Superstitious conditioning as a model of delusion formation following chronic but not acute ketamine in humans

Background

Ketamine has previously been shown to induce delusion-like or referential beliefs, both acutely in healthy volunteers and naturalistically among nonintoxicated users of the drug. Delusions are theoretically underpinned by increased superstitious conditioning or the erroneous reinforcement of random events.

Materials and methods

Using a novel and objectively measured superstitious conditioning task, experiment 1 assessed healthy volunteers before and during placebo (n?=?16), low-dose (n?=?15), and high-dose ketamine (n?=?16) under randomized and double-blind conditions. Experiment 2 used the same task to compare ketamine users (n?=?18), polydrug controls (n?=?19), and nondrug-using controls (n?=?17).

Results

In experiment 1, ketamine produced dose-dependent psychotomimetic effects but did not cause changes in superstitious conditioning. Experiment 2 found increased levels of superstitious conditioning among ketamine users compared to polydrug and nondrug-using controls, respectively, as evidenced by both objective task responses and subjective beliefs following the task.

Conclusions

Results indicate that chronic but not acute exposure to ketamine may increase the propensity to adopt superstitious conditioning. These findings are discussed in terms of acute and chronic ketamine models of delusion-like belief formation in schizophrenia.     

Taurine prevents arsenic-induced cardiac oxidative stress and apoptotic damage: Role of NF-κB, p38 and JNK MAPK pathway

Cardiac dysfunction is a major cause of morbidity and mortality worldwide due to its complex pathogenesis. However, little is known about the mechanism of arsenic-induced cardiac abnormalities and the use of antioxidants as the possible protective agents in this pathophysiology. Conditionally essential amino acid, taurine, accounts for 25% to 50% of the amino acid pool in myocardium and possesses antioxidant properties. The present study has, therefore, been carried out to investigate the underlying mechanism of the beneficial role of taurine in arsenic-induced cardiac oxidative damage and cell death. Arsenic reduced cardiomyocyte viability, increased reactive oxygen species (ROS) production and intracellular calcium overload, and induced apoptotic cell death by mitochondrial dependent caspase-3 activation and poly-ADP ribose polymerase (PARP) cleavage. These changes due to arsenic exposure were found to be associated with increased IKK and NF-κB (p65) phosphorylation. Pre-exposure of myocytes to an IKK inhibitor (PS-1145) prevented As-induced caspase-3 and PARP cleavage. Arsenic also markedly increased the activity of p38 and JNK MAPKs, but not ERK to that extent. Pre-treatment with SP600125 (JNK inhibitor) and SB203580 (p38 MAPK inhibitor) attenuated NF-κB and IKK phosphorylation indicating that p38 and JNK MAPKs are mainly involved in arsenic-induced NF-κB activation. Taurine treatment suppressed these apoptotic actions, suggesting that its protective role in arsenic-induced cardiomyocyte apoptosis is mediated by attenuation of p38 and JNK MAPK signaling pathways. Similarly, arsenic intoxication altered a number of biomarkers related to cardiac oxidative stress and other apoptotic indices in vivo and taurine supplementation could reduce it. Results suggest that taurine prevented arsenic-induced myocardial pathophysiology, attenuated NF-κB activation via IKK, p38 and JNK MAPK signaling pathways and could possibly provide a protection against As-induced cardiovascular burden.     

Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy

Cardiac hypertrophy is a common response to injury and hemodynamic stress and an important harbinger of heart failure and death. Herein, we identify the Kruppel-like factor 15 (KLF15) as an inhibitor of cardiac hypertrophy. Myocardial expression of KLF15 is reduced in rodent models of hypertrophy and in biopsy samples from patients with pressure-overload induced by chronic valvular aortic stenosis. Overexpression of KLF15 in neonatal rat ventricular cardiomyocytes inhibits cell size, protein synthesis and hypertrophic gene expression. KLF15-null mice are viable but, in response to pressure overload, develop an eccentric form of cardiac hypertrophy characterized by increased heart weight, exaggerated expression of hypertrophic genes, left ventricular cavity dilatation with increased myocyte size, and reduced left ventricular systolic function. Mechanistically, a combination of promoter analyses and gel-shift studies suggest that KLF15 can inhibit GATA4 and myocyte enhancer factor 2 function. These studies identify KLF15 as part of a heretofore unrecognized pathway regulating the cardiac response to hemodynamic stress.     

Ecological feedbacks following deforestation create the potential for a catastrophic ecosystem shift in tropical dry forest

The long-term ecological response to recurrent deforestation associated with shifting cultivation remains poorly investigated, especially in the dry tropics. We present a study of phosphorus (P) dynamics in the southern Yucatán, highlighting the possibility of abrupt shifts in biogeochemical cycling resulting from positive feedbacks between vegetation and its limiting resources. After three cultivation–fallow cycles, available soil P declines by 44%, and one-time P inputs from biomass burning decline by 76% from mature forest levels. Interception of dust-borne P (“canopy trapping”) declines with lower plant biomass and leaf area, limiting deposition in secondary forest. Potential leaching losses are greater in secondary than in mature forest, but the difference is very small compared with the difference in P inputs. The decline in new P from atmospheric deposition creates a long-term negative ecosystem balance for phosphorus. The reduction in soil P availability will feed back to further limit biomass recovery and may induce a shift to sparser vegetation. Degradation induced by hydrological and biogeochemical feedbacks on P cycling under shifting cultivation will affect farmers in the near future. Without financial support to encourage the use of fertilizer, farmers could increase the fallow period, clear new land, or abandon agriculture for off-farm employment. Their response will determine the regional balance between forest loss and forest regrowth, as well as the frequency of use and rate of recovery at a local scale, further feeding back on ecological processes at multiple scales.     

