High serum levels of transforming growth factor β1 are associated with increased cortical thickness in cingulate and right frontal areas in healthy subjects

Background

Transforming growth factor ?? (TGF-??) is a cytokine having multiple functions in the central nervous system such as promoting repair mechanisms in degenerative diseases and stroke. To date, however, its neuroprotective effects in non-disease conditions have not been studied

Methods

With the aim of exploring the relationship between peripheral TGF-??1 expression and brain structural integrity, 70 healthy participants underwent high-resolution structural T1-weighted magnetic resonance imaging scans and blood sampling. Data were processed to obtain brain cortical thickness and serum concentrations of TGF-??1. We investigated the correlation between TGF-??1 and cortical thickness using both region-of-interest- and vertex-based approaches.

Findings

Region-of-interest-based analysis of the cortical mantle showed a correlation between TGF-??1 serum concentrations and cortical thickness bilaterally in cingulate and right frontal and temporal areas. Similar results emerged in the vertex-based analysis, where significant correlations were found bilaterally in cingulate and right frontal cortices.

Conclusions

These results suggest that TGF-??1, through its role in down-regulating inflammatory processes, might have a beneficial effect on the structural integrity of the brain in physiological states.     

Prognostic factors in multiple myeloma: role of β2-microglobulin and thymidine kinase

Summary Serum ₂- microglobulin, serum thymidine kinase, and commonly used prognostic parameters were investigated for their prognostic value in a well-defined group of patients with multiple myeloma (n = 207). Multivariate analysis showed hemoglobin to be the parameter of strongest prognostic value. Only albumin, serum ₂-microglobulin and serum thymidine kinase added further prognostic information. When tested for efficiency in recognizing patients with poor (average survival time < 1 year) and good (average survival time > 5 years) prognosis, serum ₂-microglobulin was best (80%), followed by total urinary protein (78%), hemoglobin (76%), and albumin (75%).     

Genetics education in a culturally diverse population—lessons learnt,future directions

To provide equitable genetics education services, the needs of a culturally and linguistically diverse (CALD) population must be addressed. The mission of the Centre for Genetics Education (CGE) in Australia articulates a commitment to fostering community partnerships, implementing educational strategies and evaluating the impact of genetics information and technology on society. The aim of this report is to review the ways in which CALD groups have been partners in the planning and implementation of genetics educational strategies of the Centre. Responding to the community and respecting its contribution has helped forge these partnerships and implement appropriate and relevant educational strategies. The partnerships have been effective in modulating both the protocols used in producing resources, the resource content itself, and the provision of more appropriately targeted resources for these community groups.     

Genetic variants in PSEN2 and correlation to CSF β-amyloid42 levels in AD

Beta-amyloid 42 (Aβ42) concentrations in cerebrospinal fluid (CSF) are significantly decreased in Alzheimer's disease (AD). The aim of this study was to correlate genetic variability in presenilin 2 (PSEN2) in relation to Aβ42 concentrations and to confirm association of apolipoprotein E (APOE) alleles E4/E4 genotype with lower CSF Aβ42. Haplotype analysis of PSEN2 and APOE genotyping were performed in 175 Alzheimer's disease patients, as defined by clinical diagnosis and Aβ42 levels. One distinct haploblock in PSEN2 was detected and the frequent haplotypes were analyzed using 4 tagging single nucleotide polymorphisms (SNPs). We found an association between haplotype 2 and higher CSF Aβ42 concentrations (p = 0.021) and lower Aβ42 concentrations in haplotype 5 carriers (p < 0.001). APOE E4/E4 carriers had lower Aβ42 levels (p = 0.009). Additive regression analysis showed an association of Aβ42 level with APOE genotype (p = 0.024), haplotype 4 (p = 0.064), and haplotype 5 (p = 0.04), whereas gender, age at onset and Mini Mental State Examination (MMSE) remained insignificant. Using CSF Aβ42 as a biomarker we replicated genetic influences in APOE and observed a significant influence of a new haplotype in PSEN2. A better understanding of genetic influences on biomarkers like CSF Aβ42 might help to stratify patients and develop specific treatment strategies.     

