Treatment with the calcineurin inhibitor and immunosuppressant cyclosporine A impairs sensorimotor gating in Dark Agouti rats

Rationale Calcineurin is a protein regulating cytokine expression in T lymphocytes and calcineurin inhibitors such as cyclosporine A (CsA) are widely used for immunosuppressive therapy. It also plays a functional role in distinct neuronal processes in the central nervous system. Disturbed information processing as seen in neuropsychiatric disorders is reflected by deficient sensorimotor gating, assessed as prepulse inhibition (PPI) of the acoustic startle response (ASR). Objective Patients who require treatment with immunosuppressive drugs frequently display neuropsychiatric alterations during treatment with calcineurin inhibitors. Importantly, knockout of calcineurin in the forebrain of mice is associated with cognitive impairments and symptoms of schizophrenia-like psychosis as seen after treatment with stimulants. Methods The present study investigated in rats effects of systemic acute and subchronic administration of CsA on sensorimotor gating. Following a single injection with effective doses of CsA, adult healthy male Dark Agouti rats were tested for PPI. For subchronic treatment, rats were injected daily with the same doses of CsA for 1 week before PPI was assessed. Since calcineurin works as a modulator of the dopamine pathway, activity of the enzyme tyrosine hydroxylase was measured in the prefrontal cortex and striatum after accomplishment of the study. Results Acute and subchronic treatment with the calcineurin inhibitor CsA disrupted PPI at a dose of 20 mg/kg. Concomitantly, following acute CsA treatment, tyrosine hydroxylase activity was reduced in the prefrontal cortex, which suggests that dopamine synthesis was downregulated, potentially reflecting a stimulatory impact of CsA on this neurotransmitter system. Conclusions The results support experimental and clinical evidence linking impaired calcineurin signaling in the central nervous system to the pathophysiology of neuropsychiatric symptoms. Moreover, these findings suggest that therapy with calcineurin inhibitors may be a risk factor for developing neurobehavioral alterations as observed after the abuse of psychomotor stimulant drugs

Taste-immune associative learning amplifies immunopharmacological effects and attenuates disease progression in a rat glioblastoma model

Mechanistic target of rapamycin (mTOR)-signaling is one key driver of glioblastoma (GBM), facilitating tumor growth by promoting the shift to an anti-inflammatory, pro-cancerogenic microenvironment. Even though mTOR inhibitors such as rapamycin (RAPA) have been shown to interfere with GBM disease progression, frequently chaperoned toxic drug side effects urge the need for developing alternative or supportive treatment strategies. Importantly, previous work document that taste-immune associative learning with RAPA may be utilized to induce learned pharmacological placebo responses in the immune system. Against this background, the current study aimed at investigating the potential efficacy of a taste-immune associative learning protocol with RAPA in a syngeneic GBM rat model. Following repeated pairings of a novel gustatory stimulus with injections of RAPA, learned immune-pharmacological effects could be retrieved in GBM-bearing animals when re-exposed to the gustatory stimulus together with administering 10 % amount of the initial drug dose (0.5 mg/kg). These inhibitory effects on tumor growth were accompanied by an up-regulation of central and peripheral pro-inflammatory markers, suggesting that taste-immune associative learning with RAPA promoted the development of a pro-inflammatory anti-tumor microenvironment that attenuated GBM tumor growth to an almost identical outcome as obtained after 100 % (5 mg/kg) RAPA treatment. Together, our results confirm the applicability of taste-immune associative learning with RAPA in animal disease models where mTOR overactivation is one key driver. This proof-of-concept study may also be taken as a role model for implementing learning protocols as alternative or supportive treatment strategy in clinical settings, allowing the reduction of required drug doses and side effects without losing treatment efficacy

Cancer incidence in persons with type 1 diabetes : a five-country study of 9,000 cancers in type 1 diabetic individuals

