary TB in comparable populations of zTB and MtTB cases (median 63% versus 22%). Also, disparities of primary sites of extrapulmonary TB between zTB and MtTB were detected. Our findings, based on global data, confirm the widely suggested association between zTB and extrapulmonary disease. Different disability weights for zTB and MtTB should be considered and we recommend separate burden estimates for the two diseases.

Zoonotic Mycobacterium bovis-induced tuberculosis in humans.

We aimed to estimate the global occurrence of zoonotic tuberculosis (TB) caused by Mycobacterium bovis or M. caprae infections in humans by performing a multilingual, systematic review and analysis of relevant scientific literature of the last 2 decades. Although information from many parts of the world was not available, data from 61 countries suggested a low global disease incidence. In regions outside Africa included in this study, overall median proportions of zoonotic TB of ≤1.4% in connection with overall TB incidence rates ≤71/100,000 population/year suggested low incidence rates. For countries of Africa included in the study, we multiplied the observed median proportion of zoonotic TB cases of 2.8% with the continental average overall TB incidence rate of 264/100,000 population/year, which resulted in a crude estimate of 7 zoonotic TB cases/100,000 population/year. These generally low incidence rates notwithstanding, available data indicated substantial consequences of this disease for some population groups and settings.

More than a surprise: The bivalency effect in task switching

When switching tasks, if stimuli are presented that contain features that cue two of the tasks in the set (i.e., bivalent stimuli), performance slowing is observed on all tasks. This generalized slowing extends to tasks in the set which have no features in common with the bivalent stimulus and is referred to as the bivalency effect. In previous work, the bivalency effect was invoked by presenting occasionally occurring bivalent stimuli; therefore, the possibility that the generalized slowing is simply due to surprise (as opposed to bivalency) has not yet been discounted. This question was addressed in two task switching experiments where the occasionally occurring stimuli were either bivalent (bivalent version) or merely surprising (surprising version). The results confirmed that the generalized slowing was much greater in the bivalent version of both experiments, demonstrating that the magnitude of this effect is greater than can be accounted for by simple surprise. This set of results confirms that slowing task execution when encountering bivalent stimuli may be fundamental for efficient task switching, as adaptive tuning of response style may serve to prepare the cognitive system for possible future high conflict trials.

The past ecology of Abies alba provides new perspectives on future responses of silver fir forests to global warming

Paleoecology can provide valuable insights into the ecology of species that complement observation and experiment-based assessments of climate impact dynamics. New paleoecological records (e.g., pollen, macrofossils) from the Italian Peninsula suggest a much wider climatic niche of the important European tree species Abies alba (silver fir) than observed in its present spatial range. To explore this discrepancy between current and past distribution of the species, we analyzed climatic data (temperature, precipitation, frost, humidity, sunshine) and vegetation-independent paleoclimatic reconstructions (e.g., lake levels, chironomids) and use global coupled carbon-cycle climate (NCAR CSM1.4) and dynamic vegetation (LandClim) modeling. The combined evidence suggests that during the mid-Holocene (6000 years ago), prior to humanization of vegetation, A. alba formed forests under conditions that exceeded the modern (1961-1990) upper temperature limit of the species by 5-7°C (July means). Annual precipitation during this natural period was comparable to today (>700-800 mm), with drier summers and wetter winters. In the meso-Mediterranean to sub-Mediterranean forests A. alba co-occurred with thermophilous taxa such as Quercus ilex, Q. pubescens, Olea europaea, Phillyrea, Arbutus, Cistus, Tilia, Ulmus, Acer, Hedera helix, Ilex aquifolium, Taxus, and Vitis. Results from the last interglacial (ca. 130 000-115 000 BP), when human impact was negligible, corroborate the Holocene evidence. Thermophilous Mediterranean A. alba stands became extinct during the last 5000 years when land-use pressure and specifically excessive anthropogenic fire and browsing disturbance increased. Our results imply that the ecology of this key European tree species is not yet well understood. On the basis of the reconstructed realized climatic niche of the species, we anticipate that the future geographic range of A. alba may not contract regardless of migration success, even if climate should become significantly warmer than today with summer temperatures increasing by up to 5-7°C, as long as precipitation does not fall below 700-800 mm/yr, and anthropogenic disturbance (e.g., fire, browsing) does not become excessive. Our finding contradicts recent studies that projected range contractions under global-warming scenarios, but did not factor how millennia of human impacts reduced the realized climatic niche of A. alba.

La laesio enormis, la sua eredità e i suoi eredi

La laesio enormis (C. 4.44.2 [a. 285]; C. 4.44.8 [a. 293]) fu un’innovazione dioclezianea nel diritto privato romano; si trattò però di un’eccezione alla regola che permetteva di stabilire liberamente i prezzi (cfr. Ulp. D. 4.4.16.4; Paul. D. 19.2.22.3). Da allora il suo ambito applicativo si è notevolmente esteso e la laesio enormis, come eredità del diritto romano, ha esercitato una grande influenza fino alla seconda metà dell’800, epoca in cui il pensiero giuridico l’ha respinta condannandola in quanto in contraddizione con il principio della libertà contrattuale. Conseguentemente l’ha sostituita con la moderna lesione (Übervorteilung), un istituto volto a sanzionare contratti con sproporzione tra le prestazioni, conclusi sfruttando debolezze della controparte. La relazione mira ad esaminare la strada che la lesione si è fatta contemporaneamente fra Scilla della libertà (Vertragsfreiheit) e Cariddi della giustizia contrattuale (materielle Vertragsgerechtigkeit). Soprattutto saranno indagate sia la particolare posizione della laesio enormis nel diritto romano all’interno del titolo C. 4.44 de rescind. vend. sia le sue conseguenze giuridiche (Rechtsfolgen) nella prospettiva storico-comparata. Come ha dimostrato F. Bydlinski, uno studio sulla composizione delle conseguenze giuridiche contribuisce a una migliore comprensione della funzione che un istituto svolge nel diritto privato (Über prinzipiell-systematische Rechtsfindung im Privatrecht, 1995).

La laesio enormis e la stabilità contrattuale

La laesio enormis (C. 4.44.2 [a. 285]; C. 4.44.8 [a. 293]) fu un’innovazione dioclezianea nel diritto privato romano; si trattò però di un’eccezione alla regola che permetteva di stabilire liberamente i prezzi (cfr. Ulp. D. 4.4.16.4; Paul. D. 19.2.22.3). Da allora il suo ambito applicativo si è notevolmente esteso e la laesio enormis, come eredità del diritto romano, ha esercitato una grande influenza fino alla seconda metà dell’800, epoca in cui il pensiero giuridico l’ha respinta condannandola in quanto in contraddizione con il principio della libertà contrattuale. Conseguentemente l’ha sostituita con la moderna lesione (Übervorteilung), un istituto volto a sanzionare contratti con sproporzione tra le prestazioni, conclusi sfruttando debolezze della controparte. La relazione mira ad esaminare la strada che la lesione si è fatta contemporaneamente fra Scilla della libertà (Vertragsfreiheit) e Cariddi della giustizia contrattuale (materielle Vertragsgerechtigkeit). Soprattutto saranno indagate sia la particolare posizione della laesio enormis nel diritto romano all’interno del titolo C. 4.44 de rescind. vend. sia le sue conseguenze giuridiche (Rechtsfolgen) nella prospettiva storico-comparata. Come ha dimostrato F. Bydlinski, uno studio sulla composizione delle conseguenze giuridiche contribuisce a una migliore comprensione della funzione che un istituto svolge nel diritto privato (Über prinzipiell-systematische Rechtsfindung im Privatrecht, 1995).