Background: Type 2 diabetes mellitus (T2DM) is associated with increased atherogenicity and inflammatory responses, which may be related to increased levels of high mobility group box 1 (HMGB1) and Dickkopf-related protein 1 (DKK1). Objective: The role of HMGB1 and DKK1 in T2DM is examined in association with lipid and insulin profiles. Methods: Serum HMGB1 and DKK1 were measured in T2DM with and without hypertension and compared with controls. Results: HMGB1 and DKK1 are significantly higher in T2DM irrespective of hypertension. T2DM was also accompanied by increased atherogenicity indices. HMGB1 and DKK1 are significantly correlated with HbA1c, glucose, indices of insulin resistance, β-cell function, and glucose toxicity, and different atherogenic indices. A large part of the variance in the β-cell index (30.5%) and glucose toxicity (34.8%) was explained by the combined effects of HMGB1 and DKK1 and hypertension. We found that 18.3% of the variance of the atherogenic index of plasma was explained by HMGB1 and DKK1 levels and that 31.2% was explained by glucose toxicity, HMGB1 and body weight. Conclusion: The higher serum HMGB1 and DKK1 levels in T2DM patients and the associations with atherogenicity indicate that low grade inflammation and disorders in the Wnt pathways are associated with T2DM and that both HMGB1 and DKK1 may contribute to increased atherogenicity in T2DM. Moreover, both biomarkers may cause more deficits in β-cell function and increase glucose toxicity leading to the development of more inflammation and diabetic complications. HMGB1 and the Wnt pathways are new drug targets in the treatment of T2DM.

Beta-thalassemia major (β-TM) is a severe form of thalassemia caused by mutations in the β-globin gene, resulting in partial or complete deficiency of β-globin chains. This deficiency results in oxidative stress, dyserythropoiesis, and chronic anemia. Cytokine dependent hematopoietic cell linker (CLNK) belongs to the adaptor protein family and has the capacity to interact with multiple signaling proteins thereby modulating signal transduction. The aim of the present study was to examine CLNK in sera of β-TM patients and examine its association with iron overload biomarkers. Sixty β-TM patients, aged 3–12 years old and undergoing blood transfusions, and 30 healthy control children were recruited and CLNK, ferritin and iron status parameters were measured. The results showed a significant increase (p < 0.001) in serum CLNK levels in β-TM patients as compared with normal controls. The increased levels of CLNK were significantly associated with increased ferritin levels. Increased CLNK levels in β-TM may be explained by reciprocal effects between immune signaling and immature erythrocytes, which, release soluble receptors and signaling molecules, including CLNK, in the blood.

Chronic fatigue and fibromyalgia symptoms frequently occur in major depressive disorder (MDD). The pathophysiology of these symptoms may in part, be ascribed to activated immune pathways, although it is unclear whether muscular factors play a role in their onset. The aim of the present study is to examine the role of muscle proteins in major depression in association with symptoms of chronic fatigue and fibromyalgia. We measured serum levels of agrin, talin-2, titin, and creatine phosphokinase (CPK) as well as the FibroFatigue (FF), the Hamilton Depression Rating Scale (HAM-D) and the Beck Depression Inventory (BDI-II) in 60 MDD patients and 30 healthy controls. The results show a significant increase in agrin and talin-2 in MDD patients as compared with controls. There were highly significant correlations between agrin and HAM-D, BDI-II and FF scores. Agrin, but not talin or titin, was significantly and positively associated with all 12 items of the FF scale. We found that a large part of the variance in HAM-D (47.4%), BDI-II (43.4%) and FF (43.5%) scores was explained by the regression on agrin, smoking, female sex (positively associated) and education (inversely associated). CPK was significantly and inversely associated with the total FF score and with muscle and gastro-intestinal symptoms, fatigue, a flu-like malaise, headache and memory, autonomic and sleep disturbances. These results suggest that aberrations in neuromuscular (NMJs) and myotendinous junctions may play a role in MDD and that the aberrations in NMJs coupled with lowered CPK may play a role in symptoms of chronic fatigue and fibromyalgia in MDD. Moreover, the increase of agrin in MDD probably functions as part of the compensatory immune-regulatory system (CIRS).

