Increased IgA-mediated responses to the gut paracellular pathway and blood-brain barrier proteins predict delirium due to hip fracture in older adults.

Introduction: Delirium is accompanied by immune response system activation, which may, in theory, cause a breakdown of the gut barrier and blood-brain barrier (BBB). Some results suggest that the BBB is compromised in delirium, but there is no data regarding the gut barrier. This study investigates whether delirium is associated with impaired BBB and gut barriers in elderly adults undergoing hip fracture surgery. Methods: We recruited 59 older adults and measured peak Delirium Rating Scale (DRS) scores 2-3 days after surgery, and assessed plasma IgG/IgA levels (using ELISA techniques) for zonulin, occludin, claudin-6, ß-catenin, actin (indicating damage to the gut paracellular pathway), claudin-5 and S100B (reflecting BBB damage), bacterial cytolethal distending toxin (CDT), LPS-binding protein (LBP), lipopolysaccharides (LPS), Porphyromonas gingivalis, and Helicobacter pylori. Results: Results from univariate analyses showed that delirium is linked to increased IgA responses to all the self-epitopes and antigens listed above, except for LPS. Part of the variance (between 45-48.3%) in the peak DRS score measured 2-3 days post-surgery was explained by independent effects of IgA directed to LPS and LBP (or bacterial CDT), baseline DRS scores, and previous mild stroke. Increased IgA reactivity to the paracellular pathway and BBB proteins and bacterial antigens is significantly associated with the activation of M1 macrophage, T helper-1, and 17 cytokine profiles. Conclusion: Heightened bacterial translocation, disruption of the tight and adherens junctions of the gut and BBB barriers, elevated CDT and LPS load in the bloodstream, and aberrations in cell-cell interactions may be risk factors for delirium.

Methamphetamine (MA) use and MA-induced psychosis are associated with increasing aberrations in the compensatory immunoregulatory system, interleukin-1α, and CCL5 levels.

There are only a few studies reporting on the immunological profiles of methamphetamine (MA) use, MA dependency, or MA-induced psychosis (MAP). 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 controls (n = 32). We discovered that persistent MA use had a robust immunosuppressive impact on all immunological profiles. 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 associated with increased immunosuppression, as demonstrated by lower stem cell factor levels and higher IL-10 levels. MAP is related to 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, whereas MAP may be the consequence of increased IL-1α - CCL5 signaling superimposed on strongly depleted CIRS and Th-1 functions. The widespread immunosuppression established in longstanding MA use may increase the likelihood of infectious and immune illness or exacerbate disorders such as hepatitis and AIDS. Furthermore, elevated levels of CCL5, CCL11, CCL27, IL-1α, and/or IL-12p70 may play a role in the peripheral (atherosclerosis, cutaneous inflammation, immune aberrations, hypospermatogenesis) and central (neuroinflammation, neurotoxic, neurodegenerative, depression, anxiety, and psychosis) side effects of MA use.

Recommendations on data sharing in HIV drug resistance research.

• Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the development of HIV drug resistance leads to the requirement for antiretroviral drugs that may be less effective, less well-tolerated, and more expensive than those used in first-line regimens. • HIV drug resistance studies are designed to determine which HIV mutations are selected by antiretroviral drugs and, in turn, how these mutations affect antiretroviral drug susceptibility and response to future antiretroviral treatment regimens. • Such studies collectively form a vital knowledge base essential for monitoring global HIV drug resistance trends, interpreting HIV genotypic tests, and updating HIV treatment guidelines. • Although HIV drug resistance data are collected in many studies, such data are often not publicly shared, prompting the need to recommend best practices to encourage and standardize HIV drug resistance data sharing. • In contrast to other viruses, sharing HIV sequences from phylogenetic studies of transmission dynamics requires additional precautions as HIV transmission is criminalized in many countries and regions. • Our recommendations are designed to ensure that the data that contribute to HIV drug resistance knowledge will be available without undue hardship to those publishing HIV drug resistance studies and without risk to people living with HIV.

In Schizophrenia, Chronic Fatigue Syndrome- and Fibromyalgia-Like Symptoms are Driven by Breakdown of the Paracellular Pathway with Increased Zonulin and Immune Activation-Associated Neurotoxicity.