Relationship between serum levels of IL-18 and IgG1 in patients with primary Sjögren's syndrome, rheumatoid arthritis and healthy controls

Primary Sjögren's syndrome (SS) is characterized by inflammation in salivary and lachrymal glands, with a local predominance of Th1‐like cytokines, as well as the pleiotropic cytokine interleukin (IL) 18. High serum levels of polyclonal IgG are common, with a subclass imbalance in which IgG1 is increased and IgG2 is normal or low. IL‐18 is also of pathogenetic importance in rheumatoid arthritis. In the present study we looked for any relationship between serum IL‐18 as well as transforming growth factor (TGF) β1 versus IgA, IgM, and IgG subclass levels in SS (n = 16), rheumatoid arthritis (RA) (n = 15), and healthy controls (n = 15). SS was defined by the revised American‐European classification criteria. IL‐18 and TGF‐β1 were analyzed with enzyme immunoassays (EIA), and IgG1, IgG2 and IgG3 by single radial immunodiffusion. In the composite group of RA, SS and normal controls, IgG1 and IL‐18 were related (R = 0·52, P = 0·0005). No relation was found neither between IL‐18 versus IgG2, IgG3 or IgA, nor between serum TGF‐β1 versus any of the immunoglobulins. Since serum levels of IL‐18 are related to serum IgG1, IL‐18 may be of importance for IgG1 switch and/or release.     

Association study of the β-arrestin 2 gene (ARRB2) with opioid and cocaine dependence in a European-American population

The rewarding properties of drugs of abuse are mediated by the mu-opioid receptor (MOR). Genetic variations in MOR and MOR interacting proteins (MORIPs) involved in MOR signaling may increase the risk for drug dependence. The MORIP β-arrestin plays an important role in the regulation of MOR trafficking, thereby highlighting it as a candidate gene for addiction phenotypes. In this case-control association study, DNA samples from cocaine-dependent (n=336) and opioid-dependent (n=335) patients and controls (n=656) were genotyped for seven single nucleotide polymorphisms (rs11868227, rs3786047, rs4522461, rs1045280, rs2271167, rs2036657, and rs4790694) across ARRB2, the gene encoding the β-arrestin 2 protein. No significant differences were observed in genotype or allele frequency between drug-dependent and control individuals for any of the single nucleotide polymorphisms analyzed. Haplotype analysis was similarly negative. Further studies are needed to determine whether variations in ARRB2 (or other MORIPs) are relevant to cocaine or opioid dependence in different ethnic populations or whether they confer a risk that is specific to dependence on other drugs of abuse.     

Increased annexin-V and decreased TNF-α serum levels in chronic-medicated patients with schizophrenia

Schizophrenia (SZ) is a chronic severe mental disorder. Increased inflammatory processes have been shown in acute and chronic SZ. Apoptotic processes may alter the neuronal network and are involved in the pathogenesis of several neurodegenerative diseases, such as SZ. Annexin-V seems to have a role on inhibition of pro-inflammatory activities during apoptosis. Tumor necrosis factor (TNF-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines which stimulate acute phase reactions. A chronic immune activation in SZ has been shown. The aim of this study was to compare annexin-V and TNF-alpha serum levels in chronic medicated patients with SZ and healthy controls. Thirty-eight outpatients from the HCPA Schizophrenia Program and 38 healthy controls were enrolled to this study protocol. Annexin-V and TNF-alpha serum levels were measured with ELISA. Serum annexin-V levels were significantly higher in patients with SZ than in controls (p < 0.001) and TNF-alpha significantly lower (p < 0.001). The present result of increased annexin-V and decreased serum levels of TNF-alpha compared to controls may be a result of the stabilization phase of psychosis and a reduction in metabolic brain aggression. In this complex picture, increased levels of annexin-V and decreased levels of TNF-alpha in our sample would be explained by illness stability and chronic treatment. Our findings support the hypothesis of a state dependant process of inflammation in SZ. Further prospective studies to clarify the findings described in this paper are needed.     

