Effects of psilocybin therapy on personality structure.

OBJECTIVE: To explore whether psilocybin with psychological support modulates personality parameters in patients suffering from treatment-resistant depression (TRD). METHOD: Twenty patients with moderate or severe, unipolar, TRD received oral psilocybin (10 and 25 mg, one week apart) in a supportive setting. Personality was assessed at baseline and at 3-month follow-up using the Revised NEO Personality Inventory (NEO-PI-R), the subjective psilocybin experience with Altered State of Consciousness (ASC) scale, and depressive symptoms with QIDS-SR16. RESULTS: Neuroticism scores significantly decreased while Extraversion increased following psilocybin therapy. These changes were in the direction of the normative NEO-PI-R data and were both predicted, in an exploratory analysis, by the degree of insightfulness experienced during the psilocybin session. Openness scores also significantly increased following psilocybin, whereas Conscientiousness showed trend-level increases, and Agreeableness did not change. CONCLUSION: Our observation of changes in personality measures after psilocybin therapy was mostly consistent with reports of personality change in relation to conventional antidepressant treatment, although the pronounced increases in Extraversion and Openness might constitute an effect more specific to psychedelic therapy. This needs further exploration in future controlled studies, as do the brain mechanisms of postpsychedelic personality change.

Fire, climate and vegetation linkages in the Bolivian Chiquitano seasonally dry tropical forest.

South American seasonally dry tropical forests (SDTFs) are critically endangered, with only a small proportion of their original distribution remaining. This paper presents a 12 000 year reconstruction of climate change, fire and vegetation dynamics in the Bolivian Chiquitano SDTF, based upon pollen and charcoal analysis, to examine the resilience of this ecosystem to drought and fire. Our analysis demonstrates a complex relationship between climate, fire and floristic composition over multi-millennial time scales, and reveals that moisture variability is the dominant control upon community turnover in this ecosystem. Maximum drought during the Early Holocene, consistent with regional drought reconstructions, correlates with a period of significant fire activity between 8000 and 7000 cal yr BP which resulted in a decrease in SDTF diversity. As fire activity declined but severe regional droughts persisted through the Middle Holocene, SDTFs, including Anadenanthera and Astronium, became firmly established in the Bolivian lowlands. The trend of decreasing fire activity during the last two millennia promotes the idea among forest ecologists that SDTFs are threatened by fire. Our analysis shows that the Chiquitano seasonally dry biome has been more resilient to Holocene changes in climate and fire regime than previously assumed, but raises questions over whether this resilience will continue in the future under increased temperatures and drought coupled with a higher frequency anthropogenic fire regime.This article is part of the themed issue 'The interaction of fire and mankind'.

The application of medical informatics to the veterinary management programs at companion animal practices in Alberta, Canada: a case study.

Companion animals closely share their domestic environment with people and have the potential to, act as sources of zoonotic diseases. They also have the potential to be sentinels of infectious and noninfectious, diseases. With the exception of rabies, there has been minimal ongoing surveillance of, companion animals in Canada. We developed customized data extraction software, the University of, Calgary Data Extraction Program (UCDEP), to automatically extract and warehouse the electronic, medical records (EMR) from participating private veterinary practices to make them available for, disease surveillance and knowledge creation for evidence-based practice. It was not possible to build, generic data extraction software; the UCDEP required customization to meet the specific software, capabilities of the veterinary practices. The UCDEP, tailored to the participating veterinary practices', management software, was capable of extracting data from the EMR with greater than 99%, completeness and accuracy. The experiences of the people developing and using the UCDEP and the, quality of the extracted data were evaluated. The electronic medical record data stored in the data, warehouse may be a valuable resource for surveillance and evidence-based medical research.

The Tayside insulin management course: an effective education programme in type 1 diabetes.

