The role of inflammation in the association between overall and visceral adiposity and subclinical atherosclerosis.

BACKGROUND AND AIMS: Inflammation may underlie the association between obesity, atherosclerosis and cardiovascular disease. We investigated to what extent markers of inflammation mediate associations between overall and visceral body fat and subclinical atherosclerosis. METHODS AND RESULTS: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study we estimated total body fat (TBF) by bio-impedance analysis, carotid artery intima media thickness (cIMT) by ultrasound, C-reactive protein (hs-CRP) and glycoprotein acetyls (GlycA) concentrations in fasting blood samples (n = 5627), and visceral adipose tissue (VAT) by magnetic resonance imaging (n = 2247). We examined associations between TBF and VAT, and cIMT using linear regression, adjusted for potential confounding factors, and for mediators: cardiometabolic risk factors (blood pressure, glucose and low-density lipoprotein cholesterol), and inflammation using CRP and GlycA as proxies. Mean (SD) cIMT was 615 (90) µm. Per SD of TBF (8%), cIMT was 19 µm larger (95% confidence interval, CI: 10, 28). This association was 17 µm (95% CI: 8, 27) after adjustment for cardiometabolic risk factors, and did not change after adjustment for markers of inflammation. Per SD (56 cm2) VAT, cIMT was 9 µm larger (95% CI: 2, 16) which changed to 5 µm (95% CI: -3, 12) after adjustment for cardiometabolic risk factors, and did not change after adjustment for inflammatory markers. CONCLUSION: Our results suggest that associations between measures of overall and visceral body fat and subclinical atherosclerosis are not mediated by inflammation as measured by CRP and GlycA. Obesity may exert cardiovascular risk via other markers of systemic inflammation.

High trait shame undermines the protective effects of prevalence knowledge on state shame following HPV/CIN diagnosis in women.

Human papillomavirus (HPV), and the related, cervical intraepithelial neoplasia (CIN), are common yet poorly understood physical conditions. The diagnosis of HPV often elicits shame and guilt, which in turn may undermine psychological and physical health. The current study compared shame and guilt responses to diagnosis among two groups: women diagnosed with HPV/CIN and women diagnosed with Epstein-Barr Virus (EBV/IM). Eighty women recently diagnosed with HPV/CIN or EBV/IM completed measures of shame- and guilt-proneness, shame and guilt following diagnosis, and disease knowledge including prevalence estimates (HPV and EBV, respectively). HPV/CIN (vs. EBV/IM) predicted more diagnosis-related shame and guilt. Estimates of high prevalence interacted with diagnosis and shame-proneness to predict diagnosis-related shame. Simple slope analyses indicated that in women with HPV/CIN reporting low-to-average shame-proneness, high prevalence estimates reduced diagnosis-related shame; however, women high in shame-proneness experienced high diagnosis-related shame regardless of more accurate prevalence estimates. Women high in shame-proneness appear to be particularly vulnerable to HPV-related shame even when they are aware that it is very common.

MR vascular fingerprinting: A new approach to compute cerebral blood volume, mean vessel radius, and oxygenation maps in the human brain.

In the present study, we describe a fingerprinting approach to analyze the time evolution of the MR signal and retrieve quantitative information about the microvascular network. We used a Gradient Echo Sampling of the Free Induction Decay and Spin Echo (GESFIDE) sequence and defined a fingerprint as the ratio of signals acquired pre- and post-injection of an iron-based contrast agent. We then simulated the same experiment with an advanced numerical tool that takes a virtual voxel containing blood vessels as input, then computes microscopic magnetic fields and water diffusion effects, and eventually derives the expected MR signal evolution. The parameter inputs of the simulations (cerebral blood volume [CBV], mean vessel radius [R], and blood oxygen saturation [SO2]) were varied to obtain a dictionary of all possible signal evolutions. The best fit between the observed fingerprint and the dictionary was then determined by using least square minimization. This approach was evaluated in 5 normal subjects and the results were compared to those obtained by using more conventional MR methods, steady-state contrast imaging for CBV and R and a global measure of oxygenation obtained from the superior sagittal sinus for SO2. The fingerprinting method enabled the creation of high-resolution parametric maps of the microvascular network showing expected contrast and fine details. Numerical values in gray matter (CBV=3.1±0.7%, R=12.6±2.4µm, SO2=59.5±4.7%) are consistent with literature reports and correlated with conventional MR approaches. SO2 values in white matter (53.0±4.0%) were slightly lower than expected. Numerous improvements can easily be made and the method should be useful to study brain pathologies.