Increased matrix metalloproteinases as possible cause of osseoarticular tissue destruction in long-term haemodialysis and β2-microglobulin amyloidosis

Immunolocalization of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in periarticular tissues of ₂-microglobulin amyloidosis patients was investigated. MMP-1 (interstitial collagenase) the most strongly expressed of the MMPs, was localized in the synovial lining cells, mesenchymal cells in granulation tissue and nodular amyloid deposits, and chondrocytes within areas of cartilage erosion. Expression of MMP-1 was correlated with the degree of macrophage infiltration and synovial cell hyperplasia, but it was not correlated with the degree of amyloid deposition or haemodialysis period. Expression of MMP-1 appeared more intense than that of TIMP-1 and TIMP-2 in highly inflammatory cases. MMP-2 was mildly expressed in the interstitial fibroblasts and MMP-3 was faintly stained in the extracellular matrix of the synovial membrane. MMP-9 (gelatinase B) was found to be strongly positive in the osteoclasts which increased in the progressing osteolytic lesion from the destructive arthropathy. These results suggest involvement of MMPs in inflammation with an imbalance between expression of MMPs and TIMPs being closely related to pathogenesis of the destructive arthropathy.     

Heritability of serum dehydroepiandrosterone sulphate levels and pubertal development in 6∼18-year-old girls: a twin study

Background: Dehydroepiandrosterone sulphate (DHEAS), the most plentiful circulating adrenal hormone, may be considered as a marker of the onset of adrenarche and is involved in pubertal development and metabolic disorders.

Aim: The objective of this study is to determine the genetic and environmental influences on the variation of basal DHEAS levels and pubertal development in pubertal girls.

Subjects and methods: Three hundred and sixty twin girls aged 6–18-years were enrolled, consisting of 132 monozygotic pairs and 48 dizygotic pairs. Anthropometric and sexual characteristics were examined. Serum DHEAS was measured by RIA. Estimates of genetic and environmental components of variance were based on the theory of normal maximum likelihood in Mx package.

Results: Serum DHEAS concentrations of PH-II and PH-III were significantly higher than Tanner stage PH-I (p?Conclusions: Serum DHEAS concentrations of pubertal girls are mainly influenced by genetic factors, especially during the period of adrenarche. The results stress the importance of research into the genetic regulation of the endocrine regulators involved in adrenarche and related metabolic disorders in girls.     

CAR-diology—a virus receptor in the healthy and diseased heart

The interplay of diverse cell-contact proteins is required for normal cardiac function and determines the mechanical and electrical properties of the heart. A specialized structure between cardiomyocytes—the intercalated disk—contains a high density of these proteins, which are assembled into adherens junctions, desmosomes, and gap junctions. The Coxsackievirus–adenovirus receptor (CAR) as a tight junction protein of the intercalated disk has recently been implied in cardiac remodeling and electrical conductance between atria and ventricle. This review summarizes recent in vivo studies that relate CAR to heart disease and how they could translate to improved diagnosis and therapy of viral myocarditis and arrhythmia.     

Interaction of human TNF and β2-microglobulin with Tanapox virus-encoded TNF inhibitor, TPV-2L

