Publications by authors named "Elisa Schiavi"

30 Publications

  • Page 1 of 1

Treatment adherence and tolerability of immediate- and prolonged-release lithium formulations in a sample of bipolar patients: a prospective naturalistic study.

Int Clin Psychopharmacol 2021 Sep;36(5):230-237

Psychiatry 2 Unit, Department of Clinical and Experimental Medicine, University of Pisa.

The aim of this study was to compare treatment adherence and tolerability of different lithium formulations in 70 bipolar patients receiving lithium therapy for the first time. During the 1-year follow-up, information was collected regarding patient's clinical course, therapeutic adherence, side effects of the treatment and serum levels of lithium, creatinine and thyroid-stimulating hormone. At baseline, 30 patients (43%) were on prolonged-release lithium formulations and 40 (57%) on immediate-release formulations. At the final evaluation, 37 patients (53%) were considered lost to follow-up. Both prolonged- and immediate-release patients showed significant improvement in the Functioning Assessment Short Test and in the Clinical Global Impressions for Bipolar Disorder scores during the follow-up. At the first follow-up visit, the mean plasma lithium level of prolonged-release patients was higher than immediate-release patients (0.61 vs. 0.47, respectively; P = 0.063), as well as the therapeutic adherence (85 vs. 64%, respectively; P = 0.089). Fine tremor and gastrointestinal symptoms were more frequent in immediate-release patients than in prolonged-release patients at each follow-up visit, with the sole exception of gastrointestinal symptoms at the last evaluation. Prolonged-release lithium therapy could provide potential advantages over immediate-release formulations. Future naturalistic studies and clinical trials with a longer follow-up duration are needed.
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http://dx.doi.org/10.1097/YIC.0000000000000373DOI Listing
September 2021

Comparison of Emotional Dysregulation Features in Cyclothymia and Adult ADHD.

Medicina (Kaunas) 2021 May 12;57(5). Epub 2021 May 12.

Psychiatry 2 Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy.

: Emotional dysregulation is central to the problem of the overlap between attention-deficit/hyperactivity disorder (ADHD) and cyclothymia. The aim of the study was to evaluate comorbidity rates between ADHD and cyclothymic disorder and to explore demographic and clinical differences among the groups, focusing on affective temperament and emotional dysregulation. : One hundred sixty-five outpatients attending the Second Psychiatry Unit at the Santa Chiara University Hospital (Pisa) were consecutively recruited: 80 were diagnosed with ADHD, 60 with cyclothymic disorder, and 25 with both conditions. Temperament Evaluation of Memphis, Pisa, Paris, and San Diego (TEMPS-M) and the 40-item version of Reactivity, Intensity, Polarity, and Stability questionnaire (RI-PoSt-40) were administered. : Cyclothymic patients were more frequently female and older with respect to the ADHD groups. Both comorbid and non-comorbid ADHD patients showed significantly lower educational attainment and more frequently had substance use disorders. Panic disorder was common in non-comorbid cyclothymic patients, who showed significantly higher rates of familial panic disorder, major depressive disorder and suicide attempts in comparison with patients only diagnosed with ADHD. Cyclothymic patients without ADHD were also characterized by fewer hyperthymic temperamental traits, higher depressive and anxious dispositions, and a greater negative emotionality. No significant differences among groups were observed for cyclothymic temperament and overall negative emotional dysregulation, but comorbid patients with both conditions scored the highest in these subscales. This group also showed significantly higher affective instability with respect to ADHD patients without cyclothymia and was less frequently diagnosed with bipolar disorder type II than patients from both the other groups. : ADHD and cyclothymia often co-occur and show similar levels of emotional dysregulation. However, cyclothymic patients may be more prone to negative emotionality in clinical settings. Subjects with "sunny" cyclothymic features might escape the attention of clinicians unless ADHD is present.
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http://dx.doi.org/10.3390/medicina57050489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151096PMC
May 2021

Intranasal Bifidobacterium longum protects against viral-induced lung inflammation and injury in a murine model of lethal influenza infection.

EBioMedicine 2020 Oct 11;60:102981. Epub 2020 Sep 11.

Department of Medicine and School of Microbiology, APC Microbiome Ireland, National University of Ireland, Cork, Ireland.

Background: Prophylactic strategies are urgently needed for prevention of severe inflammatory responses to respiratory viral infections. Bacterial-host interactions may modify the immune response to viral infections.

Methods: We examined the contribution of Intranasal administration of two different Bifidobacterium longum strains or its isolated cell wall in controlling viral induced inflammation using a murine model of influenza infection. We monitored mortality and morbidity over a 10-day period and viral load, differential broncho alveolar lavage (BAL) fluid inflammatory cell counts, Lung tissue histology, BAL and serum cytokines, markers of vascular damage and cell death were quantified.

Findings: Intranasal administration of Bifidobacterium longum35624® or its isolated cell wall prior to virus inoculation significantly reduced viral load within the lungs and significantly improved survival. Reduced viral load was associated with reduced lung injury as suggested by cell death and vascular leakage markers, a shift from neutrophil to macrophage recruitment, reduced inflammatory cytokine levels (including IL-6), reduced type 1 and 2 interferon levels, but increased levels of interferon-λ and surfactant protein D. These protective effects were maintained when the bifidobacterial cell wall preparation was administered 24 h after viral inoculation. The protective effects were also observed for the Bifidobacterium longumPB-VIR™ strain.

Interpretation: Exposure to these bifidobacterial strains protect against the inflammatory sequelae and damage associated with uncontrolled viral replication within the lung.