Background: Essential hypertension is a major public health associated with increase pressure on the vascular walls and red blood cells (RBCs). In the present work, osmotic fragility (OF) of RBCs was reexamined in the means of its correlation with two risk factor; iron status and lipid profile. Experimental: OF, iron status parameters, and lipid profile components were measured in 60 patients and compared with the results of 30 controls. Results: The results showed a significant increase in all iron indices of hypertensive patients in comparing with healthy control group except TIBC, UIBC, and transferrin concentrations, which decrease in these patients in comparing with control group. Serum TGs, total cholesterol, VLDLc, and LDLc were increased while there is no significant in serum HDLc in patients to comparing with control group. There is no significant change in OF between patients and controls where p=0.173. The iron status parameters and lipid profile components were dependent on sex and smoking state. Hemoglobin and PCV were correlated significantly with total cholesterol and LDLc. Transferrin saturation showed a positive correlation with cholesterol, LDLc, and TGs, but negatively correlated with HDL_c. No significant correlation between all the measured parameters and OF in HT patients. There is a significant correlation between serum ferritin and systolic BP and between Hb and systolic BP. Conclusion: No significant effect on the OF in HT patients. HT patients have elevated level of iron parameters in comparing with controls. OD has no correlation with iron status parameters or with lipid profile components.

Background. The aim of this study is to examine whether biomarkers of the immune-inflammatory response (IRS) and endogenous opioid (EOS) systems are associated with affective symptoms in schizophrenia. Methods. We recruited 115 schizophrenia patients and 43 healthy controls and assessed the Hamilton Depression (HDRS) and Anxiety (HAM-A) rating Scale scores as well as serum levels of interleukin (IL)-6, IL-10, eotaxin (CCL11), high mobility group box 1 (HMGB1), Dickkopf-related protein 1 (DKK1), and mu (MOR) and kappa (KOR) opioid receptors.Results. The HDRS and HAM-A scores are significantly and positively correlated with a) psychosis, hostility, excitation, mannerism, negative symptoms, psychomotor retardation, and formal thought disorders; and b) lowered scores on semantic and episodic memory, executive functions, and attention tests as measured with the Brief Assessment of Cognition in Psychiatry. Both HDRS and HAM-A are significantly increased in non-responders to treatment as compared with partial responders. Both affective scores are strongly associated with latent vectors extracted from all symptoms, reflecting overall severity of psychosis (OSOS), and neurocognitive test scores, reflecting a generalized cognitive decline (G-CoDe). The HDRS score was strongly and positively associated with IL-6, HMGB1, KOR, and MOR levels, and the HAM-A score with IL-6, IL-10, CCL11, HMGB1, KOR, and MOR levels. A single latent trait may be extracted from OSOS, G-CoDe, and the HDRS and HAMA scores, and this latent vector score is strongly predicted by HMGB1, MOR, and DKK1.Conclusion. Immune-inflammatory and EOS pathways contribute to the phenome of schizophrenia, which comprises OSOS, affective, and physiosomatic symptoms, and G-CoDe.

