Elevated cerebral spinal fluid cytokine levels in boys with cerebral adrenoleukodystrophy correlates with MRI severity

Background

X-linked adrenoleukodystrophy (ALD) is a metabolic, peroxisomal disease that results from a mutation in the ABCD1 gene. The most severe course of ALD progression is the cerebral inflammatory and demyelinating form of the disease, cALD. To date there is very little information on the cytokine mediators in the cerebral spinal fluid (CSF) of these boys.

Methodology/Principal Findings

Measurement of 23 different cytokines was performed on CSF and serum of boys with cerebral ALD and patients without ALD. Significant elevations in CSF IL-8 (29.3±2.2 vs 12.8±1.1 pg/ml, p = 0.0001), IL-1ra (166±30 vs 8.6±6.5 pg/ml, p = 0.005), MCP-1 (610±47 vs 328±34 pg/ml, p = 0.002), and MIP-1b (14.2±1.3 vs 2.0±1.4 pg/ml, p<0.0001) were found in boys with cALD versus the control group. The only serum cytokine showing an elevation in the ALD group was SDF-1 (2124±155 vs 1175±125 pg/ml, p = 0.0001). The CSF cytokines of IL-8 and MCP-1b correlated with the Loes MRI severity score (p = 0.04 and p = 0.008 respectively), as well as the serum SDF-1 level (p = 0.002). Finally, CSF total protein was also significantly elevated in boys with cALD and correlated with both IL-8, MCP-1b (p = 0.0001 for both), as well as Loes MRI severity score (p = 0.0007).

Conclusions/Significance

IL-8, IL-1ra, MCP-1, MIP-1b and CSF total protein were significantly elevated in patients with cALD; IL-8, MCP-1b, and CSF total protein levels correlated with disease severity determined by MRI. This is the largest report of CSF cytokine levels in cALD to date, and identification of these key cytokines will provide further insight into disease progression and perhaps lead to improved targeted therapies.     

Imbalances between Matrix Metalloproteinases (MMPs) and Tissue Inhibitor of Metalloproteinases (TIMPs) in Maternal Serum during Preterm Labor

Background

Matrix metalloproteinases (MMPs) are involved in remodeling of the extracellular matrix (ECM) during pregnancy and parturition. Aberrant ECM degradation by MMPs or an imbalance between MMPs and their tissue inhibitors (TIMPs) have been implicated in the pathogenesis of preterm labor, however few studies have investigated MMPs or TIMPs in maternal serum. Therefore, the purpose of this study was to determine serum concentrations of MMP-3, MMP-9 and all four TIMPs as well as MMP:TIMP ratios during term and preterm labor.

Methods

A case control study with 166 singleton pregnancies, divided into four groups: (1) women with preterm birth, delivering before 34 weeks (PTB); (2) gestational age (GA) matched controls, not in preterm labor; (3) women at term in labor and (4) at term not in labor. MMP and TIMP concentrations were measured using Luminex technology.

Results

MMP-9 and TIMP-4 concentrations were higher in women with PTB vs. GA matched controls (resp. p = 0.01 and p<0.001). An increase in MMP-9:TIMP-1 and MMP-9:TIMP-2 ratio was observed in women with PTB compared to GA matched controls (resp. p = 0.02 and p<0.001) as well as compared to women at term in labor (resp. p = 0.006 and p<0.001). Multiple regression results with groups recoded as three key covariates showed significantly higher MMP-9 concentrations, higher MMP-9:TIMP-1 and MMP-9:TIMP-2 ratios and lower TIMP-1 and -2 concentrations for preterm labor. Significantly higher MMP-9 and TIMP-4 concentrations and MMP-9:TIMP-2 ratios were observed for labor.

Conclusions

Serum MMP-9:TIMP-1 and MMP-9:TIMP-2 balances are tilting in favor of gelatinolysis during preterm labor. TIMP-1 and -2 concentrations were lower in preterm gestation, irrespective of labor, while TIMP-4 concentrations were raised in labor. These observations suggest that aberrant serum expression of MMP:TIMP ratios and TIMPs reflect pregnancy and labor status, providing a far less invasive method to determine enzymes essential in ECM remodeling during pregnancy and parturition.     

Dexamethasone,Cerebrospinal Fluid Matrix Metalloproteinase Concentrations and Clinical Outcomes in Tuberculous Meningitis

Background

Adjunctive dexamethasone reduces mortality from tuberculous meningitis, but how it produces this effect is not known. Matrix metalloproteinases (MMPs) are important in the immunopathology of many inflammatory CNS diseases thus we hypothesized that that their secretion is important in TBM and might be influenced by dexamethasone.

