Abnormal C-reactive protein blood levels as a specific biomarker of major depression and non-remission under antidepressants in schizophrenia.

BACKGROUND: C-reactive protein (CRP) is a general marker of peripheral inflammation and has been shown to be a good marker of neuroinflammation. CRP has been found to be elevated in patients with mood disorders (especially unipolar disorders (UD) and in schizophrenia (SZ)) but also to be lowered by antidepressants. OBJECTIVE: The objectives were (i) to determine the prevalence of major depression, antidepressant prescription and remission under antidepressant in a stabilized population of SZ and UD patients consulting in a daily hospital, and (ii) to determine if CRP was a marker of major depression and remission under antidepressant in these SZ and UD populations. METHODS: Abnormal CRP was defined by a CRP blood level ≥ 3 mg/L. Depressive symptoms were assessed by the Calgary Depression Rating Scale score. The clinicians were blinded of the CRP status of the patient. RESULTS: 411 patients were included (272 SZ and 139 UD). 171 (41.6%) were diagnosed with current major depression (74 (27.2%) for SZ and 97 (69.8%) for UD). 86 SZ (31.6%) and 119 UD (85.6%) were treated by antidepressant. Only 28/74 (37.8%) of the SZ subjects with major depression were administered antidepressants vs. 87/97 (89.7%) for UD. The non-remission rate under antidepressant was 28/86(32.6%) for SZ and 87/119 (73.1%) for UD. Overall, 105 (40.1%) of SZ and 39 (28.1%) of UD patients were found to have abnormal CRP blood levels. Abnormal CRP levels were significantly associated with increased MDD and more strongly with increased rates of non-remission under antidepressants in SZ patients, independently of age, gender, psychotic symptomatology, functioning, tobacco smoking and metabolic syndrome. This result was not replicated in UD patients, which suggests that CRP may be a specific marker of major depression and remission under antidepressant in SZ patients. CONCLUSION: The development of biomarkers in psychiatry may orientate specific etiologic therapies in patients with mental disorders. The present findings suggest that major depression is frequent in SZ patients and that increased CRP levels are associated with non-remission under antidepressants in this population. Anti-inflammatory strategies may be particularly useful in this specific population.

Hypovitaminosis D is associated with negative symptoms, suicide risk, agoraphobia, impaired functional remission, and antidepressant consumption in schizophrenia.

Hypovitaminosis D has been associated with, respectively, major depressive disorder, schizophrenia (SZ), and cognitive disorders in the general population, and with positive and negative symptoms and metabolic syndrome in schizophrenia. The objective was to determine the prevalence of hypovitaminosis D and associated factors in a non-selected multicentric sample of SZ subjects in day hospital. Hypovitaminosis D was defined by blood vitamin D level < 25 nM. Depressive symptoms were assessed by the Calgary Depression Rating Scale Score and Positive and Negative Syndrome Scale Score. Anxiety disorders and suicide risk were evaluated by the Structured Clinical Interview for Mental Disorders. Functioning was evaluated with the Functional Remission of General Schizophrenia Scale. Hypovitaminosis D has been found in 27.5% of the subjects. In multivariate analysis, hypovitaminosis D has been significantly associated with, respectively, higher suicide risk (aOR = 2.67 [1.31-5.46], p = 0.01), agoraphobia (aOR = 3.37 [1.66-6.85], p < 0.0001), antidepressant consumption (aOR = 2.52 [1.37-4.64], p < 0.001), negative symptoms (aOR = 1.04 [1.01-1.07], p = 0.04), decreased functioning (aOR = 0.97[0.95-0.99], p = 0.01), and increased leucocytosis (aOR = 1.17 [1.04-1.32], p = 0.01) independently of age and gender. No association with alcohol use disorder, metabolic syndrome, peripheral inflammation, insulin resistance, or thyroid disturbances has been found (all p > 0.05). Despite some slight abnormalities, no major cognitive impairment has been associated with hypovitaminosis D in the present sample (all p > 0.05 except for WAIS similarities score). Hypovitaminosis D is frequent and associated with suicide risk, agoraphobia and antidepressant consumption in schizophrenia, and more slightly with negative symptoms. Patients with agoraphobia, suicide risk and antidepressant consumption may, therefore, benefit in priority from vitamin D supplementation, given the benefit/risk profile of vitamin D. Further studies should evaluate the impact of vitamin D supplementation on clinical outcomes of SZ subjects.