Background: Physiosomatic symptoms are an important part of schizophrenia phenomenology. The aim of this study is to examine the biomarker, neurocognitive and symptomatic correlates of physiosomatic symptoms in schizophrenia. Methods: We recruited 115 schizophrenia patients and 43 healthy controls and measured the Fibromyalgia and Chronic Fatigue Syndrome Rating (FF) scale, schizophrenia symptom dimensions, and the Brief Assessment of Cognition in Schizophrenia. We measured neuro-immune markers including plasma CCL11 (eotaxin), interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box 1 protein (HMGB1) and endogenous opioid system (EOS) markers including κ-opioid receptor (KOR), µ-opioid receptor (MOR), endomorphin-2 (EM2) and β-endorphin. Results: Patients with an increased FF score display increased ratings of psychosis, hostility, excitement, formal though disorders, psychomotor retardation and negative symptoms as compared with patients with lower FF scores. A large part of the variance in the FF score (55.1%) is explained by the regression on digit sequencing task, token motor task, list learning, IL-10, age (all inversely) and IL-6 (positively). Neural network analysis shows that the top-6 predictors of the FF score are (in descending order): IL-6, HMGB1, education, MOR, KOR and IL-10. We found that 45.1% of the variance in a latent vector extracted from cognitive test scores, schizophrenia symptoms and the FF score was explained by HMGB-1, MOR, EM2, DKK1, and CCL11. Conclusions: FF symptoms are an integral part of the phenome of schizophrenia. Neurotoxic immune and neurodegenerative pathways and to a lesser extent the EOS appear to drive FF symptoms in schizophrenia.

Patients with transfusion-dependent thalassemia (TDT) show disorders in calcium metabolism. The α-klotho protein is predominantly expressed in tissues that are involved in calcium homeostasis, and lowered levels are associated with bone disease. Aim of the study. To study the associations between low α-klotho status and calcium metabolism in relation to iron status in children with TDT. Methods. α-klotho, calcium, parathyroid hormone (PTH), calcyphosin, vitamin D3, phosphorous, fibroblast growth factor receptor 2 (FGFR2), as well as iron and erythron biomarkers were measured in 60 children with TDT and 30 healthy control children. Results. A meaningful part of TDT patients showed lowered α-klotho levels, and those children also showed low serum total and ionized calcium concentrations. TDT patients showed increased PTH, FGFR2, and calcyphosin and lowered vitamin D3 as compared with healthy children. The α-klotho levels were significantly correlated with total and ionized calcium (positively) and with iron overload biomarkers and the number of blood transfusions (inversely). Partial Least Squares path analysis showed that 40.1% of the variance in serum total calcium could be explained by the regression on α-klotho, vitamin D3 (both positively), and calcyphosin (inversely) and that the effects of the latter are mediated by iron overload and the number of blood transfusions. Conclusion. In TDT, iron overload and its consequences may induce lowered levels of α-klotho which in turn may lead to lower calcium thereby explaining at least in part the effects of TDT on bone metabolism including spontaneous pathological fractures, osteoporosis, osteopenia, and skeletal deformities.

Background: Hereditary hematologic disorders (HHDs) originate from genetic factors that cause disruptions of blood homeostasis. The Thalassemia Unit, Najaf province, Iraq, keeps all medical records of all patients with HHD from the Najaf province. Objectives: We aimed to conduct an epidemiological study to obtain a comprehensive epidemiological picture with regard to sex distribution, and effects of blood groups and consanguinity. Patients and Methods: All registered HHD patients (until May 2019) in the Thalassemia Unit (1122 patients, aged 0.5-65 years old) were included in the study. Results: The prevalence of HHD in Najaf city is 75.6 per 100,000 population. The number of patients registered as new patients is increasing over the years. There are significantly more male than female HHD patients (Male=54.37%, Female=45.63%, p=0.023). The top 3 prevalent HHD are Major thalassemia (33.15%), intermediate thalassemia (31.91%), and Thalassemia+Sickle (12.65%). The highest percentage of patients were in the center of Najaf (56.42%) followed by Kufa, Mishkhab, Haidariah, Manathera, and Abbasiya. The distribution of blood groups and Rh factors of HHD patients in the Najaf population was not significantly different from that in the normal population. The consanguinity rate observed in our patients' parents (78.24%) was significantly higher (p<0.0001) as compared with the consanguinity rate in the population (45.8%). Conclusions: During the last few years, there was an increase in HHD cases in Najaf city and, therefore, there is an urgent need to increase awareness about the effects of consanguinity marriages on HHD in order to limit the incidence of HHD.