An excess cancer incidence of 20-25% has been identified among persons with diabetes, most of whom have type 2 diabetes. We aimed to describe the association between type 1 diabetes and cancer incidence. Persons with type 1 diabetes were identified from five nationwide diabetes registers: Australia (2000-2008), Denmark (1995-2014), Finland (1972-2012), Scotland (1995-2012) and Sweden (1987-2012). Linkage to national cancer registries provided the numbers of incident cancers in people with type 1 diabetes and in the general population. We used Poisson models with adjustment for age and date of follow up to estimate hazard ratios for total and site-specific cancers. A total of 9,149 cancers occurred among persons with type 1 diabetes in 3.9 million person-years. The median age at cancer diagnosis was 51.1 years (interquartile range 43.5-59.5). The hazard ratios (HRs) (95% CIs) associated with type 1 diabetes for all cancers combined were 1.01 (0.98, 1.04) among men and 1.07 (1.04, 1.10) among women. HRs were increased for cancer of the stomach (men, HR 1.23 [1.04, 1.46]; women, HR 1.78 [1.49, 2.13]), liver (men, HR 2.00 [1.67, 2.40]; women, HR 1.55 [1.14, 2.10]), pancreas (men, HR 1.53 [1.30, 1.79]; women, HR 1.25 [1.02,1.53]), endometrium (HR 1.42 [1.27, 1.58]) and kidney (men, HR 1.30 [1.12, 1.49]; women, HR 1.47 [1.23, 1.77]). Reduced HRs were found for cancer of the prostate (HR 0.56 [0.51, 0.61]) and breast (HR 0.90 [0.85, 0.94]). HRs declined with increasing diabetes duration. Type 1 diabetes was associated with differences in the risk of several common cancers; the strength of these associations varied with the duration of diabetes.Peer reviewe

Light interception principally drives the understory response to boxelder invasion in riparian forests

Since several decades, American boxelder (Acer negundo) is replacing white willow (Salix alba) riparian forests along southern European rivers. This study aims to evaluate the consequences of boxelder invasion on understory community in riparian areas. We determined the understory species richness, composition and biomass in boxelder and white willow stands located in three riparian forests, representative of three rivers with distinct hydrological regimes. We investigated correlation of these variables to soil moisture and particle size, main soil nutrient stocks, potential nitrification and denitrification, tree canopy cover and photosynthetic active radiation (PAR) at the ground level. A greenhouse experiment was then conducted to identify the causal factors responsible for changes in the understory. The effect of soil type, PAR level and water level on the growth and the biomass production of Urtica dioica were examined. A lower plant species richness and biomass, and a modification of community composition were observed for boxelder understory in all sites, regardless of their environmental characteristics. The strongest modification that follows boxelder invasion was the decline in U. dioica, the dominant species of the white willow forest understory. These differences were mainly correlated with a lower incident PAR under boxelder canopy. The greenhouse experiment identified PAR level as the main factor responsible for the changes in U. dioica stem number and biomass. Our results indicate that adult boxelder acts as an ecosystem engineer that decreases light availability. The opportunistic invasion by boxelder leads to important understory changes, which could alter riparian ecosystem functioning

A European research agenda for somatic symptom disorders, bodily distress disorders, and functional disorders: Results of an estimate-talk-estimate delphi expert study

Background: Somatic Symptom Disorders (SSD), Bodily Distress Disorders (BDD) and functional disorders (FD) are associated with high medical and societal costs and pose a substantial challenge to the population and health policy of Europe. To meet this challenge, a specific research agenda is needed as one of the cornerstones of sustainable mental health research and health policy for SSD, BDD, and FD in Europe. Aim: To identify the main challenges and research priorities concerning SSD, BDD, and FD from a European perspective. Methods: Delphi study conducted from July 2016 until October 2017 in 3 rounds with 3 workshop meetings and 3 online surveys, involving 75 experts and 21 European countries. EURONET-SOMA and the European Association of Psychosomatic Medicine (EAPM) hosted the meetings. Results: Eight research priorities were identified: (1) Assessment of diagnostic profiles relevant to course and treatment outcome. (2) Development and evaluation of new, effective interventions. (3) Validation studies on questionnaires or semi-structured interviews that assess chronic medical conditions in this context. (4) Research into patients preferences for diagnosis and treatment. (5) Development of new methodologic designs to identify and explore mediators and moderators of clinical course and treatment outcomes (6). Translational research exploring how psychological and somatic symptoms develop from somatic conditions and biological and behavioral pathogenic factors. (7) Development of new, effective interventions to personalize treatment. (8) Implementation studies of treatment interventions in different settings, such as primary care, occupational care, general hospital and specialty mental health settings. The general public and policymakers will benefit from the development of new, effective, personalized interventions for SSD, BDD, and FD, that will be enhanced by translational research, as well as from the outcomes of research into patient involvement, GP-patient communication, consultation-liaison models and implementation. Conclusion: Funding for this research agenda, targeting these challenges in coordinated research networks such as EURONET-SOMA and EAPM, and systematically allocating resources by policymakers to this critical area in mental and physical well-being is urgently needed to improve efficacy and impact for diagnosis and treatment of SSD, BDD, and FD across Europe

