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Abstract HNPCC (Lynch syndrome) is the most common form of hereditary colorectal cancer (CRC), wherein it accounts for between 2-7 percent of the total CRC burden. When considering the large number of extracolonic cancers integral to the syndrome, namely carcinoma of the endometrium, ovary, stomach, hepatobiliary system, pancreas, small bowel, brain tumors, and upper uroepithelial tract, these estimates of its frequency are likely to be conservative. The diagnosis is based upon its natural history in concert with a comprehensive cancer family history inclusive of all anatomic sites. In order for surveillance and management to be effective and, indeed, lifesaving, among these high-risk patients, the linchpin to cancer control would be the physician, who must be knowledgeable about hereditary cancer syndromes, their molecular and medical genetics, genetic counseling, and, most importantly, the natural history of the disorders, so that the entirety of this knowledge can be melded to highly-targeted management.

Martel’s own copy of the Hovey 1912 guidebook to Mammoth Cave has his routes marked faintly in pencil on the printed cave plans. These plans are reproduced here, with his routes indicated on them. He generally followed the four standard tourist routes which now included Kaemper’s 1908 discoveries to Violet City, but instead of visiting the Maelstrom he went to Hovey’s Cathedral and Gerta’s Grotto.

As lifelong interphase cells, neurons face an array of unique challenges. A key challenge is regulating nuclear pore complex (NPC) biogenesis and localization, the mechanisms of which are largely unknown. Here we identify neuronal maturation as a period of strongly upregulated NPC biogenesis. We demonstrate that the AAA+ protein torsinA, whose dysfunction causes the neurodevelopmental movement disorder DYT-TOR1A dystonia and co-ordinates NPC spatial organization without impacting total NPC density. We generated an endogenous Nup107-HaloTag mouse line to directly visualize NPC organization in developing neurons and find that torsinA is essential for proper NPC localization. In the absence of torsinA, the inner nuclear membrane buds excessively at sites of mislocalized nascent NPCs, and the formation of complete NPCs is delayed. Our work demonstrates that NPC spatial organization and number are independently determined and identifies NPC biogenesis as a process vulnerable to neurodevelopmental disease insults., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Nuclear pore complexes (NPCs) regulate information transfer between the nucleus and cytoplasm. NPC defects are linked to several neurological diseases, but the processes governing NPC biogenesis and spatial organization are poorly understood. Here, we identify a temporal window of strongly upregulated NPC biogenesis during neuronal maturation. We demonstrate that the AAA+ protein torsinA, whose loss of function causes the neurodevelopmental movement disorder DYT-TOR1A (DYT1) dystonia, coordinates NPC spatial organization during this period without impacting total NPC density. Using a new mouse line in which endogenous Nup107 is Halo-Tagged, we find that torsinA is essential for correct localization of NPC formation. In the absence of torsinA, the inner nuclear membrane buds excessively at sites of mislocalized, nascent NPCs, and NPC assembly completion is delayed. Our work implies that NPC spatial organization and number are independently regulated and suggests that torsinA is critical for the normal localization and assembly kinetics of NPCs., Competing Interests: Competing interests: The authors declare no competing interests.