Application of sensitive enzymeimmunoassay for determination of cortisol in blood plasma of yaks (Poephagus grunniens L.)

As an alternative to radioimmunoassays, a simple, highly sensitive and quick enzymeimmunoassay (EIA) for determination of cortisol in blood plasma of yaks on microtiterplates using second antibody coating technique and cortisol-horseradish peroxidase as a label has been developed. The wells of the microtiterplate were coated with affinity-purified goat IgG (antirabbit IgG) that binds the hormone specific antibody. The EIA was carried out directly in 20 microl of heat treated plasma after 1:5 dilution with PBS. The cortisol standard curve, with doses ranged from 0.4 to 100 pg/well. The sensitivity of the assay was 20 pg/ml. Cortisol standard curve in buffer showed parallelism with serially diluted yak plasma containing high endogenous cortisol. Intra- and inter-assay coefficients of variation (CV) determined using pooled plasma was found 6.58 and 11.35%, respectively. Recovery of known concentrations of added cortisol in charcoal stripped plasma was linear (r = 0.98). For biological validation of cortisol enzymeimmunoassay, the blood samples were collected from yak cows at -48 and -24h before and 0, 12, 24, 36, 48, 60, 72, 84 and 96 h after dexamethasone administration. The plasma cortisol before dexamethasone administration was significantly (P < 0.05) higher than after dexamethasone administration. The developed EIA was further validated biologically by estimating cortisol in peri-parturient cows beginning day 10 prior to calving till day 10 post-calving; the concentrations were along with the expected lines as reported in bovine. In conclusion, the EIA developed in this study is simple, highly sensitive, valid and sufficiently reliable method for estimation of cortisol directly in bovine plasma.     

Pulmonary embolism: computer-aided detection at multidetector row spiral computed tomography

BACKGROUND: We aimed to evaluate the feasibility and performance of a computer-aided detection (CAD) tool for automated detection of segmental and subsegmental pulmonary emboli. METHODS: A CAD tool (ImageChecker CT, R2 Technology, Inc) for automated detection of pulmonary emboli was evaluated on multidetector-row CT studies of varying diagnostic quality in 23 patients (13 female, mean age 52 y) with pulmonary embolism (PE) and of 13 patients (all female, mean age 49 y) without PE. A collimation of 16 x 1 mm and a reconstructed section width of 1.25 mm had been used in each patient. The performance of the CAD tool for the detection of emboli in the segmental and subsegmental pulmonary arterial tree was assessed. Consensus reading of the same studies by 2 radiologists, with a third for adjudication, for the identification of segmental and subsegmental pulmonary emboli was used as the standard of reference. RESULTS: Consensus reading revealed 130 segmental pulmonary emboli and 107 subsegmental pulmonary emboli in the 23 patients with PE. All 23 patients with PE were correctly identified as having PE by the CAD system. In a vessel-by-vessel analysis, the sensitivity of the CAD algorithm was 92% (119/130) for the detection of segmental pulmonary emboli and 90% (92/107) for subsegmental pulmonary emboli. The overall specificity, positive predictive value (95% confidence interval) and negative predictive value (95% confidence interval) of the algorithm were 89.9%, 63.2% (57.9%-68.2%) and 97.7% (96.7%-98.4%), respectively. The average false positive rate of the CAD algorithm was 4.8 (range 1 to 9) false positive detection marks per case. CONCLUSION: CAD of segmental and subsegmental pulmonary emboli based on 1-mm multidetector-row CT studies is feasible. Application of CAD tools may improve the diagnostic accuracy and decrease the interpretation time of computed tomographic angiography for the detection of pulmonary emboli in the peripheral arterial tree and further enhance the acceptance of this test as the first line diagnostic modality for suspected PE.     

The clinical significance of the spectrum of interactions of CAP+1 (A-->C), a silent beta-globin gene mutation, with other beta-thalassemia mutations and globin gene modifiers in north Indians

OBJECTIVES: To assess the clinical significance of the interactions of CAP+1 (A-->C), a silent beta-globin gene mutation, with other beta-thalassemia mutations and globin gene modifiers in north Indians. METHODS: The clinical phenotypes associated with compound heterozygosity for the CAP+1 (A-->C) mutation with other beta-thalassemia mutations, together with the potential effect of the genetic modifiers alpha-thalassemia and the Xmn-1(G)gamma C-->T polymorphism were studied in 30 patients. The frequency of the CAP+1 (A-->C) polymorphism was determined and an analysis of the red cell indices, HbA(2) levels, iron status, and alpha-globin genes was carried out in 35 heterozygotes. RESULTS: Based on an analysis of 1075 beta-thalassemia alleles the CAP+1 (A-->C) mutation constituted 3.2% of north Indians. There was a wide spectrum of phenotypic severity in compound heterozygotes; 18 of 30 were transfusion dependent. There was a very high frequency of the -/- genotype of the Xmn-1(G)gamma polymorphism in compound heterozygotes. Analysis of 35 heterozygotes indicated that approximately half were hematologically normal and therefore genuine 'silent' carriers. CONCLUSIONS: Compound heterozygotes for CAP+1 (A-->C) and other severe beta-thalassemia alleles are phenotypically severe enough to necessitate appropriate therapy and counseling. The unexpected severity of these interactions may be due, in part, to the high frequency of beta-thalassemia alleles associated with the Xmn-1(G)gamma- allele in Indian populations. It is concluded that the CAP+1 (A-->C) mutation can pose serious difficulties in screening and counseling programs in populations in which it occurs at a significant frequency.