Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF.

AIMS: Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodeling and atrial fibrillation is frequently observed in HFpEF. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in HFpEF, and post-hoc analyses suggest atrial antiarrhythmic effects. We tested if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx, which is known to cause atrial arrhythmias, and if that is responsive to treatment with the SGTL2i empagliflozin. METHODS AND RESULTS: Cardiomyocytes were isolated from atrial biopsies of 124 patients (82 with HFpEF) undergoing elective cardiac surgery. Na influx was measured with the Na-dye Asante Natrium Green-2 AM (ANG-2). Compared to patients without heart failure (NF), Na influx was doubled in HFpEF patients (NF vs HFpEF: 0.21±0.02 vs 0.38±0.04 mmol/L/min (N=7 vs 18); p=0.0078). Moreover, late INa (measured via whole-cell patch clamp) was significantly increased in HFpEF compared to NF. Western blot and HDAC4 pulldown assay indicated a significant increase in CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment with the CaMKII inhibitor autocamtide-2 related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with NHE1 inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa in HFpEF. Multivariate linear regression analysis, adjusting for important clinical confounders, revealed HFpEF to be an independent predictor for changes in Na handling in atrial cardiomyocytes. CONCLUSION: We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to antiarrhythmic effects in patients with HFpEF.

Could CRP be a differential biomarker of illness stages in schizophrenia? A systematic review and meta-analysis.

BACKGROUND: Patients with schizophrenia display peripheral inflammation but the impact of illness phase is not clear. Our meta-analysis investigated the difference in CRP levels between patients with schizophrenia and controls according to their illness phase. METHODS: After a systematic search, all studies measuring CRP in patients with schizophrenia and controls were included. Standardized mean differences were calculated between patients and controls according to illness phase. The influence of sociodemographic and clinical variables on our results was investigated using a meta-regression analysis. RESULTS: Fifty studies were included in this meta-analysis. Patients with schizophrenia had higher CRP levels than controls in the acute (p < 0.00001) and stable (p < 0.00001) stage of their disease. Patients with acute exacerbation of schizophrenia had higher CRP levels than stable patients (p = 0.02) but this difference did not persist when considering antipsychotic-medicated patients in both phases. Meta-regressions found that the increase of CRP in acutely ill patients as compared to controls was influenced by age (p < 0.01), BMI (p = 0.01) and first episode (p = 0.02), whereas the increase in CRP levels of stable patients as compared to controls was moderated by BMI (p = 0.004). CONCLUSIONS: In conclusion, this meta-analysis provides strong evidence that patients with schizophrenia have higher CRP levels than controls, but also show an increase in inflammatory response in the acute stage of the disease as compared to the stable stage. CRP could thus be considered as a state marker and a trait marker of the disease.

Cytokines changes associated with electroconvulsive therapy in patients with treatment-resistant depression: a Meta-analysis.

One third of depressive patients do not achieve remission after several steps of treatment and are considered as treatment resistant. Electroconvulsive therapy (ECT) improves symptoms in 70 to 90% of such cases. Resistant depression is associated with a dysregulation of the immune system with a dysbalance between the pro- and the anti-inflammatory cytokines. Therefore, we aimed to measure the kinetic of cytokines levels before, during and at the end of ECT. To test this hypothesis, we performed a meta-analysis assessing cytokines plasma levels before, during and after ECT in patients with major depressive disorders. After a systematic database search, means and standard deviations were extracted to calculate standardized mean differences. We found that IL-6 levels increased after 1 or 2 ECT session (p = 0.01) then decrease after 4 ECT sessions (p < 0.01) with no difference at the end of ECT (p = 0.94). A small number of studies were included and there was heterogeneity across them. The present meta-analysis reveals that ECT induces an initial increase of IL-6 levels and a potential decrease of TNF-α levels. No changes on IL-4 and IL-10 levels were found. Further work is necessary to clarify the impact of ECT on peripheral cytokines.

Identifying a neuroanatomical signature of schizophrenia, reproducible across sites and stages, using machine learning with structured sparsity.