Objective: About a third of schizophrenia patients are treatment-resistant to antipsychotic therapy. No studies established the fingerprints or pathway-phenotypes of treatment-resistant schizophrenia. The present study aimed to delineate the pathway-phenotypes of non-responders (NRTT) and partial responders (PRTT) to treatment using machine learning. Methods: We recruited 115 schizophrenia patients and 43 healthy controls and measured schizophrenia symptom dimensions, neurocognitive tests, plasma CCL11, interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box-1 protein (HMGB1), κ- and µ-opioid receptors (KOR and MOR, respectively), endomorphin-2 (EM-2), and β-endorphin. Results: Machine learning showed that the NRTT group is a qualitatively distinct class and is significantly discriminated from PRTT with an accuracy of 100% using a neuro-immune-opioid-cognitive (NIOC) pathway-phenotype with as main determinants list learning, controlled word association, and Tower of London test scores, CCL11, IL-6, and EM2. The top-5 symptom domains separating NRTT from PRTT were in descending order: psychomotor retardation, negative symptoms, psychosis, depression, and mannerism. Moreover, a NIOC pathway also discriminated PRTT from healthy controls with an accuracy of 100% while all PRTT and controls were authenticated as belonging to their respective classes. Conclusion: A non-response to treatment with antipsychotics is determined by increased severity of specific symptom profiles coupled with deficits in executive functions, and episodic and semantic memory, and aberrations in neuro-immune and opioid pathways. No patients showed complete remission after treatment indicating that non-remitting in PRTT is attributable to increased HMGB1 and residual deficits in attention, executive functions, and semantic memory.

Background: Schizophrenia and treatment-resistant schizophrenia (TRS) are associated with aberrations in immune-inflammatory pathways. Increased High Mobility Group Protein 1 (HMGB1), an inflammatory mediator, and Dickkopf-Related Protein (DKK1), a Wnt/β-catenin signaling antagonist, affect the blood-brain-barrier and induce neurotoxic effects and neurocognitive deficits.Aim of the study: The present study aims to examine HMGB1 and DDK1 in non-responders to treatments with antipsychotics (NRTT, n=60), partial RTT (PRTT, n=55) and healthy controls (n=43) in relation to established markers of schizophrenia including IL-6, IL-10 and CLL11 (eotaxin); and to delineate whether these proteins are associated with the schizophrenia symptom subdomains and neurocognitive impairments.Results: HMGB1, DKK1, IL-6 and CCL11 were significantly higher in schizophrenia patients than in controls. DKK1 and IL-6 were significantly higher in NRTT than in PRTT and controls while IL-10 was higher in NRTT than in controls. Binary logistic regression analysis showed that schizophrenia was best predicted by increased DDK1 and HMGB1 while NRTT (versus PRTT) was best predicted by increased IL-6 and CCL11 levels. A large part of the variance in psychosis, hostility, excitation, mannerism and negative (PHEMN) symptoms, and formal thought disorders was explained by HMGB1, IL-6, and CCL11 while most neurocognitive functions were predicted by HMGB1, DDK1 and CCL11. Conclusion: The neurotoxic effects of HMGB1, DKK1, IL-6 and CCL11 including effects on the blood-brain-barrier and the Wnt/β-catenin signaling pathway may cause impairments in executive functions, and working, episodic and semantic memory and explain, in part, PHEMN symptoms and a non-response to treatment with antipsychotic drugs.

