Task-specific magnetic fields from the left human frontal cortex

Summary In this study we attempted to extend our previous results on regional specialization of frontal cortical function in humans, by means of magnetoencephalography (MEG). We used a verbal task and predicted that some part of the left frontal lobe would be active during engagement in that task, since the left hemisphere is known to be implicated in language. We did not require a motor response because in previous experiments we observed bilateral frontal magnetic activity, and we suspected that it was due to the addition of movement-related fields to our recordings. Six right handed subjects (three males and three females) participated in the study. The task consisted in silently counting the number of word pairs that matched with respect to semantic category. Experimental runs were composed by series of 120 trials or word pairs. All six subjects presented dipolar magnetic field distributions on the left fronto-temporal area of the scalp, but not on the right, during different portions of the trial duration. These fields were successfully modeled as equivalent current dipoles (ECDs). The spatial ECD coordinates were translated onto magnetic resonance image (MRI) coordinates for each subject. The dipole positions were typically near the cortical surface corresponding to areas 6 and 44 of Brodmann. No dipole-like sources were observed in the right frontal lobe.This research was supported by grant NS 29540-005A1 from the National Institutes of Health, Washington, D.C.     

Fetal heart rate and umbilico-placental Doppler flow velocity waveforms in early pregnancies with a chromosomal abnormality and/or an increased nuchal translucency thickness

Fetal heart rate, umbilical artery pulsatility index, end-diastolicflow,nuchal translucency thickness and placental thickness were recordedin 250 women with a viable singleton pregnancy undergoing chorionicvillous sampling for fetal karyotyping at 11–14 weeksof gestation. The fetal karyotype was normal in 210 cases andabnormal in 40, including 21 with trisomy 21, 13 with trisomy18, three with triploidy, two with monosomy X and one with trisomy13. A total of 52 fetuses with a normal karyotype had a nuchaltranslucency 3 mm and were considered separately. There wasa stable and significant increase in the mean fetal heart ratein trisomy 21 pregnancies compared to controls. No significantdifference was found for the other variables between the groups.In chromosomally normal fetuses with an increased nuchal thickness,the development of fetal heart rate and compliance of the umbilico-placentalcirculation were within the normal ranges. Some fetuses withtrisomy 18 or triploidy had an increased resistance to bloodflow in the umbilical artery, which was probably due to abnormalplacental development.     

Neural networks involved in mathematical thinking: evidence from linear and non-linear analysis of electroencephalographic activity

Using linear and non-linear methods, electroencephalographic (EEG) signals were measured at various brain regions to provide information regarding patterns of local and coordinated activity during performance of three arithmetic tasks (number comparison, single-digit multiplication, and two-digit multiplication) and two control tasks that did not require arithmetic operations. It was hypothesized that these measures would reveal the engagement of local and increasingly complex cortical networks as a function of task specificity and complexity. Results indicated regionally increased neuronal signalling as a function of task complexity at frontal, temporal and parietal brain regions, although more robust task-related changes in EEG-indices of activation were derived over the left hemisphere. Both linear and non-linear indices of synchronization among EEG signals recorded from over different brain regions were consistent with the notion of more "local" processing for the number comparison task. Conversely, multiplication tasks were associated with a widespread pattern of distant signal synchronizations, which could potentially indicate increased demands for neural networks cooperation during performance of tasks that involve a greater number of cognitive operations.     

Enhanced mRNA expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in breast carcinomas is correlated with adverse prognosis

Tissue inhibitor of metalloproteinase-1 (TIMP-1) has emerged as a multifunctional protein with the contrasting activities of inhibiting tissue-degrading enzymes and promoting cellular growth. In an attempt to elucidate the clinical significance of TIMP-1 in breast cancer, the expression of TIMP-1 mRNA was evaluated in 117 invasive breast carcinomas by mRNA in situ hybridization, in correlation with clinicopathological parameters, immunohistochemical prognostic factors (Ki-67, c-erb-B-2, bcl-2) and clinical outcome. TIMP-1 was detected in stromal cells in areas within the tumours and at the tumour margin. High TIMP-1 mRNA expression in the marginal portion of the tumours was significantly correlated with lymph node metastasis (p<0.05) and c-erbB-2 expression (p<0.05). On the other hand, increased TIMP-1 mRNA expression within the tumours showed a statistically significant correlation with ER detection (p<0.01). Multivariate analysis revealed worse survival for patients with high TIMP-1 mRNA expression in the marginal portion of the tumours; the subgroup of these patients co-expressing high levels of TIMP-1 mRNA within the tumours as well had even worse survival (p=0.042). In conclusion, our data support the multifunctional role of TIMP-1, particularly its growth-promoting activity, on the basis of its significant correlation with lymph node metastasis and adverse prognosis. In addition to the latter property, a probable association of TIMP-1 with tumour cell differentiation is suggested by its topographical correlation with ER detection.     

