The Calcium-Sensing Receptor Is Essential for Calcium and Bicarbonate Sensitivity in Human Spermatozoa.

Context: The calcium-sensing receptor (CaSR) is essential to maintain a stable calcium concentration in serum. Spermatozoa are exposed to immense changes in concentrations of CaSR ligands such as calcium, magnesium, and spermine during epididymal maturation, in the ejaculate, and in the female reproductive environment. However, the role of CaSR in human spermatozoa is unknown.

Heterozygous Mutation (Q459R) in the Calcium-Sensing Receptor Gene Causes Familial Hypocalciuric Hypercalcemia 1 (FHH1).

Context: Several heterozygous loss-of-function mutations in the calcium-sensing receptor gene (CASR) leading to elevated ionized serum calcium and familial hypocalciuric hypercalcemia 1 (FHH1) have been characterized. Few mutations are not pathogenic, and previous studies suggested that the Q459R mutation does not result in an FHH1 phenotype.

Objective: We identified a family with a heterozygous CASR Q459R mutation and characterized their calcium homeostasis and the pathophysiological mechanisms of a homozygous and heterozygous Q459R mutation in vitro.

Sensing Extracellular Calcium - An Insight into the Structure and Function of the Calcium-Sensing Receptor (CaSR).

The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that plays a key role in calcium homeostasis, by sensing free calcium levels in blood and regulating parathyroid hormone secretion in response. The CaSR is highly expressed in parathyroid gland and kidney where its role is well characterised, but also in other tissues where its function remains to be determined. The CaSR can be activated by a variety of endogenous ligands, as well as by synthetic modulators such as Cinacalcet, used in the clinic to treat secondary hyperparathyroidism in patients with chronic kidney disease.

Calcium-Sensing Receptor Internalization Is -Arrestin-Dependent and Modulated by Allosteric Ligands.

G protein-coupled receptor (GPCR) internalization is crucial for the termination of GPCR activity, and in some cases is associated with G protein-independent signaling and endosomal receptor signaling. To date, internalization has been studied in great detail for class A GPCRs; whereas it is not well established to what extent the observations can be generalized to class C GPCRs, including the extracellular calcium-sensing receptor (CaSR). The CaSR is a prototypical class C GPCR that maintains stable blood calcium (Ca) levels by sensing minute changes in extracellular free Ca It is thus necessary that the activity of the CaSR is tightly regulated, even while continuously being exposed to its endogenous agonist.

Accuracy and reproducibility of CT right-to-left ventricular diameter measurement in patients with acute pulmonary embolism.

Background: Right ventricular (RV) dysfunction caused by acute pulmonary embolism (PE) is associated with poor short- and long-term prognosis. RV dilatation as a proxy for RV dysfunction can be assessed by calculating the right-to-left ventricle diameter (RV/LV) ratio on standard computed tomography pulmonary angiography (CTPA) images. It is unknown whether dedicated training is required to accurately and reproducibly measure RV/LV ratio therefore we aimed to assess these parameters in residents in internal medicine without experience in CTPA reading.

Is a normal computed tomography pulmonary angiography safe to rule out acute pulmonary embolism in patients with a likely clinical probability? A patient-level meta-analysis.

A normal computed tomography pulmonary angiography (CTPA) remains a controversial criterion for ruling out acute pulmonary embolism (PE) in patients with a likely clinical probability. We set out to determine the risk of VTE and fatal PE after a normal CTPA in this patient category and compare these risk to those after a normal pulmonary angiogram of 1.7 % (95 %CI 1.

The original and simplified Wells rules and age-adjusted D-dimer testing to rule out pulmonary embolism: an individual patient data meta-analysis.

Unlabelled: Essentials Evidence for the simplified Wells rule in ruling out acute pulmonary embolism (PE) is scarce. This was a post-hoc analysis on data from 6 studies comprising 7268 patients with suspected PE. The simplified Wells rule combined with age-adjusted D-dimer testing may safely rule out PE.

Wells Rule and d-Dimer Testing to Rule Out Pulmonary Embolism: A Systematic Review and Individual-Patient Data Meta-analysis.

Background: The performance of different diagnostic strategies for pulmonary embolism (PE) in patient subgroups is unclear.