Methodology/Principal Findings

The kinetics of cerebrospinal fluid (CSF) MMP and tissue inhibitors of MMPs (TIMPs) concentrations were studied in a subset of HIV uninfected adults (n = 37) with TBM recruited to a randomized, placebo-controlled trial of adjuvant dexamethasone. Analysis followed a pre-defined plan. Dexamethasone significantly reduced CSF MMP-9 concentrations in early follow up samples (median 5 days (range 3–8) of treatment), but had no significant influence on other MMPs/TIMPs. Additionally CSF MMP-9 concentration was strongly correlated to concomitant CSF neutrophil count.

Conclusions/Significance

Dexamethasone decreased CSF MMP-9 concentrations early in treatment and this may represent one mechanism by which corticosteroids improve outcome in TBM. The strong correlation between CSF MMP-9 and neutrophil count suggests that polymorphonuclear leukocytes may play a central role in the early pathogenesis of TBM.     

No Correlation between TIMP2 -418 G>C Polymorphism and Increased Risk of Cancer: Evidence from a Meta-Analysis

Aim

Tissue inhibitor of metalloproteinase (TIMP2) is involved in the regulation of matrix metalloproteinase 2 (MMP2) and shown to implicate in cancer development and progression. The results from the published studies based on the association between TIMP2 -418 G>C polymorphism and cancer risk are inconsistent. In this meta-analysis, we aimed to evaluate the potential association between TIMP2 -418 G>C polymorphism and cancer risk.

Methodology

We searched PubMed (Medline) and EMBASE web databases to cover all studies based on relationship of TIMP2 -418 G>C polymorphism and risk of cancer until October 2013. The meta-analysis was performed for selected case-control studies and pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for all genetic models.

Results

A total of 2225 cancer cases and 2532 controls were included from ten eligible case-control studies. Results from overall pooled analysis suggested no evidence of significant risk between TIMP2 -418 G>C polymorphism and cancer risk in any of the genetic models, such as, allele (C vs. G: OR = 1.293, 95% CI = 0.882 to 1.894, p = 0.188), homozygous (CC vs. GG: OR = 0.940, 95% CI = 0.434 to 2.039, p = 0.876), heterozygous (GC vs. GG: OR = 1.397, 95% CI = 0.888 to 2.198, p = 0.148), dominant (CC+GC vs. GG: OR = 1.387, 95% CI = 0.880 to 2.187, p = 0.159) and recessive (CC vs. GG+GC: OR = 0.901, 95% CI = 0.442 to 1.838, p = 0.774) models. No evidence of publication bias was detected during the analysis.

Conclusions

The present meta-analysis suggests that the TIMP2 -418 G>C polymorphism may not be involved in predisposing risk factor for cancer in overall population. However, future larger studies with group of populations are needed to analyze the possible correlation.     

High b Value (2,000 s/mm2) Diffusion-Weighted Magnetic Resonance Imaging in Prostate Cancer at 3 Tesla: Comparison with 1,000 s/mm2 for Tumor Conspicuity and Discrimination of Aggressiveness

Objective

The objective of our study was to investigate tumor conspicuity and the discrimination potential for tumor aggressiveness on diffusion-weighted magnetic resonance imaging (DW-MRI) with high b value at 3-T.

Materials and Methods

The institutional review board approved this study and waived the requirement for informed consent. A total of 50 patients with prostate cancer (69 cancer foci; 48 in the PZ, 20 in the TZ, and one in whole prostate) who underwent multiparametric prostate MRI including DW-MRI (b values: 0, 1000 s/mm² and 0, 2000 s/mm²) on a 3-T system were included. Lesion conspicuity score (LCS) using visual assessment (1 = invisible for surrounding normal site; 2 = slightly high intensity; 3 = moderately high; and 4 = very high) and tumor-normal signal intensity ratio (TNR) were assessed, and apparent diffusion coefficient (ADC, ×10⁻³ mm²/s) of the tumor regions and normal regions were measured.

Results

Mean LCS and TNR at 0, 2000 s/mm² was significantly higher than those at 0, 1000 s/mm² (p<0.001 for both). In addition, ADC at both 0, 1000 and 0, 2000 s/mm² was found to distinguish intermediate or high risk cancer with Gleason score ≥7 from low risk cancer with Gleason score ≤6 (p<0.001 for both). Furthermore, ADC of tumor regions correlated with Gleason score at both 0, 1000 s/mm² (ρ = −0.602; p<0.001) and 0, 2000 s/mm² (ρ = −0.645; p<0.001).

