An evidence-based strategy to screen for pulmonary arterial hypertension in systemic sclerosis.

BACKGROUND: Clinical practice guidelines recommend screening all systemic sclerosis (SSc) patients for pulmonary arterial hypertension (PAH) with yearly echocardiograms. There is a paucity of evidence to support these guidelines. RESEARCH QUESTION: Can a prediction model identify SSc patients with a very low probability of PAH and therefore not requiring annual screening echocardiogram? STUDY DESIGN AND METHODS: We performed a case-control study of 925 unselected SSc subjects nested in a multi-centered, longitudinal cohort. The probability of PAH for each subject was calculated using the results of multivariate logistic regression models. A cut-off was identified for the estimated probability of PAH below which no subject developed PAH (100% sensitivity). RESULTS: Study subjects were predominantly female (87.5%), with mean (SD) age 58.6 (11.7) years and disease duration of 18.2 (12.2) years. Thirty-seven subjects developed PAH during 5407.97 person-years of observation (incidence rate 0.68 per 100 person-years). Shortness of breath (SOB), diffusing capacity for carbon monoxide (DLCO) and NT-proBNP were independent predictors of PAH. All SSc-PAH cases had a probability of PAH of >1.1%. Subjects below this cut-off, none of whom had PAH, accounted for 46.2% of the study population. INTERPRETATION: A simple prediction model identified subjects at very low probability of PAH who could potentially forego annual screening echocardiogram. This represents almost half of SSc subjects in a general SSc population. This study, which is the first evidence-based study for the rational use of follow-up echocardiograms in an unselected SSc cohort, requires validation. The scoring system is freely available online at http://pahtool.ladydavis.ca.

Neural correlates of adherence to extended-release naltrexone pharmacotherapy in heroin dependence.

Injectable extended-release naltrexone (XRNTX) presents an effective therapeutic strategy for opioid addiction, however its utility could be hampered by poor adherence. To gain a better insight into this phenomenon, we utilized blood oxygenation level-dependent functional magnetic resonance imaging (fMRI) in conjunction with a validated cue-induced craving procedure to examine neural correlates of XRNTX adherence. We operationalized treatment adherence as the number of monthly XRNTX injections (range: 0-3) administered to a group of fully detoxified heroin-dependent subjects (n=32). Additional outcomes included urine toxicology screening and self-reported tobacco use. The presented heroin-related visual cues reliably elicited heroin craving in all tested subjects. Nine, five, three and 15 of the participants, respectively, received zero, one, two and three XRNTX injections, predicted by the individual baseline fMRI signal change in response to the cues in the medial prefrontal cortex, a brain region involved in inhibitory self-control and emotional appraisal. The incidence of opioid-positive urines during the XRNTX therapy was low and remained about half the pre-treatment rate after the XRNTX ended. During the treatment, cigarette smoking behaviors followed patterns of opioid use, while cocaine consumption was increased with reductions in opioid use. The present data support the hypothesis that medial prefrontal cortex functions are involved in adherence to opioid antagonist therapy. A potential role of concurrent non-opioid addictive substances consumption during the XRNTX pharmacotherapy warrants further investigation. Our findings set the stage for further bio-behavioral investigations of the mechanisms of relapse prevention in opioid dependence.

A review of STRIDE-2 and STRIDE-2X: the case for selective endothelin receptor blockade.

