ABSTRACT
Antecedentes y objetivos: Comparar prospectivamente la tasa de detección de la PET/TC con 68Ga-DOTATATE versus 11C-colina en pacientes con cáncer de próstata en recaída bioquímica y evaluar in vivo la expresión de receptores de la somatostatina con el fin de planificar terapias dirigidas (177Lu-DOTATATE). Material y métodos: Analizamos prospectivamente 64 pacientes con recaída bioquímica (mediana PSA: 4,25 ng/mL). Se realizó una PET/TC con 11C-colina y otra con 68Ga-DOTATATE. Se midió el SUVmáx en todas las lesiones. Se consideraron como patrón de referencia las imágenes correlativas, histopatología y/o seguimiento clínico y bioquímico. Resultados: La tasa de detección global por paciente fue del 48,43% para 68Ga-DOTATATE y de 46,87% para 11C-colina. Los resultados fueron concordantes en 53 casos (82,81%). El SUV máximo de la 11C-colina fue significativamente mayor que el correspondiente al 68Ga-DOTATATE para todas las lesiones concordantes (n = 130): 6,17 (1,7-15,5) versus 4,38 (1,37-26,7), mediana (rango), para cada radiotrazador, respectivamente (P < 0,0001). Los valores por paciente de sensibilidad y especificidad fueron los mismos para ambas técnicas: 0,82 (0,65-0,93) y 0,9 (0,73-0,98), respectivamente. Aunque la diferencia no fue estadísticamente significativa, la sensibilidad fue menor para pacientes con niveles de PSA inferiores: 0,63 vs. 0,89; p = 0,13. Se encontró una correlación significativa entre el SUVmáx de ambos trazadores (r = 0,41, n = 130, p < 0,0001). Conclusiones: La PET/TC con 68Ga-DOTATATE y la PET/TC con 11C-colina parecen poseer alta capacidad de detección de lesiones patológicas en la evaluación de los pacientes con cáncer de próstata en recaída bioquímica. Se necesitan más estudios con el fin de probar el posible valor clínico complementario de estas técnicas PET/TC, y para el 68Ga-DOTATATE para la potencial planificación de terapias mediadas por los receptores de somatostatina (177Lu-DOTATATE)
Background and objectives: To prospectively compare the detection rate of 68Ga-DOTATATE versus 11C-choline PET/CT in patients with prostate cancer in biochemical relapse, and to evaluate somatostatin receptor expression in vivo to plan targeted therapies (177Lu-DOTATATE). Material and methods: We prospectively analysed 64 patients with biochemical relapse (median PSA: 4.25 ng/mL). A PET/CT was performed with 11C-choline, and another with 68Ga-DOTATATE. The SUVmax was measured in all lesions. The correlative images, histopathology and/or clinical and biochemical follow-up were taken as the reference standard. Results: The overall detection rate per patient was 48.43% for 68Ga-DOTATATE and 46.87% for 11C-choline. The results were concordant in 53 cases (82.81%). The maximum SUV of 11C-choline was significantly higher than that of 68Ga-DOTATATE for all the concordant lesions (n=130): 6.17 (1.7-15.5) versus 4.38 (1.37-26.7), median (range) for each radiotracer, respectively (p < .0001). The sensitivity and specificity values per patient were the same for both techniques: 0.82 (0.65-0.93) and 0.9 (0.73-0.98), respectively. Although the difference was not significant, the sensitivity was lower in patients with lower PSA levels: 0.63 vs. 0.89; p=.13. A significant correlation was found between the SUVmax of both tracers (r = 0.41, n = 130, p <.0001). Conclusions: 68Ga-DOTATATE PET/CT and 11C-choline PET/CT seem to have a high capacity to detect pathological lesions in the assessment of patients with prostate cancer with biochemical relapse. Further studies are required to test the potential complementary value of these PET/CT techniques, and to evaluate the potential role of 8Ga-DOTATATE for planning somostatin receptor-mediated therapies (177Lu-DOTATATE)
Subject(s)
Humans , Male , Middle Aged , Aged , Prostatic Neoplasms/diagnostic imaging , Positron Emission Tomography Computed Tomography/methods , Prostate-Specific Antigen/analysis , Prostatic Neoplasms/pathology , Prospective Studies , Receptors, Somatostatin/analysis , Gadolinium DTPA , Biomarkers, Tumor/analysisABSTRACT
BACKGROUND AND OBJECTIVES: To prospectively compare the detection rate of 68Ga-DOTATATE versus 11C-choline PET/CT in patients with prostate cancer in biochemical relapse, and to evaluate somatostatin receptor expression in vivo to plan targeted therapies (177Lu-DOTATATE). MATERIAL AND METHODS: We prospectively analysed 64 patients with biochemical relapse (median PSA: 4.25 ng/mL). A PET/CT was performed with 11C-choline, and another with 68Ga-DOTATATE. The SUVmax was measured in all lesions. The correlative images, histopathology and/or clinical and biochemical follow-up were taken as the reference standard. RESULTS: The overall detection rate per patient was 48.43% for 68Ga-DOTATATE and 46.87% for 11C-choline. The results were concordant in 53 cases (82.81%). The maximum SUV of 11C-choline was significantly higher than that of 68Ga-DOTATATE for all the concordant lesions (n=130): 6.17 (1.7-15.5) versus 4.38 (1.37-26.7), median (range) for each radiotracer, respectively (p < .0001). The sensitivity and specificity values per patient were the same for both techniques: 0.82 (0.65-0.93) and 0.9 (0.73-0.98), respectively. Although the difference was not significant, the sensitivity was lower in patients with lower PSA levels: 0.63 vs. 0.89; p=.13. A significant correlation was found between the SUVmax of both tracers (r = 0.41, n = 130, p <.0001). CONCLUSIONS: 68Ga-DOTATATE PET/CT and 11C-choline PET/CT seem to have a high capacity to detect pathological lesions in the assessment of patients with prostate cancer with biochemical relapse. Further studies are required to test the potential complementary value of these PET/CT techniques, and to evaluate the potential role of 8Ga-DOTATATE for planning somostatin receptor-mediated therapies (177Lu-DOTATATE).
