Acute Myocardial Infarction due to External Compression of the Left Main Coronary Artery by a Large Pulmonary Artery Aneurysm.

BACKGROUND: Although rare, external compression of the left main coronary artery (LMCA) by a pulmonary arterial aneurysm (PAA) as a consequence of pulmonary arterial hypertension causing stable angina pectoris is well described. However, acute myocardial infarction is extremely rare, particularly with a full array of electrocardiographic, biochemical, and echocardiographic features, as in this scenario. CASE: In this case, a 62-year-old man with a past history of severe fibrotic lung disease was hospitalised with chest pain. The patient had dynamic anterolateral ischaemic changes on electrocardiography and serially elevated high-sensitivity troponin I. Transthoracic echocardiography revealed impaired left ventricular ejection fraction with anterolateral hypokinesis. Coronary angiography with intracoronary imaging revealed external compression of the LMCA. Computer tomography (CT) scans confirmed new PAA, compared to previous scans. The patient was successfully treated by percutaneous coronary stent implantation. CONCLUSION: Progressive dilatation of the pulmonary artery due to pulmonary arterial hypertension can result in acute MI secondary to external compression of the LMCA. Clinicians should be mindful of acute coronary syndromes in patients with long-standing pulmonary hypertension presenting with chest pain.

Opposing actions of the synapse-associated protein of 97-kDa molecular weight (SAP97) and Disrupted in Schizophrenia 1 (DISC1) on Wnt/ß-catenin signaling.

It has been suggested that synapse-associated protein of 97-kDa molecular weight (SAP97) is a susceptibility factor for childhood and adult neuropsychiatric disorders. SAP97 is a scaffolding protein that shares direct and indirect binding partners with the Disrupted in Schizophrenia 1 (DISC1) gene product, a gene with strong association with neuropsychiatric disorders. Here we investigated the possibility that these two proteins converge upon a common molecular pathway. Since DISC1 modifies Wnt/ß-catenin signaling via changes in glycogen synthase kinase 3 beta (GSK3ß) phosphorylation, we asked if SAP97 impacts Wnt/ß-catenin signaling and GSK3ß phosphorylation. We find that SAP97 acts as inhibitor of Wnt signaling activity and can suppress the stimulatory effects of DISC1 on ß-catenin transcriptional activity. Reductions in SAP97 abundance also decrease GSK3ß phosphorylation. In addition, we find that over expression of DISC1 leads to an increase in the abundance of SAP97, by inhibiting its proteasomal degradation. Our findings suggest that SAP97 and DISC1 contribute to maintaining Wnt/ß-catenin signaling activity within a homeostatic range by regulating GSK3ß phosphorylation.

Pharmacokinetics and pharmacodynamics of rilotumumab: a decade of experience in preclinical and clinical cancer research.

Rilotumumab is a fully human monoclonal antibody against hepatocyte growth factor, the only known ligand of the MET receptor. Over the last decade, rilotumumab has been extensively tested in preclinical studies and in clinical studies in a variety of cancer types. In this review, we examine the pharmacokinetic and pharmacodynamic data that have been collected in the rilotumumab programme to date, and discuss retrospectively how the knowledge acquired in this programme can be applied to a number of key issues in oncology drug development, including: (i) using preclinical data to inform first-in-human study design; (ii) the role of biomarkers in the identification of a target patient population; (iii) the potential for drug interactions between therapeutic proteins and other anticancer agents; and (iv) pharmacokinetic and pharmacodynamic considerations in phase 3 study design.

Exposure-response analysis of rilotumumab in gastric cancer: the role of tumour MET expression.

BACKGROUND: Rilotumumab, an investigational, monoclonal antibody, inhibits MET-mediated signalling. In a randomized phase 2 trial of rilotumumab±epirubicin/cisplatin/capecitabine in gastric or oesophagogastric junction cancer, patients receiving rilotumumab showed a trend towards improved survival, especially in MET-positive patients, but no clear dose-response relationship was observed. Exposure-response and biomarker analyses were used for dose selection and to differentiate patient subpopulations that may benefit most from treatment. Here, we analyse rilotumumab exposure-survival and exposure-safety and the impact of MET expression on these relationships. METHODS: Individual rilotumumab exposure parameters were generated using population pharmacokinetic modelling. Relationships among rilotumumab dose (7.5 and 15 mg kg(-1)), exposure, and clinical outcomes (progression-free survival (PFS) and overall survival (OS)) were evaluated with Cox regression models and Kaplan-Meier plots. MET status and other baseline covariates were evaluated in subgroup and multivariate analyses. Treatment-emergent adverse events were summarised by exposure. RESULTS: Among MET-positive patients, higher rilotumumab exposure, vs placebo and low exposure, was associated with improved median PFS (80% CI: 7.0 (5.7-9.7) vs 4.4 (2.9-4.9) and 5.5 (4.2-6.8) months) and OS (13.4 (10.6-18.6) vs 5.7 (4.7-10.2) and 8.1 (6.9-11.1) months) without increased toxicity. No rilotumumab benefit was seen among MET-negative patients. CONCLUSIONS: Rilotumumab had an exposure-dependent treatment effect in patients with MET-positive gastric or oesophagogastric junction cancer.