Conclusions

For tumor conspicuity and characterization of prostate cancer on DW-MRI of 3-T MRI, b = 0, 2000 s/mm² is more useful than b = 0, 1000 s/mm².     

Contributions of Ocular Surface Components to Matrix-Metalloproteinases (MMP)-2 and MMP-9 in Feline Tears following Corneal Epithelial Wounding

Purpose

This study investigated ocular surface components that contribute to matrix-metalloproteinase (MMP)-2 and MMP-9 found in tears following corneal epithelial wounding.

Methods

Laboratory short-haired cats underwent corneal epithelial debridement in one randomly chosen eye (n = 18). Eye-flush tears were collected at baseline and during various healing stages. Procedural control eyes (identical experimental protocol as wounded eyes except for wounding, n = 5) served as controls for tear analysis. MMP activity was analyzed in tears using gelatin zymography. MMP staining patterns were evaluated in ocular tissues using immunohistochemistry and used to determine MMP expression sites responsible for tear-derived MMPs.

Results

The proMMP-2 and proMMP-9 activity in tears was highest in wounded and procedural control eyes during epithelial migration (8 to 36 hours post-wounding). Wounded eyes showed significantly higher proMMP-9 in tears only during and after epithelial restratification (day 3 to 4 and day 7 to 28 post-wounding, respectively) as compared to procedural controls (p<0.05). Tears from wounded and procedural control eyes showed no statistical differences for pro-MMP-2 and MMP-9 (p>0.05). Immunohistochemistry showed increased MMP-2 and MMP-9 expression in the cornea during epithelial migration and wound closure. The conjunctival epithelium exhibited highest levels of both MMPs during wound closure, while MMP-9 expression was reduced in conjunctival goblet cells during corneal epithelial migration followed by complete absence of the cells during wound closure. The immunostaining for both MMPs was elevated in the lacrimal gland during corneal healing, with little/no change in the meibomian glands. Conjunctival-associated lymphoid tissue (CALT) showed weak MMP-2 and intense MMP-9 staining.

Conclusions

Following wounding, migrating corneal epithelium contributed little to the observed MMP levels in tears. The major sources assessed in the present study for tear-derived MMP-2 and MMP-9 following corneal wounding are the lacrimal gland and CALT. Other sources included stromal keratocytes and conjunctiva with goblet cells.     

Endothelial Nitric Oxide Synthase and Superoxide Mediate Hemodynamic Initiation of Intracranial Aneurysms

Background

Hemodynamic insults at arterial bifurcations are believed to play a critical role in initiating intracranial aneurysms. Recent studies in a rabbit model indicate that aneurysmal damage initiates under specific wall shear stress conditions when smooth muscle cells (SMCs) become pro-inflammatory and produce matrix metalloproteinases (MMPs). The mechanisms leading to SMC activation and MMP production during hemodynamic aneurysm initiation are unknown. The goal is to determine if nitric oxide and/or superoxide induce SMC changes, MMP production and aneurysmal remodeling following hemodynamic insult.

Methods

Bilateral common carotid artery ligation was performed on rabbits (n = 19, plus 5 sham operations) to induce aneurysmal damage at the basilar terminus. Ligated animals were treated with the nitric oxide synthase (NOS) inhibitor LNAME (n = 7) or the superoxide scavenger TEMPOL (n = 5) and compared to untreated animals (n = 7). Aneurysm development was assessed histologically 5 days after ligation. Changes in NOS isoforms, peroxynitrite, reactive oxygen species (ROS), MMP-2, MMP-9, and smooth muscle α-actin were analyzed by immunohistochemistry.

Results

LNAME attenuated ligation-induced IEL loss, media thinning and bulge formation. In untreated animals, immunofluorescence showed increased endothelial NOS (eNOS) after ligation, but no change in inducible or neuronal NOS. Furthermore, during aneurysm initiation ROS increased in the media, but not the intima, and there was no change in peroxynitrite. In LNAME-treated animals, ROS production did not change. Together, this suggests that eNOS is important for aneurysm initiation but not by producing superoxide. TEMPOL treatment reduced aneurysm development, indicating that the increased medial superoxide is also necessary for aneurysm initiation. LNAME and TEMPOL treatment in ligated animals restored α-actin and decreased MMPs, suggesting that eNOS and superoxide both lead to SMC de-differentiation and MMP production.

Conclusion

Aneurysm-inducing hemodynamics lead to increased eNOS and superoxide, which both affect SMC phenotype, increasing MMP production and aneurysmal damage.     