Subject(s)
Choline/analogs & derivatives , Neoplasm Recurrence, Local/diagnostic imaging , Organometallic Compounds , Positron Emission Tomography Computed Tomography , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/metabolism , Receptors, Somatostatin/biosynthesis , Aged , Aged, 80 and over , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/blood , Positron Emission Tomography Computed Tomography/methods , Prospective Studies , Prostate-Specific Antigen/blood , Prostatic Neoplasms/bloodABSTRACT
Multigenerational effects can have important and sex-dependent effects on offspring. Sex allocation theory predicts that females should differentially invest in sons and daughters depending on sex-specific fitness returns and costs of investment. Maternal stress-relevant (glucocorticoid) hormones may be one mechanism driving this effect. We investigated how maternal stress hormones differentially affected sons and daughters by manipulating levels of the glucocorticoid, corticosterone (CORT), in gravid female eastern fence lizards (Sceloporus undulatus) and quantifying reproductive investment and sex ratio of resulting clutches, and the mass, snout-vent length, and body condition of sons versus daughters at hatching. We found no effect of maternal CORT-treatment on the number or size of eggs laid or on the sex ratio of resulting offspring, but sons of CORT-treated mothers were shorter, lighter, and of poorer body condition at hatching than were sons of control mothers. We found no difference in size or condition of daughters with maternal treatment. Our results suggest that maternal stress, mediated by elevations in maternal CORT concentrations, can have sex-specific effects on offspring manifesting as lower investment in sons.
Subject(s)
Lizards/physiology , Sex Ratio , Stress, Physiological , Animals , Animals, Newborn , Body Size/physiology , Clutch Size/drug effects , Corticosterone/administration & dosage , Corticosterone/pharmacology , Female , Male , Reproduction/physiologyABSTRACT
Objetivos: Considerar el diagnóstico de sarcoidosis y reacción sarcoid-like en pacientes oncológicos controlados por tomografía computada por emisión de positrones (PET/TC), que presentan adenopatías hiliomediastinales hipercaptantes, para evitar errores diagnósticos. Materiales y métodos: Se analizaron retrospectivamente 18 estudios PET/TC realizados durante 3 anos a pacientes con tumores sólidos y linfoma, que presentaron adenopatías hiliomediastinales hipermetabólicas. El patrón morfológico, la distribución y, en algunos casos, la asociación con nódulos pulmonares permitieron plantear como diagnóstico diferencial la sarcoidosis. Resultados: Las enfermedades oncológicas correspondieron a mama (n = 4), próstata (n = 3), ovario (n = 2) y otros (n = 9). En 9 pacientes se obtuvo la confirmación histopatológica. En 7 de los 18 pacientes, las adenopatías fueron catalogadas como benignas por confirmación histológica de sarcoidosis, antracosis o reacción sarcoid-like. En 5 el comportamiento evolutivo fue compatible con benignidad, en 2 la biopsia mostró secundarismo y en los 4 restantes la evolución demostró malignidad. El total de lesiones benignas fue de 12 (66%). Discusión: El hallazgo de adenopatías hiliomediastinales hipermetabólicas con patrón morfológico y de distribución que orientan a sarcoidosis lleva a plantear esta entidad. En pacientes oncológicos, se requiere biopsia para descartar recaída. El uso de nuevos marcadores PET/TC para un diagnóstico diferencial representa un desafío. Los trazadores de síntesis de aminoácidos, como la 18F-fluorotimidina (FLT) y 18F-fluorometiltirosina (FMT), han demostrado ser útiles en la diferenciación entre malignidad y enfermedades granulomatosas. Conclusión: En estudios PET/TC de pacientes oncológicos, la presencia de adenopatías hiliomediastinales bilaterales y simétricas debe plantear sarcoidosis como diagnóstico diferencial.
