Translating molecular medicine into clinical tools: doomed to fail by neglecting basic preanalytical principles

This commentary discusses a study on measurements of matrix metalloproteinase 9 (MMP-9) in serum of pseudoxanthoma elasticum patients recently published in Journal of Molecular Medicine. This study can be considered the typical "obstacle" to effective translational medicine as previously documented in JTM journal. Although serum has been frequently proven as inappropriate sample for determining numerous circulating MMPs, among them MMP-9, there are over and over again studies, as in this case, that measure MMP-9 in serum. Comparative measurements in serum and plasma samples demonstrated higher concentrations for MMP-9 in serum due to the additional release from leukocytes and platelets following the coagulation/fibrinolysis process. From this example it can be concluded that translating basic research discoveries into clinical tools needs a more intensive exchange between basic biomedical research and clinical scientists already in an early stage. Otherwise a lost of translation, as discussed in JTM journal, seems to be inevitable

Male urine signals social rank in the Mozambique tilapia (Oreochromis mossambicus)

<p>Abstract</p> <p>Background</p> <p>The urine of freshwater fish species investigated so far acts as a vehicle for reproductive pheromones affecting the behaviour and physiology of the opposite sex. However, the role of urinary pheromones in intra-sexual competition has received less attention. This is particularly relevant in lek-breeding species, such as the Mozambique tilapia (<it>Oreochromis mossambicus</it>), where males establish dominance hierarchies and there is the possibility for chemical communication in the modulation of aggression among males. To investigate whether males use urine during aggressive interactions, we measured urination frequency of dye-injected males during paired interactions between size-matched males. Furthermore, we assessed urinary volume stored in the bladder of males in a stable social hierarchy and the olfactory potency of their urine by recording of the electro-olfactogram.</p> <p>Results</p> <p>Males released urine in pulses of short duration (about one second) and markedly increased urination frequency during aggressive behaviour, but did not release urine whilst submissive. In the stable hierarchy, subordinate males stored less urine than males of higher social rank; the olfactory potency of the urine was positively correlated with the rank of the male donor.</p> <p>Conclusion</p> <p>Dominant males store urine and use it as a vehicle for odorants actively released during aggressive disputes. The olfactory potency of the urine is positively correlated with the social status of the male. We suggest that males actively advertise their dominant status through urinary odorants which may act as a 'dominance' pheromone to modulate aggression in rivals, thereby contributing to social stability within the lek.</p

Human Stiff-Person Syndrome IgG Induces Anxious Behavior in Rats

Background: Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior can occur in a variety of diseases. Stiff person syndrome (SPS) is a CNS disorder characterized by increased muscle tone and prominent agoraphobia and anxiety. Most patients have high-titer antibodies against glutamate decarboxylase (GAD) 65. The pathogenic role of these autoantibodies is unclear. Methodology/Principal Findings: We re-investigated a 53 year old woman with SPS and profound anxiety for GABA-A receptor binding in the amygdala with (11)C-flumazenil PET scan and studied the potential pathogenic role of purified IgG from her plasma filtrates containing high-titer antibodies against GAD 65. We passively transferred the IgG fraction intrathecally into rats and analyzed the effects using behavioral and in vivo electrophysiological methods. In cell culture, we measured the effect of patient IgG on GABA release from hippocampal neurons. Repetitive intrathecal application of purified patient IgG in rats resulted in an anxious phenotype resembling the core symptoms of the patient. Patient IgG selectively bound to rat amygdala, hippocampus, and frontal cortical areas. In cultured rat hippocampal neurons, patient IgG inhibited GABA release. In line with these experimental results, the GABA-A receptor binding potential was reduced in the patient’s amygdala/hippocampus complex. No motor abnormalities were found in recipient rats. Conclusion/Significance: The observations in rats after passive transfer lead us to propose that anxiety-like behavior can be induced in rats by passive transfer of IgG from a SPS patient positive for anti-GAD 65 antibodies. Anxiety, in this case, thus may be an antibody-mediated phenomenon with consecutive disturbance of GABAergic signaling in the amygdala region

Circulating Matrix Metalloproteinase-9 Is Associated with Cardiovascular Risk Factors in a Middle-Aged Normal Population

Background: Elevated levels of circulating matrix metalloproteinase-9 (MMP-9) have been demonstrated in patients with established coronary artery disease (CAD). The aim of this study was to analyse levels of MMP-9 in a population free from symptomatic CAD and investigate their associations with cardiovascular (CV) risk factors, including C-reactive protein (CRP).   Methods: A cross-sectional study was performed in a population based random sample aged 45–69 (n = 345, 50% women). MMP-9 levels were measured in EDTA-plasma using an ELISA-method. CV risk factors were measured using questionnaires and standard laboratory methods. Results: Plasma MMP-9 was detectable in all participants, mean 38.9 ng/mL (SD 22.1 ng/mL). Among individuals without reported symptomatic CAD a positive association (p&lt;0.001) was seen, for both men and women, of MMP-9 levels regarding total risk load of eight CV risk factors i.e. blood pressure, dyslipidemia, diabetes, obesity, smoking, alcohol intake, physical activity and fruit and vegetable intake. The association was significant also after adjustment for CRP, and was not driven by a single risk factor alone. In regression models adjusted for age, sex, smoking, alcohol intake and CRP, elevated MMP-9 levels were independently positively associated with systolic blood pressure (p = 0.037), smoking (p&lt;0.001), alcohol intake (p = 0.003) and CRP (p&lt;0.001). The correlation coefficient between MMP-9 and CRP was r = 0.24 (p&lt;0.001).   Conclusions: In a population without reported symptomatic CAD, MMP-9 levels were associated with total CV risk load as well as with single risk factors. This was found also after adjustment for CRP  Original Publication: Peter Garvin, Lennart Nilsson, John Carstensen, Lena Jonasson and Margareta Kristenson, Circulating Matrix Metalloproteinase-9 Is Associated with Cardiovascular Risk Factors in a Middle-Aged Normal Population, 2008, PLoS ONE, (3), 3, e1774. http://dx.doi.org/10.1371/journal.pone.0001774 Licensee: Public Library of Science (PLoS) http://www.plos.org/</p