OBJECTIVE: Structural MRI (sMRI) increasingly offers insight into abnormalities inherent to schizophrenia. Previous machine learning applications suggest that individual classification is feasible and reliable and, however, is focused on the predictive performance of the clinical status in cross-sectional designs, which has limited biological perspectives. Moreover, most studies depend on relatively small cohorts or single recruiting site. Finally, no study controlled for disease stage or medication's effect. These elements cast doubt on previous findings' reproducibility. METHOD: We propose a machine learning algorithm that provides an interpretable brain signature. Using large datasets collected from 4 sites (276 schizophrenia patients, 330 controls), we assessed cross-site prediction reproducibility and associated predictive signature. For the first time, we evaluated the predictive signature regarding medication and illness duration using an independent dataset of first-episode patients. RESULTS: Machine learning classifiers based on neuroanatomical features yield significant intersite prediction accuracies (72%) together with an excellent predictive signature stability. This signature provides a neural score significantly correlated with symptom severity and the extent of cognitive impairments. Moreover, this signature demonstrates its efficiency on first-episode psychosis patients (73% accuracy). CONCLUSION: These results highlight the existence of a common neuroanatomical signature for schizophrenia, shared by a majority of patients even from an early stage of the disorder.

HLA genetics in bipolar disorder.

OBJECTIVE: Bipolar Disorder (BD) is characterized by deregulated adaptive immune processes. Recent genome-wide association studies (GWAS) implicate the major histocompatibility complex (MHC) region in BD. The present study investigates the potential influence of variations in human leukocyte antigen (HLA) on BD risk and/or clinical presentations. This may have relevance to the dysregulated inflammatory processes commonly found in BD. METHOD: DNAs from 475 BD patients and 195 healthy controls (HC) were genotyped for classical HLA class I and II loci. RESULTS: We found that: (i) the HLA-A*02~B*44~DRB1*07 sub-haplotype is less prevalent in BD, vs. HC (pc = 2.4 × 10-2 ); (ii) the 57.1 and the 8.1-derived ancestral haplotypes i.e. HLA-A*02~B*57~Cw*06~DRB1*07~DQB1*09 and HLA-A*02~B*08~Cw*07 are associated with rapid cycling (pc = 1.9 × 10-3 and 1.05 × 10-2 , respectively); (iii) the 8.1AH-derived HLA class II-DRB*03~HLA-DQB1*02 sub-haplotype is more frequent in BD patients with a history of suicidal behaviors (pc = 2.1 × 10-2 ); and (iv) disease onset by an hypomanic episode or by psychotic symptoms are, respectively, more frequent in BD patients bearing the 7.1 AH-derived A*03~B*07~DRB1*15 sub-haplotype (pc = 8.5 × 10-3 ) and the HLA-A*02~B*07~DRB1*15 sub-haplotype (pc = 4.0 × 10-2 ). CONCLUSION: Corroborating the established link between these HLA haplotypes/sub haplotypes and common immune disorders, our findings suggest possible HLA-mediated proinflammatory processes operating in BD.

Similar white matter but opposite grey matter changes in schizophrenia and high-functioning autism.

OBJECTIVE: High-functioning autism (HFA) and schizophrenia (SZ) are two of the main neurodevelopmental disorders, sharing several clinical dimensions and risk factors. Their exact relationship is poorly understood, and few studies have directly compared both disorders. Our aim was thus to directly compare neuroanatomy of HFA and SZ using a multimodal MRI design. METHODS: We scanned 79 male adult subjects with 3T MRI (23 with HFA, 24 with SZ and 32 healthy controls, with similar non-verbal IQ). We compared them using both diffusion-based whole-brain tractography and T1 voxel-based morphometry. RESULTS: HFA and SZ groups exhibited similar white matter alterations in the left fronto-occipital inferior fasciculus with a decrease in generalized fractional anisotropy compared with controls. In grey matter, the HFA group demonstrated bilateral prefrontal and anterior cingulate increases in contrast with prefrontal and left temporal reductions in SZ. CONCLUSION: HFA and SZ may share common white matter deficits in long-range connections involved in social functions, but opposite grey matter abnormalities in frontal regions that subserve complex cognitive functions. Our results are consistent with the fronto-occipital underconnectivity theory of HFA and the altered connectivity hypothesis of SZ and suggest the existence of both associated and diametrical liabilities to these two conditions.

Is enhancing cGMP-PKG signalling a promising therapeutic target for heart failure with preserved ejection fraction?

