Psychological impact of lung cancer screening using a novel antibody blood test followed by imaging: the ECLS randomized controlled trial.

BACKGROUND: The Early CDT®-Lung antibody blood test plus serial computed tomography scans for test-positives (TPGs) reduces late-stage lung cancer presentation. This study assessed the psychological outcomes of this approach. METHODS: Randomized controlled trial (n = 12 208) comparing psychological outcomes 1-12 months post-recruitment in a subsample (n = 1032) of TPG, test-negative (TNG) and control groups (CG). RESULTS: Compared to TNG, TPG had lower positive affect (difference between means (DBM), 3 months (3m: -1.49 (-2.65, - 0.33)), greater impact of worries (DBM 1m: 0.26 (0.05, 0.47); 3m: 0.28 (0.07, 0.50)), screening distress (DBM 1m: 3.59 (2.28, 4.90); 3m: 2.29 (0.97, 3.61); 6m: 1.94 (0.61, 3.27)), worry about tests (odds ratio (OR) 1m: 5.79 (2.66, 12.63) and more frequent lung cancer worry (OR 1m: 2.52 (1.31, 4.83); 3m: 2.43 (1.26, 4.68); 6m: 2.87 (1.48, 5.60)). Compared to CG, TPG had greater worry about tests (OR 1m: 3.40 (1.69, 6.84)). TNG had lower negative affect (log-transformed DBM 3m: -0.08 (-0.13, -0.02)), higher positive affect (DBM 1m: 1.52 (0.43, 2.61); 3m: 1.43 (0.33, 2.53); 6m: 1.27 (0.17, 2.37)), less impact of worries (DBM 3m: -0.27 (-0.48, -0.07)) and less-frequent lung cancer worry (OR 3m: 0.49 (0.26, 0.92)). CONCLUSIONS: Negative psychological effects in TPG and positive effects in TNG were short-lived and most differences were small.

The impact of cardiovascular co-morbidities and duration of diabetes on the association between microvascular function and glycaemic control.

BACKGROUND: Good glycaemic control in type 2 diabetes (T2DM) protects the microcirculation. Current guidelines suggest glycaemic targets be relaxed in advanced diabetes. We explored whether disease duration or pre-existing macrovascular complications attenuated the association between hyperglycaemia and microvascular function. METHODS: 743 participants with T2DM (n = 222), cardiovascular disease (CVD = 183), both (n = 177) or neither (controls = 161) from two centres in the UK, underwent standard clinical measures and endothelial dependent (ACh) and independent (SNP) microvascular function assessment using laser Doppler imaging. RESULTS: People with T2DM and CVD had attenuated ACh and SNP responses compared to controls. This was additive in those with both (ANOVA p < 0.001). In regression models, cardiovascular risk factors accounted for attenuated ACh and SNP responses in CVD, whereas HbA1c accounted for the effects of T2DM. HbA1c was associated with ACh and SNP response after adjustment for cardiovascular risk factors (adjusted standardised beta (ß) -0.096, p = <0.008 and -0.135, p < 0.001, respectively). Pre-existing CVD did not modify this association (ß -0.099; p = 0.006 and -0.138; p < 0.001, respectively). Duration of diabetes accounted for the association between HbA1c and ACh (ß -0.043; p = 0.3), but not between HbA1c and SNP (ß -0.105; p = 0.02). CONCLUSIONS: In those with T2DM and CVD, good glycaemic control is still associated with better microvascular function, whereas in those with prolonged disease this association is lost. This suggests duration of diabetes may be a better surrogate for "advanced disease" than concomitant CVD, although this requires prospective validation.

Technical assessment of whole body angiography and cardiac function within a single MRI examination.

