Effect of lithium in pyramidal neurons of Cornu Ammonis in an animal model.

Bipolar disorder has been associated with a decrease in hippocampal size, and lithium appears to reverse this neuroanatomical abnormality. The objective of this work was to evaluate, at a cellular level, the size of both cell body and nucleus of pyramidal neurons located throughout the Cornu Ammonis (CA1 to CA4 regions). To perform this duty, we used 16 rats that were randomized into two groups: control and dietary lithium-treated. After one month, they were sacrificed and their brains removed for histopathological analysis. Serial photos of the entire Cornu Ammonis were taken and, after dividing them into 4 regions of interest, we measured the cell body and nucleus on each pyramidal neuron belonging to the first 5 photos of each region of interest. As a result of this histological analysis, cell body area and nuclear area were significantly larger in the experimental group in a specific area of the Cornu Ammonis that could correspond to CA2 or the transition between CA1 and CA2. These results suggest that the effect of lithium is not homogeneous throughout the hippocampus and allows directing future studies to a specific area of this structure.

Characterization of Mood Instability through Bipolar Disorders: A cluster-analytic approach using weekly prospective life-chart methodology.

BackgroundThe aim of this study was to characterize mood instability (MI) in Bipolar Disorder (BD) and to investigate potential differences between subtype I and II. MethodsLife-charts from weekly mood ratings of 90 patients were used to compute: weeks spent with symptoms, number of episodes, and MI. Regression analyses were conducted to assess the relationship between BD subtype and MI adjusting by all potential confounding factors. Hierarchical cluster analysis was performed to determine the appropriate number of clusters that described the data and to assign subjects to a specific cluster based on their MI. We then compared clusters on clinical and psychosocial outcomes. ResultsMedian follow-up was 5 years (IQR: 3.6-7.9). Patients spent 15.2%, 5%, and 3% of follow-up with depressive, manic, and mixed symptoms, respectively. BD type II presented higher MI (ß = 1.83, 95% CI: 0.66-3.00) and subsydromal symptoms than BD type I patients. No differences in functioning or recurrences were found between subtypes. Differences in MI between the two clusters mimicked those between type I and II but enhanced (ß = 3.86, 95%CI -4.72, -2.66). High MI (n = 43) patients presented poorer functioning and higher recurrences compared to Low MI patients (n = 43). ConclusionBD type II presented higher MI and subsyndromal symptoms than BD type I patients. However, these differences did not translate into clinically relevant outcomes. A classification based on MI may provide useful clinical insights.

A longitudinal mirror-image assessment of morbidity in bipolar disorder.

BACKGROUND: Evidence about the clinical course of bipolar disorder is inconsistent and limited. The aim of this study was to assess changes in morbidity in patients with bipolar disorder along a mean follow-up period of 80months. METHODS: Based on a mirror-image design, the follow-up period of each patient was divided into two halves. Then, three measures of morbidity - number of affective episodes, time spent ill, and cycle length - were recorded and compared between each half of the follow-up period. RESULTS: On average, there was a trend to a smaller amount of time spent with subclinical symptomatology during the second half of the follow-up period. In contrast, there were no differences in terms of number of episodes, time spent with clinical symptoms, or cycle length between the first and second half of the follow-up period. A subgroup analysis identified 21.9% of patients with consistent data of a worsening during follow-up. CONCLUSIONS: The results suggest that, on average, there is stability or slight improvement of clinical morbidity over the course of BD. Then, worsening of the clinical course may be a feature of a subgroup of patients rather than an inherent characteristic of the disorder. These subgroups or patient profiles could represent an opportunity for further studies to assess clinical, pathophysiologic, and therapeutic features associated with them.

Genomewide association study of peanut allergy reproduces association with amino acid polymorphisms in HLA-DRB1.