Purpose: To evaluate and compare the efficiency and safety of the Wells rule with fixed or age-adjusted d-dimer testing overall and in inpatients and persons with cancer, chronic obstructive pulmonary disease, previous venous thromboembolism, delayed presentation, and age 75 years or older.

Data Sources: MEDLINE and EMBASE from 1 January 1988 to 13 February 2016.

PO-07 - Excluding pulmonary embolism in cancer patients using the Wells rule and age-adjusted D-dimer testing: an individual patient data meta-analysis.

Introduction: Among patients with clinically suspected pulmonary embolism (PE), imaging and anticoagulant treatment can be safely withheld in approximately one-third of patients based on the combination of a "PE unlikely" Wells score and a D-dimer below the age-adjusted threshold. The clinical utility of this diagnostic approach in cancer patients is less clear.

Aim: To evaluate the efficiency and failure rate of the original and simplified Wells rules in combination with age-adjusted D-dimer testing in patients with active cancer.

Getting from A to B-exploring the activation motifs of the class B adhesion G protein-coupled receptor subfamily G member 4/GPR112.

The adhesion G protein-coupled receptors [ADGRs/class B2 G protein-coupled receptors (GPCRs)] constitute an ancient family of GPCRs that have recently been demonstrated to play important roles in cellular and developmental processes. Here, we describe a first insight into the structure-function relationship of ADGRs using the family member ADGR subfamily G member 4 (ADGRG4)/GPR112 as a model receptor. In a bioinformatics approach, we compared conserved, functional elements of the well-characterized class A and class B1 secretin-like GPCRs with the ADGRs.

Thromboembolic resolution assessed by CT pulmonary angiography after treatment for acute pulmonary embolism.

The systematic assessment of residual thromboembolic obstruction after treatment for acute pulmonary embolism (PE) has been understudied. This assessment is of potential clinical importance, should clinically suspected recurrent PE occur, or as tool for risk stratification of cardiopulmonary complications or recurrent venous thromboembolism (VTE). This study aimed to assess the rate of PE resolution and its implications for clinical outcome.

A simple decision rule including D-dimer to reduce the need for computed tomography scanning in patients with suspected pulmonary embolism.

Background: An 'unlikely' clinical decision rule with a negative D-dimer result safely excludes pulmonary embolism (PE) in 30% of presenting patients. We aimed to simplify this diagnostic approach and to increase its efficiency.

Methods: Data for 723 consecutive patients with suspected PE were analyzed (prevalence of PE, 22%).

Performance of a diagnostic algorithm based on a prediction rule, D-dimer and CT-scan for pulmonary embolism in patients with previous venous thromboembolism. A systematic review and meta-analysis.

Diagnostic management of suspected pulmonary embolism (PE) in patients with a history of venous thromboembolism (VTE) is complicated due to persistent abnormal D-dimer levels, residual embolic obstruction and higher clinical prediction rule (CPR) scores. We aimed to evaluate the safety and efficiency of the standard diagnostic algorithm consisting of a CPR, D-dimer test and computed tomography pulmonary angiography (CTPA) in this specific patient category. We performed a systematic literature search for prospective studies evaluating a diagnostic algorithm in consecutive patients with clinically suspected PE and a history of VTE.

Optimization of the diagnostic management of clinically suspected pulmonary embolism in hospitalized patients.

Identical diagnostic algorithms for suspected pulmonary embolism (PE) are used for hospitalized patients and outpatients, while D-dimer levels, risk factors and pre-test probability for PE differ, and the percentage of patients managed without computerized tomography pulmonary angiography (CTPA) is lower in hospitalized patients. We aimed to improve the efficiency of the diagnostic algorithm by increasing the threshold of the D-dimer, the threshold of the Wells rule and by adjustments of the Wells rule. Six-hundred and twenty-four hospitalized patients from two previously performed management studies with a PE prevalence of 26% were studied.

Diagnostic outcome management study in patients with clinically suspected recurrent acute pulmonary embolism with a structured algorithm.

Introduction: The value of diagnostic strategies in patients with clinically suspected recurrent pulmonary embolism (PE) has not been established. The aim was to determine the safety of a simple diagnostic strategy using the Wells clinical decision rule (CDR), quantitative D-dimer testing and computed tomography pulmonary angiography (CTPA) in patients with clinically suspected acute recurrent PE.