AIM: To evaluate a combined protocol for simultaneous cardiac MRI (CMR) and contrast-enhanced (CE) whole-body MR angiography (WB-MRA) techniques within a single examination. MATERIALS AND METHODS: Asymptomatic volunteers (n = 48) with low-moderate risk of cardiovascular disease (CVD) were recruited. The protocol was divided into four sections: (1) CMR of left ventricle (LV) structure and function; (2) CE-MRA of the head, neck, and thorax followed by the distal lower limbs; (3) CMR LV "late gadolinium enhancement" assessment; and (4) CE-MRA of the abdomen and pelvis followed by the proximal lower limbs. Multiple observers undertook the image analysis. RESULTS: For CMR, the mean ejection fraction (EF) was 67.3 ± 4.8% and mean left ventricular mass (LVM) was 100.3 ± 22.8 g. The intra-observer repeatability for EF ranged from 2.1-4.7% and from 9-12 g for LVM. Interobserver repeatability was 8.1% for EF and 19.1 g for LVM. No LV delayed myocardial enhancement was observed. For WB-MRA, some degree of luminal narrowing or stenosis was seen at 3.6% of the vessel segments (involving n = 29 of 48 volunteers) and interobserver radiological opinion was consistent in 96.7% of 1488 vessel segments assessed. CONCLUSION: Combined assessment of WB-MRA and CMR can be undertaken within a single examination on a clinical MRI system. The associated analysis techniques are repeatable and may be suitable for larger-scale cardiovascular MRI studies.

Detecting diabetes and impaired glucose tolerance in patients with atherosclerotic peripheral arterial disease.

AIM: In patients with peripheral arterial disease (PAD), diabetes mellitus is associated with increased mortality rates. The aim of this study was to estimate the prevalence of undiagnosed diabetes in PAD patients, and to assess whether a glucose tolerance test is more sensitive than a simple fasting glucose measurement for diagnosis in this group. METHODS: A standard glucose tolerance test and fasting glucose measurements were performed in 53 patients with PAD, who were then categorised into diagnostic groups according to each test result. RESULTS: Using the glucose tolerance test results, 11.5% of patients were diagnosed with diabetes mellitus and 28.8% had either impaired fasting glucose or impaired glucose tolerance. Using fasting glucose levels only, 7.7% received a diagnosis of diabetes mellitus and 17.3% had impaired fasting glucose. The glucose tolerance data and the fasting glucose data were in agreement in 82.7% of cases, but the glucose tolerance test identified an additional 3.8% of cases with diabetes and an additional 13.5% of cases with impaired glucose tolerance. CONCLUSION: Undiagnosed diabetes and impaired glucose homeostasis are common in patients with PAD. Routine screening using a simple glucose tolerance test should be considered in the clinical assessment of this group.

Practical control of SERRS enhancement.

The demonstration that quantitative and sensitive analysis can be carried out using surface enhanced resonance Raman scattering (SERRS) prompted a discussion and investigation of the main variables which are within the control of the analyst using colloidal silver as the substrate. Previous papers have dealt with the crucial need to obtain good chemisorption of the analyte to the surface and have reported the use of specially designed dyes for SERRS. One of the most variable processes is the aggregation of the colloid. Here, we investigate the addition of controlled amounts of an organic aggregating agent, poly-L-lysine, at concentrations which reduce the zeta potential in a controlled manner, thus aiding aggregation control. The relationship between the excitation frequency, the surface plasmon resonance frequency of the silver colloid and the frequency of the maximum absorbance of the molecular chromophore is studied using low concentrations of dye and no aggregating agent. Under these conditions, little to no aggregation is expected. The magnitude of the enhancement is strongly dependent on the frequency of the molecular chromophore as well as the plasmon resonance frequency. However, when sodium chloride is used to aggregate the colloid, a larger enhancement is obtained and the strong dependence on the molecular chromophore largely disappears. A much broader enhancement profile is obtained which appears to be related more to the specific enhancement processes caused by aggregation than the frequency of the chromophore. However, the total enhancement for SERRS is higher than for SERS thus indicating that the chromophore is still important to the process.