Heart failure with preserved ejection fraction, i.e. HFpEF, is highly prevalent in ageing populations, accounting for more than 50 % of all cases of heart failure in Western societies, and is closely associated with comorbidities such as obesity, diabetes and arterial hypertension. However, all large multicentre trials of potential HFpEF treatments conducted to date have failed to produce positive outcomes. These disappointing results suggest that a 'one size fits all' strategy may be ill-suited to HFpEF and support the use of tailored, personalised therapeutic approaches with specific treatments designed for specific comorbidity-related HFpEF phenotypes. The accumulation of a multitude of cardiovascular comorbidities over time leads to increased systemic inflammation, oxidative stress and coronary microvascular endothelial inflammation, eventually resulting in degradation of cyclic guanosine monophosphate (cGMP) via multiple pathways, thereby reducing protein kinase G (PKG) activity. The importance of cGMP-PKG pathway modulation is supported by growing evidence that suggests that this pathway may be a promising therapeutic target, evidence that is mainly based on its role in the phosphorylation of the giant cytoskeletal protein titin. This review will focus on the preclinical and early clinical evidence in the field of cGMP-enhancing therapies and PKG activation.

Primary gastrointestinal lymphomas in children: An experience of 12 years from a tertiary care center of North India.

BACKGROUND AND AIM: Lymphomas are among the dominant solid tumors in children and primary gastrointestinal lymphomas (PGILs), although rare, are the most common extranodal lymphomas and the most common malignancies affecting the gastrointestinal tract in children. This study was undertaken to analyze childhood PGIL with reference to clinical presentation, anatomic distribution, histopathologic, and immunohistochemical (IHC) characteristics. MATERIALS AND METHODS: In this 12 year combined retrospective and prospective descriptive study, all the cases of PGIL in children were selected according to Dawson's criteria. RESULTS: A total of 11 cases were found which included 9 boys and 2 girls (male:female - 4.5:1) ranging in age from 1 to 14 years (mean 6.6 years). Abdominal pain (81.8%) and intestinal obstruction (63.6%) were the most common presenting features. Grossly, most of the lesions were ulcero-infiltrative (72.7%) and involved the terminal part of the ileum (36.4%) and ileocecal region (27.3%) most commonly. Histopathologically and IHC, all the cases were high-grade lymphomas of diffuse large B-cell type except for one case of mucosa-associated lymphoid tissue lymphoma. No case of Burkitt's lymphoma was found. CONCLUSION: PGILs are an important cause of morbidity and mortality in children worldwide with considerable variation in their clinicopathological features and treatment modalities. Only some studies are available in literature for comparison. Further studies are required to define the genetic and molecular basis of the different histopathological pattern found in our setting.

Violent suicidal behaviour in bipolar disorder is associated with nitric oxide synthase 3 gene polymorphism.

OBJECTIVE: Given the importance of nitric oxide system in oxidative stress, inflammation, neurotransmission and cerebrovascular tone regulation, we postulated its potential dysfunction in bipolar disorder (BD) and suicide. By simultaneously analysing variants of three isoforms of nitric oxide synthase (NOS) genes, we explored interindividual genetic liability to suicidal behaviour in BD. METHOD: A total of 536 patients with BD (DSM-IV) and 160 healthy controls were genotyped for functionally relevant NOS1, NOS2 and NOS3 polymorphisms. History of suicidal behaviour and violent suicide attempt was documented for 511 patients with BD. Chi-squared test was used to perform genetic association analyses and logistic regression to test for gene-gene interactions. RESULTS: NOS3 rs1799983 T homozygous state was associated with violent suicide attempts (26.4% vs. 10.8%, in patients and controls, P = 0.002, corrected P (Pc) = 0.004, OR: 2.96, 95% CI = 1.33-6.34), and this association was restricted to the early-onset BD subgroup (37.9% vs. 10.8%, in early-onset BD and controls, P = 0.0003, Pc = 0.0006 OR: 5.05, 95% CI: 1.95-12.45), while we found no association with BD per se and no gene-gene interactions. CONCLUSION: Our results bring further evidence for the potential involvement of endothelial NOS gene variants in susceptibility to suicidal behaviour. Future exploration of this pathway on larger cohort of suicidal behaviour is warranted.

The "psychomicrobiotic": Targeting microbiota in major psychiatric disorders: A systematic review.