In Schizophrenia, pathway-genotypes may be constructed by combining interrelated immune biomarkers with changes in specific neurocognitive functions that represent aberrations in brain neuronal circuits. These constructs provide insight on the phenome of schizophrenia and show how pathway-phenotypes mediate the effects of genome X environmentome interactions on the symptomatology/phenomenology of schizophrenia. Nevertheless, there is a lack of knowledge how to construct pathway-phenotypes using Partial Least Squares (PLS) path modeling and Soft Independent Modeling of Class Analogy (SIMCA). This paper aims to provide a step-by-step utilization guide for the construction of pathway-phenotypes that reflect aberrations in the neuroimmune - brain circuit axis (NIBCA) in deficit schizophrenia. This NIBCA index is constructed using immune biomarkers (CCL-2, CCL-11, IL-1β, sIL-1RA, TNF-α, sTNFR1, sTNFR2) and neurocognitive tests (Brief Assessment of Cognition in Schizophrenia) predicting overall severity of schizophrenia (OSOS) in 120 deficit SCZ and 54 healthy participants. Using SmartPLS path analysis, a latent vector is extracted from those biomarkers and cognitive tests, which shows a good construct reliability (Cronbach alpha and composite reliability) and replicability and which is reflectively measured through its NIBCA manifestations. This NIBCA pathway-phenotype explains 75.0% of the variance in PHEMN (psychotic, hostility, excitation, mannerism and negative) symptoms. Using SIMCA, we constructed a NIBCA pathway-class that defines deficit schizophrenia as a qualitatively distinct nosological entity and which allows patients with deficit schizophrenia to be authenticated as belonging to the deficit schizophrenia class. In conclusion, our nomothetic approach to develop a nomological network combining neuro-immune and neurocognitive phenome markers to predict OSOS and cross-validate a diagnostic class generated replicable models reflecting the key phenome of the illness, which may mediate the effects of genome X environmentome interactions on the final outcome phenome features, namely symptomatology and phenomenology.

Beta-thalassemia major (β-TM) patients are treated with repeated blood transfusions, which may cause iron overload (IO), which in turn may induce immune aberrations. Patients with β-TM have an increased risk of major depressive disorder (MDD). The aims of the present study are to examine whether repeated blood transfusions, IO and immune-inflammatory responses are associated with MDD in children (6-12 years) with β-TM. The Children’s Depression Inventory (CDI), iron status (serum iron, ferritin, transferrin, TS%) and serum levels of CCL11, IL-1β, IL-10, and TNF-α were measured in β-TM with (n=54) and without (n=57) MDD and in healthy children (n=55). The results show that MDD in β-TM is associated with a greater number of blood transfusions, increased IO and IL-1β levels. Partial Least Squares path analysis shows that 68.8% of the variance in the CDI score is explained by the number of blood transfusions, IO, and increased levels of IL-1β and TNF-α. The latter two cytokines partly mediate the effects of IO on the CDI score, while the effects of blood transfusions on the CDI score are partly mediated by IO and the path from IO to immune activation. IO is also associated with increased IL-10 and lower CCL11 levels but these alterations are not significantly associated with MDD. In conclusion, blood transfusions may be causally related to MDD in β-TM children and their effects are in part mediated by increased IO and the consequent immune-inflammatory response. The results suggest that not only IO and its consequences including inflammation and ferroptosis, but also other factors related to the number of transfusions may cause MDD including psychosocial stressors. Current treatment modalities with folic acid and vitamin C are insufficient to attenuate IO and immune-inflammatory responses and to prevent MDD is children with β-TM undergoing blood transfusions.

Major depressive disorder (MDD) is associated with changes in the levels of the cations calcium (Ca) and magnesium (Mg) as well as circulating pro- and anti-inflammatory cytokines. The immune-inflammatory nature of MDD has encouraged researchers to use anti-inflammatory drugs as an adjuvant treatment for MDD. However, the effect of this treatment on cation levels has not been studied. The present study examined a) differences in both cations between drug-naïve MDD patients and controls, and b) the effects of a combination of sertraline and ketoprofen, an anti-inflammatory drug, on Ca and Mg (both total and ionized). In the same patients we also examined the associations between both cations and IL-1β, IL-4, IL-6, IL-18, IFN-γ, TGF-β1, zinc and indoleamine 2,3-dioxygenase (IDO). Clinical improvement was estimated using the Beck Depression Inventory-II (BDI-II) at baseline and after follow up for two months. Serum Ca and Mg (total and ionized) were significantly lower in MDD patients as compared with controls, while treatment significantly increased calcium but decreased magnesium levels. There were significant and inverse correlations between the BDI-II scores from baseline to endpoint and Ca (both total and ionized), but not Mg, levels. The effects of calcium on the BDI-II score remained significant after considering the effects of zinc, IDO and an immune activation z unit weighted composite score based on the sum of all cytokines. There was a significant and inverse association between this immune activation index and calcium levels from baseline to endpoint. In conclusion, reduced levels of both cations play a role in the pathophysiology of major depression. Increased calcium levels are coupled to the clinical efficacy of antidepressants and attenuation of immune activation. The suppressant effect of antidepressants on Mg levels may be a side effect of those drugs. New antidepressant treatments should be developed that increase the levels both Ca and Mg.