Multidisciplinary Management of Mastocytosis : Nordic Expert Group Consensus

Mastocytosis is a heterogeneous group of diseases defined by an increased number and accumulation of mast cells, and often also by signs and symptoms of mast cell activation. Disease subtypes range from indolent to rare aggressive forms. Mastocytosis affects people of all ages and has been considered rare; however, it is probably underdiagnosed with potential severe implications. Diagnosis can be challenging and symptoms may be complex and involve multiple organ-systems. In general it is advised that patients should be referred to centres with experience in the disease offering an individualized, multidisciplinary approach. We present here consensus recommendations from a Nordic expert group for the diagnosis and general management of patients with mastocytosis.Peer reviewe

Neuroendocrine studies in patients with affective disorders

Background: Affective disorders are common and a major cause for increased disability and mortality worldwide. Exogenous stressors and biological variables, including neuroendocrine factors, are assumed to contribute to an increased vulnerability to mood dysregulation. Affective disorders are highly heterogeneous and different neuroendocrine systems may play differential roles in the phenotypic expression of affective disorders in men and women. Aims: The overall aim of this thesis was to study three neuroendocrine systems in relation to underlying behavioral endophenotypes (personality traits, self-directed and interpersonal violence, and psychiatric symptoms) in patients with affective disorders. Methods: In Study I oxytocin plasma levels were assessed in 101 general psychiatric outpatients and followed-up in 36 patients after one month. Patients underwent diagnostic, symptomatic, and personality trait assessments. In Study II insulin and glucagon levels in plasma and cerebrospinal fluid (CSF) were assessed in 28 patients hospitalized after a recent suicide attempt and 19 healthy controls. Study persons were assessed regarding lifetime violence expression, psychiatric diagnoses and symptoms. In Study III serum levels of allopregnanolone, progesterone and estradiol were assessed in 14 women with severe postpartum depression and psychosis who, as previously reported, responded with rapid symptom remission during sublingual estradiol treatment. Hormonal and symptomatic assessment were performed before and after 4 weeks of estradiol treatment. 28 healthy postpartum controls were included for baseline comparison. Results: I) Plasma oxytocin levels were positively associated with personality traits of impulsiveness (monotony avoidance) and negative emotionality (psychic anxiety) with potential gender differences. II) Patients after suicide attempt had higher insulin (plasma and CSF) and lower glucagon levels (CSF) than healthy controls. Insulin levels (plasma and CSF) were higher and glucagon levels (plasma) were lower in patients and controls with higher levels of prior violence expression. III) Serum allopregnanolone decreased in women with postpartum depression and psychosis during estradiol treatment. The ratio between allopregnanolone and progesterone was significantly lower in patients than in healthy controls at baseline and it remained unchanged after symptom remission. Conclusion: Behavioral endophenotypes, rather than categorical diagnoses, of affective disorders were associated with neuroendocrine variation in three different cohorts of patients with affective disorder. Hormonal variation pointed towards an association with trait, rather than state like facets of affective behavior, constituting potential vulnerability markers for affective dysregulation.Världen över drabbas 350 miljoner människor av unipolära depressioner och bipolära sjukdomar (affektiva sjukdomar). Patienter med affektiva sjukdomar dör cirka femton år tidigare på grund av kroppsliga sjukdomar och suicid. Upp till varannan patient försöker ta sitt liv och lika många svarar inte på