BACKGROUND: Pulmonary arterial hypertension remains incurable and has previously required difficult parenteral therapy. Endothelin-1(ET-1) is an important mediator of pulmonary arterial hypertension. The recent availability of oral therapies, including endothelin receptor antagonists, has improved ease of use for patients, but most patients remain symptomatic to a significant degree. Two classes of ET-1 receptors have been described, ET(A) and ET(B). It has previously been unclear whether both receptors must be blocked in pulmonary arterial hypertension, or only the ET(A) receptor. MATERIALS AND METHODS: The Sitaxsentan To Relieve ImpaireD Exercise-2 (STRIDE-2) study followed by STRIDE-2X exposed patients with pulmonary arterial hypertension to the highly selective ET(A) antagonist sitaxsentan (n = 145), or to bosentan (n = 84), a nonselective ET(A) and ET(B) antagonist. The total exposure duration and follow-up period was 1 year. Pre-specified comparisons included time to discontinuation of monotherapy, time to clinical worsening, incidence of elevated hepatic transaminase levels > 3 x upper limit of normal and survival. RESULTS: Sitaxsentan therapy showed significant benefit over bosentan with respect to discontinuation of monotherapy at 1 year (24% vs. 43%, P = 0.002), clinical worsening at 1 year (28% vs. 39%, P = 0.0425), elevated hepatic transaminases at 1 year (4% vs. 14%, P = 0.014) and 1-year survival (96% vs. 88%, P = 0.028). CONCLUSIONS: STRIDE-2 and its extension, STRIDE-2X, suggest significant benefit of sitaxsentan compared with bosentan, in terms of efficacy and reduced hepatotoxicity. The former may be related to the high ET(A) receptor selectivity of sitaxsentan.

Towards clinical trials of lie detection with fMRI.

Recent reports of successful fMRI-based discrimination between lie and truth in single subjects raised the interest of prospective users and a public concern about the potential scope of this technology. The increased scrutiny highlighted the lack of controlled "real life", i.e. prospective clinical trials of this technology that conform to the common standards of medical device development. The ethics of conducting such trials given the paucity of data on fMRI-based lie detection has also been questioned. To probe the potential issues of translating the laboratory research into practice, we conducted a case study in which we adapted the standard Guilty Knowledge Test (GKT), a well-established model of producing deception, to the common scenario of lying on a resume. The task consisted of questions about pertinent items on the subject's resume, three of which could be independently verified as truth (KNOWN) and three that could not be verified and were thus termed UNKNOWN. The subject had an incentive to lie on all UNKNOWN items, and on debriefing confirmed that he had done so. Data was preprocessed, masked with a priori regions of interest, thresholded, and qualitatively evaluated for consistency with the previously reported prefronto-parietal Lie > Truth pattern. Deceptive responses to two out of the three UNKNOWN items were associated with the predicted prefronto-parietal fMRI pattern. In the third UNKNOWN this pattern was absent, and instead, increased limbic (amygdala and hippocampus) response was observed. Based on published prefronto-parietal Lie response pattern, only the first two items could be categorized as Lie. If confirmed, this demonstration of amygdala and hippocampus activation in a Lie > Truth contrast illustrates the need to integrate the limbic system and its emotional and cognitive correlates into the existing model of deception. Our experiment suggests an approach to a naturalistic scenario and the research questions that need to be answered in order to set the stage for prospective clinical trials of fMRI-based lie detection.

Pulmonary capillary endothelial metabolic function in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) causes physical plugging of large pulmonary arteries as well as a distal micro-vasculopathy. Pulmonary endothelium is an active metabolic tissue in normal humans. The effects of CTEPH on pulmonary endothelial metabolism are unknown. OBJECTIVES: We studied pulmonary capillary endothelium-bound angiotensin converting enzyme (ACE) activity as an index of endothelial metabolism in patients with CTEPH. PATIENTS/METHODS: We measured single-pass transpulmonary per cent metabolism (%M) and hydrolysis of an ACE synthetic substrate and calculated functional capillary surface area (FCSA), normalized to body surface area (BSA), in 13 patients with CTEPH and 23 controls. RESULTS: Mean %M for CTEPH (71.6 +/- 4.0% SE) was similar to controls (74.7 +/- 2.7%). Substrate hydrolysis (v) was similar for CTEPH (1.47 +/- 0.22) and controls (1.51 +/- 0.11). However, FCSA/BSA was reduced (P < 0.01) for CTEPH (1530 +/- 218 mL min(-1)*m(-2)) as compared with controls (2948 +/- 245). CONCLUSIONS: The metabolically functional pulmonary capillary bed is reduced in CTEPH. However, because %M and hydrolysis are preserved, this points to a reduction in functional capillary surface area rather than reduced ACE activity on the pulmonary capillary endothelial cell. The reduction in functional capillary surface area may just be a result of decreased capillary recruitment because of upstream vascular plugging by chronic organized thrombus.

fMRI investigation of the cognitive structure of the Concealed Information Test.

