CD40 is a member of the tumor necrosis factor receptor superfamily, expressed on a wide range of cell types including B cells, macrophages, and dendritic cells. CD40 is the receptor for CD40 ligand ...(CD40L), a molecule predominantly expressed by activated CD4+T cells. CD40/CD40L interaction induces the formation of memory B lymphocytes and promotes Ig isotype switching, as demonstrated in mice knocked-out for either CD40L or CD40 gene, and in patients with X-linked hyper IgM syndrome, a disease caused by CD40L/TNFSF5 gene mutations. In the present study, we have identified three patients with an autosomal recessive form of hyper IgM who fail to express CD40 on the cell surface. Sequence analysis of CD40 genomic DNA showed that one patient carried a homozygous silent mutation at the fifth base pair position of exon 5, involving an exonic splicing enhancer and leading to exon skipping and premature termination; the other two patients showed a homozygous point mutation in exon 3, resulting in a cysteine to arginine substitution. These findings show that mutations of the CD40 gene cause an autosomal recessive form of hyper IgM, which is immunologically and clinically undistinguishable from the X-linked form.
Functional recovery of B lymphocytes after hematopoietic stem cell transplantation (HSCT) can take up to 2 years. HSCT recipients may obtain protective titers of pathogen-specific antibody through ...vaccination, but optimal timing of reimmunization remains to be defined.
In this study, we evaluated the reconstitution of B-cell number and activity in 139 children given HSCT, by B-cell subset phenotyping and in vitro immunoglobulin (Ig) production.
Patients were longitudinally studied at 3, 6, 12, and 18 to 24 months after transplantation. At all time points, recipients displayed a significantly higher percentage of naive (IgD
+CD27
−) B cells and showed significantly lower production of stimulated in vitro Ig as compared to healthy controls. Moreover, during follow-up, we observed an increase in the proportion of patients who had CD27
+ B subsets and who were able to mount in vitro Ig production greater than the 5th percentile.
Similar to what has been described in adults, most children lack memory B cells and produce low amounts of Ig. However, the number of B cells, as well as their function, gradually recovered over time and the spread of data we observed suggests that the reimmunization schedule should be individualized for each patient. It remains to be defined in a prospective clinical study the time point at which a patient should start reimmunization. A reasonable hypothesis to be explored is the time point at which a percentage of memory B cells greater than the 5th percentile of normal controls is reached.
Bipolar disorder (BD) and alcohol use disorder (AUD) commonly co-occur and their interplay is influenced by several factors. Alexithymia is connected to BD and AUD; affective temperaments serve as ...risk factors for both; craving contributes to the development and maintenance of AUD. The present study tested whether alexithymia play a mediating role in the relationship between affective temperaments and craving in alcoholic bipolar patients.
151 alcoholic bipolar patients (38 % females, mean age: 45.69 ± 9.04 years) were enrolled. The Mini International Neuropsychiatric Interview (MINI), the Brief Psychiatric Rating Scale (BPRS), the Toronto Alexithymia Scale (TAS-20), the Temperament Evaluation of the Memphis, Pisa, Paris and San Diego scale (TEMPS-A), and the Typology Craving Questionnaire (CTQ) were administered. Correlations among TAS-20, TEMPS-A, CTQ were conducted. Regression analyses were applied to verify the mediating hypothesis.
Difficulty in identifying feelings mediated the association between anxious temperament and craving (Indirect effect: 0.42, BCaCI: 0.22–0.69), cyclothymic temperament and craving (Indirect effect: 0.55, BCaCI: 0.30–0.87), irritable temperament and craving (Indirect effect: 0.45, BCaCI: 0.19–0.80). TAS-20 difficulty in communicating feelings to others mediated the association between anxious temperament and craving (Indirect effect: 0.20, BCaCI: 0.06–0.41).
The sample size did not allow subgroup analyses. Data were collected cross-sectionally and in a single center. We did not investigate whether BD or AUD occurred first, although it might influence the mediation role of alexithymia.
Among alcoholic bipolar patients, assessing and targeting alexithymia may be useful to modulate craving and, in turn improve, the general mental status of patients.
•Alexithymia was significantly associated with alcohol craving.•Anxious, cyclothymic, and irritable temperaments were positively correlated with alexithymia and craving in BD-AUD subjects.•Alexithymia mediated the relationship between anxious, cyclothymic, and irritable temperaments.•Modifying alexithymia may be useful in reducing craving in BD-AUD subjects.
Background: In children of different ages investigated for failure to thrive, low (below the cut‐off for age) immunoglobulin (Ig) values can be detected, without any clinical evidence of humoral ...immunodeficiencies. To better characterize infants presenting with diminished immunoglobulin levels, we studied IgG subclasses, in vitro Ig production and B cell subpopulation.