BACKGROUND: A meaningful part of schizophrenia patients suffer from physiosomatic symptoms (formerly named psychosomatic), which are reminiscent of chronic fatigue syndrome and fibromyalgia (FF) and are associated with signs of immune activation and increased levels of tryptophan catabolites (TRYCATs). AIMS: The study aims to examine whether FF symptoms in schizophrenia are associated with the breakdown of the paracellular pathway, zonulin, lowered natural IgM responses to oxidative specific epitopes (OSEs); and whether FF symptoms belong to the behavioral-cognitive-physical-psychosocial- (BCPS)-worsening index consisting of indices of a general cognitive decline (G-CoDe), symptomatome of schizophrenia, and quality of life (QoL)-phenomenome. METHODS: FF symptoms were assessed using the Fibromyalgia and Chronic Fatigue Rating scale in 80 schizophrenia patients and 40 healthy controls and serum cytokines/chemokines, IgA levels to TRYCATs, IgM to OSEs, zonulin and transcellular/paracellular (TRANS/PARA) molecules were assayed using ELISA methods. RESULTS: A large part (42.3%) of the variance in the total FF score was explained by the regression on the PARA/TRANS ratio, pro-inflammatory cytokines, IgM to zonulin, IgA to TRYCATs (all positively), and IgM to OSEs (inversely). There were highly significant correlations between the total FF score and G-CoDe, symtopmatome, QoL phenomenome, and BCPS-worsening score. FF symptoms belong to a common core shared by G-CoDe, symtopmatome, and QoL phenomenome. CONCLUSION: The physio-somatic symptoms of schizophrenia are driven by various pathways, including increased zonulin, breakdown of the paracellular tight-junctions pathway, immune activation with induction of the TRYCAT pathway, and consequent neurotoxicity. It is concluded that FF symptoms are part of the phenome of schizophrenia and BCPS-worsening as well.

Reactivity to neural tissue epitopes, aquaporin 4 and heat shock protein 60 is associated with activated immune-inflammatory pathways and the onset of delirium following hip fracture surgery.

OBJECTIVES: Activation of the immune-inflammatory response system (IRS) and a deficiency in the compensatory immunoregulatory system (CIRS), neuronal injuries, and alterations in the glutamate receptor (GlutaR), aquaporin-4 (AQP4) and heat shock protein 60 (HSP60) are involved in delirium. Increased serum levels of neurofilament protein (NFP), glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) are biomarkers of neuronal injury. This investigation delineates whether elevated IgA/IgG reactivity against those self-antigens is associated with delirium severity and IRS activation. METHODS: We measured peak Delirium Rating Scale (DRS) scores on days 2 and 3 following surgery in 59 hip fractured older adults, and IgA and IgG antibody levels against MBP, NFP, GFAP and myelin oligodendrocyte glycoprotein (MOG), metabotropic glutamate receptors mGluRs 1 and 5, N-Methyl-D-Aspartate receptor (NMDAR) GLU1 (NR1) and GLU2 (NR2), APQ4 and HSP60. RESULTS: The IgA antibody levels against those self-antigens, especially GFAP, MBP and HSP60, strongly predict peak DRS scores on days 2 and 3 post-surgery. IgA reactivity against NMDAR and baseline DRS scores explained 40.6% of the variance in peak DRS scores, while IgA against NMDAR, IgG against MBP and age explained 29.1% of the variance in the IRS/CIRS ratio. There was no correlation between DRS scores and IgG directed against other self-antigens. CONCLUSIONS: Increased IgA levels against neuronal self-antigens, AQP4 and HSP60 are risk factors for delirium. Polyreactive antibody-associated breakdown of immune tolerance, IRS activation and injuries in the neuronal cytoskeleton, oligodendrocytes, astrocytes, glial cells, and myelin sheath are involved in the pathophysiology of delirium.

Delirium due to hip fracture is associated with activated immune-inflammatory pathways and a reduction in negative immunoregulatory mechanisms.