Bilayer membranes composed of cholesterol and phospholipids exhibit diverse forms of nonideal mixing. In particular, many previous studies document macroscopic liquid-liquid phase separation as well as nanometer-scale heterogeneity in membranes of phosphatidylcholine (PC) lipids and cholesterol. Here, we present experimental measurements of cholesterol chemical potential (μ c ) in binary membranes containing dioleoyl PC (DOPC), 1-palmitoyl-2-oleoyl PC (POPC), or dipalmitoyl PC (DPPC), and in ternary membranes of DOPC and DPPC, referenced to crystalline cholesterol. μ c is the thermodynamic quantity that dictates the availability of cholesterol to bind other factors, and notably must be equal between coexisting phases of a phase separated mixture. It is simply related to concentration under conditions of ideal mixing, but is far from ideal for the majority of lipid mixtures investigated here. Measurements of μ c can vary with phospholipid composition by 1.5 k B T at constant cholesterol mole fraction implying a more than fivefold change in its availability for binding receptors and other reactions. Experimental measurements are fit to thermodynamic models including cholesterol-DPPC complexes or pairwise interactions between lipid species to provide intuition about the magnitude of interactions. These findings reinforce that μ c depends on membrane composition overall, suggesting avenues for cells to alter the availability of cholesterol without varying cholesterol concentration., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Single molecule imaging in live cells enables the study of protein interactions and dynamics as they participate in signaling processes. When combined with fluorophores that stochastically transition between fluorescent and reversible dark states, as in super-resolution localization imaging, labeled molecules can be visualized in single cells over time. This improvement in sampling enables the study of extended cellular responses at the resolution of single molecule localization. This chapter provides optimized experimental and analytical methods used to quantify protein interactions and dynamics within the membranes of adhered live cells. Importantly, the use of pair-correlation functions resolved in both space and time allows researchers to probe interactions between proteins on biologically relevant distance and timescales, even though fluorescence localization methods typically require long times to assemble well-sampled reconstructed images. We describe an application of this approach to measure protein interactions in B cell receptor signaling and include sample analysis code for post-processing of imaging data. These methods are quantitative, sensitive, and broadly applicable to a range of signaling systems., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Single-molecule localization microscopy (SMLM) permits the visualization of cellular structures an order of magnitude smaller than the diffraction limit of visible light, and an accurate, objective evaluation of the resolution of an SMLM data set is an essential aspect of the image processing and analysis pipeline. Here, we present a simple method to estimate the localization spread function (LSF) of a static SMLM data set directly from acquired localizations, exploiting the correlated dynamics of individual emitters and properties of the pair autocorrelation function evaluated in both time and space. The method is demonstrated on simulated localizations, DNA origami rulers, and cellular structures labeled by dye-conjugated antibodies, DNA-PAINT, or fluorescent fusion proteins. We show that experimentally obtained images have LSFs that are broader than expected from the localization precision alone, due to additional uncertainty accrued when localizing molecules imaged over time., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Single-molecule localization microscopy techniques transcend the diffraction limit of visible light by localizing isolated emitters sampled stochastically. This time-lapse imaging necessitates long acquisition times, over which sample drift can become large relative to the localization precision. Here, we present an efficient and robust method for estimating drift, using a simple peak-finding algorithm based on mean shifts that is effective for single-molecule localization microscopy in two or three dimensions.

Lateral organization in the plane of the plasma membrane is an important driver of biological processes. The past dozen years have seen increasing experimental support for the notion that lipid organization plays an important role in modulating this heterogeneity. Various biophysical mechanisms rooted in the concept of liquid-liquid phase separation have been proposed to explain diverse experimental observations of heterogeneity in model and cell membranes with distinct but overlapping applicability. In this review, we focus on the evidence for and the consequences of the hypothesis that the plasma membrane is poised near an equilibrium miscibility critical point. Critical phenomena explain certain features of the heterogeneity observed in cells and model systems but also go beyond heterogeneity to predict other interesting phenomena, including responses to perturbations in membrane composition.

Objective: To determine whether, in acute non-ST elevation coronary syndrome, the benefit from early invasive coronary intervention compared with a conservative strategy of later symptom-guided intervention varies over time., Methods: In RITA 3 (Randomised Intervention Trial of unstable Angina 3) patients were randomly assigned to coronary angiography (median 2 days after randomisation) and appropriate intervention (n = 895) or to a symptom-guided conservative strategy (n = 915)., Results: In the first week patients in both groups were at highest risk of death, myocardial infarction (MI) or refractory angina (incidence rate 40 times higher than in months 5-12 of follow up). There were 22 MIs and 6 deaths in the intervention group (largely due to procedure-related events, 14 MIs and 3 deaths) versus 17 MIs and 3 deaths in the conservative group. In the rest of the year there were an additional 12 versus 27 MIs, respectively (treatment-time interaction p = 0.021). Over one year in the intervention group there was a 43% reduction in refractory angina; 22% of patients underwent coronary artery bypass surgery and 35% underwent percutaneous coronary intervention only, which reduced refractory angina but provoked some early MIs; and 43% were still treated medically, mostly because of a favourable initial angiogram., Conclusion: Any intervention policy needs to recognise the high risk of events in the first week and the substantial minority of patients not needing intervention. Intervention may be best targeted at higher risk patients, as the early hazards of the procedure are then offset by reduced subsequent events.