External Validation of the Simple Clinical Score and the HOTEL Score,Two Scores for Predicting Short-Term Mortality after Admission to an Acute Medical Unit

Background

Clinical scores can be of aid to predict early mortality after admission to a medical admission unit. A developed scoring system needs to be externally validated to minimise the risk of the discriminatory power and calibration to be falsely elevated. We performed the present study with the objective of validating the Simple Clinical Score (SCS) and the HOTEL score, two existing risk stratification systems that predict mortality for medical patients based solely on clinical information, but not only vital signs.

Methods

Pre-planned prospective observational cohort study.

Setting

Danish 460-bed regional teaching hospital.

Findings

We included 3046 consecutive patients from 2 October 2008 until 19 February 2009. 26 (0.9%) died within one calendar day and 196 (6.4%) died within 30 days. We calculated SCS for 1080 patients. We found an AUROC of 0.960 (95% confidence interval [CI], 0.932 to 0.988) for 24-hours mortality and 0.826 (95% CI, 0.774–0.879) for 30-day mortality, and goodness-of-fit test, χ² = 2.68 (10 degrees of freedom), P = 0.998 and χ² = 4.00, P = 0.947, respectively. We included 1470 patients when calculating the HOTEL score. Discriminatory power (AUROC) was 0.931 (95% CI, 0.901–0.962) for 24-hours mortality and goodness-of-fit test, χ² = 5.56 (10 degrees of freedom), P = 0.234.

Conclusion

We find that both the SCS and HOTEL scores showed an excellent to outstanding ability in identifying patients at high risk of dying with good or acceptable precision.     

IgG Antibodies against Measles,Rubella, and Varicella Zoster Virus Predict Conversion to Multiple Sclerosis in Clinically Isolated Syndrome

Background

Multiple sclerosis (MS) is characterized by a polyspecific B-cell response to neurotropic viruses such as measles, rubella and varicella zoster, with the corresponding antibodies measurable in CSF as the so-called “MRZ reaction” (MRZR). We aimed to evaluate the relevance of MRZR to predict conversion of patients with clinically isolated syndrome (CIS) to MS, and to compare it to oligoclonal bands (OCB) and MRI.

Methodology/Principal Findings

MRZR was determined in a prospective study over 2 years including 40 patients that remained CIS over follow-up (CIS-CIS) and 49 patients that developed MS (CIS-RRMS) using ELISA. Using logistic regression, a score (MRZS) balancing the predictive value of the antibody indices included in MRZR was defined (9 points measles, 8 points rubella, 1 point varicella zoster, cutpoint: sum of scores greater 10).MRZR and MRZS were significantly more frequent in CIS-RRMS as compared to CIS-CIS (p = 0.04 and p = 0.02). MRZS showed the best positive predictive value (PPV) of all parameters investigated (79%, 95%-CI: 54–94%), which could be further increased by combination with MRI (91%, 95%-CI: 59–99%).

Conclusions/Significance

Our data indicate the relevance of MRZR to predict conversion to MS. It furthermore shows the importance of weighting the different antibody indices included in MRZR and suggest that patients with positive MRZR are candidates for an early begin of immunomodulatory therapy.     

The Association of Early Childhood Cognitive Development and Behavioural Difficulties with Pre-Adolescent Problematic Eating Attitudes

Objectives

Few studies have prospectively investigated associations of child cognitive ability and behavioural difficulties with later eating attitudes. We investigated associations of intelligence quotient (IQ), academic performance and behavioural difficulties at 6.5 years with eating attitudes five years later.

Methods

We conducted an observational cohort study nested within the Promotion of Breastfeeding Intervention Trial, Belarus. Of 17,046 infants enrolled at birth, 13,751 (80.7%) completed the Children''s Eating Attitude Test (ChEAT) at 11.5 years, most with information on IQ (n = 12,667), academic performance (n = 9,954) and behavioural difficulties (n = 11,098) at 6.5 years. The main outcome was a ChEAT score ≥85^th percentile, indicative of problematic eating attitudes.

Results

Boys with higher IQ at 6.5 years reported fewer problematic eating attitudes, as assessed by ChEAT scores ≥85^th percentile, at 11.5 years (OR per SD increase in full-scale IQ = 0.87; 0.79, 0.94). No such association was observed in girls (1.01; 0.93, 1.10) (p for sex-interaction = 0.016). In both boys and girls, teacher-assessed academic performance in non-verbal subjects was inversely associated with high ChEAT scores five years later (OR per unit increase in mathematics ability = 0.88; 0.82, 0.94; and OR per unit increase in ability for other non-verbal subjects = 0.86; 0.79, 0.94). Behavioural difficulties were positively associated with high ChEAT scores five years later (OR per SD increase in teacher-assessed rating = 1.13; 1.07, 1.19).