BACKGROUND: The objectives of this study were to delineate whether delirium in older adults is associated with activation of the immune-inflammatory response system (IRS) as indicated by activation of M1, T helper (Th)1, and Th17 profiles, and/or by reduced activities of the compensatory immunoregulatory system (CIRS), including Th2 and T regulatory profiles. METHODS: We recruited 65 older adult patients with a low energy impact hip fracture who underwent hip fracture operation. The CAM-ICU and the Delirium Rating Scale, Revised-98-Thai version (DRS-R-98) were assessed pre-operatively and 1, 2 and 3 days after surgery. Blood samples (day 1 and 2) post-surgery were assayed for cytokines/chemokines using a MultiPlex assay and the neutrophil/lymphocyte ratio. RESULTS: We found that delirium and/or the DRS-R-98 score were associated with IRS activation as indicated by activated M1, Th1, Th17 and T cell growth profiles and by attenuated CIRS functions. The most important IRS biomarkers were CXCL8, interleukin (IL)-6, and tumor necrosis factor-α, and the most important CIRS biomarkers were IL-4 and soluble IL-1 receptor antagonist. We found that 42.5% of the variance in the actual changes in the DRS-R-98 score (averaged from day 1 to day 3) was explained by T cell growth factors, baseline DRS-R-98 scores and age. An increase in the NLR reflects overall IRS, M1, Th1, Th17, and Th2 activation. CONCLUSIONS: Post-hip surgery delirium is associated with activated IRS pathways and appears especially in patients with lowered CIRS functions.

Ability of Alere™ HIV Combo to diagnose acute HIV infection is based mainly on HIV-1 p24 antigen detection.

BACKGROUND: Alere™ HIV Combo is the only rapid and sensitive point-of-care 4th generation (antigen/antibody) HIV test newly available in Thailand which is advantageous of differentiating between positivity of antigen or antibody or both, especially in acute HIV infection (AHI). AHI in this study was defined by positive machine-based 4th generation test with measurable HIV-RNA but negative 3rd generation (IgM/IgG antibody only) tests. OBJECTIVE: To evaluate the performance characteristics of Alere™ HIV Combo. METHODS: Fifty stored plasma samples of subjects diagnosed with AHI were used to evaluate Alere™ HIV Combo. RESULTS: Of the 50 AHI samples, Alere™ HIV Combo was positive in 37 (74%): 5 with antibody positive only (R1), 26 with p24 antigen positive only (R2), and 6 with both p24 antigen and antibody positive (R3). Mean sample/cut-off (S/ CO) ratios from machine-based 4th generation test of R1, R2 and R3 were 21.55, 148.38 and 72.97 respectively as compared to 7.57 for the 13 non-reactive (NR) samples. The corresponding median log10 HIV-RNA of NR, R1, R2 and R3 were 5.59, 5.86, 7.00 and 6.61 copies/mL respectively. R2 and R3 had significantly higher S/CO and HIV-RNA than NR and R1. Alere™ HIV Combo detected mainly p24 antigen in AHI as seen in 32/50 (64%) subjects and could detect 11/50 (22%) antibody in AHI samples which were missed by the two 3rd generation HIV tests used in our testing algorithm. CONCLUSIONS: Alere™ HIV Combo is the ideal screening test in a setting with high AHI where machine-based 4th generation test is not available.

Immune, Blood Cell, and Blood Gas Biomarkers of Delirium in Elderly Individuals with Hip Fracture Surgery.

BACKGROUND: Postoperative delirium in elderly people with hip fracture is associated with various adverse clinical outcomes. Nevertheless, the pathophysiological processes underpinning delirium have remained elusive. OBJECTIVES: The aim of this study was to explore the associations between delirium and its features and immune-inflammatory and blood gas biomarkers. METHODS: In this prospective study, we examined 65 patients who underwent a hip fracture surgery and assessed the Confusion Assessment Method for the Intensive Care Unit, Richmond Agitation-Sedation Scale (RASS), and Delirium Rating Scale Revised-98 (DRS-R-98) before and during 4 days after the surgery. Complete blood count and venous blood gas markers were obtained at the same time points. RESULTS: Delirium was observed in 19 patients and was accompanied by significantly increased pO2, number of white blood cells, neutrophil percentage, and neutrophil/lymphocyte ratio, and lower mean platelet volume (MPV) after adjusting for age, central nervous system (CNS) disease, blood loss during surgery, sleep disorders, and body mass index. The severity of delirium was associated with lowered number of platelets and MPV. Psychomotor disorders were associated with lower bicarbonate levels. The requirement of physical restraint of the patients was predicted by increased percentages of neutrophils and lymphocytes. Prior CNS disease was together with these biomarkers a significant predictor of delirium and severity of delirium. CONCLUSION: Delirium and psychomotor disorders following hip fracture and surgery may be caused by immune-inflammatory and oxidative stress pathways probably attributable to an aseptic inflammatory process.