Objective: To investigate the value of transoesophageal echocardiography in the assessment of commissural morphology and prediction of outcome after balloon mitral valvotomy (BMV)., Design: Prospective study., Setting: Tertiary cardiac referral centre., Patients: 72 consecutive patients (mean age 61.3 years, range 38-89 years) referred for BMV., Interventions: Transoesophageal echocardiography was performed immediately before BMV and the mitral commissures were scanned systematically. Anterolateral and posteromedial commissures were scored individually according to whether non-calcified fusion was absent (0), partial (1), or extensive (2). Calcified commissures usually resist splitting and scored 0. Scores for each commissure were combined giving an overall commissure score for each valve of 0-4, higher scores reflecting increased likelihood of commissural splitting. Valve anatomy was also graded by the method of Wilkins et al, which does not include commissural assessment., Main Outcome Measures: Patients were divided into outcome groups: A (good) and B (suboptimal). "Good" was defined as final valve area > 1.5 cm2 with a > 25% increase in area and absence of severe mitral regurgitation judged by echocardiography., Results: Valve area increased from a mean (SD) of 1.1 (0.28) cm2 to 1.8 (0.46) cm2. Commissure scores were higher in group A than in group B (p < 0.01), scores > or = 2 predicting a good outcome with positive and negative accuracy of 67% and 82%, respectively (p < 0.001). Commissure score was the strongest independent predictor of outcome., Conclusion: Transoesophageal echocardiographic assessment of commissural morphology predicts outcome after BMV, adding significantly to the Wilkins score.

Background: The long-term outcome of an interventional strategy in patients with non-ST-elevation acute coronary syndrome is unknown. We tested whether an interventional strategy (routine angiography followed by revascularisation) was better than a conservative strategy (ischaemia-driven or symptom-driven angiography) over 5 years' follow-up., Methods: In a multicentre randomised trial, 1810 patients (from 45 hospitals in England and Scotland, UK) with non-ST-elevation acute coronary syndrome were randomly assigned to receive an early intervention (n=895) or a conservative strategy (n=915) within 48 h of the index episode of cardiac pain. In each group, the aim was to provide the best medical treatment, and also to undertake coronary arteriography within 72 h in the interventional strategy with subsequent management guided by the angiographic findings. Analysis was by intention to treat and the primary outcome (composite of death or non-fatal myocardial infarction) had masked independent adjudication. RITA 3 has been assigned the International Standard Randomised Control Trial Number ISRCTN07752711., Findings: At 1-year follow-up, rates of death or non-fatal myocardial infarction were similar. However, at a median of 5 years' follow-up (IQR 4.6-5.0), 142 (16.6%) patients with intervention treatment and 178 (20.0%) with conservative treatment died or had non-fatal myocardial infarction (odds ratio 0.78, 95% CI 0.61-0.99, p=0.044), with a similar benefit for cardiovascular death or myocardial infarction (0.74, 0.56-0.97, p=0.030). 234 (102 [12%] intervention, 132 [15%] conservative) patients died during follow-up (0.76, 0.58-1.00, p=0.054). The benefits of an intervention strategy were mainly seen in patients at high risk of death or myocardial infarction (p=0.004), and for the highest risk group, the odds ratio of death or non-fatal myocardial infarction was 0.44 (0.25-0.76)., Interpretation: In patients with non-ST-elevation acute coronary syndrome, a routine invasive strategy leads to long-term reduction in risk of death or non-fatal myocardial infarction, and this benefit is mainly in high-risk patients. The findings provide support for national and international guidelines in the need for more robust risk stratification in acute coronary syndrome.

Following percutaneous multivessel coronary stent implantation with full anticoagulation, a 65-year-old man suffered tamponade and cardiac arrest. After successful resuscitation, he underwent repeat coronary angiography which demonstrated extravasation of contrast from a distal circumflex subbranch. Thereafter, he was transferred to the cardiothoracic surgery unit where the leaking vessel was oversewn using the Medtronic Octopus Retractor for stabilization. This report illustrates the growing wider use of "off-pump" techniques beyond coronary artery bypass grafting. In this case, the patient was exposed to a much shorter procedure with less morbidity than could have been expected had cardiopulmonary bypass been used.