AIMS: The Tayside insulin management (TIM) course is an intensive insulin management programme for adults with type 1 diabetes. The aim was to assess its effectiveness. METHODS: Haemoglobin A1c (HbA1c) and body mass index (BMI) from individuals with type 1 diabetes were collected 3 months before, and 6 and 24 months after the programme. The programme involved a full day of education per week for 4 weeks in a row. Quality of life was assessed using the standardised Audit of Diabetes-Dependent Quality of Life (ADDQoL) questionnaire completed both before and 3 months after the course. Subjects were also asked to complete a pre- and postcourse questionnaire gathering information about aspects of their diabetes management. In addition, individual satisfaction with course content and delivery was recorded. RESULTS: Participants had a median reduction in haemoglobin A1c (HbA1c) of 4 mmol/mol (0.4%) after 6 months and 5 mmol/mol (0.5%) 2 years after the course (p < 0.001). Mean daily dose of short-acting insulin decreased from 31.5 (1.9) units to 27.3 (1.9, p < 0.001). There was no significant change in BMI. There was an improvement in all 18 domains of the ADDQoL questionnaire. There was a decrease in hypoglycaemia unawareness from 34.3 ± 47.8% of patients to 8.6 ± 28% (p < 0.001), and a decrease in self-reported lipohypertrophy from 27.8% to 11.1% (p = 0.001). There was a significant reduction in the mean number of diabetic ketoacidosis and severe hypoglycaemic episodes. The number of blood glucose checks changed from 2.8 ± 2.1 to 3.2 ± 1.1 (p = 0.058) per day. Participant satisfaction with all aspects of course content and delivery was high. CONCLUSIONS: TIM is an effective intensive education programme for patients with type 1 diabetes.

Neural stem cells reduce hippocampal tau and reelin accumulation in aged Ts65Dn Down syndrome mice.

Tau accumulation, in the form of neurofibrillary tangles (NFT), is an early neuropathological characteristic of Alzheimer's disease (AD) and early onset AD frequently seen in Down syndrome (DS). We investigated the presence of tau accumulation in the brains of aging DS mice using the Ts65Dn mouse model. All aged mice appeared to have substantial clusters of extracellular granules that were positive for tau and reelin, but not for amyloid-ß or APP. These clusters were found primarily in CA1 of the hippocampus. In addition, the aged trisomic DS mice had a significantly greater accumulation of extracellular tau/reelin granular deposits compared to disomic littermates. These granules were similar to those described by others who also found extracellular proteinous granules in the brains of non-DS mice engineered to model aging and/or AD. When neural stem cells (NSC) were implanted unilaterally into the hippocampus of the Ts65Dn mice, the tau/reelin-positive granules were significantly reduced in both trisomic and disomic mice. Our findings indicate that changes in tau/reelin-positive granules could be used as an index for neuropathological assessment in aging DS and AD. Furthermore, changes in granule density could be used to test the efficacy of novel treatments, such as NSC implantation. Lastly, it is speculated that the unique abilities of NSC to migrate and express growth factors might be a contributing factor to reducing tau/reelin accumulation in aging DS and AD.

Putting Haptics into the Ambience.

In an attentionally overloaded world, relief will come only from interfaces between humans and computation that are able to provide information in the background of our sensory and cognitive processes. Haptic displays may have a special role to play in this emerging movement toward ambient interfaces, because the touch sense is well suited to present many types of information in a way that treads lightly on our mental resources. This paper offers an introduction to the notion of ambient information display, and explores why and how the haptic channel could contribute. It begins with a discussion of the attentional problems posed by contemporary interface technology, and a broad overview of ambient interfaces themselves: their purpose, specification, features, and some general examples. Sense is made of the haptic ambient design space through a morphology of the functionality and social configurations exhibited by existing and envisioned examples. Finally, reflections on design principles and challenges for ambient haptic interfaces are aimed at inspiring, shaping, and informing future development in this area.

Designing for Feel: Contrasts between Human and Automated Parametric Capture of Knob Physics.