Tanapox virus (TPV) encodes and expresses a secreted TNF-binding protein, TPV-2L or gp38, that displays inhibitory properties against TNF from diverse mammalian species, including human, monkey, canine and rabbit. TPV-2L also has sequence similarity with the MHC-class I heavy chain and interacts differently with human TNF as compared to the known cellular TNF receptors or any of the known virus-encoded TNF receptor homologs derived from many poxviruses. In order to determine the TNF binding region in TPV-2L, various TPV-2L C-terminal truncations and internal deletions were created and the muteins were expressed using recombinant baculovirus vectors. C-terminal deletions from TPV-2L resulted in reduced binding affinity for human TNF and specific mutants of TNF that discriminate between TNF-R1 and TNF-R2. However, deletion of C-terminal 42 amino acid residues totally abolished the binding of human TNF and its mutants. Removal of any of the predicted internal domains resulted in a mutant TPV-2L protein incapable of binding to human TNF. Deletion of C-terminal residues also affected the ability of TPV-2L to block TNF-induced cellular cytotoxicity. In addition to TNF, TPV-2L can also form complexes with human β2-microglobulin to form a novel macromolecular complex. In summary, the TPV-2L protein is a bona fide MHC-1 heavy chain family member that binds and inhibits human TNF in a fashion very distinct from other known poxvirus-encoded TNF inhibitors, and also can form a novel complex with the human MHC-1 light chain, β2-microglobulin.     

Endotoxin-Induced Endothelial Fibrosis Is Dependent on Expression of Transforming Growth Factors β1 and β2

During endotoxemia-induced inflammatory disease, bacterial endotoxins circulate in the bloodstream and interact with endothelial cells (ECs), inducing dysfunction of the ECs. We previously reported that endotoxins induce the conversion of ECs into activated fibroblasts. Through endotoxin-induced endothelial fibrosis, ECs change their morphology and their protein expression pattern, thereby suppressing endothelial markers and upregulating fibrotic proteins. The most commonly used fibrotic inducers are transforming growth factor β1 (TGF-β1) and TGF-β2. However, whether TGF-β1 and TGF-β2 participate in endotoxin-induced endothelial fibrosis remains unknown. We have shown that the endotoxin-induced endothelial fibrosis process is dependent on the TGF-β receptor, ALK5, and the activation of Smad3, a protein that is activated by ALK5 activation, thus suggesting that endotoxin elicits TGF-β production to mediate endotoxin-induced endothelial fibrosis. Therefore, we investigated the dependence of endotoxin-induced endothelial fibrosis on the expression of TGF-β1 and TGF-β2. Endotoxin-treated ECs induced the expression and secretion of TGF-β1 and TGF-β2. TGF-β1 and TGF-β2 downregulation inhibited the endotoxin-induced changes in the endothelial marker VE-cadherin and in the fibrotic proteins α-SMA and fibronectin. Thus, endotoxin induces the production of TGF-β1 and TGF-β2 as a mechanism to promote endotoxin-induced endothelial fibrosis. To the best of our knowledge, this is the first report showing that endotoxin induces endothelial fibrosis via TGF-β secretion, which represents an emerging source of vascular dysfunction. These findings contribute to understanding the molecular mechanism of endotoxin-induced endothelial fibrosis, which could be useful in the treatment of inflammatory diseases.     

Do serum and red blood cell folate levels indicate iron response in hemodialysis patients?

The relationship among iron status, ferritin, and folate levels, and the possible contribution of folate measurement in the prediction of iron response in hemodialysis patients, have not been assessed. In addition to serum ferritin and transferrin saturation (TSAT), serum and red blood cell (RBC) folate levels were evaluated as indices for intravenous iron therapy responsiveness in 60 hemodialysis patients. Patients were classified as iron responders or nonresponders depending on whether they exhibited a rise in hemoglobin above 1 g/dl after administration of 1 g of iron sucrose. An inverse relation between serum ferritin concentration and RBC folate levels was found in iron responders (n=26, r=-0.62, p<0.001) but not in nonresponders (n=34, r=0.07, p=nonsignificant). Only serum and RBC folate levels could predict iron response in patients with ferritin levels above 150 microg/l (n=25), with a sensitivity of 83.3% and a specificity of 94.7%. Our findings suggest that RBC folate concentration is inversely related with ferritin levels in iron-responsive but not in non-responsive hemodialysis patients. Serum and RBC folate concentration seems to predict response to iron administration better than serum ferritin or TSAT in patients with ferritin levels above 150 microg/l; therefore, in these patients, it might be used to guide iron management.