Purposes: To describe the radiological findings of sarcoidosis or sarcoid-like reactions in cancer patients being monitored by positron emission computed tomography (PET/CT). Materials and methods: A retrospective analysis was performed on 18 PET/CT studies performed over 3 years in patients with lymphomas and solid tumours who presented with hypermetabolic hiliar-mediastinal adenopathies. The morphological pattern of these adenopathies, the distribution, and in some cases the association with pulmonary nodules, might suggest sarcoidosis as a differential diagnosis. Results: Oncological diseases corresponded to breast (4), prostate (3), ovary (2), and others (9). The adenopathies were classified in 7 of the 18 patients as benign after histological confirmation of sarcoidosis, anthracosis or sarcoid-like reaction. The evolutionary behaviour in 5 patients was compatible with benign lesions. The biopsy of 2 patients indicated secondary lesions and malignancy was confirmed by the evolution of the 4 remaining cases. There was a total of 12 (66%) benign lesions. Discussion: Sarcoidosis must be suspected in the presence of hypermetabolic hiliar-mediastinal adenopathies with a characteristic morphological pattern and pulmonary changes. However, biopsy is required to rule out oncological recurrence. The use of new PET/CT markers for differential diagnosis represents a challenge. Aminoacid synthesis tracers such as 18F-fluorothymidine (FLT) and 18F-fluoromethyltyrosine (FMT) are useful in the differentiation between malignancy and granulomatous diseases in oncologic patients. Conclusion: The differential diagnosis of sarcoidosis should be considered in the presence of bilateral symmetric mediastinal hilum lymphadenopathies.
Subject(s)
Humans , Male , Female , Adolescent , Adult , Middle Aged , Aged , Aged, 80 and over , Young Adult , Sarcoidosis/diagnostic imaging , Neoplasms/pathology , Retrospective Studies , Lymphadenopathy/diagnostic imaging , Positron Emission Tomography Computed Tomography , Medical OncologyABSTRACT
Major depression (MD) is associated with peripheral inflammation and increased cardiovascular risk. Regular physical exercise can have anti-inflammatory effects. The present study examined whether behavioral activation with exercise affects inflammatory processes in MD. Ninety-eight patients with MD were randomly assigned to cognitive-behavioral therapy (CBT) emphasizing exercise during behavioral activation (CBT-E), CBT with pleasurable low-energy activities as an active control condition (CBT-C) or a passive waiting list control group (WL). Plasma levels of C-reactive protein (CRP), interleukin (IL)-6, IL-10, lipopolysaccharide (LPS)-stimulated IL-6 production, and blood immune cell counts were analyzed at baseline and weeks 8 (post-behavioral activation) and 16 (post-treatment). Thirty non-depressed age- and sex-matched controls were included to examine potential immunological alterations in MD at baseline. Patients with MD exhibited higher levels of CRP, higher neutrophil and monocyte counts, lower IL-10 levels and reduced LPS-stimulated IL-6 production compared to controls (P<0.001-0.045). Multilevel modeling indicated that CBT-E was associated with increased anti-inflammatory IL-10 at weeks 8 and 16 compared to CBT-C and WL (P=0.004-0.018). CBT-E did not significantly affect other immunological makers in the total sample. A subgroup analysis including patients with potentially higher cardiovascular risk (CRP ⩾1 µg ml-1) indicated that CRP was reduced in CBT-E compared to CBT-C (P<0.007) and marginally reduced compared to WL (P<0.085) after week 16. The present findings provide new insights into immunological effects of behavioral treatments against depression. Behavioral activation in conjunction with exercise may have the potential to reverse, in part, immunological alterations in MD.
Subject(s)
Cardiovascular Diseases/complications , Cognitive Behavioral Therapy/methods , Depressive Disorder, Major/immunology , Exercise Therapy/methods , Inflammation/complications , Adult , C-Reactive Protein/analysis , Cell Count , Depressive Disorder, Major/therapy , Exercise/physiology , Exercise Therapy/psychology , Female , Germany/epidemiology , Humans , Inflammation/blood , Interleukin-10/blood , Interleukin-6/blood , Lipopolysaccharides/metabolism , Male , Middle Aged , Monocytes/cytology , Monocytes/metabolism , Neutrophils/cytology , Neutrophils/metabolism , Risk FactorsABSTRACT
BACKGROUND: Perceived stress seems to be a risk factor for exacerbation of ulcerative colitis. Yoga has been shown to reduce perceived stress. AIMS: To assess the efficacy and safety of yoga for improving quality of life in patients with ulcerative colitis. METHODS: A total of 77 patients (75% women; 45.5 ± 11.9 years) with ulcerative colitis in clinical remission but impaired quality of life were randomly assigned to yoga (12 supervised weekly sessions of 90 min; n = 39) or written self-care advice (n = 38). Primary outcome was disease-specific quality of life (Inflammatory Bowel Disease Questionnaire). Secondary outcomes included disease activity (Rachmilewitz clinical activity index) and safety. Outcomes were assessed at weeks 12 and 24 by blinded outcome assessors. RESULTS: The yoga group had significantly higher disease-specific quality of life compared to the self-care group after 12 weeks (Δ = 14.6; 95% confidence interval=2.6-26.7; P = 0.018) and after 24 weeks (Δ = 16.4; 95% confidence interval=2.5-30.3; P = 0.022). Twenty-one and 12 patients in the yoga group and in the self-care group, respectively, reached a clinical relevant increase in quality of life at week 12 (P = 0.048); and 27 and 17 patients at week 24 (P = 0.030). Disease activity was lower in the yoga group compared to the self-care group after 24 weeks (Δ = -1.2; 95% confidence interval=-0.1-[-2.3]; P = 0.029). Three and one patient in the yoga group and in the self-care group, respectively, experienced serious adverse events (P = 0.317); and seven and eight patients experienced nonserious adverse events (P = 0.731). CONCLUSIONS: Yoga can be considered as a safe and effective ancillary intervention for patients with ulcerative colitis and impaired quality of life. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02043600.