Funding: This work has been funded, in part, by a research grant from GlaxoSmithKline, PrecisionBiotics Group Ltd., Swiss National Science Foundation grants (project numbers CRSII3_154488, 310030_144219, 310030_127356 and 310030_144219) and Christine Kühne - Center for Allergy Research and Education (CK-CARE).
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http://dx.doi.org/10.1016/j.ebiom.2020.102981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495089PMC
October 2020

Relationships Among Delayed Sleep Phase Disorder, Emotional Dysregulation, and Affective Temperaments in Adults With Attention Deficit Hyperactivity Disorder and Cyclothymia.

J Nerv Ment Dis 2020 11;208(11):857-862

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

This study aims to explore the relationships between delayed sleep phase disorder (DSPD) and emotional dysregulation in 240 patients (134 with cyclothymia, 81 with attention deficit hyperactivity disorder [ADHD] and 25 with both conditions). DSPD was assessed using the Morningness-Eveningness Questionnaire, followed by a clinical evaluation. Affective temperaments and emotional dysregulation were also investigated through the brief version of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego and the Reactivity, Intensity, Polarity, Stability questionnaires, respectively. Clinical variables were compared in patients with and without DSPD, and a logistic regression model was used to identify the predictive value of the clinical characteristics on the presence of DSPD. DSPD patients (19% of the total sample) were significantly younger than patients without DSPD, showed an about 4 times higher lifetime history of comorbid ADHD and cyclothymia, and reported higher scores in the irritable and cyclothymic temperamental subscales and in the affective instability and impulsivity dimensions. In the multiple logistic regression, we found a negative predictive value of increasing age on the presence of DSPD, whereas comorbid cyclothymia and ADHD and cyclothymic temperament seem to represent risk factors for DSPD.
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http://dx.doi.org/10.1097/NMD.0000000000001209DOI Listing
November 2020

Resveratrol plus carboxymethyl-β-glucan in infants with common cold: A randomized double-blind trial.

Heliyon 2020 Apr 21;6(4):e03814. Epub 2020 Apr 21.

Department of Biomedical Science and Human Oncology, Neonatology and Neonatal Intensive Care Unit, "Aldo Moro" University of Bari, Bari 70100, Italy.

Objectives: To evaluate effectiveness of a nasal resveratrol/carboxymethyl-β-glucan solution compared to nasal saline solution: a) on common cold symptoms by means of a validated measure scale (CARIFS score), b) on Rhinovirus infection and CCL2, CCL5, IL8, IL6, CXCL10 and TLR2 expression in nasal swabs, c) on frequency of relapses after 30 days of follow-up.

Methods: 89 infants with respiratory infection symptoms were randomly assigned to receive either a nasal resveratrol/carboxymethyl-β-glucan solution or nasal saline solution.All patients were evaluated with CARIFS score at enrollment, after 48 h, 7 and 30 days by physicians and parents. Nasal swabs were obtained at enrollment, after 48 h and after one week.

Results: CARIFS score improved in both groups. Episodes of sneezing and cough were fewer in study group after 7 days of follow-up (p < 0.05). No significant differences were found on nasopharyngeal swabs in Rhinovirus detection and cytokines expression after 48 h, nor in 30 days relapses. TLR2 expression was significantly higher in Rhinovirus infected children of the study group. No adverse effects occurred.

Conclusions: These data suggest that a solution containing resveratrol plus carboxymethyl-β-glucan might have a positive impact on both clinical and socio-economic burden due to infant common cold.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172624PMC
April 2020

Toxoplasmosis in a Cohort of Italian Patients With Bipolar and Psychotic Disorders: How Infection May Affect Clinical Features?

J Nerv Ment Dis 2020 Feb;208(2):118-126

Section of Psychiatry, Department of Clinical and Experimental Medicine.

This study investigated the seroprevalence of Toxoplasma gondii in a cohort of 101 Italian inpatients affected by mood or schizophrenia-spectrum disorders and compared clinical features between seronegative and seropositive subjects. Patients diagnosed according to DSM-5 criteria underwent clinical assessments and blood collection to test parasite-specific IgG/IgM serum levels. Twenty-eight patients (27.7%) had IgG anti-T. gondii, and none had IgM antibodies. We found higher prevalence rate in patients aged 40 years or older, as compared with younger. No significant association was detected between T. gondii and a specific diagnostic category; however, bipolar disorder (BD)-II showed the highest positivity rate (40.9%). The seropositive status was significantly associated with a lower presence of psychotic symptoms, higher number of total episodes of predominant excitatory polarity, longer illness duration, and lower severity of current episode, particularly anxiety, depressive, and withdrawal/retardation symptoms. These preliminary results seem to point out an association between chronic toxoplasmosis and a specific subtype of BD.
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http://dx.doi.org/10.1097/NMD.0000000000001102DOI Listing
February 2020

Reactivity, Intensity, Polarity and Stability questionnaire (RIPoSt-40) assessing emotional dysregulation: Development, reliability and validity.

J Affect Disord 2019 10 5;257:187-194. Epub 2019 Jul 5.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Background: Emotional dysregulation (ED) is a heterogenous construct with great relevance in psychiatric research and clinical practice. In the present study, we validated a 40-items version of the Reactivity, Intensity, Polarity and Stability questionnaire (RIPoSt-40), a self-report measure of ED.

Methods: A non-clinical sample (N = 396) and two clinical samples of patients with cyclothymia (N = 120) and ADHD (N = 54) were recruited. Items were selected and subscales were derived based on inter-item correlations and PCA with promax rotation in the non-clinical sample. Test-retest reliability was assessed in a subsample (N = 60). Internal consistency and concurrent validity with TEMPS-M factors were evaluated in each sample. The three groups results were compared to ascertain discriminant validity.

Results: Four subscales were identified as measures of affective instability, emotional impulsivity, negative and positive emotionality. The first three subscales also sum up to a negative ED score comprising thirty items. Measures of reliability (test-retest r = 0.71-0.84) and internal consistency (Cronbach's α = 0.72-0.95) were generally high. Concurrent validity was supported by correlations with TEMPS-M factors. Discriminant validity was significant (p < 0.001) with cyclothymic and ADHD patients showing higher scores for each subscale, except for positive emotionality.