DNA Vaccine Administered by Cationic Lipoplexes or by In Vivo Electroporation Induces Comparable Antibody Responses against SARS-CoV-2 in Mice.

In view of addressing the global necessity of an effective vaccine in the SARS-CoV-2 pandemic, a plasmid DNA vaccine, expressing for the spike (S) protein and formulated in lipoplexes, was manufactured and tested for in vitro transfection and in vivo immunogenicity. Blank cationic liposomes of 130.9 ± 5.8 nm in size and with a zeta potential of +48 ± 12 mV were formulated using the thin-film layer rehydration method. Liposomes were complexed with pCMVkan-S at different N/P ratios. Ratios of 0.25:1 and 1:1 were selected according to their complex stability and controlled size compared to other ratios and tested in vitro for transfection studies and in vivo for immunogenicity. Both selected formulations showed enhanced neutralizing antibody responses compared to pCMVkan-S injected alone, as well as an increased T cell response. The titers observed were similar to those of intramuscular electroporation (IM-EP), which was set as an efficacy goal.

Brief Report: Prevalence Trend of Transmitted Drug Resistance in a Prospective Cohort of Thai People With Acute HIV Infection.

BACKGROUND: The greater availability of different antiretroviral therapy regimens in developing countries may influence the emergence of transmitted drug resistance (TDR). People with acute HIV infection (AHI) represent the best opportunity for real-time monitoring of TDR. This study assessed the TDR prevalence trends over time in a Thai cohort of predominantly men who have sex with men (MSM) with AHI. METHODS: At the time of RV254/SEARCH010 study (NCT00796146) enrollment and before starting ART, HIV genotyping was used to identify mutations in the reverse transcriptase and protease genes. Testing for TDR mutations was obtained by a validated in-house method with TRUGENE assay in a subset. Genotype sequences were analyzed using the Stanford University HIV Drug Resistance Database. RESULTS: Genotyping was performed for 573 participants with AHI. Their median age was 26 years (interquartile range 22-31), 97.4% were men, and 94.1% were MSM. Overall TDR prevalence was 7.0%, declining from 12.5% in 2009-2010 to 4.8% in 2017-2018. A declining resistance prevalence to nonnucleoside reverse transcriptase inhibitor emerged from 9.4% in 2009-2010 to 3.5% in 2017-2018 and to nucleoside reverse transcriptase inhibitor from 6.3% to 2.1%. Protease inhibitor resistance showed a decreased TDR level from 3.1% in 2009-2010 to 1.4% in 2017-2018. CONCLUSIONS: We report an encouraging declining trend in TDR prevalence in a Thai cohort of mainly MSM from 2009 to 2018; in 2017-2018, we observed a low TDR prevalence according to the World Health Organization definition.

Inflammatory and Oxidative Pathways Are New Drug Targets in Multiple Episode Schizophrenia and Leaky Gut, Klebsiella pneumoniae, and C1q Immune Complexes Are Additional Drug Targets in First Episode Schizophrenia.

Breakdown of paracellular and vascular pathways and activated neuroimmune and oxidative pathways was established in (deficit) schizophrenia. The aim of this study was to delineate (a) the differences in these pathways between stable-phase, first (FES) and multiple (MES) episode schizophrenia and (b) the pathways that determine the behavioral-cognitive-physical-psychosocial (BCPS) deterioration in FES/MES. This study included 21 FES and 58 FES patients and 40 healthy controls and measured indicants of serum C1q circulating immune complexes (CIC), leaky gut, immune activation, and oxidative stress toxicity (OSTOX). We constructed a BCPS-worsening index by extracting a latent vector from symptomatic, neurocognitive, and quality of life data. FES was associated with higher IgA CIC-C1q, IgA directed to cadherin, catenin, and plasmalemma vesicle-associated protein, and IgA/IgM to Gram-negative bacteria as compared with FES and controls. In FES patients, the BCPS-worsening score was predicted (48.7%) by IgA to Klebsiella pneumoniae and lowered paraoxonase 1 activity. In MES patients, the BCPS-worsening score was explained (42.7%) by increased tumor necrosis factor-α, OSTOX, and number of episodes. In schizophrenia, 34.0% of the variance in the BCPS-worsening score was explained by IgA to K. pneumoniae, OSTOX, and number of episodes. Increased IgA to K. pneumoniae was the single best predictor of residual psychotic symptoms in FES and MES. This study delineated different mechanistic processes in FES, including breakdown of adherens junctions, bacterial translocation, and IgA CIC-C1q formation, and MES, including immune and oxidative neurotoxic pathways. FES and MES comprise different staging subtypes, i.e., FES and MES with and without worsening.

