American Football On-Field Head Impact Kinematics: Influence of Acceleration Signal Characteristics on Peak Maximal Principal Strain.

Recorded head kinematics from head-impact measurement devices (HIMd) are pivotal for evaluating brain stress and strain through head finite element models (hFEM). The variability in kinematic recording windows across HIMd presents challenges as they yield inconsistent hFEM responses. Despite establishing an ideal recording window for maximum principal strain (MPS) in brain tissue, uncertainties persist about the impact characteristics influencing vulnerability when this window is shortened. This study aimed to scrutinize factors within impact kinematics affecting the reliability of different recording windows on whole-brain peak MPS using a validated hFEM. Utilizing 53 on-field head impacts recorded via an instrumented mouthguard during a Canadian varsity football game, 10 recording windows were investigated with varying pre- and post-impact-trigger durations. Tukey pair-wise comparisons revealed no statistically significant differences in MPS responses for the different recording windows. However, specific impacts showed marked variability up to 40%. It was found, through correlation analyses, that impacts with lower peak linear acceleration exhibited greater response variability across different pre-trigger durations. Signal shape, analyzed through spectral analysis, influenced the time required for MPS development, resulting in specific impacts requiring a prolonged post-trigger duration. This study adds to the existing consensus on standardizing HIMd acquisition time windows and sheds light on impact characteristics leading to peak MPS variation across different head impact kinematic recording windows. Considering impact characteristics in research assessments is crucial, as certain impacts, affected by recording duration, may lead to significant errors in peak MPS responses during cumulative longitudinal exposure assessments.

DNA methylation variations at CETP and LPL gene promoter loci: new molecular biomarkers associated with blood lipid profile variability.

BACKGROUND: Recent findings suggest that DNA methylation, a well-known epigenetic mechanism, is involved in high-density lipoprotein cholesterol (HDL-C) metabolism and increased cardiovascular disease risk. The aim of this study was thus to assess whether DNA methylation within key genes of lipoprotein metabolism is associated with blood lipid profile variability. METHODS AND RESULTS: Ninety-eight untreated familial hypercholesterolaemia patients (61 men and 37 women) were recruited for leucocyte DNA methylation analyses at the LDLR, CETP, LCAT and LPL gene promoter loci using bisulfite pyrosequencing. LPL DNA methylation was correlated with HDL-C (r = 0.22; p = 0.031) and HDL particle size (r = 0.47, p = 0.013). In both sex, CETP DNA methylation was negatively associated with low-density lipoprotein cholesterol levels (r < -0.32; p < 0.05). In men, CETP DNA methylation was associated with HDL-C (r = -0.36; p = 0.006), HDL-triglyceride levels (r = 0.59; p < 0.001) and HDL particle size (r = -0.44, p = 0.019). In visceral adipose tissue from 30 men with severe obesity, the associations between LPL DNA methylation, HDL-C (r = -0.40; p = 0.03) and LPL mRNA levels (r = -0.61, p < 0.001) were confirmed. CONCLUSION: CETP and LPL DNA methylation levels are associated with blood lipid profile, suggesting that further studies of epipolymorphisms should most certainly contribute to a better understanding of the molecular bases of dyslipidemia.

The g.-469G>A polymorphism in the GPIHBP1 gene promoter is associated with hypertriglyceridemia and has an additive effect on the risk conferred by LPL defective alleles.

BACKGROUND AND AIMS: Hypertriglyceridemia (hyperTG) is a component of the metabolic syndrome and a cardiovascular or pancreatitis risk factor. Although both genetic and environmental factors influence its expression, the biological component of hyperTG is still underestimated and has been reported in 10-20% of cases only. Given its key role in the lipolysis of TG-rich lipoproteins, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) is a biological candidate for hyperTG. The aim of this study was to assess the association of new GPIHBP1 gene variants with hyperTG (fasting plasma TG values ≥ 2.0 mmol/L). METHODS AND RESULTS: Sequencing the GPIHBP1 gene identified a g.-469G > A (rs72691625) polymorphism in the promoter. A sample of 541 Caucasians (263 normoTG and 278 hyperTG) was then screened for this polymorphism using a 5'nuclease TaqMan. In multivariate analyses, GPIHBP1 g.-469G > A polymorphism carriers were at significantly higher risk of hyperTG (≥ 2.0 mmol/L) than non-carriers, the odds ratio (OR) being 1.67 (p = 0.025) among heterozygotes and 5.70 (p = 0.004) in homozygotes. The simultaneous presence of loss-of-function LPL polymorphisms had an incremental additive effect on the risk of hyperTG (OR: 7.30; p < 0.001), highlighting the importance of gene-gene interactions in the expression of hyperTG. CONCLUSIONS: In this study, the g.-469G >A polymorphism in the GPIHBP1 gene promoter was associated with an increased risk of hyperTG and had an additive effect on the risk conferred by LPL defective alleles.

