Exploring the relationship between frequent cannabis use, belief updating under uncertainty and psychotic-like symptoms

Background: Cannabis users present an important group for investigating putative mechanisms underlying psychosis, as cannabis-use is associated with an increased risk of psychosis. Recent work suggests that alterations in belief-updating under uncertainty underlie psychosis. We therefore compared belief updating under uncertainty between cannabis and non-cannabis users. Methods: 49 regular cannabis users and 52 controls completed the Space Game, via an online platform used for behavioral testing. In the task, participants were asked to predict the location of the stimulus based on previous information, under different uncertainty conditions. Mixed effects models were used to identify significant predictors of mean score, confidence, performance error and learning rate. Results: Both groups showed decreased confidence in high noise conditions, and increased belief updating in more volatile conditions, suggesting that they could infer the degree and sources of uncertainty. There were no significant effects of group on any of the performance indices. However, within the cannabis group, frequent users showed worse performance than less frequent users. Conclusion: Belief updating under uncertainty is not affected by cannabis use status but could be impaired in those who use cannabis more frequently. This finding could show a similarity between frequent cannabis use and psychosis risk, as predictors for abnormal belief-updating

Adherence to antiparkinsonian medication: An in-depth qualitative study

Background: Adherence to prescribed medication is low. It is a major problem as following practitioners’ recommendations is strongly associated with good patient outcomes. Little research has been undertaken with people in the early stages of Parkinson's disease although achieving symptom control depends on regularly timing doses. Research questions: How do people with Parkinson's disease adhere to prescribed medication, and what are the antecedents of non-adherence to antiparkinsonian medication? Design: Exploratory qualitative study using semi-structured interviews. Setting: Specialist Parkinson's disease clinic in one National Health Service hospital in England. Participants: Fifteen consecutive patients not yet in the advanced stages of Parkinson's disease living at home and responsible for managing their own medication or managing medication with the help of their carer. Methods: Semi-structured interviews with open questions. Findings: Each respondent demonstrated at least one type and in most cases several different types of non-adherent behaviour. Inadvertent minor non-adherence occurred because patients forgot to take tablets or muddled doses. Minor deliberate deviations occurred when patients took occasional extra tablets or brought forward doses to achieve better symptom control, often to cater for situations that were anticipated as especially demanding. Deliberate major non-adherence was very common and always related to over-use of medication. The experiences of parkinsonism were particular to the individual. The specific circumstances that prompted an episode of non-adherence varied between patients. Nevertheless there was evidence of negotiation between respondents and the Parkinson's disease nurse specialist; medication regimes were altered in conjunction with the patient during formal consultations and by telephone. Conclusion: Non-adherence to prescribed medication for people with chronic conditions is complex and for people with Parkinson's disease it was possible to identify different types of non-adherence. The possible existence of a typology of non-adherence for people with other chronic conditions merits investigation. Further research is needed to establish whether the findings of this small scale qualitative study can be replicated with a larger, more representative sample and establish how people with Parkinson's disease might be encouraged to adhere to medication regimes to improve symptom control

Safety & efficacy of lifileucel (LN-144) tumor infiltrating lymphocyte therapy in metastatic melanoma patients after progression on multiple therapies – independent review committee data update

Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both investigator and an independent review committee (IRC), are presented

Phase II trial of the regulatory T cell-depleting agent, denileukin diftitox, in patients with unresectable stage IV melanoma