Aims: The RITA 3 trial randomized patients with non-ST-elevation myocardial infarction or unstable angina to strategies of early intervention (angiography followed by revascularization) or conservative care (ischaemia or symptom driven angiography). The aim of this analysis was to investigate the impact of gender on the effect of these two strategies., Methods and Results: In total, 1810 patients (682 women and 1128 men) were randomized. The risk factor profile of women at presentation was markedly different to men. There was evidence that men benefited more from an early intervention strategy for death or non-fatal myocardial infarction at 1 year (adjusted odds ratios 0.63, 95% confidence interval 0.41-0.98 for men and 1.79, 95% confidence interval 0.95-3.35 for women; interaction p-value=0.007). Men who underwent the assigned angiogram were more likely to be put forward for coronary artery bypass surgery, even after allowing for differences in disease severity., Conclusion: An early intervention strategy resulted in a beneficial effect in men which was not seen in women although caution is needed in interpretation. Further research is needed to evaluate why women do not appear to benefit from early intervention and to identify treatments that improve the prognosis of women.

Objective: To compare the clinical characteristics, haemodynamic findings, and symptomatic outcome in four age groups of patients in the UK undergoing percutaneous mitral balloon valvotomy., Design: A review of patients with mitral stenosis treated by balloon dilatation., Setting: Western General Hospital, Edinburgh, a cardiac referral centre., Results: Of 405 patients who had mitral balloon valvotomy, 19 were aged under 40 years, 101 aged 40-54, 173 aged 55-69, and 112 were 70 years old or more. Medical co-morbidity and Parsonnet score for risk at surgery increased notably with age. Older patients had greater symptomatic limitation and a more severe degree of mitral stenosis, with more valve degenerative change. The incidence of atrial fibrillation, mitral reflux, left ventricular impairment, coronary artery disease, and aortic valve disease increased progressively with age. Before balloon dilatation the right ventricular systolic and left atrial pressures were similar in all age groups, but younger patients had a higher transmitral gradient and cardiac output. After balloon dilatation the younger patients achieved a greater increase in valve area. Complications of balloon valvotomy were more common in the older patients. At five years after balloon dilatation the percentages of patients in each age group who were in New York Heart Association classes I and II were 87%, 63%, 36%, and 19%, respectively. Mortality at five years was 0%, 5%, 31%, and 59%., Conclusions: Percutaneous balloon valvotomy gives a good haemodynamic and symptomatic result in patients under 55. In older patients improvement is often less pronounced and less sustained, but the procedure is a well tolerated palliative treatment for those unsuitable for surgery.

The development of collateral circulation is a general vascular response which is well characterised in the heart. The most common precipitant of this is ischaemia and the most common manifestation is intra coronary collateralisation. Collateral flow between the heart and other thoracic structures is also documented albeit rarely and can be congenital or acquired. In this case report we define a unique case of collateral flow between the coronary and pulmonary circulations in a complex case of mediastinal fibrosis.

Background: Current guidelines suggest that, for patients at moderate risk of death from unstable coronary-artery disease, either an interventional strategy (angiography followed by revascularisation) or a conservative strategy (ischaemia-driven or symptom-driven angiography) is appropriate. We aimed to test the hypothesis that an interventional strategy is better than a conservative strategy in such patients., Methods: We did a randomised multicentre trial of 1810 patients with non-ST-elevation acute coronary syndromes (mean age 62 years, 38% women). Patients were assigned an early intervention or conservative strategy. The antithrombin agent in both groups was enoxaparin. The co-primary endpoints were a combined rate of death, non-fatal myocardial infarction, or refractory angina at 4 months; and a combined rate of death or non-fatal myocardial infarction at 1 year. Analysis was by intention to treat., Findings: At 4 months, 86 (9.6%) of 895 patients in the intervention group had died or had a myocardial infarction or refractory angina, compared with 133 (14.5%) of 915 patients in the conservative group (risk ratio 0.66, 95% CI 0.51-0.85, p=0.001). This difference was mainly due to a halving of refractory angina in the intervention group. Death or myocardial infarction was similar in both treatment groups at 1 year (68 [7.6%] vs 76 [8.3%], respectively; risk ratio 0.91, 95% CI 0.67-1.25, p=0.58). Symptoms of angina were improved and use of antianginal medications significantly reduced with the interventional strategy (p<0.0001)., Interpretation: In patients presenting with unstable coronary-artery disease, an interventional strategy is preferable to a conservative strategy, mainly because of the halving of refractory or severe angina, and with no increased risk of death or myocardial infarction.