Subject(s)
Colitis, Ulcerative/therapy , Self Care/methods , Yoga , Adult , Female , Humans , Male , Middle Aged , Quality of Life , Single-Blind Method , Surveys and QuestionnairesABSTRACT
Systemic inflammation is accompanied by profound behavioral and mood changes that resemble symptoms of depression. Findings in animals suggest that pro-inflammatory cytokines released by activated immune cells in the periphery evoke these behavioral symptoms by driving inflammatory changes in the brain. However, experimental data in humans are lacking. Here we demonstrate in healthy male volunteers (10 endotoxin treated, 8 placebo treated) that intravenous administration of low-dose endotoxin (0.8 ng/kg body weight), a prototypical pathogen-associated molecular pattern that activates the innate immune system, not only induces a significant increase in peripheral blood cytokine concentrations (that is, tumor necrosis factor-α, interleukin (IL)-6, IL-10) but also results, with some latency, in a robust and selective increase of IL-6 in the cerebrospinal fluid (CSF). Moreover, we found a strong association between the endotoxin-induced increase of IL-6 in the CSF and the severity of mood impairment, with larger increases in CSF IL-6 concentration followed by a greater deterioration in mood. Taken together, these findings suggest that the appearance of depressive symptoms in inflammatory conditions might be primarily linked to an increase in central IL-6 concentration, identifying IL-6 as a potential therapeutic target in mood disorders.
Subject(s)
Depression/immunology , Endotoxins/administration & dosage , Inflammation/immunology , Interleukin-6/cerebrospinal fluid , Adult , Cytokines/blood , Depression/blood , Depression/cerebrospinal fluid , Depression/metabolism , Humans , Immunity, Innate , Inflammation/blood , Inflammation/cerebrospinal fluid , Inflammation/psychology , Interleukin-6/immunology , Male , Young AdultABSTRACT
We aimed to identify statistical predictor variables of lipopolysaccharide (LPS)-induced physical sickness symptoms during the acute and late inflammatory phases using multivariate regression analyses. Data from N = 128 healthy volunteers who received i.v. LPS injection (0.4 or 0.8 ng/kg) or placebo were pooled for analyses. Physical sickness symptoms experienced during the acute (0-6h postinjection) and late (6-24h postinjection) phases were assessed with the validated General-Assessment-of-Side-Effects (GASE) questionnaire. LPS-treated subjects reported significantly more physical sickness symptoms. Physical symptoms during the acute phase were associated with LPS-induced mood impairments and interleukin (IL)-6 increases, explaining 28.5% of variance in GASE scores. During late phase, LPS-induced increases in cortisol and IL-6 plasma concentrations and baseline depression were significant predictor variables, explaining 38.5% of variance. In patients with recurrent or chronic inflammatory states, these factors may act as risk factors ultimately contributing to an exacerbation of sickness symptoms, and should be considered as potential targets for therapeutic strategies.