Limitations: The non-clinical sample was recruited through a web-survey and mainly included young and highly educated subjects. Mood and anxiety comorbidity of the clinical samples were not taken into consideration.

Conclusion: RIPoSt-40 questionnaire has proved to be a valid, reliable and useful tool to assess ED both in clinical and non-clinical contexts.
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http://dx.doi.org/10.1016/j.jad.2019.07.028DOI Listing
October 2019

A prophylactic multi-strain probiotic treatment to reduce the absorption of toxic elements: In-vitro study and biomonitoring of breast milk and infant stools.

Environ Int 2019 09 3;130:104818. Epub 2019 Jul 3.

Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, I-00185 Rome, Italy.

Potential exposure to toxic elements initially occurs during gestation and after birth via breast milk, which is the principal source of nutrients for infants during the first months of life. In this study, we evaluated whether maternal oral supplementation with a multi-strain probiotic product can protect infants from exposure to arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) via breast milk. In-vitro studies of the bacterial strains present in this probiotic product showed a high bacterial tolerance for As, Cd, Hg, and Pb, and good binding capacity for Cd, Hg, and Pb (72%, 81%, and 64%, respectively) within 1 h of contact. We evaluated concentrations (5 mg L for Cd and Pb, and 2 mg L for Hg) that largely exceeded the provisional tolerable weekly intake of these toxic elements via food or water applicable for human consumption. Changes in the levels of these elements in breast milk and newborn stools were evaluated in the control (orally supplemented with placebo) and experimental (orally supplemented with probiotic) groups at birth (t0), 15 days (t15), and 30 days (t30) after delivery. Elemental analysis of breast milk did not show significant differences between the control and experimental groups at different stages of lactation; however, stool samples obtained from newborns of mothers supplemented with the probiotic product showed that Cd levels were significantly reduced (by 26%) at t15 compared with the levels of the controls. Our data did not show an association between concentration of toxic elements in breast milk and that in newborn stools. Indeed, the concentration of Cd, Hg, and Pb in breast milk decreased during the lactation period, whereas the levels of these elements in newborn stools were stable over time. Although our in-vitro data indicate that the consortium of these probiotic strains can absorb toxic compounds, this study was limited by its small sample size and potential uncontrolled confounding effects, such as maternal diet and lifestyle. Therefore, we could not confirm whether prophylactic use of this probiotic product can reduce the absorption of toxic elements. The risk assessment in the studied population evidenced a margin of exposure (MOE) of 1, or between 1 and 10 for Pb, and lower than 50 for As. This poses a potential risk for breastfed infants, indicating that interventions aimed to avoid breastfeeding-related health risks remain a major challenge in public health.
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http://dx.doi.org/10.1016/j.envint.2019.05.012DOI Listing
September 2019

High levels of butyrate and propionate in early life are associated with protection against atopy.

Allergy 2019 04 25;74(4):799-809. Epub 2018 Nov 25.

Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.

Background: Dietary changes are suggested to play a role in the increasing prevalence of allergic diseases and asthma. Short-chain fatty acids (SCFAs) are metabolites present in certain foods and are produced by microbes in the gut following fermentation of fibers. SCFAs have been shown to have anti-inflammatory properties in animal models. Our objective was to investigate the potential role of SCFAs in the prevention of allergy and asthma.

Methods: We analyzed SCFA levels by high-performance liquid chromatography (HPLC) in fecal samples from 301 one-year-old children from a birth cohort and examined their association with early life exposures, especially diet, and allergy and asthma later in life. Data on exposures and allergic diseases were collected by questionnaires. In addition, we treated mice with SCFAs to examine their effect on allergic airway inflammation.

Results: Significant associations between the levels of SCFAs and the infant's diet were identified. Children with the highest levels of butyrate and propionate (≥95th percentile) in feces at the age of one year had significantly less atopic sensitization and were less likely to have asthma between 3 and 6 years. Children with the highest levels of butyrate were also less likely to have a reported diagnosis of food allergy or allergic rhinitis. Oral administration of SCFAs to mice significantly reduced the severity of allergic airway inflammation.

Conclusion: Our results suggest that strategies to increase SCFA levels could be a new dietary preventive option for allergic diseases in children.
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http://dx.doi.org/10.1111/all.13660DOI Listing
April 2019

Optimization and validation of a fast digestion method for the determination of major and trace elements in breast milk by ICP-MS.

Anal Chim Acta 2018 Dec 18;1040:49-62. Epub 2018 Jul 18.

Department of Chemistry, Sapienza University, Piazzale Aldo Moro 5, I-00185 Rome, Italy.

Breast milk guarantees all the nutrients required by infants during their first few months of life and remains the most important food source for their health and growth. However, the mother may transfer potentially toxic chemicals to the suckling infant through breastfeeding. The aim of this study was to optimize and validate a fast method for the determination of a total content of 34 elements (Al, As, B, Ba, Be, Bi, Ca, Cd, Co, Cr, Cs, Cu, Fe, K, Li, Mg, Mn, Mo, Na, Ni, P, Pb, Rb, Sb, Se, Si, Sn, Sr, Te, Ti, Tl, U, V, and Zn) in liquid and lyophilized breast milk. The samples were subjected to HNO:HO (2:1) digestion in an open vessel heated in a water bath (WBD; 80 °C) and subsequently analysed by quadrupole inductively coupled plasma mass spectrometry equipped with a collision-reaction interface. The performance of the proposed method was evaluated in terms of selectivity, detection and quantification limits, linearity, accuracy, and robustness by using standard reference materials and filed samples of breast milk. Compared to microwave-assisted acid digestion, the proposed open vessel digestion allows a significant reduction in treatment time and sample manipulation, while maintaining a similar analytical performance. Masses of 0.5 g of breast milk were efficiently digested with the WBD treatment allowing a residual carbon content lower than 60 mg L and a residual acidity lower than 0.87 mol L in final digested samples. Thus, it shows great potential for application to routine analysis. The method provides satisfactory detection limits and good performance (trueness and recovery percentages 80-111%; coefficient of variation <10%; and relative repeatability <15%) and allows a high sample throughput for multi-elemental determination in human biomonitoring studies.
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http://dx.doi.org/10.1016/j.aca.2018.07.037DOI Listing
December 2018

Role of Lactobacilli and Lactoferrin in the Mucosal Cervicovaginal Defense.