The gut microbiota is increasingly considered as a symbiotic partner in the maintenance of good health. Metagenomic approaches could help to discover how the complex gut microbial ecosystem participates in the control of the host's brain development and function, and could be relevant for future therapeutic developments, such as probiotics, prebiotics and nutritional approaches for psychiatric disorders. Previous reviews focused on the effects of microbiota on the central nervous system in in vitro and animal studies. The aim of the present review is to synthetize the current data on the association between microbiota dysbiosis and onset and/or maintenance of major psychiatric disorders, and to explore potential therapeutic opportunities targeting microbiota dysbiosis in psychiatric patients.

Cerebellar volume in schizophrenia and bipolar I disorder with and without psychotic features.

OBJECTIVE: There is growing evidence that cerebellum plays a crucial role in cognition and emotional regulation. Cerebellum is likely to be involved in the physiopathology of both bipolar disorder and schizophrenia. The objective of our study was to compare cerebellar size between patients with bipolar disorder, patients with schizophrenia, and healthy controls in a multicenter sample. In addition, we studied the influence of psychotic features on cerebellar size in patients with bipolar disorder. METHOD: One hundred and fifteen patients with bipolar I disorder, 32 patients with schizophrenia, and 52 healthy controls underwent 3 Tesla MRI. Automated segmentation of cerebellum was performed using FreeSurfer software. Volumes of cerebellar cortex and white matter were extracted. Analyses of covariance were conducted, and age, sex, and intracranial volume were considered as covariates. RESULTS: Bilateral cerebellar cortical volumes were smaller in patients with schizophrenia compared with patients with bipolar I disorder and healthy controls. We found no significant difference of cerebellar volume between bipolar patients with and without psychotic features. No change was evidenced in white matter. CONCLUSION: Our results suggest that reduction in cerebellar cortical volume is specific to schizophrenia. Cerebellar dysfunction in bipolar disorder, if present, appears to be more subtle than a reduction in cerebellar volume.

Cytomegalovirus seropositivity and serointensity are associated with hippocampal volume and verbal memory in schizophrenia and bipolar disorder.

INTRODUCTION: Cytomegalovirus (CMV) is a member of the herpesviridae family that has a limbic and temporal gray matter tropism. It is usually latent in humans but has been associated with schizophrenia, bipolar disorder and cognitive deficits in some populations. Hippocampal decreased volume and dysfunction play a critical role in these cognitive deficits. We hypothesized that CMV seropositivity and serointensity would be associated with hippocampal volume and cognitive functioning in patients with schizophrenia or bipolar disorder. METHODS: 102 healthy controls, 118 patients with bipolar disorder and 69 patients with schizophrenia performed the California Verbal Learning Test (CVLT) and had blood samples drawn to assess CMV IgG levels. A subgroup of 52 healthy controls, 31 patients with bipolar disorder and 27 patients with schizophrenia underwent T1 MRI for hippocampal volumetry. We analyzed the association between CMV serointensity and seropositivity with hippocampal volume. We also explored the correlation between CMV serointensity and seropositivity and CVLT scores. RESULTS: In both patient groups but not in controls, higher CMV serointensity was significantly associated with smaller right hippocampal volume. Further, in the group of patients with schizophrenia but not bipolar disorder, CMV serointensity was negatively correlated with CVLT scores. CONCLUSION: CMV IgG titers are associated with decreased hippocampal volume and poorer episodic verbal memory in patients with schizophrenia or bipolar disorder. The mechanism of this association warrants further exploration.

Effectiveness and tolerance of anti-inflammatory drugs' add-on therapy in major mental disorders: a systematic qualitative review.

OBJECTIVE: To provide a systematic review of the literature regarding the efficacy of anti-inflammatory drugs in three major mental disorders [major depressive disorder (MDD), schizophrenia and bipolar disorders]. METHOD: Four databases were explored, without any year or language restrictions. The baseline search paradigm was limited to open-labelled clinical and randomized controlled trials (RCTs). RESULTS: Four major classes of anti-inflammatory drugs were identified, namely polyunsaturated fatty acids (PUFAs), cyclooxygenase (COX) inhibitors, anti-TNFalpha and minocycline. Effectiveness and benefit/risk ratio of each class in MDD, bipolar disorders and schizophrenia was detailed when data were available. Several meta-analyses indicated effectiveness of PUFAs in MDD with a good tolerance profile. One meta-analysis indicated that COX-2 specific inhibitors showed effectiveness in schizophrenia. Anti-TNFalpha showed important effectiveness in resistant MDD with blood inflammatory abnormalities. Minocycline showed effectiveness in schizophrenia. CONCLUSION: Polyunsaturated fatty acids seem to have the best benefit/risk ratio profile but proved their effectiveness only in MDD. A number of anti-inflammatory drugs are available as adjunct treatment for treatment-resistant patients with MDD, schizophrenia and bipolar disorder. If used with caution regarding their possible side-effects, they may be reasonable therapeutic alternatives for resistant symptomatology.