Surface-enhanced resonance Raman scattering of black inkjet dyes in solution and in situ printed onto paper.

Understanding the changes that occur when dyes are absorbed onto paper is crucial for the design of new inkjet dyes. This problem is particularly difficult for black dyes that have complex chromophores, and as a result, spectroscopic information on electronic and structural changes can be of importance. Surface-enhanced resonance Raman scattering (SERRS) and electronic structure calculations were used to probe in situ changes in the chromophore in black di-azo dyes printed onto paper. The data indicate that the low-energy chromophore is due mainly to the hydrazone group and the high-energy chromophore to both the azo and hydrazone groups. A comparison of SERRS from the dyes adsorbed onto silver particles in suspension and from the dyes on paper demonstrated a broadening of the chromophore into the red for both dyes and evidence of a structural change in one dye.

Skin perfusion in patients with erythromelalgia.

BACKGROUND: Erythromelalgia (EM) is a chronic disorder characterized by intermittent pain, warmth and erythema of the extremities. Symptoms can be precipitated by increasing the temperature of the affected limb and can be partially relieved by direct cooling. MATERIALS AND METHODS: Microvascular assessment was conducted under 'hot' (28 degrees C) environmental conditions in 61 EM (EMI) patients and 30 control subjects. Twenty patients with many of the symptoms of EM were enrolled as an active control group (EMII). Using laser Doppler flowmetry, basal skin erythrocyte flux (SkEF) and the hyperaemic response to local heating (44 degrees C) were measured. RESULTS: Compared with control subjects, basal SkEF was reduced at the toe (P < 0.001), index finger (P < 0.05), dorsal and plantar aspects of the foot (P < 0.01) in both patient groups and at the medial mid-calf (P < 0.05) in EMI patients. Both EM groups also had a significantly reduced maximum SkEF at the dorsum of foot and medial mid-calf (all P < 0.001) compared with control values. In a subset of patients and control subjects, transcutaneous carbon dioxide levels were raised in EMI patients (P < 0.02) compared with levels in control subjects. Toe temperature was significantly reduced in both EM groups compared with control subjects (both P < 0. 001). CONCLUSION: Our study indicates for the first time that there is a vasoconstrictor tendency in patients with EM, which may be related to functional or structural changes in skin microvessels. Thus, the previous hypothesis that the pathophysiology of EM relates to vasodilatation is not supported in our patients. We believe that, in EM, vasoconstriction precedes reactive hyperaemia, similar to that seen in Raynaud's phenomenon.

Impaired skin vasomotor reflexes in patients with erythromelalgia.

Erythromelalgia (EM) is a chronic disorder characterized by intermittent burning pain, warmth and erythema of the extremities. Increasing the local temperature and dependency of the affected limb(s) precipitates the symptoms, whereas direct cooling and elevation of the limb(s) can provide partial relief. Our previous findings showed that patients with EM have enhanced cutaneous vascular tone at rest and during stimulation, which may be due to an increase in sympathetic neural activity. To test this, we measured skin vasoconstrictor responses to contralateral arm cold challenge (CC) and inspiratory gasp (IG) using laser Doppler flowmetry at the toe pulp and fingertip. These areas were chosen because of their dense sympathetic innervation. An index of the vasoconstrictor response (between 0 and 1) was calculated from the change in skin perfusion from baseline following CC and IG. In control subjects, vasoconstrictor responses to CC at the toe and fingertip were both 0. 70+/-0.02 (mean+/-S.E.M.), which were significantly greater (P<0. 001) than corresponding values in patients with EM (0.37+/-0.04 and 0.45+/-0.04 respectively). Similarly, vasoconstrictor responses to IG were significantly greater (P<0.001) at the toe and fingertip in control subjects (0.70+/-0.03 and 0.70+/-0.02 respectively) compared with values in EM patients (0.27+/-0.03 and 0.45+/-0.15 respectively). These data show that, in contrast with control subjects, patients with EM have diminished sympathetic vasoconstrictor responses to both CC and IG. Denervation supersensitivity may play a part by increasing vasoconstrictor responses to circulating catecholamines, leading to a reduction in skin blood flow. Therefore an interplay between neural and vasoactive agents may be involved in the pathophysiology of EM.