BACKGROUND: Genetic variants for IgE-mediated peanut allergy are yet to be fully characterized and to date only one genomewide association study (GWAS) has been published. OBJECTIVE: To identify genetic variants associated with challenge-proven peanut allergy. METHODS: We carried out a GWAS comparing 73 infants with challenge-proven IgE-mediated peanut allergy against 148 non-allergic infants (all ~ 1 year old). We tested a total of 3.8 million single nucleotide polymorphisms, as well as imputed HLA alleles and amino acids. Replication was assessed by de novo genotyping in a panel of additional 117 cases and 380 controls, and in silico testing in two independent GWAS cohorts. RESULTS: We identified 21 independent associations at P ≤ 5 × 10-5 but were unable to replicate these. The most significant HLA association was the previously reported amino acid variant located at position 71, within the peptide-binding groove of HLA-DRB1 (P = 2 × 10-4 ). Our study therefore reproduced previous findings for the association between peanut allergy and HLA-DRB1 in this Australian population. CONCLUSIONS AND CLINICAL RELEVANCE: Genetic determinants for challenge-proven peanut allergy include alleles at the HLA-DRB1 locus.

Are major depression and bipolar disorder neuropsychologically distinct? A meta-analysis of comparative studies.

BACKGROUND: Neuropsychological deficits are present in both major depression and bipolar disorder. So far, however, reports directly comparing these mood disorders with regard to cognitive outcomes have been scant and yielded inconsistent results. This work aims to combine the findings of comparative studies of cognition in major depression and bipolar disorder in order to explore whether these neuropsychiatric conditions present with distinct cognitive features. METHODS: The main online databases were extensively searched to retrieve reports assessing neurocognitive functioning in two groups of mood disorder patients, one with major depressive disorder and another with bipolar disorder, both in the same phase of illness. Between-group effect sizes for cognitive variables were obtained from selected studies and pooled by means of meta-analytic procedures. RESULTS: During euthymia, a significant overall effect size (Hedges'g=0.64, P<0.001) favoring major depressive disorder was found for verbal memory as assessed with list learning tests, whereas no significant between-group differences were found for the remaining variables analyzed. During depressive episodes, similar cognitive outcomes were observed between groups. CONCLUSION: At present, it is not possible to postulate specific neuropsychological profiles for major depression and bipolar disorder in light of available evidence. It remains to be ascertained whether the differences found for verbal memory constitute an expression of distinct underlying mechanisms or whether they are best explained by sample characteristics or differential exposure to variables with a negative impact on cognition.

Oral immunotherapy and tolerance induction in childhood.

Prevalence rates of food allergy have increased rapidly in recent decades. Of concern, rates of increase are greatest among children under 5 yrs of age and for those food allergies that persist into adulthood such as peanut or tree nut allergy and shellfish allergy. Given these trends, the overall prevalence of food allergy will compound over time as the number of children affected by food allergy soars and a greater proportion of food-allergic children are left with persistent disease into adulthood. It is therefore vital to identify novel curative treatment approaches for food allergy. Acquisition of oral tolerance to the diverse array of ingested food antigens and intestinal microbiota is an active immunologic process that is successfully established in the majority of individuals. In subjects who develop food allergy, there is a failure or loss of oral tolerance acquisition to a limited number of food allergens. Oral immunotherapy (OIT) offers a promising approach to induce specific oral tolerance to selected food allergens and represents a potential strategy for long-term curative treatment of food allergy. This review will summarize the current understanding of oral tolerance and clinical trials of OIT for the treatment of food allergy.

Mood instability and functional recovery in bipolar disorders.

OBJECTIVE: The aim of this study was to identify psychopathological factors associated with long-term functional outcome in euthymic bipolar disorder patients and to test new measures of mood instability and symptoms intensity. METHOD: Fifty-five patients with more than 12 months of follow-up were included. In addition to traditional clinical variables, the time spent ill was documented using a modified life-charting technique based on NIHM life-charting method. New measures, Mood Instability Factor, and Mood Intensity Factor were defined and assessed. Functioning Assessment Short Test (FAST) was used to assess disability. RESULTS: The follow-up period was 3.00 ± 1.51 years. Weeks with subsyndromal depressive symptoms (ß = 0.133, t = 2.556, P = 0.014), weeks with mild manic symptoms (ß = 1.441, t = 3.10, P = 0.003), and the Mood Instability Factor (ß = 0.105, t = 3.593, P = 0.001) contributed to approximately 46% of the FAST total score variance. CONCLUSION: New methodologies including subsyndromal symptoms and mood instability parameters might contribute to understand the worse long-term functional outcome that affects a considerable percentage of BD patients even after episode remission. Concerns about therapeutic approaches are discussed.