Clinical prognostic value of combined analysis of Aldh1, Survivin, and EpCAM expression in colorectal cancer.

BACKGROUND: Tumour aggressiveness might be related to the degree of main cancer hallmark acquirement of tumour cells, reflected by expression levels of specific biomarkers. We investigated the expression of Aldh1, Survivin, and EpCAM, together reflecting main cancer hallmarks, in relation to clinical outcome of colorectal cancer (CRC) patients. METHODS: Immunohistochemistry was performed using a tumour tissue microarray of TNM (Tumour, Node, Metastasis)-stage I-IV CRC tissues. Single-marker expression or their combination was assessed for associations with the clinical outcome of CRC patients (N=309). RESULTS: Increased expression of Aldh1 or Survivin, or decreased expression of EpCAM was each associated with poor clinical outcome, and was therefore identified as clinically unfavourable expression. Analyses of the combination of all three markers showed worse clinical outcome, specifically in colon cancer patients, with an increasing number of markers showing unfavourable expression. Hazard ratios ranged up to 8.3 for overall survival (P<0.001), 36.6 for disease-specific survival (P<0.001), and 27.1 for distant recurrence-free survival (P<0.001). CONCLUSIONS: Our data identified combined expression levels of Aldh1, Survivin, and EpCAM as strong independent prognostic factors, with high hazard ratios, for survival and tumour recurrence in colon cancer patients, and therefore reflect tumour aggressiveness.

The V-Y latissimus dorsi musculocutaneous flap in the reconstruction of large posterior chest wall defects.

UNLABELLED: Posterior chest wall defects are frequently encountered after excision of tumors as a result of trauma or in the setting of wound dehiscence after spine surgery. Various pedicled fasciocutaneous and musculocutaneous flaps have been described for the coverage of these wounds. The advent of perforator flaps has allowed the preservation of muscle function but their bulk is limited. Musculocutaneous flaps remain widely employed. The trapezius and the latissimus dorsi (LD) flaps have been used extensively for upper and middle posterior chest wounds, respectively. Their bulk allows for obliteration of the dead space in deep wounds. The average width of the LD skin paddle is limited to 10-12 cm if closure of the donor site is expected without skin grafting. In 2001 a modification of the skin paddle design was introduced in order to allow large flaps to be raised without requiring grafts or flaps for donor site closure. This V-Y pattern allows coverage of large anterior chest defects after mastectomy. We have modified this flap to allow its use for posterior chest wall defects. We describe the flap design, its indications, and its limitations with three clinical cases. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266.

Reconstruction using vascularized extensor indicis proprius tendon.

The choice of the donor tendon in tendon reconstruction of the hand theoretically influences the results of the surgery because of the interactions of its structure with the healing process. The objective of our study was to specify the surgical bases of vascularized extensor indicis proprius (EIP) in tendon reconstruction of the hand and to present its application from a series of observations. According to our observations, the EIP's vascularization arises from a branch of the 2nd dorsal metacarpal artery, 3-4 cm proximally to the metacarpophalangeal joint (MCP). We demonstrate the feasibility and effectiveness of a vascularized EIP graft for finger flexor tendon reconstruction, for defects of the extensor mechanism at the MCP joint level and for reconstruction of the extensor pollicis longus. Our biomimetic approach in tendon reconstruction has led us to factor in the complexity of the tendon and peritendinous structure. The use of vascularized EIP offers theoretical advantages for the tendon healing process, demonstrates encouraging first results with interesting versatility and very low iatrogenicity.

