Publications

Congenital isolated ACTH deficiency (IAD) is a rare disease characterized by low plasma ACTH and cortisol levels and preservation of all other pituitary hormones. This condition was poorly defined before we identified TPIT, a T-box transcription factor with a specific role in differentiation of the corticotroph lineage in mice and humans, as its principal molecular cause.We have enlarged our series of IAD patients to better characterize the phenotype and the genotype of this rare disease.Each exon of the TPIT gene was amplified and sequenced in IAD patients without any identified cause. A functional analysis of each new TPIT mutation was performed.We described the largest series of 91 IAD patients and identified three distinct groups: neonatal onset complete or partial IAD or late onset IAD. We did not identify any TPIT mutation in patients with partial or late-onset IAD. However, we found a TPIT mutation in 65% of patients with neonatal-onset complete IAD. These patients are homozygous or compound heterozygous for TPIT mutations, and their parents are healthy heterozygous carriers. We identified nine new mutations: four missense, one one-nucleotide deletion, three splice-site mutations, and one large deletion. TPIT mutations lead to loss of function by different mechanisms, such as non-sense-mediated mRNA decay, abnormal mRNA splicing, loss of TPIT DNA binding or protein-protein interaction defects.TPIT mutations are responsible for two thirds of neonatal-onset complete IAD but can not be detected in partial or late-onset IAD.

The use of polyunsaturated fatty acids in Attention-Deficit/Hyperactivity Disorder (ADHD) and developmental disorders has been gaining interest with preparations containing different dosages and combinations. Gamma-linolenic acid (GLA) is an ω-6 fatty acid of emerging interest with potential roles as an adjuvant anti-inflammatory agent that could be used with ω-3 PUFAs in the treatment of ADHD and associated symptoms. A narrative review was undertaken to examine the potential role(s) of the ω-6 fatty acid GLA. PubMed, Google Scholar, and Scopus were searched to examine the potential role(s) of the ω-6 fatty acid GLA as (1) an antioxidant and anti-inflammatory agent, (2) a synergistic nutrient when combined with ω-3 PUFAs, and (3) a potential etiological factor in ADHD and its treatment. The results show that GLA exerts anti-inflammatory effects by increasing dihomo-gamma-linolenic acid in immune cells. ω-3 PUFAs, such as EPA and DHA, are often co-administered with GLA because these ω-3 PUFAs may prevent the accumulation of serum arachidonic acid in response to GLA administration without limiting the storage of DGLA in immune cells. The administration of ω-3 PUFAs alone might not be sufficient to effectively treat patients with ADHD and developmental disorders. Overall studies point towards a combination of EPA and DHA with GLA in a 9:3:1 ratio appearing to be associated with ADHD symptom improvement. A combination of PUFAs may lead to better outcomes.

Abstract Background: Metabolic syndrome (MetS) is highly prevalent among adults and is frequently accompanied by depressive symptoms. While high-sensitivity C-reactive protein (hsCRP) has been proposed as a potential indicator of depression, existing evidence remains inconclusive. Objective: This study aimed to determine whether increased serum hsCRP or other immune-metabolic biomarkers are associated with depressive symptoms in drug-naïve individuals with obesity and MetS. Methods: A total of 88 drug-naïve patients with obesity and MetS but without coronary-artery disease were enrolled and serum levels of neuro-immune and metabolic biomarkers were assessed. Results: In MetS, the severity of depression, as assessed using the von Zerssen Depression Rating (VZDR) scale was significantly associated with interleukin (IL)-6, leukocyte numbers, triglyceride x glucose (Tyg) index, low-density lipoprotein cholesterol, Apolipoprotein B (all positively) and mean platelet volume (MPV), visfatin and adiponectin (all negatively). There were no significant associations between hsCRP and severity of depression. In MetS patients, hsCRP is strongly associated with increased leukocyte numbers, alkaline phosphatase, γ-glutamyl transferase, uric acid, platelet numbers and MPV, thereby shaping a distinct subtype of MetS, which is not related to depression. Conclusions: Our findings indicate that depressive symptoms in MetS patients are associated with immune–metabolic biomarkers indicating immune activation, atherogenicity and insulin resistance, but not with hsCRP. The reason is that hsCRP in MetS is a biomarker of a specific MetS subtype that is characterized by megakaryopoiesis, hepatocyte activation, and uric acid production, which were not associated with depression.

Abstract Comprehensive immunological profiles have not been studied in relation to methamphetamine (MA) use, MA dependency, or MA-induced psychosis (MAP). Using the BioPlex Pro Human Cytokine 48-Plex panel, this study measured M1 macrophage, T helper (Th)-1, Th-2, growth factor, and chemokine profiles, as well as the immune inflammatory response system (IRS) and compensatory immunoregulatory system (CIRS) in peripheral blood samples from patients with MA use (n=51), MA dependence (n=47), and MAP (n=43) in comparison with healthy controls (n=43). We discovered that persistent MA use had a robust dose-dependent suppressive impact on all immunological profiles, suggesting extensive immunosuppression. The most reliable biomarker profile of MA use is the combination of substantial CIRS suppression and a rise in selected pro-inflammatory cytokines, namely CCL27 (CTACK), CCL11 (eotaxin), and interleukin (IL)-1α. In addition, MA dependency is related with a more severe immunosuppression, as demonstrated by lower stem cell factor and higher IL-10 levels. MAP is related with a significant decrease in all immunological profiles, particularly CIRS, and an increase in CCL5 (RANTES), IL-1α, and IL-12p70 signaling. In conclusion, long-term MA use and dependency severely undermine immune homeostasis. This results in widespread immunosuppression, which may increase the likelihood of infectious and immune illness or exacerbate disorders such as hepatitis and AIDS. Elevated levels of CCL5, CCL11, CCL27, IL-1α, and/or IL-12p70 may be associated with severe peripheral (atherosclerosis, cutaneous inflammation, immune aberrations, hypospermatogenesis) and central (neuroinflammation, neurotoxic, neurodegenerative, depression, anxiety and psychosis) side effects.