High C-reactive protein levels are associated with depressive symptoms in schizophrenia.

BACKGROUND: Depressive symptoms are frequently associated with schizophrenia symptoms. C - Reactive protein (CRP), a marker of chronic inflammation, had been found elevated in patients with schizophrenia and in patients with depressive symptoms. However, the association between CRP level and depressive symptoms has been poorly investigated in patients with schizophrenia. The only study conducted found an association between high CRP levels and antidepressant consumption, but not with depressive symptoms investigated with the Calgary Depression Rating Scale for Schizophrenia (CDSS). OBJECTIVES: The aim of this study was to evaluate CRP levels and depressive symptoms in patients with schizophrenia, and to determine whether high CRP levels are associated with depressive symptoms and/or antidepressant consumption, independently of potential confounding factors, especially tobacco-smoking and metabolic syndrome. METHODS: Three hundred and seven patients with schizophrenia were enrolled in this study (mean age = 35.74 years, 69.1% male gender). Depressive symptoms was investigated with the CDSS. Patients were classified in two groups: normal CRP level (≤ 3.0mg/L) and high CRP level (> 3.0mg/L). Current medication was recorded. RESULTS: 124 subjects (40.4%) were classified in the high CRP level group. After adjusting for confounding factors, these patients were found to have higher CDSS scores than those with normal CRP levels in multivariate analyses (p = 0.035, OR = 1.067, 95% CI = 1.004-1.132). No significant association between CRP levels and antidepressants consumption was found. LIMITATIONS: The size sample is relatively small. The cut-off point for high cardiovascular risk was used to define the two groups. CRP was the sole marker of inflammation in this study and was collected at only one time point. The design of this study is cross-sectional and there are no conclusions about the directionality of the association between depression and inflammation in schizophrenia. CONCLUSION: This study found an association between high rates of CRP levels and depressive symptoms in patients with schizophrenia, but no association with antidepressant consumption. Further studies are needed to investigate the impact of inflammation in schizophrenia.

Quality of life is associated with chronic inflammation in depression: A cross-sectional study.

BACKGROUND: Inflammation may play a crucial role in the pathophysiology of depression. However, the association between chronic inflammation and health outcomes in depression remains unclear, particularly for patient-reported outcomes. METHODS: The aim of this study was to investigate the relationship between quality of life (QoL) (physical and mental health, assessed by the SF-36) and chronic inflammation assessed using C-reactive protein (CRP) in patients with current major depressive disorder. RESULTS: One hundred eighty-one patients with depression were enrolled in this study. After adjusting for key socio-demographic, clinical and biological confounding factors, patients with high levels of CRP (> 3.0mg/L) had worse physical health than those with normal CRP levels (OR = 0.95, 95% CI = 0.92-0.99). Significant associations were found between a higher rate of metabolic syndrome (OR = 0.10, 95% CI = 0.02-0.41) and high CRP levels. LIMITATIONS: The cut-off point for high cardiovascular risk was used to define the two groups: normal CRP level and high CRP level. CRP was the sole marker of inflammation in this study and was collected at only one time point. The design of this study is cross-sectional and there are no conclusions about the directionality of the association between QoL and inflammation in depression. QoL was assessed only by SF-36 scores. CONCLUSION: This study found an association between SF-36 physical health score and CRP in patients with depression, thereby showing the need to consider physical well-being in depression. This paves the way for interventions to act both on inflammation and QoL in patients with depression.

Quality of life is associated with chronic inflammation in schizophrenia: a cross-sectional study.

Inflammation may play a crucial role in the pathogenesis of schizophrenia. However, the association between chronic inflammation and health outcomes in schizophrenia remains unclear, particularly for patient-reported outcomes. The aim of this study was to investigate the relationship between quality of life (QoL) and chronic inflammation assessed using C -Reactive Protein (CRP) in patients with schizophrenia. Two hundred and fifty six patients with schizophrenia were enrolled in this study. After adjusting for key socio-demographic and clinical confounding factors, patients with high levels of CRP (>3.0 mg/l) had a lower QoL than patients with normal CRP levels (OR = 0.97, 95% CI = 0.94-0.99). An investigation of the dimensions of QoL revealed that psychological well-being, physical well-being and sentimental life were the most salient features of QoL associated with CRP. Significant associations were found between lower educational level (OR = 4.15, 95% CI = 1.55-11.07), higher body mass index (OR = 1.16, 95% CI = 1.06-1.28), higher Fagerström score (OR = 1.22, 95% CI = 1.01-1.47) and high levels of CRP. After replications with longitudinal approaches, the association between QoL and chronic inflammation may offer interesting interventional prospects to act both on inflammation and QoL in patients with schizophrenia.