Biomimicry of the flexor digitorum superficialis: Systematic literature review.

Biomimicry consists in imitating nature to solve complex human problems. The hand surgeon usually tries to copy and recreate the structure-to-function and function-to-control relationships of the native tissues after damage. With its exceptional structure and biomechanics, the flexor digitorum superficialis (FDS) has been an important source of inspiration for artificial hand system reconstruction. The present systematic literature review highlights the twenty-two artificial hand system reconstructions derived from the FDS, and presents biomimicry as an alternative approach in clinical research in hand surgery.

The association between leptin concentration and blood coagulation: Results from the NEO study.

BACKGROUND: The adipocyte-derived hormone leptin has been associated with altered blood coagulation in in vitro studies. However, it is unclear whether this association is relevant in vivo and to what extent this association is influenced by total body fat. Therefore, we aimed to examine the association between serum leptin and blood coagulation while taking total body fat into account in a population-based cohort study. METHODS: We performed a cross-sectional analysis with baseline measurements of 5797 participants of the Netherlands Epidemiology of Obesity (NEO) study, a population-based cohort of middle-aged men and women. We examined associations between serum leptin concentration and coagulation factor concentrations and parameters of platelet activation in linear regression analyses. All analyses were adjusted for multiple covariates, including total body fat. RESULTS: In multivariable adjusted analyses a 1 µg/L higher serum leptin concentration was associated with a 0.22 IU/dL (95% CI: 0.11, 0.32) higher FVIII concentration and a 0.20 IU/dL (95% CI: 0.14, 0.27) higher FIX concentration (3.5 IU/dL FVIII and 3.2 IU/dL FIX per SD leptin). Serum leptin concentration was not associated with FXI, fibrinogen, platelet count, mean platelet volume and platelet distribution width in multivariable adjusted analyses. DISCUSSION: This study showed that serum leptin concentration was associated with higher concentrations of FVIII and FIX in an observational study, which could be clinically relevant.

Cultured porcine coronary artery smooth muscle cells. A new model with advanced differentiation.

Arterial intimal thickening after endothelial injury induced in rodents has proven to be a relatively unreliable model of restenosis for testing clinically useful compounds. The same has been found for cultured rat or rabbit vascular smooth muscle cells (SMCs). To test alternative possibilities, we have studied several differentiation features of porcine coronary artery SMCs, cultured up to the 5th passage after enzymatic digestion of the media. The effects of heparin, transforming growth factor (TGF)-beta1 or TGF-beta2, and all-trans-retinoic acid (tRA) on proliferation, migration, and differentiation of these cells also were examined. Porcine arterial SMCs in culture not only express high levels of alpha-smooth muscle (SM) actin but, contrary to rodent SMCs, also maintain an appreciable expression of SM myosin heavy chain isoforms 1 and 2, desmin, and smoothelin, a recently described late differentiation marker of vascular SMCs. We demonstrate for the first time that smoothelin is colocalized with alpha-SM actin in these cells. Finally, we show that in the porcine model, heparin is more potent than TGF-beta1 or TGF-beta2 and tRA in terms of inhibition of proliferation and migration and of increasing the expression of differentiation markers. This model should be a useful complement to in vivo studies of SMC differentiation and of pathological situations such as restenosis and atheromatosis.

MR Vascular Fingerprinting in Stroke and Brain Tumors Models.