Front Immunol 2018 1;9:376. Epub 2018 Mar 1.

Department of Public Health and Infectious Diseases, University of Rome La Sapienza, Rome, Italy.

The innate defense system of the female mucosal genital tract involves a close and complex interaction among the healthy vaginal microbiota, different cells, and various proteins that protect the host from pathogens. Vaginal lactobacilli and lactoferrin represent two essential actors in the vaginal environment. Lactobacilli represent the dominant bacterial species able to prevent facultative and obligate anaerobes outnumber in vaginal microbiota maintaining healthy microbial homeostasis. Several mechanisms underlie the protection exerted by lactobacilli: competition for nutrients and tissue adherence, reduction of the vaginal pH, modulation of immunity, and production of bioactive compounds. Among bioactive factors of cervicovaginal mucosa, lactoferrin, an iron-binding cationic glycoprotein, is a multifunctional glycoprotein with antibacterial, antifungal, antiviral, and antiparasitic activities, recently emerging as an important modulator of inflammation. Lactobacilli and lactoferrin are largely under the influence of female hormones and of paracrine production of various cytokines. Lactoferrin is strongly increased in lower genital tract mucosal fluid of women affected by , and infections promoting both innate and adaptive immune responses. In vaginal dysbiosis characterized by low amounts of vaginal lactobacilli and increased levels of endogenous anaerobic bacteria, the increase in lactoferrin could act as an immune modulator assuming the role normally played by the healthy microbiota in vaginal mucosa. Then lactoferrin and lactobacilli may be considered as biomarkers of altered microbial homeostasis at vaginal level. Considering the shortage of effective treatments to counteract recurrent and/or antibiotic-resistant bacterial infections, the intravaginal administration of lactobacilli and lactoferrin could be a novel efficient therapeutic strategy and a valuable tool to restore mucosal immune homeostasis.
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http://dx.doi.org/10.3389/fimmu.2018.00376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837981PMC
May 2019

Exposure to nonmicrobial N-glycolylneuraminic acid protects farmers' children against airway inflammation and colitis.

J Allergy Clin Immunol 2018 01 17;141(1):382-390.e7. Epub 2017 Jun 17.

Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.

Background: Childhood exposure to a farm environment has been shown to protect against the development of inflammatory diseases, such as allergy, asthma, and inflammatory bowel disease.

Objective: We sought to investigate whether both exposure to microbes and exposure to structures of nonmicrobial origin, such as the sialic acid N-glycolylneuraminic acid (Neu5Gc), might play a significant role.

Methods: Exposure to Neu5Gc was evaluated by quantifying anti-Neu5Gc antibody levels in sera of children enrolled in 2 farm studies: the Prevention of Allergy Risk factors for Sensitization in Children Related to Farming and Anthroposophic Lifestyle (PARSIFAL) study (n = 299) and the Protection Against Allergy Study in Rural Environments (PASTURE) birth cohort (cord blood [n = 836], 1 year [n = 734], 4.5 years [n = 700], and 6 years [n = 728]), and we associated them with asthma and wheeze. The effect of Neu5Gc was examined in murine airway inflammation and colitis models, and the role of Neu5Gc in regulating immune activation was assessed based on helper T-cell and regulatory T-cell activation in mice.

Results: In children anti-Neu5Gc IgG levels correlated positively with living on a farm and increased peripheral blood forkhead box protein 3 expression and correlated inversely with wheezing and asthma in nonatopic subjects. Exposure to Neu5Gc in mice resulted in reduced airway hyperresponsiveness and inflammatory cell recruitment to the lung. Furthermore, Neu5Gc administration to mice reduced the severity of a colitis model. Mechanistically, we found that Neu5Gc exposure reduced IL-17 T-cell numbers and supported differentiation of regulatory T cells.

Conclusions: In addition to microbial exposure, increased exposure to non-microbial-derived Neu5Gc might contribute to the protective effects associated with the farm environment.
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http://dx.doi.org/10.1016/j.jaci.2017.04.051DOI Listing
January 2018

Is Toxoplasma gondii a Trigger of Bipolar Disorder?

Pathogens 2017 Jan 10;6(1). Epub 2017 Jan 10.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

, a ubiquitous intracellular parasite, has a strong tropism for the brain tissue, where it forms intracellular cysts within the neurons and glial cells, establishing a chronic infection. Although latent toxoplasmosis is generally assumed to be asymptomatic in immunocompetent individuals, it is now clear that it can induce behavioral manipulations in mice and infected humans. Moreover, a strong relation has emerged in recent years between toxoplasmosis and psychiatric disorders. The link between and schizophrenia has been the most widely documented; however, a significant association with bipolar disorder (BD) and suicidal/aggressive behaviors has also been detected. may play a role in the etiopathogenesis of psychiatric disorders affecting neurotransmitters, especially dopamine, that are implicated in the emergence of psychosis and behavioral -induced abnormalities, and inducing brain inflammation by the direct stimulation of inflammatory cytokines in the central nervous system. Besides this, there is increasing evidence for a prominent role of immune dysregulation in psychosis and BD. The aim of this review is to describe recent evidence suggesting a link between and BD, focusing on the interaction between immune responses and this infectious agent in the etiopathogenesis of psychiatric symptoms.
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http://dx.doi.org/10.3390/pathogens6010003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371891PMC
January 2017

The Surface-Associated Exopolysaccharide of Bifidobacterium longum 35624 Plays an Essential Role in Dampening Host Proinflammatory Responses and Repressing Local TH17 Responses.

