Left ventricular shape-luminal pressure relationship An open-chest study

Summary Left ventricular dimensions were measured in Cd²⁺ arrested (presumably diastolic), openchest rats. Aortic pressure was maintained at 137 cm H₂O (100 mm Hg) and left-ventricular (luminal) pressures were established and maintained at their chosen values, each by means of reservoir systems. The selected left-ventricular pressures were chosen to be within or to even broaden the range of conceivable diastolic pressures (–3 to 48 cm H₂O). After in situ fixation with 4 % formaldehyde and gelatin embedding, the hearts were serially sectioned in the apex base direction to obtain information at 11 levels (10, 20, ... 90, 100%). Tracings of selected sections were made along the edge of the left ventricular lumen and the pericardial surface. Volumes, surface areas, and mean external and internal radii of the left ventricle were derived. To quantify the circularity of sections a form factor (FF) was introduced (FF = 1 for a circular cross-section and less than one for other shapes). Ventricular lengths, radial dimensions, endocardial and epicardial surface areas, and total and luminal volumes increased with the increasing intraventricular pressures; as expected, the wall simultaneously thinned. Though its appearance was altered by the wall thinning, the curving muscle fascicular pattern was present over the entire pressure range examined. Endocardial surface areas increased more than did the epicardial surface areas. The endocardial FF value increased (more circular) at each section level as the pressure increased. The epicardial FF relationship was apparently constant (0.798 ± 0.014) for all section levels from 10 % through 90 %, regardless of luminal pressure. These results, when taken in conjunction with the results of our previous published studies, prompted the following speculation.The wall of the diastolic ventricle is a fluid-filled chamber with intramyocardial pressures that may be higher than ventricular pressures.     

Baseline Characteristics and Early Blood Pressure Control in the CONVINCE Trial

-Blood pressure (BP) control rates around the world are suboptimal. Part 2 of the National Health and Nutrition Educational Survey (NHANES) III indicates that only 27.4% of hypertensive Americans aged 18 to 74 years have a BP of <140/90 mm Hg. We wanted to assess BP control during the first 2 years and to describe the baseline characteristics of patients enrolled in the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Study, an international clinical trial that compares outcomes in hypertensive patients randomized to initial treatment with either controlled-onset extended-release verapamil or the investigator's choice of atenolol or hydrochlorothiazide. At randomization, BP was <140/90 mm Hg in only 20.3% of the 16 602 subjects (average+/-SD age 65.6+/-7.4 years; 56% women, 84% white/7% black/7% Hispanic). The average BP at enrollment was 148/85 mm Hg for patients taking BP medications (n=13 879) and 161/94 mm Hg for previously untreated patients (n=2723). After medication titration, with a transtelephonic computer that recommended an increase in the dose or number of antihypertensive agents whenever the BP was 140/90 mm Hg, 84.8% of the subjects attained the goal BP. During 2 years of treatment, BP control was maintained in 67% to 69% of the subjects (69% to 71% for systolic BP of <140 mm Hg and 90% for diastolic BP of <90 mm Hg). These data suggest that the control of systolic BP is more difficult than the control of diastolic BP. The US national goal of having 50% of hypertensives with a BP of <140/90 mm Hg may be achievable if a forced titration strategy is used. Interested investigators, free care and medications, and well-educated subjects may make the attainment of such a goal easier in the CONVINCE study than in the general population.     

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.     

Functional impact of a recently identified quantitative trait locus for hippocampal volume with genome-wide support

In a large brain-imaging study, a multinational consortium has recently identified a common genetic variation in rs7294919 being associated with hippocampal volume. Here, we explored whether this quantitative trait locus also affects hippocampal function using a previously established reliable neuroimaging paradigm. We observed a significant effect of rs7294919 variation in the right hippocampus showing that hippocampal activation increased with the number of risk alleles. Furthermore, the risk allele was associated with decreased performance in a verbal learning and memory task. By showing that this single-nucleotide polymorphism also relates to behavioral difference and underlying brain activation in memory, our findings support the idea that rs7294919 may affect the individual capacity to resist disease in terms of diminishing or boosting hippocampal resources.     

Prognostic value of histamine H1 receptor expression in oral squamous cell carcinoma

Objectives

Overexpression of the histamine H1 receptor (H1R) has been described in a variety of tumor models, but experience in oral squamous cell carcinomas (OSCC) is not available. Current adjuvant treatment options for OSCC can be improved by the identification of new targets of therapy. Herein, we evaluated H1R expression in a large patient cohort of OSCC.

Materials and methods

H1R immunoexpression was evaluated in 191 cases of OSCC and two OSCC cell lines BICR56 and BICR3. Scanned images were digitally analyzed using ImageJ and the immunomembrane plug-in. The combined score of computer-assisted semiquantitative analysis was correlated with manually counted percentages of tumor cells by Kendall’s tau (т) correlation coefficient. Disease-free survival times were estimated using the Kaplan–Meier method and were compared by using the log-rank test. Multivariate analyses were performed using the Cox proportional hazards model.

Results

H1R was rarely expressed in OSCC but significantly related with advanced tumor stages (n?=?21/191, mean expression 63.5 % of cancer cells in positive tumor samples, 95 % confidence interval of the mean 53.5 to 73.6 %, p?=?0.006). Following univariate analysis, patients with H1R expression showed a significant poorer prognosis (p?=?0.0004). Multivariate analysis revealed H1R expression as an independent prognostic factor (p?=?0.0164). Expression of H1R in cancer cell lines was confirmed by specific staining of OSCC cell lines BICR56 and BICR3.

Conclusion

This is the first study focusing on H1R expression showing a significant poorer DFS rate in the H1R+ patient cohort. Based on these data, H1R activation may promote carcinogenesis in OSCC.

Clinical relevance

Investigation of H1R regulation and its antagonists shows a clear rationale for future supportive anticancer therapies in OSCCs.