Microvascular abnormalities in patients with vibration white finger.

In vivo nailfold capillary microscopy was performed on 10 men with vibration white finger (VWF) and 10 age-matched male controls. The observed nailfold capillaries required adaptation of Maricq's classifications and addition of new morphological scoring systems. These new classifications produced numerical scores for assessing capillary: dropout, tortuosity, elongation, visualization of subpapillary venular plexus, and the degree of disarrangement of nailfold capillary polarity. Application of these new scores showed, for the first time, a complex pattern of abnormal-nailfold capillaries in patients with VWF. Capillary dropout was evident in 7/10 patients, with an associated disarrangement in nailfold capillary polarity in five. All 10 controls had normal capillary morphology. Tortuosity of the capillary loops and elongation of their length was observed in 30% of patients. These significant morphological alterations seen in VWF suggest a local small-vessel vasculitis.

Oral L-arginine supplementation and cutaneous vascular responses in patients with primary Raynaud's phenomenon.

OBJECTIVE: To assess the effects of oral L-arginine supplementation on cutaneous vascular responses in patients with primary Raynaud's phenomenon (RP). METHODS: Double-blind, crossover comparison of placebo versus L-arginine (8 gm/day for 28 days). Cutaneous vascular responses in the fingers were assessed during iontophoresis of acetylcholine and sodium nitroprusside, which are endothelium-dependent and endothelium-independent vasodilators. RESULTS: In comparison with control subjects, patients with primary RP had diminished endothelium-dependent and -independent vasodilatation (P < 0.05, and P < 0.005, respectively, by analysis of variance). At the 3 doses used, vascular responses to acetylcholine were reduced by 71%, 64%, and 63%, respectively, and responses to sodium nitroprusside were reduced by 67%, 73%, and 66%, respectively. L-arginine had no significant effect on cutaneous vascular responses to acetylcholine or sodium nitroprusside in control subjects or patients with primary RP. CONCLUSION: Reduced vasodilator ability in primary RP is unlikely to be due to an impairment in the L-arginine/nitric oxide pathway.

Cutaneous vascular responses to acetylcholine are mediated by a prostanoid-dependent mechanism in man.

Approximately 50% of the forearm vasodilatation to intra-arterial infusions of acetylcholine is mediated by endothelium-derived nitric oxide. These conclusions have been derived from venous occlusion plethysmographic measurements of total forearm blood flow during co-infusions of acetylcholine and NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthase. Since venous occlusion plethysmography measures total limb blood flow, the relative proportion of the measurement from skin cannot be determined precisely. To determine the effects of acetylcholine on skin specifically, we have used laser Doppler flowmetry to measure vascular responses to local iontophoresis of acetylcholine in the forearm of normal male volunteers. To elucidate the possible mechanisms of cutaneous vasodilatation to acetylcholine, vascular responses were measured before and after systemic inhibition of prostanoid production and nitric oxide synthesis by oral aspirin (600 mg daily for 3 days) and intravenous L-NMMA (3 mg/kg for 60 min), respectively. After aspirin administration, dose-dependent vascular responses to acetylcholine were reduced significantly by approximately 53% (p < 0.005, ANOVA). In contrast, intravenous L-NMMA appeared to have no significant effect on cutaneous vascular responses to acetylcholine. While the role of nitric oxide is uncertain, vasodilatation to acetylcholine in the forearm skin is mediated largely by a prostanoid-dependent mechanism. Assessment of cutaneous vascular responses to iontophoresis of acetylcholine may, therefore, be useful in diseases where abnormal endothelium-dependent prostanoid function has been implicated.