Stable inhibition of interleukin 1 receptor type II in Ishikawa cells augments secretion of matrix metalloproteinases: possible role in endometriosis pathophysiology.

Our previous studies showed a marked deficiency in interleukin 1 receptor type II (IL1R2) in the endometrial tissue of women with endometriosis, particularly in epithelial cells. We believe that such a deficiency in IL1R2, a potent and specific IL1 inhibitor, makes endometrial cells more sensitive to IL1 and less capable of buffering the cytokine's effects, which may lead to functional changes that favor endometriosis development. The main objective of our study was to stably inhibit IL1R2 expression in endometrial cells in order to evaluate the role of IL1R2 deficiency in endometriosis pathophysiology. Stable clones of Ishikawa adenocarcinoma endometrial cells transfected with IL1R2 antisense and showing downregulation of IL1R2 protein expression, or with the empty expression vector alone and showing no noticeable difference in IL1R2 expression, were selected. The downregulation of IL1R2 expression in IL1R2 antisense transfectants when compared with control cells was confirmed by ELISA, Western blot and immunofluorescence. In these cells, IL1R2 expression was markedly reduced, compared with non-transfected cells or cells transfected with the empty vector, and there was a significant increase in the basal and the IL1-beta (IL1B)-induced levels of matrix metalloproteinase (MMP)-2 and MMP-9 secretion. Furthermore, a significant decrease in IL1B-induced secretion of tissue inhibitor of MMPs-1, a known MMP-9 inhibitor, was observed. These in vitro data make plausible a role for IL1R2 deficiency in the capability of endometrial cells to invade the host tissue and develop in ectopic locations.

Cognitive behaviour therapy and medication in the treatment of obsessive-compulsive disorder.

OBJECTIVE: To compare cognitive behaviour therapy (CBT) with CBT plus medication; medication alone; and placebo in the treatment of adult obsessive-compulsive disorder (OCD). METHOD: Forty-eight participants (43 completers) were recruited into two protocols. In the first protocol, 21 people with OCD were randomly allocated to either a standard medication (fluvoxamine) or standard placebo condition for a 5-month period. Both these groups subsequently received CBT for a further 5 months. In the second protocol, 22 people with OCD received CBT, one group was already stabilized on an antidepressant of choice; the second group was drug naïve. RESULTS: All active treatments, but not the placebo, showed clinical improvement. There was no difference in treatment response to CBT regardless of whether participants had previously received medication or placebo. CONCLUSION: CBT has a more specific antiobsessional effect than medication but CBT plus medication shows greatest overall clinical improvement in mood.

Evaluation of an inference-based approach to treating obsessive-compulsive disorder.

This study evaluated an inference-based approach (IBA) to the treatment of obsessive-compulsive disorder (OCD) by comparing its efficacy with a treatment based on the cognitive appraisal model (CAM) and exposure and response prevention (ERP). IBA considers initial intrusions in OCD (e.g. "Maybe the door is open", "My hands could be dirty") as idiosyncratic inferences about possible states of affairs arrived at through inductive reasoning. In IBA such primary inferences represent the starting point of obsessional doubt, and the reasoning maintaining the doubt forms the focus for therapy. This is unlike CAM, which regards appraisals of intrusions as the maintaining factors in OCD. Fifty-four OCD participants, of whom 44 completed, were randomly allocated to CAM, ERP or IBA. After 20 weeks of treatment all groups showed a significant reduction in scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Padua Inventory. Participants with high levels of obsessional conviction showed greater benefit from IBA than CAM. Appraisals of intrusions changed in all treatment conditions. Strength of primary inference was not correlated with symptom measures except in the case of strong obsessional conviction. Strength of primary inference correlated significantly with the Y-BOCS insight item. Treatment matching for high and low conviction levels to IBA and CAM, respectively, may optimize therapy outcome.