In this study, we evaluated an MRI fingerprinting approach (MRvF) designed to provide high-resolution parametric maps of the microvascular architecture (i.e., blood volume fraction, vessel diameter) and function (blood oxygenation) simultaneously. The method was tested in rats (n = 115), divided in 3 models: brain tumors (9 L, C6, F98), permanent stroke, and a control group of healthy animals. We showed that fingerprinting can robustly distinguish between healthy and pathological brain tissues with different behaviors in tumor and stroke models. In particular, fingerprinting revealed that C6 and F98 glioma models have similar signatures while 9 L present a distinct evolution. We also showed that it is possible to improve the results of MRvF and obtain supplemental information by changing the numerical representation of the vascular network. Finally, good agreement was found between MRvF and conventional MR approaches in healthy tissues and in the C6, F98, and permanent stroke models. For the 9 L glioma model, fingerprinting showed blood oxygenation measurements that contradict results obtained with a quantitative BOLD approach. In conclusion, MR vascular fingerprinting seems to be an efficient technique to study microvascular properties in vivo. Multiple technical improvements are feasible and might improve diagnosis and management of brain diseases.

Mechanisms of neointima formation and remodeling in the porcine coronary artery.

BACKGROUND: To characterize the cells responsible for neointima formation after porcine coronary artery wall injury, we studied the expression of smooth muscle cell (SMC) differentiation markers in 2 models: (1) self-expanding stent implantation resulting in no or little interruption of internal elastic lamina and (2) percutaneous transluminal coronary angioplasty (PTCA) resulting in complete medial rupture and exposure of adventitia to blood components. METHODS AND RESULTS: The expression of alpha-smooth muscle (SM) actin, SM myosin heavy chain isoforms 1 and 2, desmin, and smoothelin was investigated by means of immunohistochemistry and Western blots in tissues of the arterial wall collected at different time points and in cell populations cultured from these tissues. The expression of smoothelin, a marker of late SMC differentiation, was used to discriminate between SMCs and myofibroblasts. Both stent- and PTCA-induced neointimal tissues and their cultured cell populations expressed all 4 markers. The adventitial tissue underlying PTCA-induced lesions temporarily expressed alpha-SM actin, desmin, and SM myosin heavy chain isoforms, but not smoothelin. When placed in culture, adventitial cells expressed only alpha-SM actin. CONCLUSIONS: Our results suggest that SMCs are the main components of coronary artery neointima after both self-expanding stent implantation and PTCA. The adventitial reaction observed after PTCA evolves with a chronology independent of that of neointima formation and probably corresponds to a myofibroblastic reaction.

High mobility group proteins 1 and 2 bind preferentially to brominated poly(dG-dC).poly(dG-dC) in the Z-DNA conformation but not to other types of Z-DNA.

Three proteins from bull testis, previously thought to be Z-DNA-binding proteins but recently found to recognize brominated poly(dG-dC). poly(dG-dC) by criteria different from the Z-conformation, were partially sequenced. Of these, the 31 kDa protein was identified as a member of the high mobility group 2 protein family, and the 33 kDa protein as a member of the high mobility group 1 protein family. Both proteins had molecular weights approximately 30% higher than expected, indicating considerable posttranslational modification. In contrast, the 58 kDa protein remained unidentified for lack of any significant homology with known protein sequences.

A novel volumetric magnetic resonance imaging paradigm to study upper airway anatomy.

STUDY OBJECTIVES: We utilized novel three-dimensional volumetric analysis techniques with magnetic resonance imaging (MRI) to study the upper airway and surrounding soft-tissue structures. These MRI techniques allowed us to objectively quantify the volume of the tongue, soft palate, parapharyngeal fat pads, and lateral pharyngeal walls. DESIGN: We first validated our volumetric imaging techniques on a phantom and then demonstrated that our results were reliable and reproducible in normal subjects who did not lose weight. Finally, we studied 12 obese, nonapneic women during wakefulness before and after weight loss. We hypothesized that our novel magnetic-resonance computer-reconstruction techniques would allow us to detect small reductions in the volume of the tongue, soft palate, lateral pharyngeal walls, and parapharyngeal fat pads and increases in the volume of the upper airway with weight loss. SETTING: University medical center. PARTICIPANTS: Normal controls and 12 obese nonapneic women. INTERVENTIONS: Weight loss. MEASUREMENTS AND RESULTS: Following a mean 17.1+/-8.62 kg (17.3%) reduction in weight, upper airway volume increased (p = 0.06) in both the retropalatal and retroglossal regions. This increase in upper airway volume was mediated by significant reductions in the volume of the lateral pharyngeal wall (p = 0.0001) and parapharyngeal fat pads (p = 0.001). However, the volume of the tongue (p = 0.35) and soft palate (p = 0.39) were not reduced significantly with weight loss. CONCLUSIONS: These data indicate that volumetric MRI is a powerful tool to study anatomic changes in the upper airway and surrounding soft-tissue structures and is sensitive enough to detect changes in these structures.

