Ceruloplasmina y su importancia clínica como factor indicador del riesgo cardiovascular en una población de escolares de Granada.

Also known as ferroxidase ceruloplasmin, belongs to the family of inflammation-sensitive proteins, and its main function to transport copper in the blood. Although, in addition to this transport function, at present, there are numerous studies that have attempted to use the determination of serum concentrations as a predictive indicator of cardiovascular risk in patients who are overweight or obese. The results of this study confirm the existence of a significant correlation between serum ceruloplasmin and nutritional status of the subjects, which means that for the population of students assessed, serum levels of this protein are an important predictor the risk of cardiovascular disease.

VEGF gene expression in adult human thymus fat: a correlative study with hypoxic induced factor and cyclooxygenase-2.

It is well known that the adult human thymus degenerates into fat tissue; however, it has never been considered as a potential source of angiogenic factors. Recently, we have described that this fat (TAT) produces angiogenic factors and induces human endothelial cell proliferation and migration, indicating its potential angiogenic properties. DESIGN Adult thymus fat and subcutaneous adipose tissue specimens were obtained from 28 patients undergoing cardiac surgery, making this tissue readily available as a prime source of adipose tissue. We focused our investigation on determining VEGF gene expression and characterizing the different genes, mediators of inflammation and adipogenesis, and which are known to play a relevant role in angiogenesis regulation. RESULTS We found that VEGF-A was the isoform most expressed in TAT. This expression was accompanied by an upregulation of HIF-1alpha, COX-2 and HO-1 proteins, and by increased HIF-1 DNA binding activity, compared to SAT. Furthermore, we observed that TAT contains a high percentage of mature adipocytes, 0.25% of macrophage cells, 15% of endothelial cells and a very low percentage of thymocyte cells, suggesting the cellular variability of TAT, which could explain the differences in gene expression observed in TAT. Subsequently, we showed that the expression of genes known as adipogenic mediators, including PPARgamma1/gamma2, FABP-4 and adiponectin was similar in both TAT and SAT. Moreover the expression of these latter genes presented a significantly positive correlation with VEGF, suggesting the potential association between VEGF and the generation of adipose tissue in adult thymus. CONCLUSION Here we suggest that this fat has a potential angiogenic function related to ongoing adipogenesis, which substitutes immune functions within the adult thymus. The expression of VEGF seems to be associated with COX-2, HO-1 and adipogenesis related genes, suggesting the importance that this new fat has acquired in research in relation to adipogenesis and angiogenesis.

Personality disorders and the Five-Factor Model among French speakers in Africa and Europe

Objective: Several authors have suggested that Personality Disorders (PDs) might be more accurately described using a dimensional model instead of a categorical one. The aim of this study was to describe the relationship between PDs and the Five-Factor Model (FFM)-a dimensional model describing normal personality traits known for its invariance across cultures-in two different cultural settings. Method: Subjects from nine French-speaking African countries (n = 2,014) and from Switzerland (n = 697) completed both the French-version of the IPDE screening questionnaire, assessing the ten DSM-IV PDs, and the French-version of the NEO-PI-R, assessing the five domains and thirty facets of the FFM. Results: Correlations between PDs and the five domains of the FFM were similar in both samples. For example, Neuroticism was highly correlated with Borderline, Avoidant, and Dependent PDs in both Africa and Switzerland. The total rank-order correlation (rho) between the two correlation matrices was very high (rho = 0.93) and significant (P < 0.001), as were the rhos for all domains of the FFM and all PDs, except Paranoid and Dependent PDs. However, the rhos for PDs across facet-scales were all highly significant (P < 0.001). Moreover, 80% of Widiger and colleagues' predictions and 70 % of Lynam and Widiger's prototypes, concerning the relationship between PDs and the FFM, were confirmed in both samples. Conclusions: The relationship between PDs and the FFM was stable in two samples separated by a great cultural distance. These results suggest that a dimensional approach and in particular the FFM might be useful for describing PDs in a variety of cultural settings.

Antiretroviral therapy as a factor protective against anal dysplasia in HIV-infected males who have sex with males.

