Toll-like receptor-4 deficiency attenuates doxorubicin-induced cardiomyopathy in mice

BACKGROUND: Cardiac inflammation and generation of oxidative stress are known to contribute to doxorubicin (Dox)-induced cardiomyopathy. Toll-like receptors (TLRs) are a part of the innate immune system and are involved in cardiac stress reactions. Since TLR4 might play a relevant role in cardiac inflammatory signalling, we investigated whether or not TLR4 is involved in Dox-induced cardiotoxicity. METHODS AND RESULTS: Five days after a single injection of Dox (20 mg/kg; i.p.), left ventricular pressure-volume loops were measured in wild-type and TLR4-deficient mice (TLR4-/-) Dox-treated and control mice. Analyses of possible pathophysiological mechanisms were performed in left ventricular tissue and isolated myocytes, respectively. Dox injection resulted in an impairment of left ventricular function and neurohumoral activation, indexed by increased ET-1 expression. This was further associated with an increase in cardiac oxidative stress, inflammation and apoptosis, as indicated by an up-regulation of cardiac lipid peroxidation, TNF-alpha expression and enhanced content of TUNEL-positive cells. In contrast, TLR4-/- Dox mice showed improved left ventricular function with reduced oxidative and inflammatory stress response including reduced cardiac apoptosis. These results were found to be associated with an increase of GATA-4 expression. CONCLUSIONS: TLR4 deficiency improves left ventricular function and attenuates pathophysiological key mechanisms in Dox-induced cardiomyopathy.     

Prognosis of Mild Cognitive Impairment in General Practice: Results of the German AgeCoDe Study

PURPOSE

The concept of mild cognitive impairment (MCI) has recently been introduced into the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as mild neurocognitive disorder, making it a formal diagnosis. We investigated the prognostic value of such a diagnosis and analyzed the determinants of the future course of MCI in the AgeCoDe study (German Study on Ageing, Cognition, and Dementia in Primary Care Patients).

METHODS

We recruited 357 patients with MCI aged 75 years or older from primary care practices and conducted follow-up with interviews for 3 years. Depending on the course of impairment over time, the patients were retrospectively split into 4 groups representing remittent, fluctuating, stable, and progressive courses of MCI. We performed ordinal logistic regression analysis and classification and regression tree (CART) analysis.

RESULTS

Overall, 41.5% of the patients had remission of symptoms with normal cognitive function 1.5 and 3 years later, 21.3% showed a fluctuating course, 14.8% had stable symptoms, and 22.4% had progression to dementia. Patients were at higher risk for advancing from one course to the next along this spectrum if they had symptoms of depression, impairment in more than 1 cognitive domain, or more severe cognitive impairment, or were older. The result on a test of the ability to learn and reproduce new material 10 minutes later was the best indicator at baseline for differentiating between remittent and progressive MCI. Symptoms of depression modified the prognosis.

CONCLUSIONS

In primary care, about one-quarter of patients with MCI have progression to dementia within the next 3 years. Assessments of memory function and depressive symptoms are helpful in predicting a progressive vs a remittent course. When transferring the concept of MCI into clinical diagnostic algorithms (eg, DSM-5), however, we should not forget that three-quarters of patients with MCI stayed cognitively stable or even improved within 3 years. They should not be alarmed unnecessarily by receiving such a diagnosis.     

Reservoir and excess pressures predict cardiovascular events in high-risk patients

Background

Analysis of the arterial pressure curve plays an increasing role in cardiovascular risk stratification. Measures of wave reflection and aortic stiffness have been identified as independent predictors of risk. Their determination is usually based on wave propagation models of the circulation. Another modeling approach relies on modified Windkessel models, where pressure curves can be divided into reservoir and excess pressure. Little is known of their prognostic value.

Methods and results

The aim of this study is to evaluate the predictive value of parameters gained from reservoir theory applied to aortic pressure curves in a cohort of high-risk patients. Furthermore the relation of these parameters to those from wave separation analysis is investigated.Central pressure curves from 674 patients with preserved ejection fraction, measured by radial tonometry and a validated transfer function, were analyzed. A high correlation between the amplitudes of backward traveling pressure waves and reservoir pressures was found (R = 0.97). Various parameters calculated from the reservoir and excess pressure waveforms predicted cardiovascular events in univariate Cox proportional hazards modeling. In a multivariate model including several other risk factors such as brachial blood pressure, the amplitude of reservoir pressure remained a significant predictor (HR = 1.37 per SD, p = 0.016).

Conclusions

Based on very different models, parameters from reservoir theory and wave separation analysis are closely related and can predict cardiovascular events to a similar extent. Although Windkessel models cannot describe all of the physiological properties of the arterial system, they can be useful to analyze its behavior and to predict cardiovascular events.     