Automated cardiopulmonary resuscitation using a load-distributing band external cardiac support device for in-hospital cardiac arrest: a single centre experience of AutoPulse-CPR.

BACKGROUND: Poor quality cardiopulmonary resuscitation (CPR) predicts adverse outcome. During invasive cardiac procedures automated-CPR (A-CPR) may help maintain effective resuscitation. The use of A-CPR following in-hospital cardiac arrest (IHCA) remains poorly described. AIMS & METHODS: Firstly, we aimed to assess the efficiency of healthcare staff using A-CPR in a cardiac arrest scenario at baseline, following re-training and over time (Scenario-based training). Secondly, we studied our clinical experience of A-CPR at our institution over a 2-year period, with particular emphasis on the details of invasive cardiac procedures performed, problems encountered, resuscitation rates and in-hospital outcome (AutoPulse-CPR Registry). RESULTS: Scenario-based training: Forty healthcare professionals were assessed. At baseline, time-to-position device was slow (mean 59 (±24) s (range 15-96s)), with the majority (57%) unable to mode-switch. Following re-training time-to-position reduced (28 (±9) s, p<0.01 vs baseline) with 95% able to mode-switch. This improvement was maintained over time. AutoPulse-CPR Registry: 285 patients suffered IHCA, 25 received A-CPR. Survival to hospital discharge following conventional CPR was 28/260 (11%) and 7/25 (28%) following A-CPR. A-CPR supported invasive procedures in 9 patients, 2 of whom had A-CPR dependant circulation during transfer to the catheter lab. CONCLUSION: A-CPR may provide excellent haemodynamic support and facilitate simultaneous invasive cardiac procedures. A significant learning curve exists when integrating A-CPR into clinical practice. Further studies are required to better define the role and effectiveness of A-CPR following IHCA.

Romiplostim dose response in patients with immune thrombocytopenia.

A pharmacodynamic model was developed for platelet counts in 52 patients with immune thrombocytopenia (ITP) receiving subcutaneous romiplostim in 3 phase I/II studies (dose range, 0.2-10 µg/kg). The model consisted of a drug-sensitive progenitor cell compartment linked to a peripheral blood compartment through 4 transition compartments. The baseline platelet count, mean transit time, and kinetics of drug effect constant were 11.1 × 10(9)/L, 170 hours, and 0.6 day(-1), respectively. The ITP patients had a shorter platelet life span and lower progenitor cell production rates than healthy volunteers. Romiplostim response was described for 2 subpopulations. The romiplostim stimulatory effect in ITP patients was 351%/100 µg/wk and 12%/100 µg/wk in 68% and 32% of patients, respectively. Visual and numerical predictive checks suggested accurate prediction of platelet time course and durable response rate in ITP patients. Model-based simulations confirmed the effectiveness of dose reduction to prevent platelet counts >400 × 10(9)/L.

Changes in weight and metabolic parameters during treatment with antipsychotics and metformin: do the data inform as to potential guideline development? A systematic review of clinical studies.

BACKGROUND: Changes in weight and metabolic parameters have been commonly reported in patients with schizophrenia. Metformin has been evaluated in clinical studies to prevent or reduce weight gain and changes in metabolic parameters in non-diabetic subjects. We undertook a systematic review of the efficacy and safety of metformin in reducing weight gain and metabolic abnormalities in non-diabetic subjects with schizophrenia or bipolar disorder taking antipsychotic medication to establish if these data could potentially drive guideline development. METHODS: Medical databases were searched using terms including 'antipsychotic', 'atypical antipsychotic agent', 'antipsychotic agents', 'antipsychotic-drug' and 'metformin' and 'weight'. Studies reporting weight and/or metabolic outcomes in non-diabetic subjects with schizophrenia and bipolar disorder were included regardless of methodological type and subject age. RESULTS: Nine randomised double-blind studies and two open cohort studies evaluating metformin and changes in weight in trials up to 16 weeks were identified. In all, 495 participants received antipsychotics (mostly olanzapine), and three studies were in subjects aged < 18 years. The adult studies predominantly utilised non-Caucasian subjects with chronic schizophrenia. Weight and lifestyle intervention programmes were provided to all cohorts in eight studies, which confounded interpretation of the data. In ten studies, the addition of metformin to antipsychotic treatment was associated with either significantly attenuated weight gain or weight loss compared with control groups. Nine studies measured various glucose parameters. In four studies, subjects prescribed metformin had significantly improved glucose parameters relative to controls. The two studies of metformin in patients with first-episode schizophrenia demonstrated the largest improvement in weight and glucose parameters. CONCLUSIONS: Metformin may have some value in reducing or preventing weight gain and changes in metabolic parameters during treatment with antipsychotic medication particularly in first-episode psychosis; however, it has been predominantly studied short-term and in non-Caucasian populations. A number of new trials are due to report data 2009-2013 to aid definitive interpretation of the role of metformin. Further longer-term studies are warranted before definitive guidelines can be established.