Methods: We monitored 17 children (12 boys and five girls, age range 1–18 years) with low serum levels of one or more Ig isotypes but without any clinical or laboratory features of immunodeficiency.
Results: Low IgM levels were frequent (52.9%). During the follow up, six of 17 cases (35.3%) normalized their immunoglobulin levels. Frequently, in the observed patients, low levels of immunoglobulins were not limited to the period of infancy. In all patients, in vitro Ig production and B lymphocyte subpopulations were within normal ranges.
Conclusions: We suggest a quantification of serum Ig levels in children who fail to thrive in order to identify patients with low Ig levels. These children should be monitored until Ig levels normalize to exclude any immunodeficiency status. Early recognition of children with persistent hypogammaglobulinemia would allow prompt and appropriate clinical interventions.
Abstract Background The aim of this study was to assess whether different affective temperaments could be related to a specific mood disorder diagnosis and/or to different therapeutic choices in ...inpatients admitted for an acute relapse of their primary mood disorder. Method Hundred and twenty-nine inpatients were consecutively assessed by means of the Structured and Clinical Interview for axis-I disorders/Patient edition and by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego auto-questionnaire, Young Mania Rating Scale, Hamilton Scale for Depression and for Anxiety, Brief Psychiatry Rating Scale, Clinical Global impression, Drug Attitude Inventory, Barratt Impulsiveness Scale, Toronto Alexithymia Scale, and Symptoms Checklist-90 items version, along with records of clinical and demographic data. Results The following prevalence rates for axis-I mood diagnoses were detected: bipolar disorder type I (BD-I, 28%), type II (31%), type not otherwise specified (BD-NOS, 33%), major depressive disorder (4%), and schizoaffective disorder (4%). Mean scores on the hyperthymic temperament scale were significantly higher in BD-I and BD-NOS, and in mixed and manic acute states. Hyperthymic temperament was significantly more frequent in BD-I and BD-NOS patients, whereas depressive temperament in BD-II ones. Hyperthymic and irritable temperaments were found more frequently in mixed episodes, while patients with depressive and mixed episodes more frequently exhibited anxious and depressive temperaments. Affective temperaments were associated with specific symptom and psychopathology clusters, with an orthogonal subdivision between hyperthymic temperament and anxious/cyclothymic/depressive/irritable temperaments. Therapeutic choices were often poorly differentiated among temperaments and mood states. Limits Cross-sectional design; sample size. Conclusions Although replication studies are needed, current results suggest that temperament-specific clusters of symptoms severity and psychopathology domains could be described.
Background. Antibodies directed against alloantigens are implicated in the pathogenesis of several immune reactions complicating transplantation, including humoral rejection after solid organ ...transplantation. Mesenchymal stem cells (MSCs) have immunomodulatory capacity, since in vivo they may prolong skin graft survival in the animal model and can rescue patients with life-threatening graft-versus-host disease. Methods. To investigate whether MSCs exert an inhibitory effect on antibody production during allostimulation, we stimulated peripheral blood mononuclear cells, obtained from healthy controls or sensitized patients undergoing dialysis for end-stage renal failure, in mixed lymphocyte culture (MLC), and evaluated immunoglobulin production either in the absence or in the presence of third-party allogeneic MSCs. We also evaluated the effect of MSCs on B-cell allostimulation performed adding to MLC a polyclonal stimulus delivered by an agonist anti-CD40 monoclonal antibody. Results. We found that the addition of MSCs at the beginning of MLC considerably inhibited immunoglobulin production in standard MLC, irrespective of the MSC dose employed. Conversely, immunoglobulin secretion induced by direct CD40-CD40L binding was not significantly inhibited. Furthermore, we demonstrated, in one sensitized patient, that secretion of donor-specific anti-HLA class I antibodies detected both in baseline serum and in the supernatant of control MLC was inhibited by the addition of MSCs. Mechanistically, the addition of MSCs induced a striking decrease of IL-5 production in the cultures. Conclusions. Our findings suggest that third-party MSC are able to suppress allo-specific antibody production in vitro, and may therefore help overcome a positive cross-match in sensitized transplant recipients.
Alcohol withdrawal syndrome (AWS) is a medical emergency, rare in the general population, but very common among alcoholic individuals, which can lead to severe complications when unrecognized or late ...treated. It represents a clinical condition which can evolve in few hours or days following an abrupt cessation or reduction of alcohol intake and is characterized by hyperactivity of the autonomic nervous system resulting in the development of typical symptoms. According to DSM-5 criteria, the alcohol withdrawal syndrome is defined as such: if patients present at least two of typical signs and symptoms. The Clinical Institute Withdrawal Assessment of Alcohol Scale, revised version (CIWA-Ar), is the tool for assessing the severity of AWS. The support to patient with AWS includes pharmacological intervention as well as general support, restoration of biochemical imbalances and specific therapy. Regarding the pharmacological treatment, benzodiazepines represent the gold standard, in particular long-acting benzodiazepines, administered with a gradual reduction up to cessation.