Materials And Methods: Multicenter clinical outcome study in 516 consecutive patients with clinically suspected acute recurrent PE without using anticoagulants.

Quality of life after pulmonary embolism as assessed with SF-36 and PEmb-QoL.

Introduction: Although quality of life (QoL) is recognized as an important indicator of the course of a disease, it has rarely been addressed in studies evaluating the outcome of care for patients with pulmonary embolism (PE). This study primarily aimed to evaluate the QoL of patients with acute PE in comparison to population norms and to patients with other cardiopulmonary diseases, using a generic QoL questionnaire. Secondary, the impact of time period from diagnosis and clinical patient characteristics on QoL was assessed, using a disease-specific questionnaire.

Variable D-dimer thresholds for diagnosis of clinically suspected acute pulmonary embolism.

Background: Computed tomography pulmonary angiography (CTPA) is frequently requested using diagnostic algorithms for suspected pulmonary embolism (PE). For suspected deep vein thrombosis, it was recently shown that doubling the D-dimer threshold in patients with low pretest probability safely decreased the number of ultrasonograms. We evaluated the safety and efficiency of a similar strategy in patients with suspected PE.

Chronic pulmonary embolism and pulmonary hypertension.

Incomplete resolution of acute pulmonary embolism (PE) is frequently observed after acute PE and may rarely result in chronic thromboembolic pulmonary hypertension (CTEPH). The underlying pathophysiological mechanism is largely unknown. Evidence underlines the concept of a dual pulmonary vascular compartment model consisting of increased pulmonary vascular resistance by both large vessel obstruction and distal small vessel obliteration, the latter initiated by pathological vascular remodeling.

Imaging tests in the diagnosis of pulmonary embolism.

Imaging modalities play an essential role in diagnosing pulmonary embolism (PE). Clinical outcome studies demonstrated that PE can be safely ruled out in patients with unlikely clinical probability in combination with a normal D-dimer test result; in all other patients additional imaging is needed. The aim is to accurately confirm or rule out the diagnosis of PE, after which, if indicated, anticoagulant treatment can be initiated.

The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded.

Four clinical decision rules (CDRs) (Wells score, Revised Geneva Score (RGS), simplified Wells score and simplified RGS) safely exclude pulmonary embolism (PE), when combined with a normal D-dimer test. Recently, an age-adjusted cut-off of the D-dimer (patient's age x 10 μg/l) safely increased the number of patients above 50 years in whom PE could safely be excluded. We validated the age-adjusted D-dimer test and assessed its performance in combination with the four CDRs in patients with suspected PE.

Computed tomography pulmonary angiography as a single imaging test to rule out pulmonary embolism.

Purpose Of Review: The aim is to review the evidence on the diagnostic value of computed tomography pulmonary angiography (CTPA) as a single test to rule out acute pulmonary embolism by focussing on the most recent literature and potential alternative and additional imaging modalities or diagnostic strategies.

Recent Findings: Clinical outcome studies have demonstrated that, using algorithms with sequential diagnostic tests, pulmonary embolism can be safely ruled out in patients with a clinical probability indicating pulmonary embolism to be unlikely and a normal D-dimer test result. This obviates the need for additional radiological imaging tests in around one-third of patients.

Performance of 4 clinical decision rules in the diagnostic management of acute pulmonary embolism: a prospective cohort study.

Background: Several clinical decision rules (CDRs) are available to exclude acute pulmonary embolism (PE), but they have not been directly compared.

Objective: To directly compare the performance of 4 CDRs (Wells rule, revised Geneva score, simplified Wells rule, and simplified revised Geneva score) in combination with d-dimer testing to exclude PE.

Design: Prospective cohort study.

Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.

Background: Traditionally, patients with pulmonary embolism (PE) are initially treated in the hospital with low molecular weight heparin (LMWH). The results of a few small non-randomized studies suggest that, in selected patients with proven PE, outpatient treatment is potentially feasible and safe.

Objective: To evaluate the efficacy and safety of outpatient treatment according to predefined criteria in patients with acute PE.