Molecular characteristics of Human Endogenous Retrovirus type-W in schizophrenia and bipolar disorder.

Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type 'W' family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10-4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders.

Increased cardiovascular risk in rats with primary renal dysfunction; mediating role for vascular endothelial function.

Primary chronic kidney disease is associated with high cardiovascular risk. However, the exact mechanisms behind this cardiorenal interaction remain unclear. We investigated the interaction between heart and kidneys in novel animal model for cardiorenal interaction. Normal Wistar rats and Munich Wistar Fromter rats, spontaneously developing renal dysfunction, were subjected to experimental myocardial infarction to induce cardiac dysfunction (CD) and combined cardiorenal dysfunction (CRD), respectively (N = 5-10). Twelve weeks later, cardiac- and renal parameters were evaluated. Cardiac, but not renal dysfunction was exaggerated in CRD. Accelerated cardiac dysfunction in CRD was indicated by decreased cardiac output (CD 109 ± 10 vs. CRD 79 ± 8 ml/min), diastolic dysfunction (E/e') (CD 26 ± 2 vs. CRD 50 ± 5) and left ventricular overload (LVEDP CD 10.8 ± 2.8 vs. CRD 21.6 ± 1.7 mmHg). Congestion in CRD was confirmed by increased lung and atrial weights, as well as exaggerated right ventricular hypertrophy. Absence of accelerated renal dysfunction, measured by increased proteinuria, was supported by absence of additional focal glomerulosclerosis or further decline of renal blood flow in CRD. Only advanced peripheral endothelial dysfunction, as found in CRD, appeared to correlate with both renal and cardiac dysfunction parameters. Thus, proteinuric rats with myocardial infarction showed accelerated cardiac but not renal dysfunction. As parameters mimic the cardiorenal syndrome, these rats may provide a clinically relevant model to study increased cardiovascular risk due to renal dysfunction. Peripheral endothelial dysfunction was the only parameter that correlated with both renal and cardiac dysfunction, which may indicate a mediating role in cardiorenal interaction.

[Programmes against depression]. / Les programmes d'action contre la dépression.

BACKGROUND: Depressive disorders represent a major public health concern, regarding their high frequency and their important cost. Depression impair the quality of life more than any other disease, sometimes leading to suicidal ideas or behavior. Indeed, 50% of patients with severe major depression commit suicide. Numerous studies showed that depressive disorders are frequently not recognised, and regularly untreated. In France, where at least 3 millions of inhabitants are concerned, 38% of depressed patients are not using any health system. When they are asking for care, the majority of depressed patients visit their general practitioner (51%), whereas less than 10% visit a psychiatrist. Even when the diagnostic is correct, the treatment prescribed is not systematically relevant. The treatment is, for example, frequently proposed for a too short period, and sometimes the prescribed product does not have proven antidepressive efficacy. Furthermore, as incorrect informations are frequently given to patients, and as there is a general biased judgement about psychotropic drugs in the general population, the compliance is usually poor for antidepressive treatment. Therefore, only a small minority of depressed patients benefits from an adequate care. Public health information methodological asserts. To improve this situation, delivering simple and clear-cut recommendations cannot be considered as sufficiently effective, and public health interventions are required. Different programs improving the recognition of depressive disorders have already been tested in some countries with encouraging results. These programs are based on information campaigns given to the public, and the training of general practitioners about the management of depressive disorders. The "Defeat Depression" campaign in Great-Britain and the "National Depression Screening Day" in the United-States of America may represent informative examples. Restricting these programs to general practitioners only is frequently criticized, as this may reduce efficacy. A multilevel approach is crucial for the success of action programmes against depression, because synergistic effects can be expected. In Germany, the "Nürnberger Bündnis gegen Depression" project was based on four levels, and effectively reduced the suicide rate. These levels of action included "cooperation with GPs", such as training sessions based on video, and presence of a phone hotline, "public relations activities", "training sessions for multipliers", such as priests, social workers and media, and "special offers for high risk groups and self-help activities". In France, such a program is clearly required.