We studied the cognitive basis of the functional magnetic resonance imaging (fMRI) pattern of deception in three participants performing the Concealed Information Test (CIT). In all participants, the prefrontoparietal lie activation was similar to the pattern derived from the meta-analysis (N = 40) of our previously reported fMRI CIT studies and was unchanged when the lie response was replaced with passive viewing of the target items. When lies were replaced with irrelevant responses, only the left inferior gyrus activation was common to all subjects. This study presents a systematic strategy for testing the cognitive basis of deception models, and a qualitative approach to single-subject truth-verification fMRI tests.

[Treatment of pulmonary arterial hypertension by endothelin receptor antagonists in 2008]. / La prise en charge thérapeutique de l'hypertension artérielle pulmonaire par les antagonistes des récepteurs de l'endothéline en 2008.

PURPOSE: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by an elevation of pulmonary-artery pressure and pulmonary-vascular resistance, leading to right-ventricular failure and death. Conventional therapy for PAH may include anticoagulation, digoxin, diuretics, supplemental oxygen and less often calcium-channel blockers. Protaglandins and sildenafil improve exercise capacity and hemodynamics. CURRENT KNOWLEDGE AND KEY POINTS: Endothelin-1 (ET-1) has been recognized as a major mediator in the pathogenesis of PAH. ET-1 receptor antagonists have been recently developed. Selective ET(A) receptor antagonists, which preserve endothelial ET(B) receptor vasodilatory and clearance activity, may offer more benefit than nonselective ET(A) plus ET(B) antagonists. Two ET-1 receptor antagonists, orally active, can be used: bosentan (ET(A)/ET(B)=20) is nonselective and sitaxentan (ET(A)/ET(B)=6500) is highly selective. In short-term studies, these two treatments showed similar efficacy. In the Sitaxentan To Relieve ImpaireD Exercise-2X (STRIDE-2X) one-year trial, which compared the two treatments, sitaxentan caused less liver toxicity and showed trends to higher efficacy than bosentan. FUTURE PROSPECTS AND PROJECTS: Individualized treatment for PAH should take into account the type of PAH, the comorbidities (liver disease), treatment interactions, and long-term efficacy.

Classifying spatial patterns of brain activity with machine learning methods: application to lie detection.

Patterns of brain activity during deception have recently been characterized with fMRI on the multi-subject average group level. The clinical value of fMRI in lie detection will be determined by the ability to detect deception in individual subjects, rather than group averages. High-dimensional non-linear pattern classification methods applied to functional magnetic resonance (fMRI) images were used to discriminate between the spatial patterns of brain activity associated with lie and truth. In 22 participants performing a forced-choice deception task, 99% of the true and false responses were discriminated correctly. Predictive accuracy, assessed by cross-validation in participants not included in training, was 88%. The results demonstrate the potential of non-linear machine learning techniques in lie detection and other possible clinical applications of fMRI in individual subjects, and indicate that accurate clinical tests could be based on measurements of brain function with fMRI.

The 6-min walk test (6MW) as an efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect.