Conclusion

Lower IQ, worse non-verbal academic performance and behavioural problems at early school age are positively associated with risk of problematic eating attitudes in early adolescence.     

Mitral Tissue Inhibitor of Metalloproteinase 2 Is Associated with Mitral Valve Surgery Outcome

Background

Matrix metalloproteinases play a role in regulating cardiac remodeling. We previously reported an association between tissue inhibitor of metalloproteinase 2 (TIMP-2) expression and mitral valve (MV) disease. However, the determinants and prognostic value of mitral TIMP2 after MV surgery are unknown.

Methods

This retrospective study of 164 patients after MV surgery in a tertiary medical center in Taiwan assessed mitral TIMP2 on a semiquantitative scale (0–2) by immunohistochemical staining. The primary endpoints were the composite of cardiovascular death and heart failure admission.

Results

Mean age was 50.4±13.7 years. After a mean follow-up period of 101±59 months, primary endpoints had occurred in 25 (15.2%) subjects. Patients with and without primary endpoint events significantly differed in terms of age (56.6±14.4 vs. 49.2±13.4 years, respectively; p = 0.013) and left ventricular end-systolic diameter (LVESD) (39.7±8.2 vs. 35.5±7.5 mm, p = 0.010) at surgery. The TIMP2 had a significant dose-dependent association with development of a primary endpoint (p = 0.002). Kaplan–Meier analysis showed that TIMP2 expression has a significant positive association with primary endpoint-free survival (log-rank test; p = 0.004). Cox regression analysis showed that independent predictors of primary endpoints were TIMP2 (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.12–0.65; p = 0.003), age (HR 1.05; 95% CI 1.02–1.09; p = 0.003) and LVESD (HR 1.05; 95% CI 1.01–1.10; p = 0.020).

Conclusions

The lack of mitral TIMP2 expression is associated with increases in cardiovascular death and heart failure following MV surgery.     

Association of Matrix Metalloproteinase-3 -1171(5A>6A) Polymorphism with Cancer Risk: A Meta-Analysis of 41 Studies

Background and Objective

Evidence has shown that matrix metalloproteinases-3 (MMP3) is important for cancer progression. Recent studies about the association between the -1171(5A>6A) polymorphism in MMP3 promoter region and cancer risk have yielded conflicting results.

Methodology/Principal Findings

We performed a meta-analysis of 41 studies including 11112 cases and 11091 controls to determine whether the -1171(5A>6A) polymorphism of MMP3 was associated with cancer risk. We assessed the strength of association and performed sub-group analyses by cancer types, ethnicity, smoking status, genotyping method, source of controls and sample size. The pooled results revealed that no significant association of the -1171(5A>6A) polymorphism with overall cancer risk in any of four models. Further sub-group analysis revealed that individuals with the 6A allele had lower risk of gastrointestinal cancer in two models: heterozygote comparison (6A/5A vs. 5A/5A: OR = 0.74, 95%CI: 0.60—0.91; I² = 1.9%), and dominant model (6A/6A+6A/5A vs. 5A/5A: OR = 0.77, 95%CI: 0.64—0.94; I² = 29.0%). Additionally, the associations were significant in Asian populations for three models: homozygote comparison (6A/6A vs. 5A/5A, OR = 0.68, 95%CI: 0.52—0.90; I² = 26.7%), heterozygote comparison (6A/5A vs. 5A/5A: OR = 0.75, 95%CI: 0.58—0.98; I² = 0.0%), and dominant model (6A/6A+6A/5A vs. 5A/5A: OR = 0.69, 95%CI: 0.54—0.88; I² = 0.5%). It was noteworthy that we had a contrary finding in non-smokers: the variant 6A/6A homozygote might statistically increase cancer risk compared with 6A/5A+5A/5A genotype (OR = 1.92, 95%CI: 1.25—2.96; I² = 72.7%).

Conclusion

This meta-analysis suggests that the -1171(5A>6A) polymorphism in MMP3 promoter region is not associated with overall cancer risk, but it may contribute to decreased cancer risk in Asian population when compared with Caucasian population and significantly reduce the risk of gastrointestinal cancer.     