Structural and functional reorganization of working memory system during the first decade in schizophrenia. A cross-sectional study.

INTRODUCTION: Progressive atrophy occurs in brain regions involved in the working memory network along the schizophrenia's course, but without parallel evolution of working memory impairment. We investigated the functional organization inside this network at different stages of the disease. METHODS: Twenty-eight patients with schizophrenia (16 with long disease duration (>60 months) and 12 with short disease duration (<60 months)) and eleven healthy controls underwent structural and functional MRI during an n-back task to determine atrophy and activation patterns. RESULTS: At similar n-back performances and relative to short disease duration patients, long disease duration patients activated more frontal temporal parietal and frontal network during 0-back and 1-back tasks respectively. n-back scores were correlated to atrophy in the frontal-temporal areas. DISCUSSION: Functional reorganization in the working memory network may play a compensatory role during the first ten years of schizophrenia.

Heat shock proteins (chaperones) in fish and shellfish and their potential role in relation to fish health: a review.

Heat shock proteins (HSPs), also known as stress proteins and extrinsic chaperones, are a suite of highly conserved proteins of varying molecular weight (c. 16-100 kDa) produced in all cellular organisms when they are exposed to stress. They develop following up-regulation of specific genes, whose transcription is mediated by the interaction of heat shock factors with heat shock elements in gene promoter regions. HSPs function as helper molecules or chaperones for all protein and lipid metabolic activities of the cell, and it is now recognized that the up-regulation in response to stress is universal to all cells and not restricted to heat stress. Thus, other stressors such as anoxia, ischaemia, toxins, protein degradation, hypoxia, acidosis and microbial damage will also lead to their up-regulation. They play a fundamental role in the regulation of normal protein synthesis within the cell. HSP families, such as HSP90 and HSP70, are critical to the folding and assembly of other cellular proteins and are also involved in regulation of kinetic partitioning between folding, translocation and aggregation within the cell. HSPs also have a wider role in relation to the function of the immune system, apoptosis and various facets of the inflammatory process. In aquatic animals, they have been shown to play an important role in health, in relation to the host response to environmental pollutants, to food toxins and in particular in the development of inflammation and the specific and non-specific immune responses to bacterial and viral infections in both finfish and shrimp. With the recent development of non-traumatic methods for enhancing HSP levels in fish and shrimp populations via heat, via provision of exogenous HSPs or by oral or water administration of HSP stimulants, they have also, in addition to the health effects, been demonstrated to be valuable in contributing to reducing trauma and physical stress in relation to husbandry events such as transportation and vaccination.

Pan-steatitis in farmed northern bluefin tuna, Thunnus thynnus (L.), in the eastern Adriatic.

Clinical, gross and histopathological investigations were carried out into large-scale mortalities on eastern Mediterranean bluefin tuna, Thunnus thynnus (L.), farms. Fish showed only nervous signs and darkened colour. At post-mortem the liver was bronze coloured and the pyloric area waxy in consistency. There was no evidence of any other gross pathology. Histopathology showed severe hepatic necrosis and lipidosis. Peri-pancreatic lipoid tissue was heavily infiltrated with an inflammatory round cell infiltrate. Fish on all three farms had been fed on a North African pilchard diet rather than traditional local or Baltic species. Once the diet was modified, losses ceased. A diagnosis of pan-steatitis as seen in other farmed fish species, as well as in terrestrial animals, on particular fish-based diets was made, although the actual factor within the diet which induced the inflammatory effect is not known.

Characterization of two outer membrane protein antigens of Porphyromonas gingivalis that are protective in a murine lesion model.

Porphyromonas gingivalis is a key periodontal pathogen that has been implicated in the aetiology of chronic adult periodontitis. The aim of this study was to characterize two potential vaccine candidates (PG32 and PG33) identified from a previous genomic sequence analysis. Gene knockout studies suggested that these proteins play an important role in bacterial growth and are transcriptionally linked. Analysis of 14 laboratory and clinical isolates of P. gingivalis found that in all strains, both genes were present with a high level of conservation and that the two proteins were also expressed in vitro. Truncated recombinant PG32 and PG33 proteins were produced in Escherichia coli in an attempt to increase the solubility of the proteins while retaining their native conformation. While most of the truncated proteins remained insoluble, two truncated proteins showed good solubility and high levels of protection in the P. gingivalis murine lesion model and may be considered as potential vaccine candidates for further testing in models of human periodontal disease.