Cycle-dependent expression of macrophage migration inhibitory factor in the human endometrium.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that was shown to promote angiogenesis and tissue remodelling. Our previous studies identified MIF as one of the principal bioactive molecules involved in endothelial cell proliferation released by ectopic endometrial cells. METHODS AND RESULTS: In the present study, we examined the expression of MIF in the human endometrium and found an interesting distribution and temporal pattern of expression throughout the menstrual cycle. Immunoreactive MIF was predominant in the glands and surface epithelium. Dual immunofluorescence analysis further identified endothelial cells, macrophages and T-lymphocytes as cells markedly expressing MIF in the stroma. Quantitative assessment of MIF protein showed a regulated cycle phase-dependent expression pattern. MIF expression increased in the late proliferative/early Secretory phase of the menstrual cycle was moderate during the receptive phase or what is commonly called the implantation window before increasing again at the end of the cycle. This pattern paralleled MIF mRNA expression determined by northern blot. CONCLUSION: The cycle phase-specific expression of MIF suggests a tight regulation and perhaps different roles for this factor in the reparative, reproductive and inflammatory-like processes that occur in human endometrium during every menstrual cycle.

Preparation and biological activities of potential vasopressin photoaffinity labels.

Several potential photoaffinity analogues of the peptide hormone vasopressin (VP) were prepared by classical solid-phase peptide synthesis using two different pathways. Peptide sequences were built by introduction of (a) Nar-protected aminophenylalanine or (b) nitrophenylalanine in the photolabeling position. Conversion to the azido peptide was completed in pathway a after cleavage and before purification and in pathway b from small quantities of purified nitrophenylalanine-containing precursor peptides. V1 receptor binding properties were measured using membranes prepared from rat liver cells. The binding potential of agonistic VP structures was abolished by the introduction of an azido or a nitro group into the aromatic side chain at position 3. Cyclo desamino-beta,beta-dialkyl-Cys1-type VP antagonist structures were prepared with the photoactivable moiety in position 2 and an iodination residue in position 9. One particular compound, [Dmpa1, Phe(N3)2, Val4, Lys8,D-Tyr9]VP (8), containing beta,beta-dimethyl-beta-mercaptopropionic acid in position 1, had excellent binding properties, both in the radioiodinated (Kd = 4.8 +/- 1.9 x 10(-10) M) and noniodinated form (Kd = 6.4 +/- 0.98 x 10(-10) M). The analogues with long-chain beta-alkylation (diethyl and pentamethylene) and the linear antagonist photolabel showed significantly less affinity. Optimal binding properties were obtained within a very narrow range of hydrophobicity; greater or lesser hydrophobicity was correlated to less potent binding. The precursor analogues, containing nitrophenylalanine, displayed a structure-activity relationship similar to that of the azido peptides. The most potent analogues will be used for receptor labeling studies. A linear antagonist structure having a photosensitive group in position 1, has also been prepared, but this compound displayed much less affinity than the cyclic antagonists. The most potent compounds were also highly selective for the V1 receptor and did not recognize the V2 receptor from other preparations.

Fluorescent peptide hormones: development of high affinity vasopressin analogues.

Highly potent and specific peptide hormone analogues with fluorescent reporter groups are current research goals. Until now, however, only moderately potent analogues have been described. We report here several types of vasopressin (VP) analogues with different fluorophores attached to the peptide. In a first series, fluorophores were attached to the free epsilon amino function of [des-amino1-lysine8]VP (dLVP), producing agonistic analogues. In a second series, reporter groups were added to the N-terminal of open-chain antagonist structures. The biological activities of these analogues were assessed by two different sets of experiments: 1) The measurement of their binding affinities towards the V1a-vasopressin receptor subtype from WRK1 cells or rat liver membrane preparations; 2) Their ability to stimulate the phospholipase C activity in WRK1 cells. As expected, a simple acylation of fluorophores to dLVP resulted in a considerable loss of affinity. If however, the Lys8 side chain was extended through double Schiff-base formation with glutaraldehyde-ethylenediamine followed by reduction to an aminoalkyl aminoalkylamine, single fluorophores could be added without loss of affinity compared to VP. The open-chain analogues, on the other hand, while displaying weak affinity, nevertheless exhibited pure antagonistic behavior.