Objective: To compare the planned and actual revascularisation techniques used in patients undergoing cardiac surgery for refractory angina when excimer transmyocardial laser revascularisation (TMR) is available., Methods: Observational series of 31 patients (mean age 65 years) with severe angina [mean CCS score (SD) 3.8 (0.4)] and three-vessel coronary artery disease judged unsuitable for conventional bypass surgery alone. All patients underwent cardiac surgery: revascularisation techniques were determined by the operative findings., Results: Pre-operative strategy was altered by the intra-operative findings in 13 patients (42%). In 5 (16%), the coronary vessels proved graftable and TMR was unnecessary. Conversely, in 6 patients (19%) an anticipated graft could not be performed and TMR was used as an alternative. In 2 patients (7%), neither strategy was possible. Overall, TMR was performed as a stand-alone procedure in 9 (29%) and combined with CABG in 17 (55%). Operative mortality was low: 0% at 30 days and 6% at 6 months. Mean CCS class (SD) improved post-operatively from 3.8 (0.4) to 1.7 (1.1) (p < 0.01)., Conclusions: The pre-operative coronary angiogram is an imperfect predictor of which coronary vessels are suitable for grafting. The availability of laser TMR allows the cardiac surgeon to accept cases which would otherwise be considered inoperable and to respond better to intraoperative findings. The combination of laser TMR and bypass grafts provides good short- and medium-term symptomatic improvement with a low post-operative mortality., (Copyright 2001 S. Karger AG, Basel)

Objective: To evaluate the significance of commissural calcification, identified by transthoracic echocardiography, on the haemodynamic and symptomatic outcome of mitral balloon valvotomy., Methods: Commissural calcification was graded from 0-4 using parasternal short axis transthoracic views. The morphology of the mitral valve was also assessed using the Massachusetts General Hospital echo score., Setting: A tertiary cardiac centre in Scotland., Patients: 300 patients were studied, 85 retrospectively and 215 prospectively. Mean (SD) age was 59.8 (12.7) years, range 13 to 87; 30% had been judged unsuitable for surgery. Median echo score was 6.8 (3.0), range 2-16., Main Outcome Measures: Immediate increase in mitral valve area and in New York Heart Association functional class 1-3 months after balloon valvotomy., Results: On univariate and multivariate analysis, commissural calcification grade was a significant predictor of achieving a mitral valve area of > 1.50 cm(2) without severe mitral reflux. Its influence was greatest in patients with an echo score 1.50 cm(2) were 67% and 46%, respectively (p < 0.05). In patients with an echo score of > 8, the influence of commissural calcification was smaller and not significant., Conclusions: Commissural calcification as assessed by transthoracic echocardiography is a useful predictor of outcome in patients with otherwise "good" valves (echo score

BACKGROUND: The technique of coronary stenting has evolved over recent years, with improved stent technology and effective antiplatelet therapies to prevent stent thrombosis. In Europe, reductions in stent and equipment costs have resulted from increased market competition. The impact of these changes on the in-hospital procedural cost of percutaneous coronary intervention (PCI) in the current clinical setting is not known. METHODS: We compared the initial equipment and pharmaceutical costs of one hundred consecutive, unselected patients undergoing PCI in 1998 to a similar population who underwent PCI in 1994. RESULTS: Similar patient characteristics were noted, yet more complex disease (multivessel, AHA type B2/C lesions) was treated in the 1998 population. The stent utilization rate (83% vs 15%, p < 0.0001) and use of intravenous and/or oral antiplatelet therapy (abciximab, ticlopidine) (64% vs 4%, p < 0.0001) was higher in 1998. Similar angiographic success was achieved in each group with low complication rates. Mean hospital stay was reduced in the 1998 group (2.6 +/- 2.8 vs 4.3 +/- 3.8 days, p < 0.001). Repeat PCI was required more frequently in the 1994 population (26% vs 9%, p < 0.001). Overall there was no significant difference in the mean equipment cost between the two groups ( pound 1551 vs pound 1422, p=ns). CONCLUSION: Despite the widespread use of coronary stenting and antiplatelet therapies there appears to be no difference in current in-hospital equipment costs for PCI compared to 1994. Improved clinical outcomes in the 1998 population imply that stenting is a cost-effective therapy.