OBJECTIVES Chronic infection with oncogenic HPV genotype is associated with the development of anal dysplasia. Antiretroviral therapy (ART) has been shown to decrease the incidence of cervical carcinoma in women with HIV. We sought to: 1) describe the prevalence and grade of anal dysplasia and HPV infection in our study subjects; 2) analyze the grade of correlation between anal cytology, PCR of high-risk HPV, and histology; 3) identify the factors associated with the appearance of ≥ AIN2 lesions. DESIGN Cross-sectional, prospective study. METHODS A cohort of HIV-positive males (n = 140, mean age  = 37 years) who have sex with males (MSM) had epidemiological, clinical and analytical data collected. Anal mucosa samples were taken for cytology, HPV PCR genotyping, and anoscopy for histological analysis. RESULTS Within the cohort, 77.1% were being treated with ART, 8.5% anoscopy findings were AIN2, and 11.4% carcinoma in situ; 74.2% had high-risk (HR), 59.7% low-risk (LR) HPV genotypes and 46.8% had both. The combination of cytology with PCR identifying HR-HPV better predicts the histology findings than either of these factors alone. Logistic regression highlighted ART as a protective factor against ≥ AIN2 lesions (OR: 0.214; 95%CI: 0.054-0.84). Anal/genital condylomas (OR: 4.26; 95%CI: 1.27-14.3), and HPV68 genotype (OR: 10.6; 95%CI: 1.23-91.47) were identified as risk factors. CONCLUSIONS In our cohort, ART has a protective effect against dysplastic anal lesions. Anal/genital warts and HPV68 genotype are predictors of ≥ AIN2 lesions. Introducing PCR HPV genotype evaluation improves screening success over that of cytology alone.

Complement Factor B Polymorphism and the Phenotype of Early Age-related Macular Degeneration.

Abstract Purpose: Age-related macular degeneration (AMD) has been associated with a number of polymorphisms in genes in the complement pathway. We examined the potential genotype-phenotype correlation of complement factor B (CFB) (R32Q) polymorphisms in Caucasian patients with AMD. Methods: Data from a Central European cohort of 349 patients with early AMD in at least one eye were analyzed for potential associations of the CFB (R32Q/rs641153) polymorphism with phenotypic features of early AMD. Early AMD was classified according to the International Classification and Grading System into predominant drusen size, largest drusen, drusen covered surface, central or ring-like location, peripheral drusen, and pigmentary changes. The potential association with single nucleotide polymorphisms on CFB (R32Q/rs641153) was evaluated for all patients, corrected for age, sex, and the polymorphisms of CFH (Y402H) and ARMS2 (A69S). Results: CFB (R32Q) polymorphisms showed a significant association with smaller drusen size (largest drusen ≤250 µm, p = 0.021, predominant drusen ≤125 µm, p = 0.016), with smaller surface covered by drusen (≤10%; p = 0.02), and with more frequent occurrence of peripheral drusen (p = 0.007). No association was found for pigmentary changes. Conclusions: The CFB (R32Q) polymorphism was associated with AMD characterized by small drusen only, and appeared to be protective of large drusen (OR 0.48/0.45) and of larger drusen covered area (OR 0.34). Furthermore, peripheral drusen were more frequently found (OR 2.27). This result supports the role of complement components and their polymorphisms in drusen formation and may enable a better understanding of AMD pathogenesis.

Blood levels of brain-derived neurotrophic factor correlate with several psychopathological symptoms in anorexia nervosa patients

Background: Evidence of a role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of eating disorders (ED) has been provided by association studies and by murine models. BDNF plasma levels have been found altered in ED and in psychiatric disorders that show comorbidity with ED. Aims: Since the role of BDNF levels in ED-related psychopathological symptoms has not been tested, we investigatedthe correlation of BDNF plasma levels with the Symptom Checklist 90 Revised (SCL-90R) questionnaire in a total of 78 ED patients. Methods: BDNF levels, measured bythe enzyme-linked immunoassay system, and SCL-90R questionnaire, were assessed in a total of 78 ED patients. The relationship between BDNF levels and SCL-90R scales was calculated using a general linear model. Results: BDNF plasma levels correlated with the Global Severity Index and the Positive Symptom Distress Index global scales and five of the nine subscales in the anorexia nervosa patients. BDNF plasma levels were able to explain, in the case of the Psychoticism subscale, up to 17% of the variability (p = 0.006). Conclusion: Our data suggest that BDNF levels could be involved in the severity of the disease through the modulation of psychopathological traits that are associated with the ED phenotype.

Monitoring multiple angiogenesis-related molecules in the blood of cancer patients shows a correlation between VEGF-A and MMP-9 levels before treatment and divergent changes after surgical vs. conservative therapy.