Subject(s)
Affective Symptoms , Endotoxemia , Hydrocortisone/analysis , Inflammation , Interleukin-6/analysis , Lipopolysaccharides , Pain , Adult , Affective Symptoms/diagnosis , Affective Symptoms/etiology , Endotoxemia/etiology , Endotoxemia/immunology , Endotoxemia/physiopathology , Endotoxemia/psychology , Healthy Volunteers , Humans , Inflammation/etiology , Inflammation/immunology , Lipopolysaccharides/administration & dosage , Lipopolysaccharides/immunology , Male , Pain/diagnosis , Pain/etiology , Research Design , Surveys and Questionnaires , Symptom Assessment/methods , Time FactorsABSTRACT
Maternal immune activation can increase the vulnerability of the offspring to develop neuroimmune and behavioral abnormalities in response to stress in puberty. In offspring of immune-challenged mothers, stress-induced inflammatory processes precede the adult onset of multiple behavioral dysfunctions. Here, we explored whether an early anti-inflammatory intervention during peripubertal stress exposure might prevent the subsequent emergence of adult behavioral pathology. We used an environmental two-hit model in mice, in which prenatal maternal administration of the viral mimetic poly(I:C) served as the first hit, and exposure to sub-chronic unpredictable stress during peripubertal maturation as the second hit. Using this model, we examined the effectiveness of the tetracycline antibiotic minocycline (MINO) given during stress exposure to block stress-induced inflammatory responses and to prevent subsequent behavioral abnormalities. We found that combined exposure to prenatal immune activation and peripubertal stress caused significant deficits in prepulse inhibition and increased sensitivity to the psychotomimetic drugs amphetamine and dizocilpine in adulthood. MINO treatment during stress exposure prevented the emergence of these behavioral dysfunctions. In addition, the pharmacological intervention blocked hippocampal and prefrontal microglia activation and interleukin-1ß expression in offspring exposed to prenatal infection and peripubertal stress. Together, these findings demonstrate that presymptomatic MINO treatment can prevent the subsequent emergence of multiple behavioral abnormalities relevant to human neuropsychiatric disorders with onset in early adulthood, including schizophrenia. Our epidemiologically informed two-hit model may thus encourage attempts to explore the use of anti-inflammatory agents in the early course of brain disorders that are characterized by signs of central nervous system inflammation during development.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Hippocampus/drug effects , Interferon Inducers/pharmacology , Microglia/drug effects , Minocycline/pharmacology , Poly I-C/pharmacology , Schizophrenia , Stress, Psychological/psychology , Amphetamine/pharmacology , Animals , Central Nervous System Stimulants/pharmacology , Disease Models, Animal , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Female , Interleukin-1beta/drug effects , Interleukin-1beta/metabolism , Mice , Prefrontal Cortex/drug effects , Pregnancy , Pregnancy Complications, Infectious , Prenatal Exposure Delayed Effects , Prepulse Inhibition/drug effects , Psychoses, Substance-InducedABSTRACT
AIMS: The objective of this study was to assess the efficacy profile of Nx4 (Neurexan ®) in an acute experimental stress setting. An acute stress reaction is a biopsychological condition arising in response to an event that is individually regarded as emotionally stressful. Medications can mitigate stress perception and stress reactions, but may also have side effects. MATERIALS AND METHODS: Sixty-four healthy male and female volunteers participated in this prospective two-arm two-site study following an explorative randomized placebo-controlled double-blind study design. Participants took six tablets of either Nx4 or placebo during a time period of 2.5h before exposure to an acute psychological stressor (Trier Social Stress Test), and were subsequently monitored for 1.5h. Subjective stress ratings as well as cardiovascular and neuroendocrine parameters were analyzed before and after stress exposure. KEY FINDINGS: All changes in primary and secondary efficacy parameters corresponded well with the experimental acute stress setting. Nx4 did not affect subjective stress ratings but significantly diminished stress-induced increases in salivary cortisol and plasma adrenaline. Nx4 was as safe as placebo and very well tolerated. SIGNIFICANCE: The results suggest an attenuated neuroendocrine stress response in healthy volunteers induced by Nx4. However, further investigations are needed to confirm these observations as well as to better understand why some parameters were affected while others were not. Future investigations should be extended to chronically stressed individuals with a greater disposition to experience stress in everyday life. ClinicalTrials.gov Identifier: NCT01703819.
Subject(s)
Plant Extracts/therapeutic use , Stress, Psychological/drug therapy , Stress, Psychological/psychology , Adult , Chronic Disease , Double-Blind Method , Emotions , Epinephrine/blood , Female , Hemodynamics/drug effects , Humans , Hydrocortisone/blood , Male , Plant Extracts/adverse effects , Prospective Studies , Sex Characteristics , Treatment OutcomeABSTRACT
Taste aversion learning is a type of conditioning where animals learn to associate a novel taste (conditioned stimulus; CS) with a stimulus inducing symptoms of poisoning or illness (unconditioned stimulus; US). As a consequence animals later avoid this taste, a reaction known as conditioned taste aversion (CTA). An established CTA extinguishes over time when the CS is repeatedly presented in the absence of the US. However, inter-individual differences in CTA extinction do exist. Using a model of behavioral conditioning with saccharin as CS and the immunosuppressant cyclosporine A as US, the present study aimed at further elucidating the factors underlying individual differences in extinction learning by investigating whether extinction of an established CTA is related to the strength of the initially acquired CS-US association. In addition, we analyzed the expression of the neuronal activation marker c-fos in brain structures relevant for acquisition and retrieval of the CTA, such as the insular cortex and the amygdala. We here show that animals, displaying a strong CS-US association during acquisition, maintained a strong CTA during unreinforced CS re-exposures, in contrast to animals with moderate CS-US association. Moreover, the latter animals showed increased c-fos mRNA expression in the insular cortex. Our data indicate that CTA extinction apparently depends on the strength of the initially learned CS-US association. In addition, these findings provide further evidence that the memory for the initial excitatory conditioning and its subsequent extinction is probably stored in those structures that participate in the processing of the CS and the US.