Appl Environ Microbiol 2016 12 21;82(24):7185-7196. Epub 2016 Nov 21.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland

The immune-modulating properties of certain bifidobacterial strains, such as Bifidobacterium longum subsp. longum 35624 (B. longum 35624), have been well described, although the strain-specific molecular characteristics associated with such immune-regulatory activity are not well defined. It has previously been demonstrated that B. longum 35624 produces a cell surface exopolysaccharide (sEPS), and in this study, we investigated the role played by this exopolysaccharide in influencing the host immune response. B. longum 35624 induced relatively low levels of cytokine secretion from human dendritic cells, whereas an isogenic exopolysaccharide-negative mutant derivative (termed sEPS) induced vastly more cytokines, including interleukin-17 (IL-17), and this response was reversed when exopolysaccharide production was restored in sEPS by genetic complementation. Administration of B. longum 35624 to mice of the T cell transfer colitis model prevented disease symptoms, whereas sEPS did not protect against the development of colitis, with associated enhanced recruitment of IL-17 lymphocytes to the gut. Moreover, intranasal administration of sEPS also resulted in enhanced recruitment of IL-17 lymphocytes to the murine lung. These data demonstrate that the particular exopolysaccharide produced by B. longum 35624 plays an essential role in dampening proinflammatory host responses to the strain and that loss of exopolysaccharide production results in the induction of local T17 responses.

Importance: Particular gut commensals, such as B. longum 35624, are known to contribute positively to the development of mucosal immune cells, resulting in protection from inflammatory diseases. However, the molecular basis and mechanisms for these commensal-host interactions are poorly described. In this report, an exopolysaccharide was shown to be decisive in influencing the immune response to the bacterium. We generated an isogenic mutant unable to produce exopolysaccharide and observed that this mutation caused a dramatic change in the response of human immune cells in vitro In addition, the use of mouse models confirmed that lack of exopolysaccharide production induces inflammatory responses to the bacterium. These results implicate the surface-associated exopolysaccharide of the B. longum 35624 cell envelope in the prevention of aberrant inflammatory responses.
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http://dx.doi.org/10.1128/AEM.02238-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118929PMC
December 2016

Bipolar Disorder With Psychotic Features and Ocular Toxoplasmosis: A Possible Pathogenetic Role of the Parasite?

J Nerv Ment Dis 2017 Mar;205(3):192-195

*Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Pisa; †Department of Medical Sciences, Section of Infectious Diseases, University of Ferrara, Ferrara; ‡Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste; and §Department of Translational Research, N.T.M.S., School of Medicine, University of Pisa, Pisa, Italy.

Recent evidence suggests the involvement of Toxoplasma gondii infection in the emergence of psychotic and affective disorders. In this report, we describe the case of a young Brazilian woman affected by recurrent ocular toxoplasmosis and presenting with a manic episode with psychotic features in the context of a diagnosis of Bipolar Disorder (BD), type I. We observed a relationship between ocular manifestations and the clinical course of bipolar illness, confirmed by molecular analyses (nested-PCR), as well as by the high level of T. gondii specific IgG. This case report is the first showing the presence of circulating parasite DNA at the time of occurrence of psychiatric symptoms, thus providing further support for a possible role of the parasite in the pathogenesis of some cases of BD.
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http://dx.doi.org/10.1097/NMD.0000000000000496DOI Listing
March 2017

Genome Analysis and Characterisation of the Exopolysaccharide Produced by Bifidobacterium longum subsp. longum 35624™.

PLoS One 2016;11(9):e0162983. Epub 2016 Sep 22.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland.

The Bifibobacterium longum subsp. longum 35624™ strain (formerly named Bifidobacterium longum subsp. infantis) is a well described probiotic with clinical efficacy in Irritable Bowel Syndrome clinical trials and induces immunoregulatory effects in mice and in humans. This paper presents (a) the genome sequence of the organism allowing the assignment to its correct subspeciation longum; (b) a comparative genome assessment with other B. longum strains and (c) the molecular structure of the 35624 exopolysaccharide (EPS624). Comparative genome analysis of the 35624 strain with other B. longum strains determined that the sub-speciation of the strain is longum and revealed the presence of a 35624-specific gene cluster, predicted to encode the biosynthetic machinery for EPS624. Following isolation and acid treatment of the EPS, its chemical structure was determined using gas and liquid chromatography for sugar constituent and linkage analysis, electrospray and matrix assisted laser desorption ionization mass spectrometry for sequencing and NMR. The EPS consists of a branched hexasaccharide repeating unit containing two galactose and two glucose moieties, galacturonic acid and the unusual sugar 6-deoxy-L-talose. These data demonstrate that the B. longum 35624 strain has specific genetic features, one of which leads to the generation of a characteristic exopolysaccharide.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033381PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162983PLOS
September 2016

Histamine Receptor 2 is Required to Suppress Innate Immune Responses to Bacterial Ligands in Patients with Inflammatory Bowel Disease.

Inflamm Bowel Dis 2016 07;22(7):1575-86

*Department of Clinical Immunology, Wroclaw Medical University, Wroclaw, Poland; †"ALL-MED" Medical Research Institute, Wroclaw, Poland; ‡Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; §Alimentary Health Pharma Davos, Davos, Switzerland; and ¶Christine Kühne-Center for Allergy Research and Education, Zurich, Switzerland.

Background: Histamine is a key immunoregulatory mediator in immediate-type hypersensitivity reactions and chronic inflammatory responses, in particular histamine suppresses proinflammatory responses to bacterial ligands, through histamine receptor 2 (H2R). The aim of this study was to investigate the effects of histamine and H2R on bacteria-induced inflammatory responses in patients with IBD.

Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with Crohn's disease, patients with ulcerative colitis, and healthy controls. PBMC histamine receptor expression was evaluated by flow cytometry. Cytokine secretion following Toll-like receptor (TLR)-2, TLR-4, TLR-5, or TLR-9 stimulation in the presence or absence of histamine or famotidine (H2R antagonist) was quantified. Biopsy histamine receptor gene expression was evaluated using reverse transcription-polymerase chain reaction. The in vivo role of H2R was evaluated in the T-cell transfer murine colitis model.

Results: The percentage of circulating H2R monocytes was significantly reduced in patients with IBD. Histamine effectively suppressed TLR-induced cytokine secretion from healthy volunteer PBMCs but not for PBMCs from patients with IBD. Famotidine reversed this suppressive effect. H1R, H2R, and H4R gene expression was increased in inflamed gastrointestinal mucosa compared with noninflamed mucosa from the same patient and expression levels correlated with proinflammatory cytokine gene expression. Mice receiving lymphocytes from H2R donors, or treated with famotidine, displayed more severe weight loss, higher disease scores and increased numbers of mucosal IFN-γ and IL-17 T cells.

Conclusion: Patients with IBD display dysregulated expression of histamine receptors, with diminished anti-inflammatory effects associated with H2R signaling. Deliberate manipulation of H2R signaling may suppress excessive TLR responses to bacteria within the gut.
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http://dx.doi.org/10.1097/MIB.0000000000000825DOI Listing
July 2016

Human dendritic cell DC-SIGN and TLR-2 mediate complementary immune regulatory activities in response to Lactobacillus rhamnosus JB-1.

PLoS One 2015 27;10(3):e0120261. Epub 2015 Mar 27.

Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland.

The microbiota is required for optimal host development and ongoing immune homeostasis. Lactobacilli are common inhabitants of the mammalian large intestine and immunoregulatory effects have been described for certain, but not all, strains. The mechanisms underpinning these protective effects are beginning to be elucidated. One such protective organism is Lactobacillus rhamnosus JB-1 (Lb. rhamnosus JB-1). Lb. murinus has no such anti-inflammatory protective effects and was used as a comparator organism. Human monocyte-derived dendritic cells (MDDCs) were co-incubated with bacteria and analysed over time for bacterial adhesion and intracellular processing, costimulatory molecule expression, cytokine secretion and induction of lymphocyte polarization. Neutralising antibodies were utilized to identify the responsible MDDC receptors. Lb. rhamnosus JB-1 adhered to MDDCs, but internalization and intracellular processing was significantly delayed, compared to Lb. murinus which was rapidly internalized and processed. Lb. murinus induced CD80 and CD86 expression, accompanied by high levels of cytokine secretion, while Lb. rhamnosus JB-1 was a poor inducer of costimulatory molecule expression and cytokine secretion. Lb. rhamnosus JB-1 primed MDDCs induced Foxp3 expression in autologous lymphocytes, while Lb. murinus primed MDDCs induced Foxp3, T-bet and Ror-γt expression. DC-SIGN was required for Lb. rhamnosus JB-1 adhesion and influenced IL-12 secretion, while TLR-2 influenced IL-10 and IL-12 secretion. Here we demonstrate that the delayed kinetics of bacterial processing by MDDCs correlates with MDDC activation and stimulation of lymphocytes. Thus, inhibition or delay of intracellular processing may be a novel strategy by which certain commensals may avoid the induction of proinflammatory responses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120261PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376398PMC
March 2016

Intestinal dendritic cells.

Curr Opin Gastroenterol 2015 Mar;31(2):98-103

aSwiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Zurich, Switzerland bALL-MED Medical Research Institute cDepartment of Clinical Immunology, Wroclaw Medical University, Wroclaw, Poland.

Purpose Of Review: The intestinal immune system is constantly exposed to foreign antigens, which for the most part should be tolerated, but the immune system retains the ability to react rapidly and effectively to eliminate pathogens. Dendritic cells are at the front line in maintaining intestinal integrity as they are widely distributed within the intestinal lamina propria, Peyer's patches and mesenteric lymph nodes.

Recent Findings: The identification of dendritic cell subsets and phenotypic markers within the healthy and diseased intestine has progressed significantly, including improved identification of dendritic cell subsets within the human intestine. Recently, the role for dietary factors and the microbiome in modulating the intestinal dendritic cell functions has begun to be better investigated, resulting in a number of new findings relating to retinoic acid metabolism, pattern recognition receptor triggering and G-protein-coupled receptor activation. In addition, the interactions between goblet cells and mucin with intestinal dendritic cells are being better defined.

Summary: In this review, we discuss the recent findings relating to intestinal dendritic cells, in particular the importance of dendritic cells in sensing the intestinal microenvironment and the consequences for health and disease.
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http://dx.doi.org/10.1097/MOG.0000000000000155DOI Listing
March 2015

Histamine receptor 2 is a key influence in immune responses to intestinal histamine-secreting microbes.

J Allergy Clin Immunol 2014 Sep 20;134(3):744-746.e3. Epub 2014 Jun 20.

Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2014.04.034DOI Listing
September 2014

Probiotic VSL#3-induced TGF-β ameliorates food allergy inflammation in a mouse model of peanut sensitization through the induction of regulatory T cells in the gut mucosa.

Mol Nutr Food Res 2013 Dec 14;57(12):2233-44. Epub 2013 Aug 14.

Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy.

Scope: Among food allergies, peanut allergy is frequently associated with severe anaphylactic reactions. In the need for safe and effective therapeutic strategies, probiotics may be considered on the basis of their immunomodulatory properties. The aim of the present study was to investigate the immunological mediators involved in the effects of probiotic VSL#3 oral supplementation on Th2 inflammation and anaphylaxis in a mouse model of peanut allergy.