Anti-angiogenic therapies are currently in cancer clinical trials, but to date there are no established tests for evaluating the angiogenic status of a patient. We measured 11 circulating angiogenesis-associated molecules in cancer patients before and after local treatment. The purpose of our study was to screen for possible relationships among the different molecules and between individual molecules and tumor burden. We measured VEGF-A, PlGF, SCF, MMP-9, EDB+ -fibronectin, sVEGFR-2, sVEGFR-1, salphaVbeta3, sTie-2, IL-8 and CRP in the blood of 22 healthy volunteers, 17 early breast, 17 early colorectal, and 8 advanced sarcoma/melanoma cancer patients. Breast cancer patients had elevated levels of VEGF-A and sTie-2, colorectal cancer patients of VEGF-A, MMP-9, sTie-2, IL-8 and CRP, and melanoma/sarcoma patients of sVEGFR-1. salphaVbeta3 was decreased in colorectal cancer patients. A correlation between VEGF-A and MMP-9 was found. After tumor removal, MMP-9 and salphaVbeta3 significantly decreased in breast and CRP in colorectal cancer, whereas sVEGFR-1 increased in colorectal cancer patients. In sarcoma/melanoma patients treated regionally with TNF and chemotherapy we observed a rise in VEGF-A, SCF, VEGFR-2, MMP-9, Tie-2 and CRP, a correlation between CRP and IL-8, and a decreased in sVEGFR-1 levels. In conclusion, among all factors measured, only VEGF-A and MMP-9 consistently correlated to each other, elevated CRP levels were associated with tumor burden, whereas sVEGF-R1 increased after tumor removal in colorectal cancer. Treatment with chemotherapy and TNF induced changes consistent with an angiogenic switch. These results warrant a prospective study to compare the effect of surgical tumor removal vs. chemotherapy on some of these markers and to evaluate their prognostic/predictive value.

Increased endometrial placenta growth factor (PLGF) gene expression in women with successful implantation.

Objective: To analyze the vascularization of the endometrium via hysteroscopy and to assess its correlation with angiogenic factor gene expression and embryo implantation rate.Design: Cross-sectional study.Setting: Public university hospital.Patient(s): Patients undergoing hysteroscopy for supposed infertility.Intervention(s): Endometrial quality assessment according to Sakumoto-Masamoto, performed in the early secretory phase of the cycle. Collection of an endometrial tissue biopsy.Main Outcome Measure(s): RNA extraction, reverse transcription, and determination of gene expression of angiogenesis- and implantation-relevant factors using quantitative polymerase chain reaction. Retrieval of pregnancy information from the medical records.Result(s): Good quantity/quality RNA with infertility history was obtained from 63 participating women. Those with a "good" endometrium and subsequent pregnancy showed increased gene expression for placenta growth factor when compared with patients with a "bad" endometrium and who did not succeed with pregnancy to date. Nonpregnant women with a "good" endometrium presented an intermediate result. No significant differences were observed for several other genes tested, but trends in the same direction were observed.Conclusion(s): This study demonstrates for the first time that endometrial PLGF expression corresponds to the hysteroscopic appearance of the endometrium, and therefore has potential as a clinically relevant prognosticator for infertility treatment success. (Fertil Steril (R) 2011;96:663-8. (C)2011 by American Society for Reproductive Medicine.)

ZNRD1 (zinc ribbon domain-containing 1) is a host cellular factor that influences HIV-1 replication and disease progression.

BACKGROUND: Human immunodeficiency virus (HIV) takes advantage of multiple host proteins to support its own replication. The gene ZNRD1 (zinc ribbon domain-containing 1) has been identified as encoding a potential host factor that influenced disease progression in HIV-positive individuals in a genomewide association study and also significantly affected HIV replication in a large-scale in vitro short interfering RNA (siRNA) screen. Genes and polymorphisms identified by large-scale analysis need to be followed up by means of functional assays and resequencing efforts to more precisely map causal genes. METHODS: Genotyping and ZNRD1 gene resequencing for 208 HIV-positive subjects (119 who experienced long-term nonprogression [LTNP] and 89 who experienced normal disease progression) was done by either TaqMan genotyping assays or direct sequencing. Genetic association analysis was performed with the SNPassoc package and Haploview software. siRNA and short hairpin RNA (shRNA) specifically targeting ZNRD1 were used to transiently or stably down-regulate ZNRD1 expression in both lymphoid and nonlymphoid cells. Cells were infected with X4 and R5 HIV strains, and efficiency of infection was assessed by reporter gene assay or p24 assay. RESULTS: Genetic association analysis found a strong statistically significant correlation with the LTNP phenotype (single-nucleotide polymorphism rs1048412; [Formula: see text]), independently of HLA-A10 influence. siRNA-based functional analysis showed that ZNRD1 down-regulation by siRNA or shRNA impaired HIV-1 replication at the transcription level in both lymphoid and nonlymphoid cells. CONCLUSION: Genetic association analysis unequivocally identified ZNRD1 as an independent marker of LTNP to AIDS. Moreover, in vitro experiments pointed to viral transcription as the inhibited step. Thus, our data strongly suggest that ZNRD1 is a host cellular factor that influences HIV-1 replication and disease progression in HIV-positive individuals.