Type 2 diabetes mellitus (T2DM) is an endocrine illness associate with various changes in the immune system and adaptor protein levels. Cytokine dependent hematopoietic cell linker (CLNK) is an adapter protein that regulates immune receptor signaling and acts as a regulator of the receptor signaling of T-cells and natural killer T-cell. The role of CLNK in T2DM is not studied previously. In the present study, serum CLNK level was measured and correlated with some sociodemographic and insulin resistance (IR) parameters. This is achieved by performing measurement of CLNK and insulin parameters (glucose, insulin, and HbA1c in addition to the calculation of the functions of IR (HOMA2IR), insulin sensitivity (HOMA%S), and beta-cell function (HOMA%B)) in 60 T2DM patients and 30 controls. The results indicated a significant increase (p=0.025) in serum CLNK in patients group in comparison with the controls. Multivariate generalized linear model (GLM) analysis revealed no significant effect of age, BMI, and sex on the CLNK level. The results of tests for between-subjects showed that the CLNK affects diagnosis significantly (F=7.445, p=0.008, partial η² =0.081) and its effect is approximately the same as the effect of insulin (F=8.107, p=0.006, partial η² =0.087). The correlation study showed a highly significant positive correlation between CLNK and the duration of disease (rho=0.420, p<0.001). It can be concluded that the increase CLNK in T2DM revealing the role of the adaptor proteins level in the nature of disease. Elevation of CLNK level may be used as a predictor for diabetes complications, which needs more investigations.

Objective: Rheumatoid Arthritis (RA) is a chronic inflammatory disease affecting the synovium and articular cartilage that initiates joint damage. RA associates with a change in many inflammatory biomarkers. The present study aims to measure the levels of inflammatory adipocytokines (chemerin and visfatin) and their ratio in addition to some related biomarkers in RA patients group in comparison to healthy control group and find out their efficacy in diagnosis of RA.Methods: The study included 60 RA patients and 30 healthy control group. Serum visfatin and chemerin were measured by using ELISA technique, while other biomarkers were determined spectrophotometrically. Multivariate general linear model analysis and Receiver operating curve was used to study the opportunity of using chemerin and visfatin as diagnostic tools for RA.Results: The results indicated that there was a significant increase (p<0.05) in all lipid profile components, except HDLc that decreased, in RA patients in comparison with healthy control group; while significant decrease (p<0.001) in high density lipoprotein-cholesterol of RA patients in comparison with control group. Serum chemerin, visfatin, C-reactive protein, and uric acid levels were significantly higher (p<0.05) in RA patients than those of control group. The results showed a relatively good sensitivity and specificity of chemerin (sensitivity=88.1, specificity=75.9) at a concentration=187.88ng in diagnosis of RA.Conclusions: chemerin is able to diagnose RA efficiently but this diagnoses, due to relatively small specificity, may interfere with other inflammatory disorders. However, with adjuvant with other diagnostic parameters, chemerin may represent a useful addition in diagnosis of RA.