It has long been appreciated that alcohol use disorder (AUD) is associated with increased risk of psychiatric disorder. As well, people with history of mental disorder are more likely to develop ...lifetime AUD. Nevertheless, the treatment of dual diagnosis (DD) in alcohol addiction still remains a challenge. The efficacy of pharmacological treatment for these patients has been widely investigated with controversial results. Patients with untreated psychiatric disorder are at higher risk to return to drinking and tend to do so more quickly. The aim of this review was to collect clinical data for developing guidelines for the pharmacological treatment of psychiatric diseases in a population with AUD.
A literature review was conducted using the following databases: PubMed-NCBI, Cochrane database, Embase
Web of Science, and Scopus, including studies published between 1980 and 2015. Search terms were: “guideline”, “treatment”, “comorbidity”, “substance abuse”, “alcohol”, “dual-diagnosis”, “antidepressant”, “antipsychotic”, “mood-stabilizer”. Out of 1521 titles, 84 studies were included for their relevance on pharmacological treatment of psychiatric disorders in people with AUD.
Different drugs were collected in major pharmacological classes (antidepressant, mood-stabilizer, antipsychotic), in order to identify their proved efficacy for treating specific psychiatric disorder in the AUD population. Data were selected and verified for publications from randomized clinical trials, open-label trials and case reports.
DD in alcohol dependence is a complex clinical entity, and its high prevalence is supported by epidemiological data. Pharmacological management of psychiatric disorders in patients with AUD remains partially anecdotal. Based on reviewed articles, we propose a classification of psychiatric medications for treatment of mental disorders comorbid with AUD, listed with evidence-based recommendations. More research is needed to obtain and collect clinical data, in order to organize and share evidence-based guidelines.
The term “dual diagnosis” (DD) has been used in clinical practice for years. However, there is confusion about
these medical cases, which consist in the presence of both a psychiatric disorder and a ...substance abuse disorder (in this case, alcohol). There are evidences that in the alcohol use disorder (AUD) population, 50.3% of patients had a psychiatric comorbidity during their lifetime. Nevertheless, to these days there are not any thorough guidelines for the management of these patients. A precise nosography would prevent delay in diagnosis and treatment and all the self-evident negative outcomes of those delays.
A literature search was performed in PubMed, Web of Science, and Scopus, including studies published between 1980 and 2015. Search terms were: “guidelines”, “treatment”, “comorbidity”, “substance abuse”, “alcohol”, “dual-diagnosis”, “etiopathogenesis”, “outpatient”, “inpatient”, “unit”, “diagnosis”. Out of 1045 titles, 43 studies were included in this article for their relevance on definition and nosography of DD.
Taking into account the state of art available in the literature, we contributed to clarify the definition of DD in the alcohol addiction field. Clinical data confirm high prevalence of DD, and allow to better describe and understand the complex relationship between alcohol dependence and other psychiatric diseases.
We believe that a clear nosographic framework and a precise diagnostic process are essential for a timely
management of every case, using specific guidelines to standardize and improve clinical practice. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which introduces dimensional approach, could be a useful tool to improve diagnostic accuracy.
Background aims Because of their capacity to modulate the immune response and promote tissue repair, mesenchymal stromal cells (MSC) represent a potential novel treatment for autoimmune/inflammatory ...diseases, including Crohn's disease (CD). The aim of the study was in vitro characterization of MSC from active CD patients for future clinical application. Methods MSC from the bone marrow (BM) of seven CD patients (median age 32 years) were expanded ex vivo in the presence of 5% platelet lysate; cells were investigated for clonogenic efficiency, proliferative capacity, morphology, immunophenotype, differentiation potential, genetic stability and ability to suppress in vitro proliferation of both autologous and allogeneic lymphocytes to polyclonal mitogens. Results were compared with those of BM MSC of four healthy donors (HD). Results MSC were successfully expanded from all patients. Colony-forming unit–fibroblast (CFU-F) frequency and proliferative capacity were comparable in CD and HD MSC. CD MSC showed typical spindle-shaped morphology and differentiated into osteoblasts, adipocytes and chondrocytes. Surface immunologic markers did not differ between CD and HD MSC, with the only exception of sizeable levels of HLA-DR at early culture passages 12–84% at passage (P)1 in the former. CD MSC ceased their growth at variable passages (from P8 to P25) and entered senescence without any change in morphology/proliferation rate. Array-comparative genomic hybridization demonstrated that CD MSC do not show imbalanced chromosomal rearrangements. Both CD and HD MSC inhibited in vitro proliferation of lymphocytes to mitogens. Conclusions CD MSC show biologic characteristics similar to HD MSC and can be considered for anti-inflammatory and reparative cell therapy approaches in patients with refractory disease.
PDF