<p>Abstract</p> <p>Background</p> <p>We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted CD4⁺CD25^HIFoxp3⁺regulatory T cells and expanded melanoma-specific CD8⁺T cells. The goal of this study was to assess the clinical efficacy of DAB/IL2 in an expanded cohort of stage IV melanoma patients.</p> <p>Methods</p> <p>In a single-center, phase II trial, DAB/IL2 (12 μg/kg; 4 daily doses; 21 day cycles) was administered to 60 unresectable stage IV melanoma patients and response rates were assessed using a combination of 2-[¹⁸F]-fluoro-2-deoxy-glucose (FDG)-positron emission tomography (PET) and computed tomography (CT) imaging.</p> <p>Results</p> <p>After DAB/IL2 administration, 16.7% of the 60 patients had partial responses, 5% stable disease and 15% mixed responses. Importantly, 45.5% of the chemo/immuno-naïve sub-population (11/60 patients) experienced partial responses. One year survival was markedly higher in partial responders (80 ± 11.9%) relative to patients with progressive disease (23.7 ± 6.5%; <it>p </it>value < 0.001) and 40 ± 6.2% of the total DAB/IL2-treated population were alive at 1 year.</p> <p>Conclusions</p> <p>These data support the development of multi-center, randomized trials of DAB/IL2 as a monotherapy and in combination with other immunotherapeutic agents for the treatment of stage IV melanoma.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00299689">NCT00299689</a></p

Discrimination against HIV-Infected People and the Spread of HIV: Some Evidence from France

BACKGROUND: Many people living with HIV/AIDS (PLWHA) suffer from stigma and discrimination. There is an ongoing debate, however, about whether stigma, fear and discrimination actually fuel the persisting spread of HIV, or slow it down by reducing contacts between the whole population and high-risk minorities. To contribute to this debate, we analysed the relationship between perceived discrimination and unsafe sex in a large sample of French PLWHAs. METHODOLOGY/PRINCIPAL FINDINGS: In 2003, we conducted a national cross-sectional survey among a random sample of HIV-infected patients. The analysis was restricted to sexually active respondents (N = 2,136). Unsafe sex was defined as sexual intercourse without a condom with a seronegative/unknown serostatus partner during the prior 12 months. Separate analyses were performed for each transmission group (injecting drug use (IDU), homosexual contact, heterosexual contact). Overall, 24% of respondents reported experiences of discrimination in their close social environment (relatives, friends and colleagues) and 18% reported unsafe sex during the previous 12 months. Both prevalences were higher in the IDU group (32% for perceived discrimination, 23% for unsafe sex). In multivariate analyses, experience of discrimination in the close social environment was associated with an increase in unsafe sex for both PLWHAs infected through IDU and heterosexual contact (OR = 1.65 and 1.80 respectively). CONCLUSIONS: Our study clearly confirms a relationship between discrimination and unsafe sex among PLWHAs infected through either IDU or heterosexual contact. This relationship was especially strong in the heterosexual group that has become the main vector of HIV transmission in France, and who is the more likely of sexual mixing with the general population. These results seriously question the hypothesis that HIV-stigma has no effect or could even reduce the infection spread of HIV

HIV-related discrimination reported by people living with HIV in London, UK

The objective was to examine the extent to which people living with HIV in London reported being discriminated against because of their infection. In 2004–2005, people living with HIV attending NHS outpatient HIV clinics in north east London were asked: “Have you ever been treated unfairly or differently because of your HIV status—in other words discriminated against?”. Of the 1,687 people who returned a questionnaire (73% response rate), data from 1,385 respondents were included in this analysis; 448 heterosexual women and 210 heterosexual men of black African origin, 727 gay/bisexual men (621 white, 106 ethnic minority). Overall, nearly one-third of respondents (29.9%, 414/1,385) said they had been discriminated against because of their HIV infection. Of those who reported experiencing HIV-related discrimination, almost a half (49.6%, 200/403) said this had involved a health care worker including their dentist (n = 102, 25.3%) or primary care physician (n = 70, 17.4%)

Reverse Effect of Mammalian Hypocalcemic Cortisol in Fish: Cortisol Stimulates Ca2+ Uptake via Glucocorticoid Receptor-Mediated Vitamin D3 Metabolism