A Late Role for bmp2b in the Morphogenesis of Semicircular Canal Ducts in the Zebrafish Inner Ear

BACKGROUND:The Bone Morphogenetic Protein (BMP) genes bmp2 and bmp4 are expressed in highly conserved patterns in the developing vertebrate inner ear. It has, however, proved difficult to elucidate the function of BMPs during ear development as mutations in these genes cause early embryonic lethality. Previous studies using conditional approaches in mouse and chicken have shown that Bmp4 has a role in semicircular canal and crista development, but there is currently no direct evidence for the role of Bmp2 in the developing inner ear. METHODOLOGY/PRINCIPAL FINDINGS:We have used an RNA rescue strategy to test the role of bmp2b in the zebrafish inner ear directly. Injection of bmp2b or smad5 mRNA into homozygous mutant swirl (bmp2b(-/-)) embryos rescues the early patterning defects in these mutants and the fish survive to adulthood. As injected RNA will only last, at most, for the first few days of embryogenesis, all later development occurs in the absence of bmp2b function. Although rescued swirl adult fish are viable, they have balance defects suggestive of vestibular dysfunction. Analysis of the inner ears of these fish reveals a total absence of semicircular canal ducts, structures involved in the detection of angular motion. All other regions of the ear, including the ampullae and cristae, are present and appear normal. Early stages of otic development in rescued swirl embryos are also normal. CONCLUSIONS/SIGNIFICANCE:Our findings demonstrate a critical late role for bmp2b in the morphogenesis of semicircular canals in the zebrafish inner ear. This is the first demonstration of a developmental role for any gene during post-embryonic stages of otic morphogenesis in the zebrafish. Despite differences in the early stages of semicircular canal formation between zebrafish and amniotes, the role of Bmp2 in semicircular canal duct outgrowth is likely to be conserved between different vertebrate species

Salespeople’s Renqing Orientation, Self-esteem, and Selling Behaviors: An Empirical Study in Taiwan

The purpose of this study was to investigate how salespeople’s renqing orientation and self-esteem jointly affect their selling behavior. Data were obtained from a survey of salespeople from 17 pharmaceutical and consumer-goods companies in Taiwan (n = 216). Salespeople’s renqing orientation (i.e., their propensity to adhere to the accepted norm of reciprocity) compensates the negative effect of self-esteem on their selling behaviors, such as adaptive selling and hard work. Our study results underscore the critical role of the character trait of renqing orientation in a culture emphasizing a norm of reciprocity. Therefore, it would be useful to consider a strategy of recruiting salespeople with either a high self-esteem or a combination of high renqing orientation and low self-esteem. The existing literature of industrial/organizational psychology and marketing primarily relies on constructs that are derived from Western cultural contexts. However, the present paper extended these literatures by investigating the possible joint effects of self-esteem with a trait originated from the Chinese culture on salespeople’s selling behaviors

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Increased Levels of Leukocyte-Derived MMP-9 in Patients with Stable Angina Pectoris

Objective: There is a growing interest for matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in plasma as novel biomarkers in coronary artery disease (CAD). We aimed to identify the sources of MMP-8, MMP-9, TIMP-1 and TIMP-2 among peripheral blood cells and further explore whether gene expression or protein release was altered in patients with stable angina pectoris (SA). Methods: In total, plasma MMP-9 was measured in 44 SA patients and 47 healthy controls. From 10 patients and 10 controls, peripheral blood mononuclear cells (PBMC) and neutrophils were isolated and stimulated ex vivo. MMPs, TIMPs and myeloperoxidase were measured in plasma and supernatants by ELISA. The corresponding gene expression was measured by real-time PCR. Results: Neutrophils were the dominant source of MMP-8 and MMP-9. Upon moderate stimulation with IL-8, the neutrophil release of MMP-9 was higher in the SA patients compared with controls (p,0.05). In PBMC, the TIMP-1 and MMP-9 mRNA expression was higher in SA patients compared with controls, p,0.01 and 0.05, respectively. There were no differences in plasma levels between patients and controls except for TIMP-2, which was lower in patients, p,0.01. Conclusion: Measurements of MMPs and TIMPs in plasma may be of limited use. Despite similar plasma levels in SA patients and controls, the leukocyte-derived MMP-9 and TIMP-1 are significantly altered in patients. The findings indicate that th