Hypertension management in the Multiple Risk Factor Intervention Trial (MRFIT). Six-year intervention results for men in special intervention and usual care groups

The Multiple Risk Factor Intervention Trial was a large collaborative primary prevention trial designed to test the effects of lowering cardiovascular risk factors (ie, diastolic blood pressure [DBP], serum cholesterol, and cigarette smoking) on mortality rate from coronary heart disease in 12,866 high-risk men aged 35 to 57 years. Men were randomly assigned to either special intervention (SI) or usual care (UC) groups. Usual care men were referred to their regular source of medical care. Special intervention men were seen frequently and underwent intensive intervention initially followed by maintenance intervention in 22 different clinical centers. Hypertension intervention in SI men primarily consisted of a stepped-care pharmacologic approach designed to lower blood pressure (BP). After six years, 58.2% of SI men and 47.0% of UC men were given antihypertensive medication. In both study groups, mean systolic and diastolic BPs decreased from baseline; after six years, overall DBP was 3.2 mm Hg lower in SI men compared with UC men. In hypertensive men (DBP greater than or equal to 90 mm Hg or those taking antihypertensive medication at baseline), after six years, DBP was 4.4 mm Hg lower in the SI group compared with the UC group. Use of specific antihypertensive agents differed substantially between the two groups. Self-reported complaints while taking antihypertensive drugs were minimal in both groups. Weight loss was associated with BP lowering in both study groups, regardless of treatment status.     

Deep Artificial Neural Networks Reveal a Distributed Cortical Network Encoding Propositional Sentence-Level Meaning

Understanding how and where in the brain sentence-level meaning is constructed from words presents a major scientific challenge. Recent advances have begun to explain brain activation elicited by sentences using vector models of word meaning derived from patterns of word co-occurrence in text corpora. These studies have helped map out semantic representation across a distributed brain network spanning temporal, parietal, and frontal cortex. However, it remains unclear whether activation patterns within regions reflect unified representations of sentence-level meaning, as opposed to superpositions of context-independent component words. This is because models have typically represented sentences as “bags-of-words” that neglect sentence-level structure. To address this issue, we interrogated fMRI activation elicited as 240 sentences were read by 14 participants (9 female, 5 male), using sentences encoded by a recurrent deep artificial neural-network trained on a sentence inference task (InferSent). Recurrent connections and nonlinear filters enable InferSent to transform sequences of word vectors into unified “propositional” sentence representations suitable for evaluating intersentence entailment relations. Using voxelwise encoding modeling, we demonstrate that InferSent predicts elements of fMRI activation that cannot be predicted by bag-of-words models and sentence models using grammatical rules to assemble word vectors. This effect occurs throughout a distributed network, which suggests that propositional sentence-level meaning is represented within and across multiple cortical regions rather than at any single site. In follow-up analyses, we place results in the context of other deep network approaches (ELMo and BERT) and estimate the degree of unpredicted neural signal using an “experiential” semantic model and cross-participant encoding.SIGNIFICANCE STATEMENT A modern-day scientific challenge is to understand how the human brain transforms word sequences into representations of sentence meaning. A recent approach, emerging from advances in functional neuroimaging, big data, and machine learning, is to computationally model meaning, and use models to predict brain activity. Such models have helped map a cortical semantic information-processing network. However, how unified sentence-level information, as opposed to word-level units, is represented throughout this network remains unclear. This is because models have typically represented sentences as unordered “bags-of-words.” Using a deep artificial neural network that recurrently and nonlinearly combines word representations into unified propositional sentence representations, we provide evidence that sentence-level information is encoded throughout a cortical network, rather than in a single region.     

Influence of clodronate and compressive force on IL-1ß-stimulated human periodontal ligament fibroblasts

Objectives

The aim of this study was to investigate in vitro the effect of clodronate on interleukin-1ß (IL-1ß)–stimulated human periodontal ligament fibroblasts (HPdLFs) with the focus on inflammatory factors of orthodontic tooth movement with and without compressive force.

Materials and methods

HPdLFs were incubated with 5 μM clodronate and 10 ng/mL IL-1ß. After 48 h, cells were exposed to 3 h of compressive force using a centrifuge. The gene expression of cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), matrix metalloproteinase 8 (MMP-8), and the tissue inhibitor of MMP (TIMP-1) was analyzed using RT-PCR. Prostaglandin E2 (PGE-2), IL-6, and TIMP-1 protein syntheses were quantified via ELISA.