Subject(s)
Avoidance Learning/physiology , Cerebral Cortex/metabolism , Extinction, Psychological/physiology , Taste Perception/physiology , Amygdala/metabolism , Animals , Conditioning, Classical , Cyclosporine , Male , Proto-Oncogene Proteins c-fos/metabolism , Rats , SaccharinABSTRACT
BACKGROUND: Altered pain anticipation likely contributes to disturbed central pain processing in chronic pain conditions like irritable bowel syndrome (IBS), but the learning processes shaping the expectation of pain remain poorly understood. We assessed the neural circuitry mediating the formation, extinction, and reactivation of abdominal pain-related memories in IBS patients compared to healthy controls (HC) in a differential fear conditioning paradigm. METHODS: During fear acquisition, predictive visual cues (CS(+)) were paired with rectal distensions (US), while control cues (CS(-)) were presented unpaired. During extinction, only CSs were presented. Subsequently, memory reactivation was assessed with a reinstatement procedure involving unexpected USs. Using functional magnetic resonance imaging, group differences in neural activation to CS(+) vs CS(-) were analyzed, along with skin conductance responses (SCR), CS valence, CS-US contingency, state anxiety, salivary cortisol, and alpha-amylase activity. The contribution of anxiety symptoms was addressed in covariance analyses. KEY RESULTS: Fear acquisition was altered in IBS, as indicated by more accurate contingency awareness, greater CS-related valence change, and enhanced CS(+)-induced differential activation of prefrontal cortex and amygdala. IBS patients further revealed enhanced differential cingulate activation during extinction and greater differential hippocampal activation during reinstatement. Anxiety affected neural responses during memory formation and reinstatement. CONCLUSIONS & INFERENCES: Abdominal pain-related fear learning and memory processes are altered in IBS, mediated by amygdala, cingulate cortex, prefrontal areas, and hippocampus. Enhanced reinstatement may contribute to hypervigilance and central pain amplification, especially in anxious patients. Preventing a 'relapse' of learned fear utilizing extinction-based interventions may be a promising treatment goal in IBS.
Subject(s)
Brain/physiopathology , Fear/physiology , Irritable Bowel Syndrome/physiopathology , Irritable Bowel Syndrome/psychology , Learning/physiology , Abdominal Pain/psychology , Adult , Anxiety , Brain Mapping , Conditioning, Classical/physiology , Dilatation, Pathologic , Extinction, Psychological/physiology , Female , Galvanic Skin Response , Humans , Magnetic Resonance Imaging , Male , Mental Recall/physiology , Middle Aged , Rectum/physiopathologyABSTRACT
Akin to other physiological responses, immune functions can be modified through behavioral conditioning as part of a learned placebo response. However, like every learning process, learned immune responses are subject to extinction. We analyzed the extinction of learned immunosuppression in healthy male volunteers, using an established conditioning paradigm with the immunosuppressive drug cyclosporin A (CsA) as unconditioned stimulus (US) and a gustatory stimulus as conditioned stimulus (CS). We observed a learned suppression of T-cell function after two and four reexposures to the CS, which was extinguished after 14 unreinforced CS reexposures. However, administration of "subtherapeutic" CsA dosages together with the CS counteracted the extinction of the learned immunosuppression. These findings provide the basis for a potentially successful implementation of conditioning paradigms as supportive therapy to immunopharmacological regimens in clinical settings. The aim is to reduce the required amount of medication while maximizing the therapeutic outcome for the patient's benefit.
Subject(s)
Cyclosporine/pharmacology , Immunosuppression Therapy/methods , Immunosuppressive Agents/pharmacology , Placebo Effect , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Adolescent , Adult , Cells, Cultured , Double-Blind Method , Humans , Male , Pilot Projects , Treatment Outcome , Young AdultABSTRACT
OBJECTIVES: There is an overlap regarding Pittsburgh compound B (PIB) retention in patients clinically diagnosed as Alzheimer's disease (AD) and non-AD dementia. The aim of the present study was to investigate whether there are any differences between PIB-positive and PIB-negative patients in a mixed cohort of patients with neurodegenerative dementia of mild severity regarding neuropsychological test performance and regional cerebral glucose metabolism measured with [(18)F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). METHODS: Eighteen patients clinically diagnosed as probable AD or frontotemporal dementia were examined with PIB PET, FDG PET and neuropsychological tests and followed for 5-9 years in a clinical setting. RESULTS: The PIB-positive patients (7 out of 18) had slower psychomotor speed and more impaired visual episodic memory than the PIB-negative patients; otherwise performance did not differ between the groups. The initial clinical diagnoses were changed in one third of the patients (6 out of 18) during follow-up. CONCLUSIONS: The subtle differences in neuropsychological performance, the overlap of hypometabolic patterns and clinical features between AD and non-AD dementia highlight the need for amyloid biomarkers and a readiness to re-evaluate the initial diagnosis.