Expression of the proto-oncogene c-fos in three-dimensional fetal brain cell cultures and the lack of correlation with maturation-inducing stimuli.

Previous work has shown that aggregating fetal brain cell cultures are able to attain a highly differentiated state, and that their development is greatly enhanced by growth and/or differentiation factors such as epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and the protein kinase C-activating tumor promoter mezerein. The present study shows that in these 3-dimensional cultures the peptide growth factors EGF and bFGF as well as mezerein are able to induce the expression of the proto-oncogene c-fos. This induction was rapid and transient, in good agreement with observations reported from a wide variety of cell types in vitro. The maximal levels of c-fos mRNA found after stimulation were low in immature cultures and increased greatly as maturation progressed. Of the three factors tested, mezerein was the most potent inducer of c-fos. In contrast to the peptide growth factors EGF and bFGF which were found to induce c-fos only in glial cells, mezerein was stimulatory in glial cells as well as in neurons. A similar cell type specificity has been observed previously for the maturation-enhancing response in immature aggregate cultures. However, in the present study no correlation was found between the degree of c-fos induction and the extent of the maturation-enhancing stimulation. Immature cultures known to be most sensitive and responsive to these maturation-enhancing agents required relatively high doses of peptide growth factors for the induction of c-fos, and the maximal levels of c-fos mRNA elicited were much lower than those in differentiated cultures which did not show any long-term response to these stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

hMMP9 as predictive factor for response and progression free survival in breast cancer patients treated with bevacizumab and pegylated liposomal doxorubicin (PLD)

Background: The anti-angiogenic drug, bevacizumab (Bv), is currently used in the treatment of different malignancies including breast cancer. Many angiogenesis-associated molecules are found in the circulation of cancer patients. Until now, there are no prognostic or predictive factors identified in breast cancer patients treated with Bv. We present here the first results of the prospective monitoring of 6 angiogenesis-related molecules in the peripheral blood of breast cancer patients treated with a combination of Bv and PLD in the phase II trial, SAKK 24/06. Methods: Patients were treated with PLD (20 mg/m2) and Bv (10 mg/kg) on days 1 and 15 of each 4-week cycle for a maximum of 6 cycles, followed by Bv monotherapy maintenance (10 mg/m2 q2 weeks) until progression or severe toxicity. Plasma and serum samples were collected at baseline, after 2 months of therapy, then every 3 months and at treatment discontinuation. Enzyme-linked immunosorbent assays (Quantikine, R&D Systems and Reliatech) were used to measure the expression levels of human vascular endothelial growth factor (hVEGF), placental growth factor (hPlGF), matrix metalloproteinase 9 (hMMP9) and soluble VEGF receptors hsVEGFR-1, hsVEGFR-2 and hsVEGFR-3. The log-transformed data (to reduce the skewness) for each marker was analyzed using an analysis of variance (ANOVA) model to determine if there was a difference between the mean of the subgroups of interest (where α = 0.05). The untransformed data was also analyzed in the same manner as a "sensitivity" check. Results: 132 blood samples were collected in 41 out of 43 enrolled patients. Baseline levels of the molecules were compared to disease status according to RECIST. There was a statistically significant difference in the mean of the log-transformed levels of hMMP9 between responders [CR+PR] versus the mean in patients with PD (p-value=0.0004, log fold change=0.7536), and between patients with disease control [CR+PR+SD] and those with PD (p-value=<0.0001, log fold change=0.81559), with the log-transformed level of hMMP9 being higher for the responder group. The mean of the log-transformed levels of hsVEGFR-1 was statistically significantly different between patients with disease control [CR+PR+SD] and those with PD (p-value=0.0068, log fold change=-0.6089), where the log-transformed level of hsVEGFR-1 was lower for the responder group. The log-transformed level of hMMP9 at baseline was identified as a significant prognostic factor in terms of progression free survival (PFS): p-value=0.0417, hazard ratio (HR)=0.574 with a corresponding 95% confidence interval (0.336 - 0.979)). No strong correlation was shown either between the log-transformed levels of hsVEGF, hPlGF, hsVEGFR-2 or hsVEGFR-3 and clinical response or the occurrence of severe toxicity, or between the levels of the different molecules. Conclusions: Our results suggest that baseline plasma level of the matrix metalloproteinase, hMMP9, could predict tumor response and PFS in patients treated with a combination of Bv and PLD. These data justify further investigation in breast cancer patients treated with anti-angiogenic therapy.