Fetal radiation dose from CT pulmonary angiography in late pregnancy: a phantom study.

Pulmonary embolism (PE) is the leading direct cause of maternal mortality in the UK. Accurate diagnosis is important but, even though CT pulmonary angiography (CTPA) is the recommended imaging modality for PE in the general population, there is limited guidance for pregnant patients. Knowledge of the radiation doses to both the mother and the fetus is therefore important in the justification of CTPA in this situation. Dose measurements were made on three helical CT scanners, with an anthropomorphic phantom representing the chest and abdomen in late gestation. Estimated fetal doses from CT scans of the maternal chest were in the range of 60-230 microGy. Fetal dose reduction strategies (mA modulation, shielding with a lead coat, and a 5 cm shorter scan length) were investigated. These reduced the fetal dose by 10%, 35% and 56%, respectively. Fetal doses from a scan projection radiograph (SPR) of the maternal chest were insignificant when compared with the dose from a CT scan. However, if the SPR was not stopped before the "fetus" was directly irradiated, the dose measured on one scanner was 20 microGy.

Folate, homocysteine, endothelial function and cardiovascular disease. What is the link?

Elevated plasma homocysteine concentrations are associated with an increased risk of cardiovascular disease, but the relationship has not been proven to be causal. Folate is the strongest nutritional and pharmacological determinant of plasma homocysteine concentrations, which also interact with the genetic variation in methylenetetrahydrofolate reductase (MTHFR). Endothelial dysfunction due to reduced nitric oxide bioavailability is an early feature of vascular pathology. This can be assessed noninvasively by measurement of flow-mediated dilatation. Human studies on folic acid, homocysteine and endothelial function are reported. It is proposed that folic acid in high doses may have beneficial effects on endothelial function, which are independent of homocysteine lowering.

Flow-mediated dilatation following wrist and upper arm occlusion in humans: the contribution of nitric oxide.

Flow-mediated dilatation (FMD) of the brachial artery assessed by high-resolution ultrasound is widely used to measure endothelial function. However, the technique is not standardized, with different groups using occlusion of either the wrist or the upper arm to induce increased blood flow. The validity of the test as a marker of endothelial function rests on the assumption that the dilatation observed is endothelium-dependent and mediated by nitric oxide (NO). We sought to compare the NO component of brachial artery dilatation observed following wrist or upper arm occlusion. Dilatation was assessed before and during intra-arterial infusion of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) following occlusion of (i) the wrist (distal to ultrasound probe) and (ii) the upper arm (proximal to ultrasound probe) for 5 min in ten healthy males. Dilatation was significantly greater after upper arm occlusion (upper arm, 11.62+/-3.17%; wrist, 7.25+/-2.49%; P=0.003). During L-NMMA infusion, dilatation after wrist occlusion was abolished (from 7.25+/-2.49% to 0.16+/-2.24%; P<0.001), whereas dilatation after upper arm occlusion was only partially attenuated (from 11.62+/-3.17% to 7.51+/-2.34%; P=0.006). The peak flow stimulus was similar after wrist and upper arm occlusion. We conclude that dilatation following upper arm occlusion is greater than that observed after wrist occlusion, despite a similar peak flow stimulus. L-NMMA infusion revealed that FMD following wrist occlusion is mediated exclusively by NO, while dilatation following upper arm occlusion comprises a substantial component not mediated by NO, most probably related to tissue ischaemia around the brachial artery. FMD following wrist occlusion may be a more valid marker of endothelial function than dilatation following upper arm occlusion.

Thyroglossal duct carcinoma: a large case series.

Thyroglossal duct cysts (TDCs) are common congenital abnormalities of thyroid development. Carcinoma occurs rarely in patients with TDCs. In a large case series drawn from medical records at a health maintenance organization from 1971 through 1995, 14 cases of carcinoma in a TDC were found. This represents the largest known reported case series to date. Demographics, diagnosis, and treatment methods are reviewed. We recommend the Sistrunk operation and evaluation of the thyroid gland and neck for potential abnormality that would necessitate thyroidectomy and lymph node dissection. Long-term follow-up incorporating clinical examination is mandatory.