We examine a crucial aspect of a tool intended to support designing for feel: the ability of an objective physical-model identification method to capture perceptually relevant parameters, relative to human identification performance. The feel of manual controls, such as knobs, sliders, and buttons, becomes critical when these controls are used in certain settings. Appropriate feel enables designers to create consistent control behaviors that lead to improved usability and safety. For example, a heavy knob with stiff detents for a power plant boiler setting may afford better feedback and safer operations, whereas subtle detents in an automobile radio volume knob may afford improved ergonomics and driver attention to the road. To assess the quality of our identification method, we compared previously reported automated model captures for five real mechanical reference knobs with captures by novice and expert human participants who were asked to adjust four parameters of a rendered knob model to match the feel of each reference knob. Participants indicated their satisfaction with the matches their renderings produced. We observed similar relative inertia, friction, detent strength, and detent spacing parameterizations by human experts and our automatic estimation methods. Qualitative results provided insight on users' strategies and confidence. While experts (but not novices) were better able to ascertain an underlying model in the presence of unmodeled dynamics, the objective algorithm outperformed all humans when an appropriate physical model was used. Our studies demonstrate that automated model identification can capture knob dynamics as perceived by a human, and they also establish limits to that ability; they comprise a step towards pragmatic design guidelines for embedded physical interfaces in which methodological expedience is informed by human perceptual requirements.

Electrical control of spin relaxation in a quantum dot.

We demonstrate electrical control of the spin relaxation time T1 between Zeeman-split spin states of a single electron in a lateral quantum dot. We find that relaxation is mediated by the spin-orbit interaction, and by manipulating the orbital states of the dot using gate voltages we vary the relaxation rate W identical withT1(-1) by over an order of magnitude. The dependence of W on orbital confinement agrees with theoretical predictions, and from these data we extract the spin-orbit length. We also measure the dependence of W on the magnetic field and demonstrate that spin-orbit mediated coupling to phonons is the dominant relaxation mechanism down to 1 T, where T1 exceeds 1 s.

Foundations of Transparency in Tactile Information Design.

This paper places contemporary literature on the topic of unimodal, single-site display of information using complex tactile signals in the context of progress towards the achievement of transparent communication - placing minimal load on the user's attentional resources. We discuss recent evidence that more is possible with purely haptic display than is commonly believed, as well as procedural developments that support systematic design of transparent tactile information display; and we frame the advances required to realize significant benefits with the technology we have now. Examples used and objectives thus identified focus on establishing effective information representations, and outlining efficient tools and processes for perceptually guiding icon design. Our discussion is inspired by Weiser's vision of calm technology based on locatedness and seamless movement between center and periphery, and it is organized along the lines of potential utility, form and learning.

Betaine supplementation improves the atherogenic risk factor profile in a transgenic mouse model of hyperhomocysteinemia.

OBJECTIVE: To investigate the lipotropic action of betaine on plasma lipoproteins and tissue lipids. METHODS AND RESULTS: Adult mice, wild type (+/+) or heterozygous (+/-) for a disruption of the methylenetetrahydrofolate reductase (Mthfr) gene, were supplemented with betaine for 1 year and compared with mice on control diets. Outcome measures were plasma homocysteine and lipoprotein levels, aortic and liver morphology, and liver staining for 3-nitrotyrosine (oxidative stress marker) and Apolipoprotein A-I (ApoA-I). We also investigated short-term effects of supplemental betaine on plasma lipoproteins in Mthfr +/+ and +/- mice. Both genotypes showed significantly lower plasma homocysteine after long-term betaine supplementation, and lower plasma triglycerides and higher HDL-cholesterol after both short- and long-term betaine. Lipid accumulation in liver and aortic wall tended to be lower in Mthfr+/+ compared to Mthfr+/- mice and in betaine-supplemented compared to unsupplemented mice. Nitrotyrosine staining was higher and ApoA-I staining was lower in livers of Mthfr+/- compared to Mthfr+/+ mice. Betaine did not affect staining of nitrotyrosine but increased ApoA-I staining. A significant negative correlation was observed between plasma homocysteine and liver ApoA-I. CONCLUSIONS: Mild MTHFR deficiency in mice is associated with increased risk for atherosclerotic disease. Betaine has a lipotropic effect, which is associated with a reduction in homocysteine, an increase in ApoA-I and an amelioration of the atherogenic risk profile.

Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression.