Methods And Results: VSL#3 supplementation to peanut-sensitized mice was effective in ameliorating anaphylaxis and Th2-mediated inflammation, by promoting regulatory responses in the jejunum mucosa and in the mesenteric lymph node, as evaluated by ELISA, real-time PCR, histologic, and immunohistochemical analysis. Probiotic-induced TGF-β mediates its protective effects through the induction of regulatory T cells expressing FOXP3 and/or latency-associated peptide, as proven by in vivo blockade of TGF-β in VSL#3-treated mice with a neutralizing monoclonal antibody one day before challenge.

Conclusion: TGF-β, induced in the gut by VSL#3 supplementation, is capable of reducing the Th2 inflammation associated with food anaphylaxis in a mouse model of peanut sensitization. TGF-β acts through the induction/maintenance of regulatory T cells expressing FOXP3 and/or latency-associated peptide. Probiotics supplementation may represent an effective and safe strategy for treating food allergies in adult population.
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http://dx.doi.org/10.1002/mnfr.201300028DOI Listing
December 2013

Negative dimension in psychiatry. Amotivational syndrome as a paradigm of negative symptoms in substance abuse.

Riv Psichiatr 2013 Jan-Feb;48(1):1-9

Department of Psychiatry NFB, University of Pisa, Italy.

Negative symptoms, conceptualized as clinical manifestations of schizophrenia, and subsequently described in other psychiatric disorders, include the loss of normal arousal, drive and affective reactivity. In the field of substance abuse, an interesting analogy can be detected between negative symptoms, in their classical meaning, and the amotivational syndrome (AS), which has been described as a form of chronic cannabis intoxication. AS also shows a close resemblance to the reward deficiency syndrome (RDS) of alcoholics and stimulant abusers, and to the post-withdrawal syndrome (PWS) of detoxified heroin addicts. A variety of substances share a common tropism for the dopaminergic system, leading to a state of hypophoria, which seems to represent a common pathway for chronic substance abusers. In the light of these convergences, a common treatment principle for addictive disorders can be enunciated. This consists in resorting to pro-dopaminergic drugs, that are supposed to replace damaged functions and control craving, and in avoiding anti-dopaminergic drugs, that are expected to exacerbate craving and impede the reversal of the reward deficiency.
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http://dx.doi.org/10.1708/1228.13610DOI Listing
April 2013

Plasma fluvoxamine levels and OCD symptoms/response in adult patients.

Hum Psychopharmacol 2012 Jul;27(4):397-402

Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Pisa, Italy.

Objective: In this study, we explored the possible relationships between plasma fluvoxamine levels and clinical features and/or response in adult obsessive-compulsive disorder (OCD) patients treated with this drug for 6 months.

Methods: Twenty OCD outpatients of both sexes who were already taking fluvoxamine (mean dose ± SD: 216.7 ± 86.2) for at least 4 weeks were included in the study. The severity of OCD was assessed by means of the Yale-Brown obsessive-compulsive scale (Y-BOCS). The fluvoxamine plasma levels were measured by high-performance liquid chromatography analysis. All evaluations were performed after 4 weeks (t1) and 6 months (t2) of fluvoxamine intake.

Results: The plasma levels of fluvoxamine remained stable at the two assessment times, with no sex-related differences. Sixteen (80%) patients responded to treatment as shown by the significant (>35%) decrease of the Y-BOCS total score. Men's compulsions improved more than those of women. Significant and positive correlations were detected between fluvoxamine plasma levels at t1 and t2 and the difference (delta) of the Y-BOCS total and compulsion subscale scores between t1 and t2. Another significant, albeit negative, correlation was measured between the difference of the compulsion subscale score and the difference of fluvoxamine levels at t1 and t2.

Conclusions: These findings underline the potential importance of evaluating fluvoxamine plasma levels in OCD and their relationships with the clinical response that may be gender-related on specific symptoms.
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http://dx.doi.org/10.1002/hup.2240DOI Listing
July 2012

Depressive symptoms in Parkinson's disease.

Compr Psychiatry 2012 Aug 30;53(6):727-31. Epub 2011 Dec 30.

Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnologies, University of Pisa, Via Roma 67, 56126 Pisa, Italy.

Objective: We aimed to investigate the relationship between the presence and severity of depression and the degree of motor and functional disability in Parkinson's disease (PD).

Methods: One hundred twenty-two outpatients with PD were enrolled in a neurology department: 65 satisfied the Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition criteria for major depression, and 57 did not (PD-C). Depressive symptoms were assessed by means of the Hamilton Rating Scale for Depression (HRSD), and the PD severity was assessed according to the Hoehn and Yahr System. Activities of daily living and motor symptoms were measured by the Unified PD Rating Scale (UPDRS), parts II and III.

Results: Twenty-nine patients had a mild depression (HRSD total score ranging between 8 and 17), 30 had a moderate depression (HRSD total score ranging between 18 and 24), and 6 had a severe depression (HRSD total score, ≥25). By comparing the 3 groups of patients, it emerged that those with a severe depression showed significantly higher scores at the UPDRS II, UPDRS III, and HY scales than did PD-C or patients with a mild depression. Moreover, patients with a moderate depression scored significantly higher on the UPDRS II, UPDRS III, and HY scales than did PD-C or those with a mild depression.

Conclusions: Our findings suggest that depression and motor symptoms/well-being are highly intertwined in patients with PD.
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http://dx.doi.org/10.1016/j.comppsych.2011.11.002DOI Listing
August 2012

Do methadone and buprenorphine have the same impact on psychopathological symptoms of heroin addicts?

Ann Gen Psychiatry 2011 May 15;10:17. Epub 2011 May 15.