Induced Sputum MMP-1, -3 & -8 Concentrations during Treatment of Tuberculosis

Introduction

Tuberculosis (TB) destroys lung tissues and this immunopathology is mediated in part by Matrix Metalloproteinases (MMPs). There are no data on the relationship between local tissue MMPs concentrations, anti-tuberculosis therapy and sputum conversion.

Materials and Methods

Induced sputum was collected from 68 TB patients and 69 controls in a cross-sectional study. MMPs concentrations were measured by Luminex array, TIMP concentrations by ELISA and were correlated with a disease severity score (TBscore). 46 TB patients were then studied longitudinally at the 2nd, 8th week and end of treatment.

Results

Sputum MMP-1,-2,-3,-8,-9 and TIMP-1 and -2 concentrations are increased in TB. Elevated MMP-1 and -3 concentrations are independently associated with higher TB severity scores (p<0.05). MMP-1, -3 and -8 concentrations decreased rapidly during treatment (p<0.05) whilst there was a transient increase in TIMP-1/2 concentrations at week 2. MMP-2, -8 and -9 and TIMP-2 concentrations were higher at TB diagnosis in patients who remain sputum culture positive at 2 weeks and MMP-3, -8 and TIMP-1 concentrations were higher in these patients at 2nd week of TB treatment.

Conclusions

MMPs are elevated in TB patients and associate with disease severity. This matrix-degrading phenotype resolves rapidly with treatment. The MMP profile at presentation correlates with a delayed treatment response.     

Influence of Body Mass Index (BMI) on Functional Improvements at 3 Years Following Total Knee Replacement: A Retrospective Cohort Study

Background

The number of patients presenting for total knee replacement who are classified as obese is increasing. The functional benefits of performing TKR in these patients are unclear.

Aim

To assess the influence pre-operative body mass index has upon knee specific function, general health status and patient satisfaction at 3 years following total knee replacement.

Design

Retrospective comparative cohort study using prospectively collected data from an institutional arthroplasty register.

Methods

1367 patients were assessed using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and Medical Outcomes Trust Short Form-36 (SF-36) scores supplemented by a validated measure of satisfaction pre-operatively and subsequently at 1,2 and 3 year post-operatively. Comparisons were made by dividing the cohort into 4 groups based on body mass index (BMI) 18.5–25.0 kg/m² (n = 253);>25.0–30.0 kg/m² (n = 559);>30.0−35.0 kg/m² (n = 373);>35.0 kg/m² (n = 182).

Results

Despite lower pre-operative, 1 and 3 year WOMAC and SF-36 scores patients with the highest BMIs >35.0 kg/m² experienced similar improvements to patients with a ‘normal‘ BMI (18.5–25.0 kg/m²) at 1 year (Difference in WOMAC improvement = 0.0 (95%CI −5.2 to 5.2), p = 1.00) and this improvement was sustained at up to 3 years (Difference in 1 year to 3 year improvement = 2.2 (95%CI: −2.1 to 6.5), p = 1.00). This effect was also observed for the SF-36 mental and physical component scores. Despite equivalent functional improvements levels of satisfaction in the >35.0 kg/m² group were lower than for any other BMI group (>35.0 kg/m² = 84.6% satisfied versus 18.5–5.0 kg/m² = 93.3% satisfied,p = 0.01) as was the proportion of patients who stated they would have the operation again (>35.0 kg/m² = 69.6% versus 18.5–25.0 kg/m² = 82.2%,p = 0.01).

Conclusion

Obese and morbidly obese patients gain as much functional benefit from total knee replacement as patients with lesser body mass indexes. This benefit is maintained for up to 3 years following surgery. However, these patients are less satisfied with their knee replacement and almost a third would not have the operation again.     

Screening Accuracy and Clinical Application of the Brief Infant-Toddler Social and Emotional Assessment (BITSEA)

Background

The Brief Infant-Toddler Social and Emotional Assessment (BITSEA) is a promising questionnaire for the early detection of psychosocial problems in toddlers. The screening accuracy and clinical application were evaluated.

Methods

In a community sample of 2-year-olds (N = 2060), screening accuracy of the BITSEA Problem scale was examined regarding a clinical CBCL1.5-5 Total Problem score. For the total population and subgroups by child’s gender and ethnicity Receiver Operating Characteristic (ROC) curves were calculated, and across a range of BITSEA Problem scores, sensitivity, specificity, likelihood ratio’s, diagnostic odds ratio and Youden’s index. Clinical application of the BITSEA was examined by evaluating the relation between the scale scores and the clinical decision of the child health professional.