Menstruation distress is strongly associated with hormone-immune-metabolic biomarkers.

OBJECTIVE: To examine the associations between menstruation features and symptoms and hormone-immune-metabolic biomarkers. METHODS: Forty-one women completed questionnaires assessing characteristic menstruation symptoms, duration of menstrual cycle and number of pads used/day and completed the Daily Record of Severity of Problems (DRSP) during the consecutive days of their menstrual cycle. Menses-related symptoms (MsRS) were computed from the sum of 10 pre- and post-menses symptoms and the menstruation blood and duration index (MBDI) was computed based on the daily number of pads and duration of menses. We assayed serum levels of various biomarkers at days 7, 14, 21, and 28 of the subjects' menstrual cycle. RESULTS: MBDI was significantly associated with a) MsRS including low abdominal cramps, and gastro-intestinal (GI) and pain symptoms (positively); b) plasma levels of haptoglobin (Hp), CCL5, insulin growth factor (IGF)-1, and plasminogen activator inhibitor (PAI)1 (all positively); and c) estradiol and paraoxonase (PON)1 arylesterase activity (both inversely). MsRS were significantly predicted by CCL5 and IGF-1 (both positively) and progesterone (inversely). Low-abdominal cramps, and gastro-intestinal and pain symptoms were associated with lower progesterone levels. The MBDI+MsRS score was significantly predicted by the cumulative effects of (in descending order of importance): Hp, IGF-1, PON1 arylesterase, estradiol and PAI. CONCLUSION: Menstruation-related features including estimated blood loss, duration of menses, cramps, pain, and gastro-intestinal symptoms are associated with hormone-immune-metabolic biomarkers, which mechanistically may explain those features. Future research should construct a cross-validated algorithm using MBDI+MsRS features in a larger study group to delineate a useful case-definition of menstruation-related distress.

Identification of a Novel Pathogen Using Family-Wide PCR: Initial Confirmation of COVID-19 in Thailand.

In resource-limited countries, early detection of novel pathogens is often challenging, due to financial and technical constraints. This study reports the efficacy of family-wide polymerase chain reaction (PCR) in screening, detecting, and identifying initial cases of the novel SARS-CoV-2 in Thailand. Respiratory secretions were collected from suspected individuals traveling from Wuhan, China to Thailand at the beginning of January 2020. Family-wide PCR assays yielded positive results for coronavirus in one traveler within 12 h on January 8, 2020. Nucleotide sequences (290 bp) showed 100% similarity to SARS-CoV-2. The whole genome sequence was further characterized by Next Generation Sequencing (NGS) for confirmation. Combining family-wide PCR, as a rapid screening tool, with NGS, for full genome characterization, could facilitate early detection and confirmation of a novel pathogen and enable early containment of a disease outbreak.

Lowered Antioxidant Defenses and Increased Oxidative Toxicity Are Hallmarks of Deficit Schizophrenia: a Nomothetic Network Psychiatry Approach.