BACKGROUND: PAH trials traditionally use 6MW as the primary endpoint. Concerns regarding a "ceiling effect" masking efficacy have led to exclusion of patients with milder disease from most trials (BL 6MW>450 m). STRIDE I evaluated the selective endothelin A receptor antagonist, sitaxsentan (SITAX), in a 12-week randomized, double-blind, trial (178 patients) employing placebo (PBO), 100 mg or 300 mg SITAX orally once daily in PAH and included patients with NYHA class II, congenital heart disease and a BL 6MW>450 m, groups often excluded from previous trials. METHODS: We analyzed 6MW effects For All Pts (intention-to treat) and those meeting Traditional enrollment criteria, defined as patients with NYHA class III or IV and 6MW< or =450 m at BL with idiopathic PAH or PAH related to connective tissue disease. The 100 mg and 300 mg SITAX arms are pooled based on similar treatment effects on 6MW. CONCLUSION: Existence of a "ceiling effect" is supported by these data. The magnitude of the treatment effect and statistical power when using 6MW as the endpoint. Comparisons between PAH trials that do not adjust for the effects of differing enrollment criteria require caution.

Brain activity during simulated deception: an event-related functional magnetic resonance study.

TheGuilty Knowledge Test (GKT) has been used extensively to model deception. An association between the brain evoked response potentials and lying on the GKT suggests that deception may be associated with changes in other measures of brain activity such as regional blood flow that could be anatomically localized with event-related functional magnetic resonance imaging (fMRI). Blood oxygenation level-dependent fMRI contrasts between deceptive and truthful responses were measured with a 4 Tesla scanner in 18 participants performing the GKT and analyzed using statistical parametric mapping. Increased activity in the anterior cingulate cortex (ACC), the superior frontal gyrus (SFG), and the left premotor, motor, and anterior parietal cortex was specifically associated with deceptive responses. The results indicate that: (a) cognitive differences between deception and truth have neural correlates detectable by fMRI, (b) inhibition of the truthful response may be a basic component of intentional deception, and (c) ACC and SFG are components of the basic neural circuitry for deception.

Interhemispheric asymmetry of regional cerebral blood flow in prepubescent boys with attention deficit hyperactivity disorder.

The prefrontal cortex is asymmetric in both structure and function. In normal subjects, the right prefrontal cortex is activated more than the left during response inhibition. Patients with attention deficit hyperactivity disorder (ADHD) have impaired response inhibition and altered structural interhemispheric asymmetry. This study was conducted to examine the functional interhemispheric asymmetry during response inhibition in children with ADHD. Subjects were divided into three groups according to the level of motor hyperactivity. Blood flow tracer (99m)Tc-ethyl cysteinate dimer was injected while subjects were performing a response inhibition task (RIT), followed by single photon emission computerized tomography (SPECT). After three-dimensional reconstruction, filtering and smoothing, individual scans were morphed to a template. Three average group images were created from individual scans. Each average group image was subtracted voxel-by-voxel from its mirror image to compare the regional cerebral blood flow (rCBF) in the right and left cerebral hemispheres, yielding images of significant interhemispheric rCBF asymmetry. The severe hyperactivity group exhibited most prefrontal left>right rCBF asymmetry and left>right occipitoparietal asymmetry. Reversal of functional prefrontal asymmetry in boys with severe motor hyperactivity supports the hypothesis of right prefrontal cortex dysfunction in ADHD.

Pulmonary capillary endothelial dysfunction in early systemic sclerosis.