Objectives: To study the safety and benefit of mitral balloon valvotomy (MBV) in patients aged > or =80 years., Setting: A tertiary cardiac centre, Design: A retrospective study of 20 octogenarians (mean age 83, range 80-89 years) in whom percutaneous MBV was performed as a definitive or palliative treatment for severe mitral stenosis. All were in New York Heart Association (NYHA) symptom class III or IV. Fourteen had been judged unfit for cardiac surgery. Hemodynamic data was recorded before and after MBV. Symptomatic outcome was documented at 1 month for all patients. Outcome at 1 year was available for 16 patients., Results: Dilatation of the mitral valve was achieved in all patients without major complications. Mean mitral valve area increased 106% from 0.81 (+/-0.3) to 1.67 (+/- 0.8) cm2, transvalvular gradient decreased from 11.8 (+/- 4.8) to 5.6 (+/-2.9) mm Hg, cardiac output increased from 3.1 (+/- 0.6) to 4.1 (+/- 1.4) l/min (all P<.01). Eight of these 20 patients obtained a valve area > or =1.5 cm2, and 16 obtained an area > or = 1.2 cm2. One month after BMV, all patients were alive, and 16 of the 20 patients were improved by at least one NYHA class. This improvement was sustained in 7 of 16 patients followed up for 1 year. More severe mitral valve degenerative change, determined by echocardiography, was associated with poorer outcome., Conclusions: In this group of very old and frail patients, MBV was safe and resulted in significant immediate improvement. Sustained symptomatic benefit at 1 year was obtained in those with less extensive leaflet and subvalvular disease. In patients with severe degenerative valve disease on echocardiography, but unacceptable surgical risk, MBV offers short-term palliation.

Objective: To assess the immediate haemodynamic improvement and long term symptomatic benefit of percutaneous mitral balloon valvotomy in patients aged over 70 years., Design: Pre- and postprocedure haemodynamic data and follow up for 1 to 10 years by clinic visit or telephone contact., Setting: Tertiary referral centre in Scotland., Subjects: 80 patients age 70 and over who had mitral balloon dilatation: 55 were considered unsuitable for surgical treatment because of frailty or associated disease. In an additional four patients mitral dilatation was not achieved., Main Outcome Measures: Increase in valve area after balloon dilatation and survival, freedom from valve replacement, and symptom class at follow up., Results: Mean (SD) valve area increased by 89% from 0.84 (0.28) to 1. 59 (0.67) cm(2). There was a low rate of serious complications, with only two patients having long term major sequelae. Of 55 patients unsuitable for surgical treatment, 28 (51%) were alive without valve replacement and with improvement by at least one symptom class at one year, and 14 (25%) at five years. In the 25 patients considered suitable for surgical treatment, 16 (64%) achieved this outcome at one year and nine (36%) at five years., Conclusions: Percutaneous mitral balloon valvotomy is a safe and useful palliative procedure in elderly patients who are unsuitable for surgery. Balloon dilatation should also be used for elderly patients whose valve appears suitable for improvement by commissurotomy, but echo score is an imperfect predictor of haemodynamic improvement.

Chest pain accounts for much of the rising numbers of emergency admissions, but in-patient assessment is not necessarily the best way of dealing with these patients. We ran a 'rapid-assessment chest pain clinic' to provide an alternative route of assessment, and audited its outcome. General practitioners referred patients with recent-onset chest pain, increasing chest pain, chest pain at rest, or other chest pain of concern, on the understanding that they would be seen within 24 h. During 8 1/2 months, 334 patients were referred and 317 patients were seen, most of whom had exercise electrocardiography. A median of 6 months later, 278 patients were personally contacted to determine outcome. Of these, 18% had been admitted immediately with acute coronary syndromes, and 49% had been diagnosed as non-coronary chest pain (none of whom subsequently infarcted or died). Continuing symptoms were infrequent, and satisfaction was high, although 13% of patients had been revascularized. A significant number of patients required immediate admission and/or ultimate revascularization, but many more did not. The majority of these patients had non-coronary chest pain, and this diagnosis was substantiated by their excellent outcome and (in some cases) by further investigation.