Beta thalassemia major (β-TM) disorder characterized by the lack, or severe reduction in the production of hemoglobin β-globin chains. The standard protocol for the management of β-TM is blood transfusion and iron chelation therapy to reduce the iron overload state. The present study aimed to investigate the relationships between two iron regulatory hormones, hepcidin (HEPC) and erythroferrone (ERFE) levels and iron status parameters (ISPs) in Iraqi patients with β-TM. ISPs and hormones were measured in sixty patients and compared with thirty healthy controls. The results indicated significant changes in different iron status parameters, while ferritin (FRT) with the ~11 fold increase showed the most change. Significant reduction in HEPC and increase in ERFE levels were detected in patients as compared to the control group, while no direct correlation was identified with the other measured ISPs. Receiver operating characteristic (ROC) analysis showed that the z-score of the composite of ERFE+FRT has a full diagnostic ability for β-TM. In conclusion, our finding indicated the correlation between different ISPs, FRT as the leading predictor of iron overload and tow main iron regulatory hormones.

Background: Aberrations in endothelial cells, immune and oxidative pathways are associated with atherosclerosis (ATS) and unstable angina (UA). The role of trace elements, minerals, and the endogenous opioid system (EOS) in UA are less well established. Methods: We measured lipid, insulin resistance (IR), and immune, trace element (copper and zinc), mineral (magnesium, calcium), EOS (β-endorphin and mu-opioid receptor (MOR)) and antioxidant (vitamin D3) biomarkers in patients with ATS (n=60) and UA (n=60) and healthy controls (n=58). Results: ATS patients showed increased atherogenic and IR indices, IL-6, IL-10, β-endorphin, copper and magnesium, and lower zinc than healthy controls. Logistic regression showed that UA was significantly discriminated from ATS without UA with an accuracy of 85.5% using calcium, IL-10, β-endorphin, MOR, triglycerides, IR (all positively), and copper and vitamin D3 (inversely). Neural networks showed that UA was discriminated from ATS without UA with an area under the ROC curve of 0.942 using MOR, β-endorphin, calcium, insulin resistance, vitamin D3 and copper as input variables. We found that 50.0% of the variance in IR was explained by the regression on copper, IL-10, IL-6 (all positively), and zinc (inversely), while 32.9% of the variance in the atherogenic index of plasma was explained by copper, IL-10 (both positively), and magnesium (inversely). Conclusion: UA is not only mediated by insulin resistance, atherogenicity, and immune disorders, but also by aberrations in the endogenous opioid system and trace elements as well as lowered antioxidant levels. Copper appears to play a key role in IR and atherogenicity.

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.

Background: Activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS) play a key role in SCZ and treatment resistant SCZ. There are only few data on immune and endogenous opioid system (EOS) interactions in SCZ and treatment resistant SCZ.Aim of the study: We examined serum β-endorphin, endomorphin-2 (EM2), mu-opioid (MOR) and kappa-opioid (KOR) receptors, and interleukin (IL)-6 and IL-10 in 60 non responders to treatment (NRTT), 55 partial RTT (PRTT) and 43 normal controls.Results: Serum EM2, KOR, MOR, IL-6 and IL-10 were significantly increased in SCZ as compared with controls. β-endorphin, EM2, MOR and IL-6 were significantly higher in NRTT than in PRTT. There were significant correlations between IL-6, on the one hand, and β-endorphin, EM2, KOR, and MOR, on the other, while IL-10 was significantly correlated with MOR only. A large part of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation and formal thought disorders was explained by the combined effects of EM2 and MOR with or without IL-6 while increased KOR was significantly associated with all symptom dimensions. Increased MOR, KOR, EM2 and IL-6 were also associated with neurocognitive impairments including in episodic, semantic and working memory and executive functions.Conclusion: The EOS contributes to SCZ symptomatology, neurocognitive impairments and a non-response to treatment. In SCZ, EOS peptides/receptors may exert CIRS functions, whereas increased KOR levels may contribute to the pathophysiology of SCZ and EM2 and KOR to a non-response to treatment.