Interleukin-1 receptor antagonist gene (IL-1RN) polymorphism is a predictive factor of clinical pregnancy after IVF.

BACKGROUND: Only 25% of IVF transfer cycles lead to a clinical pregnancy, calling for continued technical progress but also more in depth analysis of patients' individual characteristics. The interleukin-1 (IL-1) system and matrix metalloproteinases (MMPs) are strongly implicated in embryo implantation. The genes coding for IL-1Ra (gene symbol IL-1RN), IL-1beta, MMP2 and MMP9 bear functional polymorphisms. We analysed the maternal genetic profile at these polymorphic sites in IVF patients, to determine possible correlations with IVF outcome. METHODS: One hundred and sixty women undergoing an IVF cycle were enrolled and a buccal smear was obtained. The presence of IL-1RN variable number of tandem repeats and IL-1B + 3953, MMP2-1306 and MMP9-1562 single nucleotide substitutions were determined. Patients were divided into pregnancy failures (119), biochemical pregnancies (8) and clinical pregnancies (33). RESULTS: There was a 40% decrease in IL-1RN*2 allele frequency (P = 0.024) and a 45% decrease in IL-1RN*2 carrier status in the clinical pregnancy group as compared to the pregnancy failure group (P = 0.017). This decrease was still statistically significant after a multivariate logistic regression analysis. The likelihood of a clinical pregnancy was decreased accordingly in IL-1RN*2 carriers: odds ratio = 0.349, 95% confidence interval = 0.2-0.8, P = 0.017. The IL-1B, MMP2 and MMP9 polymorphisms showed no correlation with IVF outcome. CONCLUSIONS: IL-1RN*2 allele carriage is associated with a poor prognosis of achieving a pregnancy after IVF.

Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH).

FGFR1 mutations have been identified in both Kallmann syndrome and normosmic HH (nIHH). To date, few mutations in the FGFR1 gene have been structurally or functionally characterized in vitro to identify molecular mechanisms that contribute to the disease pathogenesis. We attempted to define the in vitro functionality of two FGFR1 mutants (R254W and R254Q), resulting from two different amino acid substitutions of the same residue, and to correlate the in vitro findings to the patient phenotypes. Two unrelated GnRH deficient probands were found to harbor mutations in FGFR1 (R254W and R254Q). Mutant signaling activity and expression levels were evaluated in vitro and compared to a wild type (WT) receptor. Signaling activity was determined by a FGF2/FGFR1 dependent transcription reporter assay. Receptor total expression levels were assessed by Western blot and cell surface expression was measured by a radiolabeled antibody binding assay. The R254W maximal receptor signaling capacity was reduced by 45% (p<0.01) while R254Q activity was not different from WT. However, both mutants displayed diminished total protein expression levels (40 and 30% reduction relative to WT, respectively), while protein maturation was unaffected. Accordingly, cell surface expression levels of the mutant receptors were also significantly reduced (35% p<0.01 and 15% p<0.05, respectively). The p.R254W and p.R254Q are both loss-of-function mutations as demonstrated by their reduced overall and cell surface expression levels suggesting a deleterious effect on receptor folding and stability. It appears that a tryptophan substitution at R254 is more disruptive to receptor structure than the more conserved glutamine substitution. No clear correlation between the severity of in vitro loss-of-function and phenotypic presentation could be assigned.

Stress intensity factor of wood from crack-tip displacement fields obtained from digital image processing

Abstract

Immunohistochemistry as a valuable tool to assess CD30 expression in peripheral T-cell lymphomas: high correlation with mRNA levels.

The extended use of brentuximab-vedotin was reported for CD30(+) nonanaplastic peripheral T-cell lymphomas (PTCLs) with promising efficacy. CD30 status assessment is thus a critical factor for therapeutic decision, but the reliability of immunohistochemistry (IHC) in evaluating its expression remains to be defined. This prompted us to investigate the correlation between semiquantitative CD30 protein assessment by IHC and messenger RNA (mRNA) assessment by microarrays in a cohort of 376 noncutaneous PTCLs representative of the main entities. By IHC, CD30 expression was heterogeneous across and within entities and significantly associated with large tumor cell size. In addition to 100% anaplastic large-cell lymphomas, 57% of other PTCL entities were CD30-positive at a 5% threshold. CD30 protein expression was highly correlated to mRNA levels. mRNA levels were bimodal, separating high from low CD30-expressing PTCL cases. We conclude that IHC is a valuable tool in clinical practice to assess CD30 expression in PTCLs.