behandling eller får återfall trots behandling. Det är mycket vanligt med sociala svårigheter som påverkar familj- och arbetsliv. Medan män har större risk att ta sina liv löper kvinnor ökad risk att göra suicidförsök och att utveckla depression. Efter en förlossning är risken att drabbas av svåra affektiva sjukdomar förhöjd som kan uttrycka sig i form av svåra depressioner, manier eller psykoser. Dessa tillstånd ökar risken för att modern tar sitt liv och i sällsynta fall även barnets liv. Vissa människor är särskilt sårbara att utveckla affektiva sjukdomar. Sårbarheten påverkas av genetiska faktorer och livshändelser. Det är dock oklart hur patienternas emotionella, kognitiva och kroppsliga symtom uppstår och hur dessa hänger ihop med förändringar i hjärnan och generna. Ökad kunskap om dessa processer skulle sannolikt förbättra möjligheten att behandla och förebygga affektiva sjukdomar. Patienter i gruppen affektiva sjukdomar är väldigt olika; de skiljer sig avseende emotionella, kognitiva och kroppsliga symtom, avseende risker för sjukdomsutveckling samt återfallsrisk och behandlingssvar. Ett sätt att försöka koppla sjukdomstecken och förändringar i hjärnan är att undersöka mer enhetliga grupper av patienter som till exempel patienter som gjort suicidförsök eller kvinnor efter förlossningen. Ett annat sätt är att undersöka särskilda underliggande aspekter som till exempel personlighet. Hos många patienter med psykisk sjukdom har man hittat förändringar i stressystemet. Vid stress påverkas bland annat hormonella system. Hormoner påverkar inte enbart kroppens men även hjärnans funktion. Genom att undersöka kopplingen av hormonella faktorer med kroppsliga, mentala och beteendeuttryck kan man indirekt dra slutsatser om hjärnans funktion vid affektiva sjukdomar. I den här avhandlingen har vi undersökt hur tre olika hormonella system är kopplade till särskilda underliggande aspekter av affektiva sjukdomar. Avhandlingen består av tre olika studier. I den första frågade vi oss om oxytocin är kopplad till personlighetsdrag som har relevans för patienternas sociala svårigheter. Detta undersökte vi i en stor grupp av öppenvårdspatienter med olika psykiska sjukdomar. I den andra ville vi veta om patienter som hade gjort självmordsförsök hade förändrade nivåer av insulin och glukagon och om detta var kopplad till våldsamt beteende. I den tredje studien undersökte vi om kvinnor med svår depression och psykos efter förlossningen uppvisade förändringar av allopregnanolon och progesteron. Dessutom kunde vi undersöka förändringar av dessa hormon under behandling med estradiol när kvinnorna hade tillfrisknat. I den första studien visade vi att patienter med psykiska sjukdomar som hade mer impulsiva och negativ emotionella personlighetsdrag hade högre oxytocin nivåer. Dessa patienter hade särskilda drag av ångest och var mer extroverta. Möjligen var dessa samband särskild tydliga hos män. I den andra studien visade vi att patienter som hade gjort självmordsförsök hade högre nivåer av insulin i blodet och i ryggmärgsvätskan än friska kontroll-personer. Dessutom hade de lägre nivåer av glukagon i blodet. Högre nivåer av insulin och lägre nivåer av glukagon var kopplade till självrapporterat interpersonellt våld sedan femton års ålder hos patienter och friska kontroller. I den tredje studien visade vi att allopregnanolon minskade under estradiol behandling för postpartum depression och postpartum psykos. Patienterna uppvisade både före och under behandlingen förändringar i relationen mellan allopregnanolon och progesteron jämfört med friska kvinnor. Sammanfattningsvis tyder resultaten på att särskilda underliggande aspekter av affektiva sjukdomar är kopplade med förändringar i hormonella system. Dessa förändringar ter sig vara kopplade med långvariga drag hellre än akuta sjukdomsuttryck och kan på så sätt tyda på sårbarhetsfaktorer för affektiva sjukdomar. Resultaten bidrar till ökad förståelse om särskilda hormonella aspekter hos specifika grupper av personer med affektiva sjukdomar