Biomechanical Evaluation of Platform Switching: Different Mismatch Sizes,Connection Types,and Implant Protocols

Background: It is not yet well understood to what extent different implant–abutment mismatch sizes and implant–abutment connection types may influence the peri‐implant biomechanical environment of implants in different clinical situations. Methods: Computed tomography–based finite element models comprising a maxillary central incisor socket and 4.5 × 13 mm outer‐diameter implants with external and internal hex connection types were constructed. The abutments were designed with diameters of 3.5 mm (platform switching [PS] with 1 mm of diametral mismatch [PS ? 1]), 4.0 mm (PS with 0.5 mm of diametral mismatch [PS ? 0.5]), and 4.5 mm (conventional matching implant–abutment design [CD]). Analysis of variance at the 95% confidence interval was used to evaluate peak equivalent strain (EQV strain) in the bone, bone volume affected by a strain >4,000 με (EQV strain >4,000 με), the peak von Mises stress (EQV stress) in abutment screw, and the bone–implant relative displacement. Results: Similar bone strain levels (EQV strain and EQV strain >4,000 με) were encountered in PS ? 1, PS ? 0.5, and CD models for immediately placed implants, independent of the connection type. For immediately loaded implants, slightly smaller peak EQV strain and EQV strain >4,000 με were found for PS ? 1. However, for both connection types in osseointegrated models, the higher the mismatch size, the lesser the amount of strain found. Conclusions: The increase in mismatch size of PS configuration results in a significant decrease of strain levels in bone for osseointegrated implants, principally for external hex connections. No significant effect of PS could be noted in immediately placed implants.     

Impact of COMT genotype on serotonin-1A receptor binding investigated with PET

Alterations of the inhibitory serotonin-1A receptor (5-HT_1A) constitute a solid finding in neuropsychiatric research, particularly in the field of mood and anxiety disorders. Manifold factors influencing the density of this receptor have been identified, e.g., steroid hormones, sunlight exposure and genetic variants of serotonin-related genes. Given the close interactions between serotonergic and dopaminergic neurotransmission, we investigated whether a common single-nucleotide-polymorphism of the catechol-O-methyltransferase (COMT) gene (VAL158MET or rs4680) coding for a key enzyme of the dopamine network that is associated with the pathogenesis of mood disorders and antidepressant treatment response, directly affects 5-HT_1A receptor binding potential. Fifty-two healthy individuals (38 female, mean age ± standard deviation = 40.48 ± 14.87) were measured via positron emission tomography using the radioligand [carbonyl-¹¹C]WAY-100635. Genotyping for rs4680 was performed using DNA isolated from whole blood with the MassARRAY platform of the software SEQUENOM^®. Whole brain voxel-wise ANOVA resulted in a main effect of genotype on 5-HT_1A binding. Compared to A carriers (AA + AG) of rs4680, homozygote G subjects showed higher 5-HT_1A binding potential in the posterior cingulate cortex (F _(2,49) = 17.7, p = 0.05, FWE corrected), the orbitofrontal cortex, the anterior cingulate cortex, the insula, the amygdala and the hippocampus (voxel-level: p < 0.01 uncorrected, t > 2.4; cluster-level: p < 0.05 FWE corrected). In light of the frequently reported alterations of 5-HT_1A binding in anxiety and mood disorders, this study proposes a potential implication of the COMT genotype, more specifically the VAL158MET polymorphism, via modulation of the serotonergic neurotransmission.     

Biochemical analysis of the articular disc of the temporomandibular joint with magnetic resonance T2 mapping: a feasibility study

Objectives

Symptoms of temporomandibular joint (TMJ) dysfunction can seriously compromise patients' quality of life. The aim of our study was to use magnetic resonance imaging (MRI) T2 mapping of the articular disc to determine whether T2 mapping of the TMJ disc is feasible in routine clinical imaging and to assess the normal T2 relaxation time distribution within the TMJ.

Methods

Included were ten asymptomatic volunteers without pain, any mouth-opening limitations, or any clicking phenomena. MR imaging was performed on a 3-T MR scanner using a flexible, dedicated, eight-channel multielement coil. T2 mapping was performed in the oblique sagittal plane. The regions of interest (ROIs) for the T2 relaxation time maps of the disc were selected manually.

Results

The mean values for ROIs ranged between 22.4 and 28.8 ms, and the mean for all ROIs was 26.0?±?5.0 ms. Intraclass correlation (ICC) for interobserver variability was 0.698, and ICC for intraobserver variability was 0.861. There was no statistically significant difference between raters (p?=?0.091) or sides (p?=?0.810).

Conclusion

The T2 mapping technique enables ultrastructural analysis of the composition of TMJ disc. This biochemical technique is feasible in vivo, as shown in our study, when a high-field (3 T) MR and a dedicated TMJ coil are used.

Clinical relevance

T2 mapping as a biochemical technique, together with morphological MRI, may help to gain more insights into the physiology and into the pathophysiology of the articular disc in the TMJ noninvasively and in vivo.     

Concomitant overexpression of the EGFR and erbB-2 genes in renal cell carcinoma (RCC) is correlated with dedifferentiation and metastasis

Gene amplification or structural alteration of different erbB genes exerts a transforming effect in a variety of human neoplasms. Overexpression of the EGF receptor is associated with tumor initiation and progression of renal cell carcinoma (RCC). However, the role of erbB-2 in these processes remains unknown. We investigated 34 renal cell carcinomas for gene amplification and expression of the EGFR and erbB-2 genes at the mRNA and protein level and their relationship to pathological and clinical parameters. No amplification of both genes has been observed. However, high expression of the EGF receptor protein and p185erbB2 was frequent in RCC and statistically significantly related to higher tumor grades. We could demonstrate a close correlation of p185erbB2 overexpression with high EGF receptor levels. Co-overexpression of both receptor types was significantly associated with metastatic disease. Our results suggest a synergistic involvement of both EGF receptor and p185erbB2 in the progression of RCC. © 1996 Wiley-Liss, Inc.