A role for computer simulation in solving the riddles of autoreceptor-mediated regulation of GABA release.

The autoreceptor-mediated control of GABA release was simulated on a personal computer using commercially available software (STELLA/ITHINK). The experimental data to be matched were taken from previous publications. A basic model was able to fairly accurately reproduce frequency dependencies of GABA release in the presence and absence of uptake inhibition as well as concentration-response curves for changes in release produced by the agonist, (-)-baclofen, or by relatively low concentrations of the antagonists, phaclofen and CGP 35348. Obvious mismatch was observed at high concentrations of a potent antagonist, at a stimulation frequency of 2 Hz. Whereas the experimental data indicate a 3-fold increase in release as compared to controls, simulation predicts a 7-fold increase. By adaptation of the model, simulation data were obtained indicating that this mismatch was not due to (a) the autoreceptor occurring as two subtypes with different affinities for antagonists, (b) the occurrence of an agonist and antagonist state of the autoreceptor, with the latter prevailing at low synaptic concentrations of endogenous GABA, and (c) overruling of uptake inhibition by markedly elevated synaptic GABA concentrations. On the other hand, a simple restriction of the amount of transmitter able to be released per time unit produced much better matching data. A refined model assuming a restricted replacement capacity for exocytotically emptied synaptic vesicles at their docking sites gave similar results. As a consequence, we shall attempt to address this possibility experimentally. Simulation can never prove a case in the positive sense. It can, however, help to exclude ill-matching solutions of a problem and to prioritize among possible ones, which then must be experimentally addressed. We found simulation with this user-friendly software extraordinarily useful, also and not least because it necessitates and stimulates very intense dealing with a subject.

Minimally invasive fixation versus conservative treatment of undisplaced scaphoid fractures: a cost-effectiveness study.

This study compares the direct and indirect costs of conservative and minimally invasive treatment for undisplaced scaphoid fractures. Costs data concerning groups of non-operated and operated patients were analysed. Direct costs were higher in operated patients. Although highly variable, indirect costs were significantly smaller in operated patients and the total costs were higher in non-operated patients. In conclusion, operative treatment of scaphoid fractures is initially more expensive than conservative treatment but markedly decreases the work compensation costs.

Imaging brain oxygenation with MRI using blood oxygenation approaches: methods, validation, and clinical applications.

SUMMARY: In many pathophysiologic situations, including brain neoplasms, neurodegenerative disease, and chronic and acute ischemia, an imbalance exists between oxygen tissue consumption and delivery. Furthermore, oxygenation changes following a stress challenge, such as with carbogen gas or acetazolamide, can yield information about cerebrovascular reactivity. The unique sensitivity of the BOLD effect to the presence of deoxyhemoglobin has led to its widespread use in the field of cognitive neurosciences. However, the high spatial and temporal resolution afforded by BOLD imaging does not need to be limited to the study of healthy brains. While the complex relationship between the MR imaging signal and tissue oxygenation hinders a direct approach, many different methods have been developed during the past decade to obtain specific oxygenation measurements. These include qBOLD, phase- and susceptibility-based imaging, and intravascular T2-based approaches. The aim of this review is to give an overview of the theoretic basis of these methods as well as their application to measure oxygenation in both healthy subjects and those with disease.