There is now evidence that schizophrenia and deficit schizophrenia are neuro-immune conditions and that oxidative stress toxicity (OSTOX) may play a pathophysiological role. Aims of the study: to compare OSTOX biomarkers and antioxidant (ANTIOX) defenses in deficit versus non-deficit schizophrenia. We examined lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products (AOPP), sulfhydryl (-SH) groups, paraoxonase 1 (PON1) activity and PON1 Q192R genotypes, and total radical-trapping antioxidant parameter (TRAP) as well as immune biomarkers in patients with deficit (n = 40) and non-deficit (n = 40) schizophrenia and healthy controls (n = 40). Deficit schizophrenia is characterized by significantly increased levels of AOPP and lowered -SH, and PON1 activity, while no changes in the OSTOX/ANTIOX biomarkers were found in non-deficit schizophrenia. An increased OSTOX/ANTIOX ratio was significantly associated with deficit versus non-deficit schizophrenia (odds ratio = 3.15, p < 0.001). Partial least squares analysis showed that 47.6% of the variance in a latent vector extracted from psychosis, excitation, hostility, mannerism, negative symptoms, psychomotor retardation, formal thought disorders, and neurocognitive test scores was explained by LOOH+AOPP, PON1 genotype + activity, CCL11, tumor necrosis factor (TNF)-α, and IgA responses to neurotoxic tryptophan catabolites (TRYCATs), whereas -SH groups and IgM responses to MDA showed indirect effects mediated by OSTOX and neuro-immune biomarkers. When overall severity of schizophrenia increases, multiple immune and oxidative (especially protein oxidation indicating chlorinative stress) neurotoxicities and impairments in immune-protective resilience become more prominent and shape a distinct nosological entity, namely deficit schizophrenia. The nomothetic network psychiatry approach allows building causal-pathway-phenotype models using machine learning techniques.

The role of immune and oxidative pathways in menstrual cycle associated depressive, physio-somatic, breast and anxiety symptoms: Modulation by sex hormones.

OBJECTIVE: To examine whether 1) immune and nitro-oxidative stress (IO&NS) biomarkers are associated with premenstrual syndrome (PMS); and 2) changes in IO&NS biomarkers during the menstrual cycle (MC) are associated with PMS symptoms and plasma estradiol and progesterone. METHODS: This longitudinal study examined 41 women who completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days and assayed plasma levels of complement C3 and C4, highly sensitive C-reactive protein (hsCRP), haptoglobin (Hp), advanced oxidation protein products (AOPP), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP), sulfhydryl (-SH) groups and the activity of paraoxonase (PON)1 at days 7 (D7), 14 (D14), 21 (D21) and 28 (D28) of the MC. MC Associated Syndrome (MCAS) was diagnosed when the summed DRSP score during the MC is >0.666 percentile. RESULTS: All biomarkers, except hsCRP, showed significant alterations during the MC. Arylesterase (AREase) was lowered at D28, while LOOH increased at D14 and C4 at D21 in MCAS. Total DRSP scores were predicted by the combined effects of C4 (positively) and AREase and malondialdehyde (MDA) (both inversely associated). Progesterone lowered levels of LOOH, AOPP and C3 and estradiol lowered levels of Hp while both sex hormones increased 4-(chloromethyl)phenyl acetate (CMPA)ase and AREase activities and levels of -SH groups. CONCLUSION: PMS/MCAS is not accompanied by a peripheral inflammatory response. Lowered MDA and antioxidant defenses and increased C4 may play a role in MC symptoms while sex hormones may have a protective effect against oxidative stress toxicity.

Increased Oxidative Stress Toxicity and Lowered Antioxidant Defenses in Temporal Lobe Epilepsy and Mesial Temporal Sclerosis: Associations with Psychiatric Comorbidities.

Oxidative stress toxicity (OSTOX), as well as lowered antioxidant defenses (ANTIOX), plays a role in temporal lobe epilepsy (TLE). Nevertheless, the associations between OSTOX/ANTIOX and psychiatric comorbidities in TLE are largely unknown. Thus, this study examines plasma malondialdehyde (MDA), lipid hydroperoxides (LOOH), advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP), and sulfhydryl (-SH) groups in depression due to TLE (n = 25); anxiety disorders due to TLE (n = 27); psychotic disorder due to TLE (n = 25); "pure TLE" (n = 27); and healthy controls (n = 40). TLE and mesial temporal sclerosis (MTS) were characterized by significant increases in OSTOX (MDA, AOPP, LOOH) and lowered ANTIOX (-SH groups, TRAP). The discrimination of pure TLE from controls yielded a significant area under the ROC curve for MDA (0.999), AOPP (0.851), -SH groups (0.899), and the OSTOX/ANTIOX ratio (0.996). Seizure frequency is significantly associated with increased MDA and lowered LOOH and NOx levels. Increased MDA was associated with the severity of depressive and physiosomatic symptoms, while increased AOPP levels predicted suicidal ideation. Depression and anxiety disorders co-occurring with TLE showed significantly lower MDA levels than TLE without any comorbidities. The psychotic and negative symptoms of TLE are associated with increased MDA levels and excitation with increased LOOH and lowered TRAP levels. These results indicate that oxidative stress toxicity especially protein oxidation and aldehyde formation coupled with lowered -SH groups plays a key role in the pathophysiology of TLE/MTS. Increased aldehyde formation also impacts psychopathology and psychosis, as well as negative and depressive symptoms.