The sphingoplipid ceramide is responsible for a diverse range of biochemical and cellular responses including a putative role in modulating cell cycle progression. Herein, we describe that an accumulation of ceramide, achieved through the exogenous application of C(6)-ceramide or exposure to sphingomyelinase, induces a G(2) arrest in Rhabdomyosarcoma (RMS) cell lines. Utilizing the RMS cell line RD, we show that this G(2) arrest required the rapid induction of p21(Cip1/Waf1) independent of DNA damage. This was followed at later time points (48 h) by the commitment to apoptosis. Apoptosis was prevented by Bcl-2 overexpression, but permitted the maintenance of elevated p21(Cip1/Waf1) protein expression and the stabilization of the G(2) arrest response. Inhibition of p21(Cip1/Waf1) protein synthesis with cyclohexamide (CHX) or silencing of p21(Cip1/Waf1) with siRNA, prevented ceramide-mediated G(2) arrest and the late induction of apoptosis. Further, adopting the recent discovery that murine double minute 2 (MDM2) controls p21(Cip1/Waf1) expression by presenting this CDK inhibitor to the proteasome for degradation, RD cells overexpressing MDM2 abrogated ceramide-mediated p21(Cip1/Waf1) induction, G(2) arrest and the late ensuing apoptosis. Collectively, these data further support the notion that ceramide accumulation can modulate cell cycle progression. Additionally, these observations highlight MDM2 expression and proteasomal activity as key determinants of the cellular response to ceramide accumulation.

Energy-dependent tunneling in a quantum dot.

We present measurements of the rates for an electron to tunnel on and off a quantum dot, obtained using a quantum point contact charge sensor. The tunnel rates show exponential dependence on drain-source bias and plunger gate voltages. The tunneling process is shown to be elastic, and a model describing tunneling in terms of the dot energy relative to the height of the tunnel barrier quantitatively describes the measurements.

SLUG (SNAI2) overexpression in embryonic development.

The Snail-related zinc-finger transcription factor, SLUG (SNAI2), is critical for the normal development of neural crest-derived cells and loss-of-function SLUG mutations have been proven to cause piebaldism and Waardenburg syndrome type 2 in a dose-dependent fashion. However, little is known about the consequences of SLUG overexpression in embryonic development. We report SLUG duplication in a child with a unique de novo 8q11.2-->q13.3 duplication associated with tetralogy of Fallot, submucous cleft palate, renal anomalies, hypotonia and developmental delay. To investigate the effects of Slug overexpression on development, we analyzed mice carrying a Slug transgene. These mice were morphologically normal at birth, inferring that Slug overexpression is not sufficient to cause overt morphogenetic defects. In the adult mice, there was a 20% incidence of sudden death, cardiomegaly and cardiac failure associated with incipient mesenchymal tumorigenesis. These findings, while not directly implicating Slug in congenital and acquired heart disease, raise the possibility that Slug overexpression may contribute to specific cardiac phenotypes and cancer development.

Loss of Cited2 affects trophoblast formation and vascularization of the mouse placenta.

Cited2 is widely expressed in the developing embryo and in extraembryonic tissues including the placenta. Gene expression can be induced by a number of factors; most notably by the hypoxia inducible transcription factor, HIF1, under low oxygen conditions. Cited2 encodes for a transcriptional co-factor that in vitro can act as both a positive and negative regulator of transcription. This function is due to its interaction with CBP/p300 and appears to depend on whether Cited2 enables CBP/p300 to interact with the basic transcriptional machinery, or if its binding prevents such an interaction from occurring. Here, we report a novel function for Cited2 in placenta formation, following gene deletion in mouse. In the absence of Cited2 the placenta and embryo are significantly small from 12.5 and 14.5 dpc respectively, and death occurs in utero. Cited2 null placentas have fewer differentiated trophoblast cell types; specifically there is a reduction in trophoblast giant cells, spongiotrophoblasts and glycogen cells. In addition, the fetal vasculature of the placenta is disorganised and there are fewer anastomosing capillaries. Given that Cited2 is expressed in both trophoblasts and the fetal vasculature, the observed defects fit well with the sites of gene expression. We conclude that Cited2 is required for normal placental development and vascularisation, and hence for embryo viability.

Pulmonary haemorrhage and cardiac dysfunction in a neonate with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

UNLABELLED: We report on a favourable case of MCAD deficiency (homozygous 985A > G) that presented as lethargy, poor feeding, pulmonary haemorrhage and cardiac arrest without hypoglycaemia. The cessation of intralipid and the commencement of carnitine supplementation were associated with a rapid clinical improvement. CONCLUSION: Mild carnitine depletion and secondary impairment of long-chain fatty acid metabolism may have contributed to post-asphyxial myocardial dysfunction and ventricular arrhythmias. Metabolic disorders must be kept in mind as a differential diagnosis in acutely ill infants, but it must also be emphasized that carnitine therapy is not uniformly effective in all MCAD patients.