Melano-macrophage centres and their role in fish pathology.

Melano-macrophage centres, also known as macrophage aggregates, are distinctive groupings of pigment-containing cells within the tissues of heterothermic vertebrates. In fish they are normally located in the stroma of the haemopoietic tissue of the spleen and the kidney, although in amphibians and reptiles, and some fish, they are also found in the liver. They may also develop in association with chronic inflammatory lesions elsewhere in the body and during ovarian atresia. In higher teleosts, they often exist as complex discrete centres, containing lymphocytes and macrophages, and may be primitive analogues of the germinal centres of lymph nodes. Melano-macrophage centres usually contain a variety of pigments, including melanins, and these increase in range and volume in older fish or in the presence of cachectic disease. Melano-macrophage centres act as focal depositories for resistant intracellular bacteria, from which chronic infections may develop. Iron capture and storage in haemolytic diseases appears to be a primary function, but antigen trapping and presentation to lymphocytes, sequestration of products of cellular degradation and potentially toxic tissue materials, such as melanins, free radicals and catabolic breakdown products are among other functions that have been ascribed. Recent work suggests that they are a site of primary melanogenesis rather than mere storage. Melano-macrophage centres increase in size or frequency in conditions of environmental stress and have been suggested as reliable biomarkers for water quality in terms of both deoxygenation and iatragenic chemical pollution.

Identification of vaccine candidate antigens from a genomic analysis of Porphyromonas gingivalis.

Porphyromonas gingivalis is a key periodontal pathogen which has been implicated in the etiology of chronic adult periodontitis. Our aim was to develop a protein based vaccine for the prevention and or treatment of this disease. We used a whole genome sequencing approach to identify potential vaccine candidates. From a genomic sequence, we selected 120 genes using a series of bioinformatics methods. The selected genes were cloned for expression in Escherichia coli and screened with P. gingivalis antisera before purification and testing in an animal model. Two of these recombinant proteins (PG32 and PG33) demonstrated significant protection in the animal model, while a number were reactive with various antisera. This process allows the rapid identification of vaccine candidates from genomic data.

Synthetic peptides representing sequences within gp41 of HIV as immunogens for murine T- and B-cell responses.

Within the gp41 glycoprotein of the human immunodeficiency virus type 1 (HIV-1) there is a relatively conserved region which appears accessible to the immune system during the course of HIV infection and is recognised by antibody from virtually all patients with AIDS. This region has also been shown to function as a target for human T cells. We have examined synthetic peptides spanning this sequence, between residues 572 and 604, with a view to evaluating their potential as immunogens. Peptides 572GIKQLQARILAVERYLKDQQ591 and 579RILAVERYLKDQQLLGGIWGCSGK601 were good immunogens in two different strains of mice while peptide 576LQARILAVERYLKDQQ591 was an inferior immunogen, and peptide 593LGIWGCSGKLIC604 was non-immunogenic unless coupled to a carrier protein. For both antibody and T cell responses it was apparent that sequences that could function as determinants within one peptide could not do so in the context of a different peptide immunogen. It follows that by judicious choice of immunogen sequence it may be possible to direct the immune response towards a desired fine specificity. Unwanted responses by CD4+ T cells isolated from certain peptide-primed animals were also observed. These T cells showed an unusual reactivity in that they were incapable of recognising their determinant AVERYLKDQQ if it was extended at the C-terminal end with the native sequence and as such would not be expected to recognise the native molecule unless processing created the identical C-terminus.

Comparative studies of the structural proteins and glycoproteins of equine herpesviruses 2 and 5.