Complementary and alternative medicines usage in bipolar patients from Argentina and Colombia: associations with satisfaction and adherence to treatment.

BACKGROUND: The use of Complementary and Alternative Medicines (CAM) has been reported by around half the patients undergoing medical treatment for chronic conditions. CAM use could be higher in people affected by bipolar disorders (BD). Some questions about CAM use in BD have not been investigated enough. We report here the results of an anonymous survey on CAM-use conducted among BD outpatients of two centers located in Argentina and Colombia. METHODS: an anonymous self-survey was administrated to bipolar euthymic outpatients treated at each center. The survey included a self-report measure of adherence to psychiatric treatment and a modified version of CGI to asses satisfaction with the current treatment. RESULTS: 200 patients completed the survey. Although samples differ in socio-economic profile, they do not differ in their reported CAM-usage (more than 40%). CAM-usage did not modify the adherence or satisfaction with the psychiatric treatment reported level. Thirty eight percent of those who were still resorting to CAM failed to inform it to their clinician. CAM-usage was rated as "useful" or "very useful" by 52% of patients. LIMITS: adherence to current medical treatment and satisfaction with current treatment were investigated by a self-reported instrument. DISCUSSION: the prevalence of CAM usage found is similar to that of other studies. CAM usage seems to be ubiquitous, which takes to posit that a subgroup of patients may be in need of treatment with greater magical-religious components. Half of these patients were reluctant to disclose CAM use. Clinicians may need to consider coexistence between "traditional" treatments and CAM for these patients.

Social cognition in euthymic bipolar disorder: systematic review and meta-analytic approach.

OBJECTIVE: Deficits in social cognition have been reported in euthymic subjects with bipolar disorder (BD). However, some studies have failed to find differences favoring controls. As most investigations have been conducted with small samples, they have not had sufficient power to detect statistically significant differences. Furthermore, studies communicating positive results have scarcely attempted to estimate effect sizes for patient-control differences. The aim of this study was to summarize the findings of reports on social cognition in patients with euthymic BD and to combine their data to identify possible deficits and quantify their magnitude. METHOD: Systematic literature review and meta-analysis. RESULTS: Impairments of moderate magnitude (0.5 < d < 0.8) were noted across mentalizing skills, whereas small but significant effect sizes (d < 0.5) were observed for facial emotion recognition. No patient-control differences were found for decision-making. CONCLUSION: Meta-analytic findings provide evidence for emotion processing and theory of mind deficits in remitted bipolar patients. However, it is not yet clear whether these areas of impairment are related to neurocognitive dysfunctions or to medication effects. The results are discussed with regard to targets for future neuropsychological research on BDs.

Dopamine sudden depletion as a model for mixed depression.

Up to date research on Bipolar Disorders' phenomenology is in keeping with early descriptions made by E. Kraëpelin regarding the overlap in clinical presentation of both manic and depressive symptoms, namely, mixed states. The latter constitute a highly prevalent and characteristic clinical presentation of Bipolar Disorders' and entail therapeutic difficulties, prognostic implications and increased suicidal risk. Notwithstanding, mixed states', more specifically mixed depression, have been underestimated and bypassed to the point where currently neither diagnostic criteria nor specific therapeutic recommendations are provided. In addition to the lack of agreement on nosography and diagnostic criteria, mixed depression is usually excluded from Bipolar Disorders' neurobiological models. Furthermore, renewed interest in the role of dopamine in Bipolar Disorders' physiopathology has left aside hypothesis that may account for the aforementioned clinical presentation. Interestingly enough, other syndromes arising from sudden dopamine depletion such as neuroleptic dysphoria or withdrawal syndromes from dopaminergic drugs, bear remarkable clinical similarities with mixed depression. These syndromes have been subject of further research and may thus provide a model for mixed states' physiopathology. Indeed, this article accounts for clinical similarities between mixed depression, neuroleptic induced dysphoria, and other behavioural syndromes arising from sudden dopamine depletion. After reviewing neurochemical basis of such syndromes we present, to the best of our knowledge, the first neurobiological hypothesis for mixed depression. Specifically, such hypothesis regards over activation symptoms as auto regulatory attempts to compensate for sudden dopaminergic depletion. This hypothesis provides with a beginning step for the neglected problem of mixed depression, a non-antithetic link between the dopaminergic hypothesis for both manic and depressive symptoms, a plausible explanation regarding inter individual variability to mixed depression susceptibility, and suggests new approaches for the development of novel treatments in which dopamine dysregulation should be targeted.