'Vincent P, Dole' Dual Diagnosis Unit, Santa Chiara University Hospital, Department of Psychiatry, NPB, University of Pisa, Pisa, Italy.

Background: The idea that the impact of opioid agonist treatment is influenced by the psychopathological profile of heroin addicts has not yet been investigated, and is based on the concept of a specific therapeutic action displayed by opioid agents on psychopathological symptoms. In the present report we compared the effects of buprenorphine and methadone on the psychopathological symptoms of 213 patients (106 on buprenorphine and 107 on methadone) in a follow-up study lasting 12 months.

Methods: Drug addiction history was collected by means of the Drug Addiction History Rating Scale (DAH-RS) and psychopathological features were collected by means of the Symptom Checklist-90 (SCL-90), using a special five-factor solution. Toxicological urinalyses were carried out for each patient during the treatment period.

Results: No statistically significant differences were detected in psychopathological symptoms, including 'worthlessness-being trapped', 'somatization', and 'panic-anxiety'. Methadone proved to be more effective on patients characterized by 'sensitivity-psychoticism', whereas buprenorphine was more effective on patients displaying a 'violence-suicide' symptomatology.

Conclusions: Heroin-dependent patients with psychiatric comorbidities may benefit from opioid agonist treatment not only because it targets their addictive problem, but also, precisely due to this, because it is effective against their mental disorder too.
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http://dx.doi.org/10.1186/1744-859X-10-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113325PMC
May 2011

Temperamental traits of women applying for a type of job that has been characterized historically by male identity: the military career as case study.

J Affect Disord 2011 Apr 5;130(1-2):275-9. Epub 2010 Nov 5.

Santa Chiara University Hospital, Department of Psychiatry, University of Pisa, Italy.

Background: Over the past fifty years in the Western world the professions and activities that were once practised only by males, are now available to females, too. Affective temperaments, in line with their adaptive function, influence career choices. In general, males and females have proved to have different temperamental profiles. In this study we inquire into the question whether gender differences in temperament have continued unchanged in a field, such as the military career, that has been historically characterized by a male identity.

Methods: 1426 males and 122 females wishing to become a cadet in the Italian Air Force were tested using TEMPS-A[P] (the Temperament Evaluation of Memphis, Pisa, Paris and San Diego self-questionnaire, Pisan version).

Results: Univariate and multivariate analyses failed to distinguish males from females. Both males and females tend to have a high score on the hyperthymic scale (generally, a typical male temperament) and a very low one on the cyclothymic scale (generally, a typical female temperament), with low scores on the depressive and the irritable scales.

Conclusions: This study supports the idea that different gender-related temperaments are functional to differences in the roles played by males and females during the biological and social evolutionary process.
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http://dx.doi.org/10.1016/j.jad.2010.10.006DOI Listing
April 2011

Health-related quality of life and functioning in remitted bipolar I outpatients.

Compr Psychiatry 2007 Jul-Aug;48(4):323-8. Epub 2007 Apr 11.

Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, 56127 Pisa, Italy.

The aim of this study was to characterize the health-related quality of life (HR-QOL) and functioning in 90 bipolar I remitted outpatients. According to Diagnostic and Statistical Manual of Mental Disorders IV remission specifiers, patients were categorized into 4 groups: group 1, fully remitted; group 2, less than 2 months remitted; group 3, with persisting manic symptoms; group 4, with persisting depressive symptoms. The severity of psychopathology was evaluated by using the Bech-Rafaelsen Mania-Melancholia Scale. The HR-QOL, functioning, and insight were assessed via the medical outcomes study 36-item short form, the global assessment of functioning scale, and the scale to assess unawareness of mental disorder, respectively. Fully remitted patients reported the highest scores in almost all domains of medical outcomes study 36-item short form, and had significantly higher scores on physical functioning, general health, social functioning, and mental health compared to patients with persisting depressive symptoms. Furthermore, patients with persisting manic symptoms reported significantly higher scores on general health, vitality and mental health than the group with persisting depressive symptoms. In contrast, the global assessment of functioning scale score differed among the 4 groups, with fully remitted patients reporting higher, although not statistically significant, scores than the other groups. Our data suggest that the persistence of depressive or manic symptoms seem to affect self-report measures of HR-QOL. An affectively biased cognition may explain the gap between patient's perception of functioning and estimated functional adjustment, as assessed by clinicians.
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http://dx.doi.org/10.1016/j.comppsych.2006.12.007DOI Listing
July 2007

Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments.

J Affect Disord 2008 Jan 5;105(1-3):279-83. Epub 2007 Jun 5.

Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Pisa, Italy.

Background: Brain-derived neurotrophic factor (BDNF) has been hypothesized to be involved in the neurobiology of major depression. The aim of this study was to assess the possible relationships between depressive symptoms and serum and/or plasma BDNF levels during 1 year of antidepressant treatment.

Methods: Plasma and serum BDNF levels were assayed in 15 drug-free depressed patients and in 15 healthy control subjects at baseline and the 1st, 3rd, 6th and 12th month of antidepressant treatment.

Results: At baseline, patients' serum and plasma BDNF levels were significantly lower (p<.001 and p=.004, respectively) than those found in healthy control subjects. However, while from the 1st month of treatment patients' plasma BDNF levels did not differ significantly from those observed in healthy control subjects, serum BDNF levels in patients remained significantly lower at all times.

Limitations: The main limitations of the current study are represented by the small sample size and the high discontinuation rate.

Conclusions: Untreated depressed patients showed reduced baseline serum and plasma BDNF levels, as compared with control subjects. The clinical improvement paralleled the normalization of plasma BDNF after 1 month of treatment, while, at every assessment time, patients' serum BDNF levels were lower than those of control subjects. This would suggest that serum BDNF might represent a non-specific trait marker of depression.
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http://dx.doi.org/10.1016/j.jad.2007.05.005DOI Listing
January 2008
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