The structural proteins of equine herpesvirus 2 (EHV-2) and EHV-5, recently shown to be gammaherpesviruses, were identified and compared. Labelled proteins and glycoproteins were separated by SDS-PAGE and although EHV-2 and EHV-5 had similar protein profiles, bands in some positions were virus-specific. Six glycoproteins, with distinct profiles, were identified for both EHV-2 and EHV-5. Rabbit antisera to EHV-2 and EHV-5 and horse antiserum to EHV-2 were used in radioimmunoprecipitations, Western blot analysis and ELISA to investigate the immunogenicity and cross-reactivity of virus proteins. These analyses revealed that while EHV-2 and EHV-5 proteins share many common epitopes, they also possess type-specific epitopes. A 0.71 kb region of the EHV-2 glycoprotein B (gB) gene was expressed as a fusion protein in Escherichia coli. Antiserum raised in a rabbit to the EHV-2 fusion protein was used to identify a 64K EHV-2 protein as EHV-2 gB. Antiserum to EHV-2 gB was used to identify a 66K EHV-5 protein as EHV-5 gB. These proteins, which may represent subunits of gB rather than the entire molecule, appear the most immunodominant of the structural virion proteins as identified by Western blot.

Equine herpesviruses 2 and 5 are gamma-herpesviruses.

Equine herpesviruses 2 and 5 (EHV-2 and EHV-5) have biological properties and genome structures that support their classification as members of the Betaherpesvirinae. In order to investigate whether this is supported by genetic data, we analysed the sequences of random DNA fragments and identified 25 EHV-2 and 28 EHV-5 genes that encode amino acid sequences with significant homology to proteins from other herpesviruses. Greatest similarity was to proteins specified by the gamma-herpesviruses Epstein-Barr virus (a gamma 1-herpesvirus) and herpesvirus saimiri (a gamma 2-herpesvirus), and the level of similarity was marginally greater to the latter. Also, like other gamma-herpesviruses, the EHV-2 and EHV-5 genomes are deficient in the CG dinucleotide, suggesting that latent genomes are methylated. EHV-2 and EHV-5 are related to each other more closely than they are to other herpesviruses, but are clearly distinct gamma-herpesviruses. The data support the establishment of at least one more subdivision of the gamma-herpesviruses (the gamma 3-herpesviruses).

Equine herpesvirus 5: comparisons with EHV2 (equine cytomegalovirus), cloning, and mapping of a new equine herpesvirus with a novel genome structure.

A new equine herpesvirus, provisionally designated equine herpesvirus 5 (EHV5; Browning and Studdert (1987) J. Gen. Virol. 68, 1441-1447), was examined for the degree of genomic difference from equine herpesvirus 2 (EHV2) by Southern hybridizations. EHV5 and EHV2 whole genomic DNA probes were highly specific for homologous DNA only, indicating that significant genomic difference exists between the two viruses. Restriction endonuclease analysis of EHV5 strain 2-141 (EHV5.2-141) revealed that the genome is 179 kb and exists as a single isomer. Clones representing 82% of the genome were obtained and used to construct restriction maps for four restriction endonucleases. Hybridization experiments indicated that the EHV5.2-141 genome does not contain large terminal or internal repeats, although some evidence for very short repeated sequences in the genomic termini was obtained. Such a genome structure makes EHV5 unique among the equine herpesviruses but similar to the mouse, rat, and guinea pig cytomegaloviruses and the tupaiid herpesvirus. Sequence analysis of one of the genomic termini of EHV5.2-141 revealed the presence of a 30-bp sequence (pac-1; Deiss et al. (1986) J. Virol. 59, 605-618) which is highly conserved among herpesviruses.

Effect of streptozotocin on the glutathione S-transferases of mouse liver cytosol.

Streptozotocin (STZ) increased the activity of mouse hepatic glutathione (GSH) S-transferases assayed with 1-chloro-2,4-dinitrobenzene. Nicotinamide administered prior to STZ prevented the hyperglycemia indicative of STZ-induced diabetes, but had no effect on the increase in GSH S-transferase activity caused by the drug. Another diabetogenic agent, alloxan, did not alter GSH S-transferase activity. Thus, streptozotocin may be increasing GSH S-transferase activity directly, and not as a result of the diabetic state the drug induces. Two transferases were characterized from mouse liver cytosol. One was a homodimer with a subunit molecular weight of about 28,000 and a pI of about 8.2. The other was also a homodimer with a subunit molecular weight of about 27,500 and a pI of about 9.2. The pI 8.2 GSH S-transferase was induced by STZ, while the pI 9.2 transferase was decreased by the drug. At least one other transferase appeared to be induced by STZ. Two other nitroso compounds, chlorozotocin and diethylnitrosamine, also increased GSH S-transferase activity, suggesting that this effect may be nitroso related.