ABSTRACT
Large interindividual differences exist in the presence and extent of placebo responses in both experimental and clinical studies, but little is known about possible predictors of these responses. We employed a behaviorally conditioned immunosuppression paradigm in healthy men to analyze predictors of learned placebo responses. During acquisition, the subjects received either the immunosuppressant cyclosporin A (n = 32) or a placebo (n = 14) (unconditioned stimuli (US)) together with a novel-tasting drink (conditioned stimulus (CS)). During evocation, the subjects were reexposed to the CS alone. In responders (n = 15), the CS alone caused a significant inhibition of interleukin (IL)-2 production by anti-CD3-stimulated peripheral blood T cells, closely mimicking the drug effect. Nonresponders (n = 17) did not show responses different from those of the controls. Multiple-regression analyses showed that baseline IL-2, plasma noradrenaline, and state anxiety predicted nearly 60% of the variance in the conditioned IL-2 response. These data provide first evidence for putative biological and psychological predictors of learned placebo responses.
Subject(s)
Anxiety/psychology , Conditioning, Classical/physiology , Cyclosporine/pharmacology , Immunosuppression Therapy/psychology , Norepinephrine/blood , Placebo Effect , Anxiety/immunology , Humans , Immunosuppression Therapy/methods , Interleukin-2/blood , Male , TasteABSTRACT
CONTEXT: The risk to develop dementia is significantly increased in diabetes mellitus. Memantine, an N-methyl-D-aspartate receptor antagonist, which is clinically applied in dementia, has been shown to exert neuroprotective effects under hypoglycemic conditions in rats. OBJECTIVE: We hypothesized that memantine may prevent hypoglycemia-induced decrements in the cerebral high-energy phosphate, i.e. ATP, metabolism to exert its neuroprotective action under these conditions. DESIGN AND PARTICIPANTS: In a randomized, double-blind crossover design, we applied memantine vs. placebo in 16 healthy male subjects and examined the cerebral high-energy phosphate metabolism by (31)phosphor magnetic resonance spectroscopy, hormonal counterregulation, and neurocognitive performance during hypoglycemic glucose clamp conditions. RESULTS: We found increments in hormonal counterregulation and reduced neurocognitive performance during hypoglycemia (P < 0.05). Cerebral ATP levels increased upon hypoglycemia in the memantine condition as compared with placebo (P = 0.006) and remained higher after renormalizing blood glucose concentrations (P = 0.018), which was confirmed by ATP to inorganic phosphate ratio (P = 0.046). Phosphocreatine levels and phosphocreatine to inorganic phosphate ratio remained stable throughout the experiments and did not differ between conditions (P > 0.1 for both). CONCLUSION: Our data demonstrate that memantine preserves the cerebral energy status during experimentally induced hypoglycemia in healthy subjects. An improved neuronal energy status may thus be involved in the neuroprotective effect under these conditions and may qualify memantine as potential future option to combat cognitive impairments and dementia in diabetes.
Subject(s)
Brain Chemistry/drug effects , Energy Metabolism/drug effects , Hypoglycemia/metabolism , Hypoglycemia/prevention & control , Memantine/pharmacology , Neuroprotective Agents , Adenosine Triphosphate/metabolism , Adult , Blood Glucose/metabolism , Cross-Over Studies , Dizocilpine Maleate/pharmacology , Double-Blind Method , Glucose Clamp Technique , Hormones/blood , Humans , Hyperinsulinism/blood , Insulin/blood , Magnetic Resonance Imaging , Male , Memory, Short-Term/drug effects , Phosphorus Isotopes , Stroop Test , Young AdultABSTRACT
BACKGROUND: There is an urgent need for individualized treatment of malignant bone disease (MBD), as the clinical benefit from bone-targeted therapies is moderate. We assessed the predictive value of the bone formation marker procollagen type I N-propeptide (PINP) for skeletal morbidity in patients with MBD receiving pamidronate. METHODS: Seventy patients with advanced MBD were randomized to receive pamidronate 60 mg (n = 35) or 90 mg (n = 35) every 3 weeks for six cycles in a double-blind study. PINP was analyzed at baseline and before each administration of pamidronate, using a validated ELISA. Serum PINP concentrations were compared with pain response (visual analog scale VAS, composite pain score) and skeletal morbidity (skeletal-related events, SRE) using Student's T-test, Wilcoxon rank-sum and log-rank test, respectively. RESULTS: Patients with ≥20% pain reduction in the VAS had lower baseline PINP concentrations when compared to patients with <20% VAS response (P < 0.0001). A high baseline serum PINP concentration (highest tertile versus lower two tertiles) was significantly associated with a shorter duration of pain response (P < 0.0001) and a shorter time interval to first SRE (P < 0.008). Sensitivity of a low baseline PINP serum concentration for freedom from SRE at 1 year from randomization was 75% (15 out of 20 patients), while specificity was 82% (27 out of 33 patients). CONCLUSIONS: Serum PINP has been shown to be a significant predictor for skeletal morbidity in patients with MBD on pamidronate treatment. Prospective validation of PINP in patients with MBD to assess the prognosis or individualize bone-targeted treatment is justified.
