Publications

Background:There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities, including variations on cytokine levels. The results of previous studies, however, are heterogeneous due to several confounding factors, such as the effects of antipsychotic drugs. Therefore, research on drug-naïve first-episode psychosis (FEP) patients is essential to elucidate the role of immune processes in that disorder.

Increased intestinal permeability with heightened translocation of Gramnegative bacteria, also known as "leaky gut", is associated with the pathophysiology of neuroimmune disorders, such as Major Depressive Disorder (MDD), Chronic Fatigue Syndrome (CSF) and (deficit) schizophrenia, as well as with general medical disorders, including irritable bowel syndrome. This review aims to summarize clinical biochemistry and molecular immunology tests that may aid in the recognition of leaky gut in clinical practice.We searched online libraries, including PubMed/MEDLINE, Google Scholar and Scopus, with the key words "diagnosis" or "biomarkers" and "leaky gut", "bacterial translocation", and "intestinal permeability" and focused on papers describing tests that may aid in the clinical recognition of leaky gut.To evaluate tight junction barrier integrity, serum IgG/IgA/IgM responses to occludin and zonulin and IgA responses to actomyosin should be evaluated. The presence of cytotoxic bacterial products in serum can be evaluated using IgA/IgM responses to sonicated samples of common Gram-negative gut commensal bacteria and assays of serum lipopolysaccharides (LPSs) and other bacterial toxins, including cytolethal distenting toxin, subunit B. Major factors associated with increased gut permeability, including gut dysbiosis and yeast overgrowth, use of NSAIDs and alcohol, food hypersensitivities (IgE-mediated), food intolerances (IgG-mediated), small bacterial overgrowth (SIBO), systemic inflammation, psychosocial stressors, some infections (e.g., HIV) and dietary patterns, should be assessed. Stool samples can be used to assay gut dysbiosis, gut inflammation and decreased mucosal defenses using assays of fecal growth of bacteria, yeast and fungi and stool assays of calprotectin, secretory IgA, β-defensin, α- antitrypsin, lysozyme and lactoferrin. Blood and breath tests should be used to exclude common causes of increased gut permeability, namely, food hypersensitivities and intolerances, SIBO, lactose intolerance and fructose malabsorption.Here, we propose strategies to recognize "leaky gut" in a clinical setting using the most adequate clinical chemistry and molecular immunology assays.

The aims of this study were to delineate cytokine profiles of systemic lupus erythematosus (SLE), construct prediction models for diagnosis and disease activity using those profiles, and to examine the associations between TNFB Ncol polymorphism, body mass index (BMI) and vitamin D levels with cytokine levels. Two hundred SLE patients and 196 healthy controls participated in this case–control study. Plasma cytokines levels of tumor necrosis factor (TNF)‐α, interferon (IFN)‐γ, interleukin (IL)‐1β, IL‐ 4, IL‐6, IL‐10, IL‐12 and IL‐17 were measured and cytokines profiles were computed. IL‐6, IL‐12, IL‐17, IFN‐γ and IL‐10 levels were significantly higher in SLE, while IL‐4 was lower in SLE. The Th1/Th2 and Th1+Th17/Th2 profiles were significantly higher in SLE than in healthy controls, whereas there were no significant differences in the proinflammatory cytokine profile (TNFα+IL‐6+IL‐1β). In total, 90.4% of all subjects were correctly classified using Th1+Th17 profile and IL‐10 (positively associated) and IL‐4 (negatively associated) as predictor variables (sensitivity=66.7% and specificity=96.9%). In all, 20.9% of the variance in the SLE Disease Activity Index was predicted by the Th1+Th17/Th2 ratio, IL‐10 and BMI (all positively) and proinflammatory profile (inversely associated). B1/B1 genotype is accompanied by increased IL‐17 and Th17/Th2 ratio, while B1/B2 genotype is accompanied by higher IL‐4 and IFNγ values. 25‐OH vitamin D was inversely associated with IFN‐γ levels. SLE is accompanied by Th1, Th17 and Treg profile and lowered IL‐4 production. Lowered vitamin D levels and B1/B1 genotype, but not BMI, contribute to changes in cytokines profiles. Future treatments should target Th1, Th2 and Th17 profiles rather than inflammatory cytokines.