Breaking symmetry: a clinical overview of left-right patterning.

It is increasingly recognized that mutations in genes and pathways critical for left-right (L-R) patterning are involved in common isolated congenital malformations such as congenital heart disease, biliary tract anomalies, renal polycystic disease, and malrotation of the intestine, indicating that disorders of L-R development are far more common than a 1 in 10,000 incidence of heterotaxia might suggest. Understanding L-R patterning disorders requires knowledge of molecular biology, embryology, pediatrics, and internal medicine and is relevant to day-to-day clinical genetics practice. We have reviewed data from mammalian (human and mouse) L-R patterning disorders to provide a clinically oriented perspective that might afford the clinician or researcher additional insights into this diagnostically challenging area.

Kousseff syndrome: a causally heterogeneous disorder.

The existence of Kousseff syndrome as a distinct entity has been thrown into doubt by a recent study conducted on the family originally reported by Kousseff. In all cases where chromosome 22q11.2 FISH testing has been undertaken, including the original sibship, a chromosome 22q11.2-microdeletion has been identified. We report two cases of sacral myelomeningocele associated with a conotruncal cardiac anomaly or "Kousseff syndrome." The first case, a 4-year-old girl, had a sacral myelomeningocele, tetralogy of Fallot, microcephaly, hydrocephalus, hypoplasia of the corpus callosum and mild-moderate developmental delay. Chromosome 22q11.2 FISH was normal and the facial phenotype was not that of velocardiofacial syndrome. Sequencing of the entire coding region of CITED2 did not reveal a mutation. The second case, a male infant, was found to have a 22q11.2-microdeletion. These cases confirm Kousseff syndrome to be a causally heterogeneous disorder.

A variant microcephalic osteodysplastic slender-bone disorder with growth hormone deficiency and a pigmentary retinopathy.

We present the case of a 3-year-old boy with post-natal growth failure, microcephaly, developmental delay, facial dysmorphism, an evolving pigmentary retinopathy, pituitary hypoplasia, micropenis, and growth hormone (GH) deficiency. He has a microcephalic osteodysplastic slender-bone disorder with disharmonic delayed osseous maturation, most closely resembling patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II). Intrauterine growth retardation, a universal finding in the MOPD II, was absent in our patient.

Cellular zinc content is a major determinant of iron chelator-induced apoptosis of thymocytes.

Desferrioxamine (DFO) and the hydroxypiridinone (HPO) deferiprone (CP20) chelate iron as well as other metals. These chelators are used clinically to treat iron overload, but they induce apoptosis in thymocytes. Thymocyte apoptosis is potentiated by zinc deficiency, suggesting that these iron chelators may induce apoptosis by depleting stores of zinc. Exposure of murine thymocytes to either DFO or deferiprone resulted in significant reductions in the labile intracellular zinc pool. Moreover, increasing intracellular zinc levels, by chronic zinc dietary supplementation to mice or in vitro loading with zinc, abrogated deferiprone-induced murine thymocyte apoptosis. Bidentate hydroxypyridinones such as deferiprone interact with intracellular zinc pools in a manner distinct from that of DFO, which is a hexadentate iron chelator. Whereas deferiprone acts synergistically with the zinc chelator NNNN-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) to induce apoptosis, DFO does not. This difference is most likely due to the ability of HPOs but not DFO to "shuttle" zinc onto acceptors such as metallothioneins. By nature of its structure, DFO is larger than deferiprone and is thus less able to access some intracellular zinc pools. Additionally, metal complexes of DFO are more stable than those of HPOs and thus are less likely to donate zinc to other acceptors. The ability of deferiprone to preferentially access zinc pools was also demonstrated by inhibition of a zinc-containing enzyme phospholipase C, particularly when combined with TPEN. These findings suggest that bidentate iron chelators access intracellular zinc pools not available to DFO and that zinc chelation is a mechanism of apoptotic induction by such chelators in thymocytes.