Subject(s)
Antineoplastic Agents/therapeutic use , Bone Neoplasms/diagnosis , Bone and Bones/drug effects , Collagen Type I/metabolism , Diphosphonates/therapeutic use , Osteolysis/diagnosis , Peptide Fragments/blood , Procollagen/blood , Aged , Biomarkers/blood , Bone Neoplasms/drug therapy , Bone Neoplasms/pathology , Bone Neoplasms/secondary , Bone and Bones/pathology , Bone and Bones/physiopathology , Double-Blind Method , Female , Humans , Male , Osteolysis/drug therapy , Osteolysis/pathology , Pain/physiopathology , Pamidronate , Predictive Value of Tests , Prospective StudiesABSTRACT
BACKGROUND: New in vivo amyloid PET imaging tracers, such as (11)C-PIB, provide possibilities to deeper understand the underlying pathological processes in Alzheimer's disease (AD). In this study we investigated how (11)C-PIB retention is related to cerebral glucose metabolism, episodic memory and CSF biomarkers. METHOD: Thirty-seven patients with mild AD and 21 patients with mild cognitive impairment (MCI) underwent PET examinations with the amyloid tracer (11)C-PIB, (18)F-FDG for measurement of regional cerebral metabolic rate of glucose (rCMRglc), assessment of episodic memory and assay of cerebral spinal fluid (CSF) levels of amyloid-beta (Abeta(1-42)), total tau and phosphorylated tau respectively. Analyses were performed using Statistical Parametric Mapping (SPM) and regions of interest (ROIs). RESULTS: Pooled data from AD and MCI patients showed strong correlations between (11)C-PIB retention, levels of CSF biomarkers (especially Abeta(1-42)), rCMRglc and episodic memory. Analysis of the MCI group alone revealed significant correlations between (11)C-PIB retention and CSF biomarkers and between CSF biomarkers and episodic memory respectively. A strong correlation was observed in the AD group between rCMRglc and episodic memory as well as a significant correlation between (11)C-PIB retention and rCMRglc in some cortical regions. Regional differences were observed as sign for changes in temporal patterns across brain regions. CONCLUSIONS: A complex pattern was observed between pathological and functional markers with respect to disease stage (MCI versus AD) and brain regions. Regional differences over time were evident during disease progression. (11)C-PIB PET and CSF Abeta(42) allowed detection of prodromal stages of AD. Amyloid imaging is useful for early diagnosis and evaluation of new therapeutic interventions in AD.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/diagnostic imaging , Benzothiazoles , Biomarkers/cerebrospinal fluid , Radiopharmaceuticals , Aged , Aged, 80 and over , Alzheimer Disease/physiopathology , Aniline Compounds , Early Diagnosis , Enzyme-Linked Immunosorbent Assay , Female , Fluorodeoxyglucose F18 , Glucose/metabolism , Humans , Image Interpretation, Computer-Assisted , Male , Memory Disorders/diagnostic imaging , Memory Disorders/etiology , Memory Disorders/metabolism , Middle Aged , Positron-Emission Tomography , ThiazolesABSTRACT
Previous theoretical investigations on thermal flow in a horizontal fluid layer have shown that the critical temperature difference, where heat transfer changes from diffusion to convective flow, depends on the frequency of a time-modulated driving force. The driving force of thermal convection is the buoyancy force resulting from the interaction of gravity and the density gradient provided by a temperature difference in the vertical direction of a horizontal fluid layer. An experimental investigation of such phenomena fails because of technical problems arising if buoyancy is to be changed by altering the temperature difference or gravitational acceleration. The possibility of influencing convective flow in a horizontal magnetic fluid layer by magnetic forces might provide us with a means to solve the problem of a time-modulated magnetic driving force. An experimental setup to investigate the dependence of the critical temperature difference on the frequency of the driving force has been designed and implemented. First results show that the time modulation of the driving force has significant influence on the strength of the convective flow. In particular a pronounced minimum in the strength of convection has been found for a particular frequency.
ABSTRACT
[(11)C]-PIB positron emission tomography ([(11)C]-PIB PET) is a sensitive marker of amyloid in Alzheimer's disease (AD), but its specificity has not been fully evaluated. Vascular amyloid-beta deposition is common in Parkinson's disease (PD) and alpha-synuclein, the major component of the Lewy bodies in PD, forms amyloid fibrils. We investigated five apparently cognitively normal PD patients with [(11)C]-PIB PET. The results were compared to 16 patients with AD and six healthy controls from a previous study. [(11)C]-PIB retention was not significantly increased in our patients who all had early stage PD. Further studies of more advanced PD patients are warranted.