OBJECTIVE: Pulmonary capillary endothelium-bound angiotensin-converting enzyme (PCEB-ACE) activity is a sensitive and quantifiable index of endothelial function in vivo. Systemic sclerosis (SSc) is characterized by endothelial damage and excess collagen formation, causing mainly pulmonary hypertension (PH) in the limited cutaneous SSc (lcSSc) subset and interstitial lung disease with pulmonary interstitial fibrosis (PIF) in the diffuse cutaneous SSc (dcSSc) subset. This study was undertaken to investigate the hypothesis that PCEB-ACE activity is reduced early in SSc, in the absence of PH or PIF. METHODS: Applying indicator-dilution techniques, we measured single-pass transpulmonary hydrolysis and percent metabolism (%M) of a synthetic ACE substrate and calculated functional capillary surface area (FCSA) in 25 SSc patients and 11 controls. Substrate hydrolysis and %M reflect ACE activity per capillary; FCSA reflects ACE activity per vascular bed. RESULTS: PCEB-ACE activity was decreased in both SSc subsets. Among patients without PH, substrate hydrolysis and %M were decreased in patients with lcSSc and more profoundly in those with dcSSc; loss of FCSA normalized to body surface area (FCSA/BSA) was observed in dcSSc, but not in lcSSc. High-resolution computed tomography of the lung, performed in all SSc patients, revealed no correlation between substrate %M, hydrolysis, or FCSA/BSA and the degree of PIF; 5 dcSSc and 5 lcSSc patients with no detectable PIF exhibited decreases in hydrolysis and %M, while FCSA/BSA was decreased only in dcSSc. CONCLUSION: Depression of PCEB-ACE activity, indicating pulmonary endothelial dysfunction, occurs early in SSc, in the absence of PH or PIF, and is more pronounced, at this early pulmonary disease stage, in dcSSc than in lcSSc.

Non-visualization of sentinel lymph node in patients with breast cancer.

Histological evaluation of the first draining lymph node (sentinel node) in the axilla of patients with breast cancer has dramatically altered the surgical approach to these patients, with sparing of the axilla if no tumour cells are identified. In a fraction of patients imaged after peri-tumoural injection of the breast, there is no visualization of the sentinel node. We retrospectively analysed the status of patients whose nodes were visualized and of patients whose nodes failed to visualize, to define the variables associated with non-visualization of the sentinel node. Seventy-four breast cancer patients were imaged following peri-tumoural injection of filtered 99Tc(m)-sulfur colloid, immediately and up to 5.5 h post-injection. The scintigraphic data were analysed with reference to the patient's age, histology, grade, site and size of tumour, previous diagnostic procedure and time interval to scan, using univariate analysis and a logistic regression model. A sentinel node was visualized in 53 of 74 women (72%). Comparison of patients with non-visualized versus visualized sentinel nodes disclosed no statistically significant univariate relation to age of the patients (P = 0.10), size of tumour (P = 0.46), site (P = 0.26), histology [invasive ductal carcinoma in 16 of 20 (80%) non-visualized cases, and in 43 of 53 (81%) visualized patients], prior excision biopsy (P = 0.36) and time interval to surgery (P = 0.29). Tumour grade was the only significant variable on univariate analysis (P = 0.03), though multivariate analysis showed that none of the independent parameters were statistically significant. In 39 patients with an upper outer quadrant tumour, the location of the sentinel node was not limited to the axilla and even crossed the midline of the breast. Our results show that none of the independent variables is associated with non-visualization of sentinel lymph node on preoperative lymphoscintigraphy of patients with breast cancer, though the tumour grade may have contributed to non-visualization of this node. The non-axillary drainage from upper outer quadrant tumours suggests the routine use of lymphoscintigraphy prior to axillary dissection.

PET in differentiation of recurrent brain tumor from radiation injury.

The annual incidence of primary intracranial tumors is 7 to 19 cases per 100,000 people. The general approach to the treatment of brain neoplasms is surgical resection of solitary lesions or limited disease, followed by radiation therapy with or without chemotherapy. Multiple metastatic lesions are usually treated with whole-brain radiation. Radiation injury occurs in 5% to 37% of cases and can be difficult to differentiate from residual or recurrent malignancy by MRI. PET has been used to differentiate radiation injury from malignancy on the basis of differences in glucose uptake. Recent studies have reported the sensitivity and specificity of PET to be 81% to 86% and 40% to 94%, respectively. This article reviews the classification of primary brain tumors, the histologic changes associated with radiation injury, and the diagnostic and prognostic information provided by PET.