T-cell activation genes differentially expressed at birth in CD4+ T-cells from children who develop IgE food allergy.

BACKGROUND: Presymptomatic immaturity in neonatal T-cell function is a consistent antecedent of allergic disease, including reduced responsiveness to polyclonal activation. METHODS: To elucidate the underlying mechanisms, we examined for differences in T-cell gene expression in longitudinal samples collected at birth and at 1 year of age in children with (n = 30) and without IgE-mediated food allergy (n = 30). We employed a low-level soluble anti-CD3 stimulus to activate the T-cell receptor (TCR) and surveyed gene expression by DNA microarray in purified CD4(+) T-cells. Allergen-specific responses were assessed in parallel functional studies. RESULTS: At birth, the allergic group showed a reduced number of genes up regulated in response to anti-CD3 treatment on the microarray and a reduced lympho proliferative capacity, suggesting clear differences in T-cell signalling pathways. Polymerase chain reaction (PCR) validation of candidate genes confirmed significantly lower expression of a number of genes in the allergic group including RELB, NFKB2, LIF and FAS. By 12 months of age, there were marked changes in the anti-CD3 response in all infants, culminating in upregulation of cytokine genes (IL-5, IL-13, IL-17 and IL-22). Neonatal differences were no longer apparent. Instead, the allergic group, all symptomatic by this age, showed differential expression of T-cell lineage pathways including GATA-3, MAL and FcER1 in unstimulated T-cells. Allergen stimulation induced significantly higher cytokines production (IL-5, IL-13 and IFNγ) in the allergic group. CONCLUSION: Although transient, suboptimal neonatal T-cell activation pathways that signal through the NF-κB complex may affect the developmental transition of T-cell phenotypes in the periphery shortly after birth and may increase the risk of food allergy.

Decision making in euthymic bipolar I and bipolar II disorders.

BACKGROUND: The main aim of this study was to compare a large population of patients with bipolar disorder (BD) types I and II strictly defined as euthymic with healthy controls on measures of decision making. An additional aim was to compare performance on a decision-making task between patients with and without a history of suicide attempt. METHOD: Eighty-five euthymic patients with BD-I or BD-II and 34 healthy controls were included. All subjects completed tests to assess verbal memory, attention and executive functions, and a decision-making paradigm (the Iowa Gambling Task, IGT). RESULTS: Both groups of patients had worse performance than healthy controls on measures of verbal memory, attention and executive function. No significant differences were found between BD-I, BD-II and healthy controls on measures of decision making. By contrast, patients with a history of suicide attempt had lower performance in the IGT than patients without a history of suicide attempt. CONCLUSIONS: Patients with euthymic BD-I and BD-II had intact decision-making abilities, suggesting that this does not represent a reliable trait marker of the disorder. In addition, our results provide further evidence of an association between impairments in decision making and vulnerability to suicidal behavior.

Silent mysteries: epigenetic paradigms could hold the key to conquering the epidemic of allergy and immune disease.