Regulation of T-cell receptor signalling by membrane microdomains

There is now considerable evidence suggesting that the plasma membrane of mammalian cells is compartmentalized by functional lipid raft microdomains. These structures are assemblies of specialized lipids and proteins and have been implicated in diverse biological functions. Analysis of their protein content using proteomics and other methods revealed enrichment of signalling proteins, suggesting a role for these domains in intracellular signalling. In T lymphocytes, structure/function experiments and complementary pharmacological studies have shown that raft microdomains control the localization and function of proteins which are components of signalling pathways regulated by the T-cell antigen receptor (TCR). Based on these studies, a model for TCR phosphorylation in lipid rafts is presented. However, despite substantial progress in the field, critical questions remain. For example, it is unclear if membrane rafts represent a homogeneous population and if their structure is modified upon TCR stimulation. In the future, proteomics and the parallel development of complementary analytical methods will undoubtedly contribute in further delineating the role of lipid rafts in signal transduction mechanisms.     

Effects of Three Different Family-Based Interventions in Overweight and Obese Children: The “4 Your Family” Randomized Controlled Trial

Childhood overweight and obesity prevalence has risen dramatically in the past decades, and family-based interventions may be an effective method to improve children’s eating behaviors. This study aimed to evaluate the effectiveness of three different family-based interventions: group-based, individual-based, or by website approach. Parents and school aged overweight or obese children, 8–12 years of age, were eligible for the study. A total of 115 children were randomly allocated in one of the three interventions, and 91 completed the study (79% compliance); Group 1 (n = 36) received group-based interventions by various experts; Group 2 (n = 30) had interpersonal family meetings with a dietitian; and Group 3 (n = 25) received training through a specifically developed website. Anthropometric, dietary, physical activity, and screen time outcomes were measured at baseline and at the end of the study. Within-group comparisons indicated significant improvement in body weight, body mass index (BMI)-z-score, physical activity, and screen time from baseline in all three study groups (p < 0.05). Furthermore, total body fat percentage (%TBF) was also decreased in Groups 2 and 3. Between-group differences varied with body weight and %TBF change, being larger in Group 3 compared to Groups 1 and 2, in contrast to BMI-z-score, screen time, and health behaviors, which were significantly larger in Group 2 than the other two groups. In conclusion, personalized family-based interventions are recommended to successfully improve children’s lifestyle and body weight status.     

Dietary Interventions with Polyphenols in Osteoarthritis: A Systematic Review Directed from the Preclinical Data to Randomized Clinical Studies

Osteoarthritis (OA) is the most common form of arthritis and a major cause of limited functionality and thus a decrease in the quality of life of the inflicted. Given the fact that the existing pharmacological treatments lack disease-modifying properties and their use entails significant side effects, nutraceuticals with bioactive compounds constitute an interesting field of research. Polyphenols are plant-derived molecules with established anti-inflammatory and antioxidant properties that have been extensively evaluated in clinical settings and preclinical models in OA. As more knowledge is gained in the research field, an interesting approach in the management of OA is the additive and/or synergistic effects that polyphenols may have in an optimized supplement. Therefore, the aim of this review was to summarize the recent literature regarding the use of combined polyphenols in the management of OA. For that purpose, a PubMed literature survey was conducted with a focus on some preclinical osteoarthritis models and randomized clinical trials on patients with osteoarthritis from 2018 to 2021 which have evaluated the effect of combinations of polyphenol-rich extracts and purified polyphenol constituents. Data indicate that combined polyphenols may be promising for the treatment of osteoarthritis in the future, but more clinical trials with novel approaches in the identification of the in-between relationship of such constituents are needed.     

Correction to: A systematic review of economic evaluations of enzyme replacement therapy in Lysosomal storage diseases

In December 2019, the Digital Health Care Act (“Digitale-Versorgung-Gesetz”) introduced a general entitlement to the provision and reimbursement of digital health applications (DiGA) for insured persons in the German statutory health insurance. As establishing a new digital service area within the solidarity-based insurance system implies several administrative and regulatory challenges, this paper aims to describe the legal framework for DiGA market access and pricing as well as the status quo of the DiGA market. Furthermore, we provide a basic approach to deriving value-based DiGA prices. To become eligible for reimbursement, the Federal Institute for Drugs and Medical Devices evaluates the compliance of a DiGA with general requirements (e.g., safety and data protection) and its positive healthcare effects (i.e., medical benefit or improvements of care structure and processes) in a fast-track process. Manufacturers may provide evidence for the benefits of their DiGA either directly with the application for the fast-track process or generate it during a trial phase that includes temporary reimbursement. After one year of \]reimbursement, the freely-set manufacturer price is replaced by a price negotiated between the National Association of Statutory Health Insurance Funds and the manufacturer. By February 2022, 30 DiGA had successfully completed the fast-track process. 73% make use of the trial phase and have not yet proven their benefit. Given this dynamic growth of the DiGA market and the low minimum evidence standards, fair pricing remains the central point of contention. The regulatory framework makes the patient-relevant benefits of a DiGA a pricing criterion to be considered in particular. Yet, it does not indicate how the benefits of a DiGA should be translated into a reasonable price. Our evidence-based approach to value-based DiGA pricing approximates the SHI’s willingness to pay by the average cost-effectiveness of one or more established therapy in a field of indication and furthermore considers the positive healthcare effects of a DiGA. The proposed approach can be fitted into DiGA pricing processes under the given regulatory framework and can provide objective guidance for price negotiations. However, it is only one piece of the pricing puzzle, and numerous methodological and procedural issues related to DiGA pricing are still open. Thus, it remains to be seen to what extent DiGA prices will follow the premise of value-based pricing.