Results

The area under the ROC curve (95% confidence interval) of the Problem scale was 0.97(0.95–0.98), there were no significant differences between subgroups. The association between clinical decision and BITSEA Problem score (B = 2.5) and Competence score (B = −0.7) was significant (p<0.05).

Conclusions

The results indicate that the BITSEA Problem scale has good discriminative power to differentiate children with and without psychosocial problems. Referred children had less favourable scores compared to children that were not referred. The BITSEA may be helpful in the early detection of psychosocial problems.     

Two-Dimensional Echocardiography in the Assessment of Long-Term Prognosis in Patients with Pulmonary Arterial Hypertension

Objective

To investigate the relationship between cardiac diastolic dysfunction and outcomes in patients with pulmonary arterial hypertension (PAH) and to clarify the potential effect of two-dimensional echocardiography (2D-echo) on prognostic value in patients with PAH.

Methods

Patients diagnosed with PAH (as WSPH (World Symposia on Pulmonary Hypertension) classification I) confirmed by right heart catheterization (RHC), received targeted monotherapy or combination therapy. 2D-echo parameters, World Health Organization (WHO) functional classification and 6-minute walking distance (6MWD) were recorded. The clinical prognosis of patients was assessed by the correlation between echo parameters and clinical 6MWD using receiver operating characteristic (ROC) curve analysis.

Results

Fifty-eight patients were included. Left and right ventricular diastolic dysfunction (LVDD and RVDD) scores measured by 2D-echo had good correlation with 6MWD at baseline (r_LVDD  = −0.699; r_RVDD  = −0.818, both P<0.001) and at last follow-up (r_LVDD  = −0.701; r_RVDD  = −0.666, both P<0.001). Furthermore, bi-ventricular (LVDD+RVDD) scores measured by 2D-echo had a better correlation with 6MWD at baseline and last follow-up (r = −0.831; r = −0.771, both P<0.001). ROC curve analysis showed that the area under curves (AUCs) for LVDD score, RVDD score and (LVDD+RVDD) scores were 0.823 (P<0.0001), 0.737 (P = 0.0002), and 0.825 (P<0.0001), respectively. Compared with ROC analysis of other single parameters, cardiac diastolic function score was more accurate in predicting survival in patients with PAH.

Conclusion

LVDD score, RVDD score and (LVDD+RVDD) scores yielded a comprehensive quantitative assessment of LV and RV diastolic function that correlated moderately with clinical functional parameters and might be useful in the assessment of PAH.     

Serum MMP-8: A Novel Indicator of Left Ventricular Remodeling and Cardiac Outcome in Patients after Acute Myocardial Infarction

Objective

Left ventricular (LV) remodeling following myocardial infarction (MI) is characterized by progressive alterations of structure and function, named LV remodeling. Although several risk factors such as infarct size have been identified, LV remodeling remains difficult to predict in clinical practice. Changes within the extracellular matrix, involving matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), are an integral part of left ventricular (LV) remodeling after myocardial infarction (MI). We investigated the temporal profile of circulating MMPs and TIMPs and their relations with LV remodeling at 1 year and clinical outcome at 3 years in post-MI patients.

Methods

This prospective multicentre study included 246 patients with a first anterior MI. Serial echocardiographic studies were performed at hospital discharge, 3 months, and 1 year after MI, and analysed at a core laboratory. LV remodeling was defined as the percent change in LV end-diastolic volume (EDV) from baseline to 1 year. Serum samples were obtained at hospital discharge, 1, 3, and 12 months. Multiplex technology was used for analysis of MMP-1, -2, -3, -8, -9, -13, and TIMP-1, -2, -3, -4 serum levels.

Results

Baseline levels of MMP-8 and MMP-9 were positively associated with changes in LVEDV (P = 0.01 and 0.02, respectively). When adjusted for major baseline characteristics, MMP-8 levels remained an independent predictor LV remodeling (P = 0.025). By univariate analysis, there were positive relations between cardiovascular death or hospitalization for heart failure during the 3-year follow-up and the baseline levels of MMP-2 (P = 0.03), MMP-8 (P = 0.002), and MMP-9 (P = 0.03). By multivariate analysis, MMP-8 was the only MMP remaining significantly associated with clinical outcome (P = 0.02).

Conclusion

Baseline serum MMP-8 is a significant predictor of LV remodeling and cardiovascular outcome after MI and may help to improve risk stratification.     