Epigenetic mechanisms provide new insights into how environmental changes may mediate the increasing propensity for complex immune diseases such as allergic disease. There is now strong evidence that early environmental exposures play a key role in activating or silencing genes by altering DNA and histone methylation, histone acetylation and chromatin structure. These modifications determine the degree of DNA compaction and accessibility for gene transcription, altering gene expression, phenotype and disease susceptibility. While there is already evidence that a number of early environmental exposures are associated with an increased risk of allergic disease, several new studies indicate in utero microbial and dietary exposures can modify gene expression and allergic disease propensity through epigenetic modification. This review explores the evidence that immune development is under clear epigenetic regulation, including the pattern of T helper (Th)1 and Th2 cell differentiation, regulatory T cell differentiation, and more recently, Th17 development. It also considers the mechanisms of epigenetic regulation and early immune defects in allergy prone neonates. The inherent plasticity conferred by epigenetic mechanisms clearly also provides opportunities for environmental strategies that can re-programme gene expression for disease prevention. Identifying genes that are differentially silenced or activated in relation to subsequent disease will not only assist in identifying causal pathways, but may also help identify the contributing environmental factors.

Relationship between early intestinal colonization, mucosal immunoglobulin A production and systemic immune development.

BACKGROUND: Variations in early intestinal colonization patterns have been implicated in the predispostion to allergic disease through effects on mucosal and systemic immune function. METHODS: Colonization patterns and mucosal IgA production at 6 months of age were examined in relation to early exposures, systemic immune development and early allergic outcomes. This was performed in a cohort (n=189) who had received either Lactobacillus acidophilus or a placebo since birth. RESULTS: Children who developed sensitization to one or more allergens by 12 months of age had significantly higher total (but not secretory) IgA levels at 6 months (P=0.024), but this was independent of probiotic treatment. There were no relationships between colonization patterns and IgA (total or secretory IgA) levels or allergic outcomes (sensitization, atopic dermatitis or food allergies). Breastfeeding, and the use of yoghurt or probiotic supplements were independently associated with significantly higher proportions of 'favourable' lactobacilli and bifidobacteria species. Caesarean delivery and the use of antibiotics during the first 6 months were not associated with significant variations in colonization. Higher proportions of 'favourable' bacteria (notably bifidobacteria) were associated with reduced production of most cytokine response to allergens, but increased expression of regulatory cell markers (P=0.009) and transforming growth factor-beta (P=0.016). CONCLUSION: 'Favourable' colonization, particularly with bifidobacteria, was associated with effects on cellular immune function, but this was not associated with mucosal immunity (secretory IgA) or reduced risk of allergic disease.

Immunogenicity of a fucosyl-GM1-keyhole limpet hemocyanin conjugate vaccine in patients with small cell lung cancer.

Although small cell lung cancer (SCLC) is highly responsive to chemotherapy, relapses are common, and most patients die within 2 years of diagnosis. After initial therapy, standard treatment is observation alone. We have been investigating immunization against selected gangliosides as adjuvant therapy directed against residual and presumably resistant disease persisting after chemotherapy and irradiation. Previously, we reported that the presence of anti-GM2 ganglioside antibodies is associated with a prolonged disease-free survival in patients with melanoma, and that SCLC patients immunized with BEC2, an anti-idiotypic monoclonal antibody that mimics the ganglioside GD3, had a prolonged survival compared with historical controls. In the present trial, fucosyl-alpha1-2Galbeta1-3GalNAcbeta1-4(NeuAcalpha2-3) Galbeta1-4Glcbeta1-1Cer (Fuc-GM1), a ganglioside expressed on the SCLC cell surface, was selected as a target for active immunotherapy. Fuc-GM1 is present on most SCLCs but on few normal tissues. SCLC patients achieving a major response to initial therapy were vaccinated s.c. on weeks 1, 2, 3, 4, 8, and 16 with Fuc-GM1 (30 microg) conjugated to the carrier protein keyhole limpet hemocyanin and mixed with the adjuvant QS-21. Ten patients received at least five vaccinations and are evaluable for response. All patients demonstrated a serological response, with induction of both IgM and IgG antibodies against Fuc-GM1, despite prior treatment with chemotherapy with or without radiation. Posttreatment flow cytometry demonstrated binding of antibodies from patients' sera to tumor cells expressing Fuc-GM1. In the majority of cases, sera were also capable of complement-mediated cytotoxicity. Mild transient erythema and induration at injection sites were the only consistent toxicities. The Fuc-GM1-KLH + QS-21 vaccine is safe and immunogenic in patients with SCLC. Continued study of this and other ganglioside vaccines is ongoing.