The uterine-chemokine-brain axis: menstrual cycle-associated symptoms (MCAS) are in part mediated by CCL2, CCL5, CCL11, CXCL8 and CXCL10.

OBJECTIVE: To examine associations between chemokines and menstrual cycle associated symptoms (MCAS). METHODS: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days of the menstrual cycle. MCAS is diagnosed when the total daily DRSP score during the menstrual cycle is > 0.666 percentile. We assayed plasma CCL2, CCL5, CCL11, CXCL8, CXCL10, EGF, IGF-1, and PAI-1 at days 7, 14, 21 and 28 of the menstrual cycle. RESULTS: CCL2, CCL5, CCL11 and EGF are significantly higher in women with MCAS than in those without. Increased CCL2, CXCL10, CXCL8, CCL11 and CCL5 levels are significantly associated with DRSP scores while CCL2 is the most significant predictor explaining 39.6% of the variance. The sum of the neurotoxic chemokines CCL2, CCL11 and CCL5 is significantly associated with the DRSP score and depression, physiosomatic, breast-craving and anxiety symptoms. The impact of chemokines on MCAS symptoms differ between consecutive weeks of the menstrual cycle with CCL2 being the most important predictor of increased DRSP levels during the first two weeks, and CXCL10 or a combination of CCL2, CCL11 and CCL5 being the best predictors during week 3 and 4, respectively. DISCUSSION: The novel case definition "MCAS" is externally validated by increased levels of uterus-associated chemokines and EGF. Those chemokines are involved in MCAS and are regulated by sex hormones and modulate endometrium functions and brain neuro-immune responses, which may underpin MCAS symptoms. As such, uterine-related chemokines may link the uterus with brain functions via a putative uterine-chemokine-brain axis.

Increased Levels of Plasma Tumor Necrosis Factor-α Mediate Schizophrenia Symptom Dimensions and Neurocognitive Impairments and Are Inversely Associated with Natural IgM Directed to Malondialdehyde and Paraoxonase 1 Activity.

Accumulating evidence suggests that TNF-α-mediated immune-neurotoxicity contributes to cognitive impairments and the overall severity of schizophrenia (OSOS). There are no data whether peripheral IL-6 and IL-4 may affect the phenome of schizophrenia above and beyond the effects of TNF-α and whether those cytokines are regulated by lowered natural IgM to malondialdehyde (MDA) and paraoxonase 1 enzyme activity. We assessed the aforementioned biomarkers in a cross-sectional study that enrolled schizophrenia patients with (n = 40) and without (n = 40) deficit schizophrenia and 40 healthy controls. Deficit schizophrenia was best predicted by a combination of increased IL-6 and PON1 status (QQ genotype and lowered CMPAase activity) and lowered IgM to MDA. Partial least squares bootstrapping shows that 41.0% of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, and formal thought disorders was explained by increased TNF-α and PON1 status (QQ genotype and lowered CMPAase activity), which lowered IL-4 and IgM to MDA as well as male sex and lowered education. We found that 47.9% of the variance in verbal fluency, word list memory, true recall, Mini-Mental State Examination, and executive functions was predicted by increased TNF-α and lowered IL-4, IgM to MDA, and education. In addition, both TNF-α and IL-4 levels were significantly associated with lowered IgM to MDA, while TNF-α was correlated with PON1 status. These data provide evidence that the symptomatic (both the deficit subtype and OSOS) and cognitive impairments in schizophrenia are to a large extent mediated by the effects of immune-mediated neurotoxicity as well as lowered regulation by the innate immune system.