Results

Compressive force and IL-1ß induced an overexpression of COX-2 gene expression (61.8-fold; p < 0.05 compared with control), diminished by clodronate (41.1-fold; p < 0.05 compared with control). Clodronate slowed down the compression and IL-1ß induced IL-6 gene expression (161-fold vs. 85.6-fold; p < 0.05 compared with control). TNF-α was only slightly affected without statistical significance. Clodronate reduced IL-1ß-stimulated MMP-8 expression with and without compressive force. TIMP-1 on gene and protein level was downregulated in all groups. Analyzing the MMP-8/TIMP-1 ratio, the highest ratio was detected in IL-1ß-stimulated HPdLFs with compressive force (21.2-fold; p < 0.05 compared with control). Clodronate diminished IL-1ß-induced upregulation of MMP-8/TIMP-1 ratio with (11.5-fold; p < 0.05 compared with control) and without (12.5-fold; p < 0.05 compared with control) compressive force.

Conclusion

Our study demonstrates a slightly anti-inflammatory effect by clodronate under compressive force in vitro. Additionally, the periodontal remodeling presented by the MMP-8/TIMP-1 ratio seems to be diminished by clodronate.

Clinical relevance

Reduction of pro-inflammatory factors and reduction of periodontal remodeling might explain reduced orthodontic tooth movement under clodronate intake.

     

Tumor-Stroma-Interaktionen im Harnblasenkarzinom

Die Urologie - Der histopathologische Aufbau maligner Tumoren schließt zwei Kompartimente ein – das Tumorparenchym mit den transformierten Zellen selbst und jene Strukturen, die deren...     

A focus on riociguat in the treatment of pulmonary arterial hypertension

Current treatment of pulmonary arterial hypertension (PAH) targets three signalling pathways: the nitric oxide (NO) pathway, the endothelin pathway and the prostacyclin pathway. Riociguat is a soluble guanylate cyclase stimulator, acting via the NO pathway in a new way: unlike other common drugs targeting this pathway (eg tadalafil and sildenafil), riociguat acts independently of endogenous NO. This MiniReview focuses on PAH treatment with riociguat and on its advantages and disadvantages compared with other drugs targeting the NO pathway. In the PATENT‐1 trial (NCT00810693), riociguat improved significantly the 6‐minute walking distance in patients suffering from PAH, with a mean difference (MD) of 36 m compared with a placebo group. The results are comparable to those found for its competitors tadalafil (MD of 33 m) and sildenafil (MD of 50 m) in the PHIRST‐1 trial (NCT00125918) and the SUPER‐1 trial (NCT00644605). No obvious advantages were found regarding pharmacokinetic features and adverse events. In the RESPITE study (NCT02007629), patients with PAH with insufficient response to treatment with tadalafil or sildenafil were switched to riociguat. These results indicate that riociguat might be superior regarding efficacy to PDE‐5 inhibitors in a patient group, where endogenous NO production might be insufficient. This finding was further examined in the REPLACE study (NCT02891850). Moreover, riociguat has shown promising anti‐proliferative, anti‐inflammatory and anti‐fibrotic effects in animal models. Further investigations are needed to determine whether this applies also to human beings. Taken together, riociguat induces vasodilation of the pulmonary arteries and leads to an improvement in the ability to carry out physical activity.     

State-Dependent Effects of Prefrontal Repetitive Transcranial Magnetic Stimulation on Emotional Working Memory

BackgroundA growing body of findings illustrates the importance of state-dependency in studies using brain stimulation.ObjectiveWe aimed to investigate the effects of tDCS priming followed by rTMS applied over the right dorsolateral prefrontal cortex (DLPFC) on emotional working memory.MethodsIn a randomized single-blind within-subjects design, participants performed an emotional 3-back task at baseline and after tDCS priming (anodal, cathodal) and subsequent low-frequency rTMS (active, sham) of the right DLPFC. Stimuli consisted of words related to the distinct emotion categories fear and anger as well as neutral words.ResultsTask accuracy increased for fear-related words and decreased for neutral words across stimulation conditions. No general state-dependent effects of prefrontal rTMS on working memory were found. We further showed a detrimental effect of negative emotional content on working memory performance.ConclusionsOur findings support a hemispheric lateralization of emotion processing by demonstrating that the withdrawal-related emotion fear is associated with the right DLPFC and contribute to clarifying the interaction between working memory and emotion.