Objective: A previous study showed that schizophrenia is accompanied by lowered levels of trace/metal elements including cesium. There are no data whether changes in cesium, rubidium and rhenium are associated with activated immune-inflammatory pathways, cognitive impairments, and the symptomatology of schizophrenia. Methods: This study measured cesium, rubidium, and rhenium, cognitive impairments (using the Brief Assessment of Cognition in Schizophrenia) and the cytokines/chemokines interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and CCL11 (eotaxin) in 120 schizophrenia patients and 54 healthy controls. Severity of illness was assessed using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), the Fibromyalgia and Chronic Fatigue Syndrome Rating (FF) Scale and the Hamilton Depression Rating Scale (HAM-D). Results: Serum cesium was significantly lower in schizophrenia patients as compared with controls. Serum cesium was significantly and inversely associated with CCL11 and TNF-α, but not IL-1β. Moreover, there were significant inverse associations between serum cesium levels and the BPRS, FF, HAM-D and SANS scores and positive correlations between cesium and neurocognitive probe results including the Tower of London, Symbol Coding, Controlled Word Association, Category Instances, Digit Sequencing Task, and List Learning tests. Conclusion: The results suggest that lowered serum cesium levels may play a role in the pathophysiology of SCZ, specific symptom domains including negative, depressive and fatigue symptoms, neurocognitive impairments (spatial working, episodic and semantic memory and executive functions) and neuro-immune pathways as well.

It has been established that thyrotropin-releasing hormone (TRH) affects several aspects of immunoreactivity, e.g. production of pro-inflammatory cytokines, and enhances therapeutic efficiency of classic tricyclic antidepressants. On the other hand, it has been suggested that pro-inflammatory cytokines play a role in the etiology of depression, whereas the therapeutic efficacy of antidepressants is related to their negative immunoregulatory effect. In order to verify the hypothesis that the TRH-induced increase in the therapeutic efficiency of classic tricyclic antidepressants results from synergistic inhibitory effects of those two agents on the secretion of pro-inflammatory cytokines, we studied the effect of imipramine appliedjointly with TRH on the production of IFN-gamma and IL-10 by human whole blood cells stimulated in vitro by mitogens. A significant decrease in the production of IFN-gamma and IL-10 cytokines, by 36% and 34%, respectively, was observed in cells stimulated with mitogens and co-incubated with imipramine and TRH (either given at a dose of 10(-5) M). Under the same conditions, TRH alone did not change the production of those cytokines. Furthermore, imipramine alone decreased, not statistically significantly, though, the production of IFN-gamma. Hence our data only partly support the above-mentioned hypothesis, since TRH and imipramine applied jointly suppress the production of both the pro-inflammatory IFN-gamma and the anti-inflammatory IL-10 cytokines.

To determine the role of hypoinsulinemia and liver somatogenic (GH) receptors in growth retardation and decreased serum insulin-like growth factor I (IGF-I) levels during protein restriction, we have used a rat model where the effects of a low protein intake on body weight (BW), serum IGF-I concentration, and liver GH binding could be evaluated in the presence of low or high insulin concentrations. Two days after being made diabetic with streptozotocin (60 mg/kg BW), 6-week-old female rats (nine per group) were begun on a low (5%) or normal (15%) protein diet, without or with insulin supplementation (3 U lente daily). Nondiabetic rats fed both diets were used as controls (nine per group). In the nondiabetic animals, 7 days of protein restriction reduced BW gain by 50% (P less than 0.001), serum insulin by 44% (P less than 0.025), and serum IGF-I concentrations by 28% (P less than 0.001) without significantly changing liver GH binding. By day 9, BW was decreased in the diabetic animals by 12%, serum insulin by 80%, serum IGF-I by 55%, and liver GH binding by 62%; these effects were similar in the 5% and 15% protein-fed rats (P less than 0.001 vs. the corresponding controls). In the diabetes fed the normal diet, insulin treatment restored BW gain, serum IGF-I, and liver GH binding to normal values. In contrast, in the diabetics fed a protein-restricted diet and treated with insulin, BW gain and serum IGF-I concentrations remained low, similar to those in the malnourished controls. This diet-induced growth attenuation was observed despite high circulating insulin (2-3 times normal values), appropriate glucose control (63 +/- 9 mg/dl), and near restoration of liver GH binding. We conclude that while both protein restriction and diabetes attenuate growth and reduce IGF-I concentrations, the effects of protein restriction are independent of the effects of insulin and probably act by alteration of postreceptor mechanisms.