Cortisol was reported to downregulate body-fluid Ca2+ levels in mammals but was proposed to show hypercalcemic effects in teleostean fish. Fish, unlike terrestrial vertebrates, obtain Ca2+ from the environment mainly via the gills and skin rather than by dietary means, and have to regulate the Ca2+ uptake functions to cope with fluctuating Ca2+ levels in aquatic environments. Cortisol was previously found to regulate Ca2+ uptake in fish; however, the molecular mechanism behind this is largely unclear. Zebrafish were used as a model to explore this issue. Acclimation to low-Ca2+ fresh water stimulated Ca2+ influx and expression of epithelial calcium channel (ecac), 11β-hydroxylase and the glucocorticoid receptor (gr). Exogenous cortisol increased Ca2+ influx and the expressions of ecac and hydroxysteroid 11-beta dehydrogenase 2 (hsd11b2), but downregulated 11β-hydroxylase and the gr with no effects on other Ca2+ transporters or the mineralocorticoid receptor (mr). Morpholino knockdown of the GR, but not the MR, was found to impair zebrafish Ca2+ uptake function by inhibiting the ecac expression. To further explore the regulatory mechanism of cortisol in Ca2+ uptake, the involvement of vitamin D3 was analyzed. Cortisol stimulated expressions of vitamin D-25hydroxylase (cyp27a1), cyp27a1 like (cyp27a1l), 1α-OHase (cyp27b1) at 3 dpf through GR, the first time to demonstrate the relationship between cortisol and vitamin D3 in fish. In conclusion, cortisol stimulates ecac expression to enhance Ca2+ uptake functions, and this control pathway is suggested to be mediated by the GR. Lastly, cortisol also could mediate vitamin D3 signaling to stimulate Ca2+ uptake in zebrafish

Metabolic alterations during the growth of tumour spheroids

Solid tumours undergo considerable alterations in their metabolism of nutrients in order to generate sufficient energy and biomass for sustained growth and proliferation. During growth, the tumour microenvironment exerts a number of influences (e.g. hypoxia and acidity) that affect cellular biology and the flux or utilisation of fuels including glucose. The tumour spheroid model was used to characterise the utilisation of glucose and describe alterations to the activity and expression of key glycolytic enzymes during the tissue growth curve. Glucose was avidly consumed and associated with the production of lactate and an acidified medium, confirming the reliance on glycolytic pathways and a diminution of oxidative phosphorylation. The expression levels and activities of hexokinase, phosphofructokinase-1, pyruvate kinase and lactate dehydrogenase in the glycolytic pathway were measured to assess glycolytic capacity. Similar measurements were made for glucose-6-phosphate dehydrogenase, the entry point and regulatory step of the pentose-phosphate pathway (PPP) and for cytosolic malate dehydrogenase, a key link to TCA cycle intermediates. The parameters for these key enzymes were shown to undergo considerable variation during the growth curve of tumour spheroids. In addition, they revealed that the dynamic alterations were influenced by both transcriptional and posttranslational mechanisms

Metabolic alterations during the growth of tumour spheroids

Solid tumours undergo considerable alterations in their metabolism of nutrients in order to generate sufficient energy and biomass for sustained growth and proliferation. During growth, the tumour microenvironment exerts a number of influences (e.g. hypoxia and acidity) that affect cellular biology and the flux or utilisation of fuels including glucose. The tumour spheroid model was used to characterise the utilisation of glucose and describe alterations to the activity and expression of key glycolytic enzymes during the tissue growth curve. Glucose was avidly consumed and associated with the production of lactate and an acidified medium, confirming the reliance on glycolytic pathways and a diminution of oxidative phosphorylation. The expression levels and activities of hexokinase, phosphofructokinase-1, pyruvate kinase and lactate dehydrogenase in the glycolytic pathway were measured to assess glycolytic capacity. Similar measurements were made for glucose-6-phosphate dehydrogenase, the entry point and regulatory step of the pentose-phosphate pathway (PPP) and for cytosolic malate dehydrogenase, a key link to TCA cycle intermediates. The parameters for these key enzymes were shown to undergo considerable variation during the growth curve of tumour spheroids. In addition, they revealed that the dynamic alterations were influenced by both transcriptional and posttranslational mechanisms