Age-Correction of Test Scores Reduces the Validity of Mild Cognitive Impairment in Predicting Progression to Dementia

Objectives

A phase of mild cognitive impairment (MCI) precedes most forms of neurodegenerative dementia. Many definitions of MCI recommend the use of test norms to diagnose cognitive impairment. It is, however, unclear whether the use of norms actually improves the detection of individuals at risk of dementia. Therefore, the effects of age- and education-norms on the validity of test scores in predicting progression to dementia were investigated.

Methods

Baseline cognitive test scores (Syndrome Short Test) of dementia-free participants aged ≥65 were used to predict progression to dementia within three years. Participants were comprehensively examined one, two, and three years after baseline. Test scores were calculated with correction for (1) age and education, (2) education only, (3) age only and (4) without correction. Predictive validity was estimated with Cox proportional hazard regressions. Areas under the curve (AUCs) were calculated for the one-, two-, and three-year intervals.

Results

82 (15.3%) of initially 537 participants, developed dementia. Model coefficients, hazard ratios, and AUCs of all scores were significant (p<0.001). Predictive validity was the lowest with age-corrected scores (−2 log likelihood  = 840.90, model fit χ² (1)  = 144.27, HR  = 1.33, AUCs between 0.73 and 0.87) and the highest with education-corrected scores (−2 log likelihood  = 815.80, model fit χ² (1)  = 171.16, HR  = 1.34, AUCs between 0.85 and 0.88).

Conclusion

The predictive validity of test scores is markedly reduced by age-correction. Therefore, definitions of MCI should not recommend the use of age-norms in order to improve the detection of individuals at risk of dementia.     

The Normal Transverse Mesocolon and Involvement of the Mesocolon in Acute Pancreatitis: An MRI Study

Objective

To study the MRI findings of the normal transverse mesocolon and the involvement of the mesocolon in acute pancreatitis (AP) as well as the relationship between the involvement of the mesocolon and the severity of AP.

Materials and Methods

Forty patients without pancreatic disorders were retrospectively analyzed to observe the normal transverse mesocolon using MRI; 210 patients with AP confirmed by clinical and laboratory tests were retrospectively analyzed using MRI to observe transverse-mesocolon involvement (TMI). The severity of TMI was recorded as zero points (no abnormalities and transverse-mesocolon vessel involvement), one point (linear and patchy signal in the transverse mesocolon) or two points (transverse-mesocolon effusion). The AP severity was graded by the MRI severity index (MRSI) and the Acute Physiology And Chronic Healthy Evaluation II (APACHE II) scoring system. The correlations of TMI with MRSI and APACHE-II were analyzed.

Results

In a normal transverse mesocolon, the display rates of the middle colic artery, the middle colic vein and the gastrocolic trunk on MRI were 95.0%, 82.5% and 100.0%, respectively. Of the 210 patients with AP, 130 patients (61.9%) had TMI. According to the TMI grading, 40%, 39% and 20% of the patients were graded at zero, one and two points, respectively. TMI was strongly correlated with the MRSI score (r = 0.759, P = 0.000) and the APACHE-II score (r = 0.384, P = 0.000).

Conclusion

MRI could be used to visualize transverse-mesocolon involvement. The severity of TMI could reflect that of AP in the clinical setting and imaging. TMI might be a supplementary indicator of the severity of AP.     

Cognitive Functions in Middle Aged Individuals Are Related to Metabolic Disturbances and Aerobic Capacity: A Cross-Sectional Study

Aims

Metabolic disturbances may contribute to cognitive dysfunction in patients with type 2 diabetes. We investigated the relation between cognitive impairment and metabolic deteriorations, low physical fitness, low-grade inflammation and abdominal obesity in middle aged individuals.

Methods

We conducted a cross-sectional study including 40 to 65 year-old patients with type 2 diabetes and limited co morbidity (N = 56), age-matched individuals with impaired glucose tolerance (N = 56) as well as age-matched controls with normal glucose tolerance (N = 72). Specific cognitive functions were assessed with focus on verbal memory, processing speed, executive functions, and a composite overall mean score. Oral glucose tolerance test, VO₂max test, systemic inflammation, DXA scanning and abdominal MRI were measured.

Results

Multiple linear regression analyses adjusting for age, gender and verbal intelligence demonstrated that a low score in processing speed, executive functions and overall cognitive function were related to high fasting C-peptide, as well as low insulin sensitivity, beta-cell function and VO₂max. Measurements of blood glucose, obesity and inflammation were not associated with cognitive function.

Conclusion

Low cognitive scores are seen in middle aged individuals with hyperinsulinemia, low insulin sensitivity, beta-cell function and low aerobic capacity. These findings emphasize the importance of appropriate lifestyle and not only blood glucose control in prevention of cognitive disability.