Objective: To determine whether spectral analysis of unprocessed radiofrequency (RF) signal offers advantages over standard videodensitometric analysis in identifying the morphology of coronary atherosclerotic plaques., Methods: 97 regions of interest (ROI) were imaged at 30 MHz from postmortem, pressure perfused (80 mm Hg) coronary arteries in saline baths. RF data were digitised at 250 MHz. Two different sizes of ROI were identified from scan converted images, and relative amplitudes of different frequency components were analysed from raw data. Normalised spectra was used to calculate spectral slope (dB/MHz), y-axis intercept (dB), mean power (dB), and maximum power (dB) over a given bandwidth (17-42 MHz). RF images were constructed and compared with comparative histology derived from microscopy and radiological techniques in three dimensions., Results: Mean power was similar from dense fibrotic tissue and heavy calcium, but spectral slope was steeper in heavy calcium (-0.45 (0.1)) than in dense fibrotic tissue (-0.31 (0.1)), and maximum power was higher for heavy calcium (-7.7 (2.0)) than for dense fibrotic tissue (-10.2 (3.9)). Maximum power was significantly higher in heavy calcium (-7.7 (2.0) dB) and dense fibrotic tissue (-10.2 (3.9) dB) than in microcalcification (-13.9 (3.8) dB). Y-axis intercept was higher in microcalcification (-5.8 (1.1) dB) than in moderately fibrotic tissue (-11.9 (2.0) dB). Moderate and dense fibrotic tissue were discriminated with mean power: moderate -20.2 (1.1) dB, dense -14.7 (3.7) dB; and y-axis intercept: moderate -11.9 (2.0) dB, dense -5.5 (5.4) dB. Different densities of fibrosis, loose, moderate, and dense, were discriminated with both y-axis intercept, spectral slope, and mean power. Lipid could be differentiated from other types of plaque tissue on the basis of spectral slope, lipid -0.17 (0.08). Also y-axis intercept from lipid (-17.6 (3.9)) differed significantly from moderately fibrotic tissue, dense fibrotic tissue, microcalcification, and heavy calcium. No significant differences in any of the measured parameters were seen between the results obtained from small and large ROIs., Conclusion: Frequency based spectral analysis of unprocessed ultrasound signal may lead to accurate identification of atherosclerotic plaque morphology.

Mitral regurgitation which is more than mild in severity is usually regarded as a relative contraindication to balloon mitral commissurotomy (BMC) because it is commonly believed that it may be worsened by the procedure. The aim of this study was to investigate the effects of BMC on pre-existing mitral regurgitation. Transthoracic and biplane transoesophageal echocardiography (TTE, TEE) combined with colour flow mapping (CFM) were performed prospectively on 50 consecutive patients immediately before and within 24 h after Inoue BMC. Before BMC, mitral regurgitation (MR) was diagnosed by TEE and left ventriculography in 36 and 13 patients respectively. Angiographic MR was mild in all 13 cases. The precise origins of MR jets were carefully sought by scanning in multiple TTE and TEE views. The maximal area of colour flow MR jets detected by TEE was measured by planimetry. After BMC mean mitral valve area increased from 1.0 +/- 0.3 to 1.7 +/- 0.8 cm2, p < 0.0001, mean left atrial pressure and volume decreased from 23.7 +/- 5.6 mm Hg to 21.6 +/- 7.5 ml, p = 0.039, and from 105 +/- 56 to 90 +/- 46 ml, p = 0.002, respectively. MR jets as assessed by TEE CFM disappeared in 12 patients, in all of whom MR had been undetected by angiography. MR jets remained within 20% of their original sizes in 16 (44%) patients and more than doubled in only 3 patients. However, the latter had only mild angiographic MR after BMC. BMC created new MR jets, distinct from pre-existing ones, in 27 (75%) patients. Their aetiologies were commissural splitting in 24, leaflet tears in 2 and chordal rupture in 1 case. New MR jets were co-existent with old jets in 17 (47%) cases and in 10 (28%) cases old jets were replaced by new jets. The severity of angiographic MR was unchanged in 21 (58%) of the 36 patients; new jets, all originating from one or both commissures, were found in 13 (65%) patients on TEE. Angiographic MR increased by 1 grade in 11 (33%) patients; new jets were detected in 9 patients, 8 from the commissures and 1 due to chordal rupture; in only 1 of the 11 patients did the increase in MR appear to be due to a worsening of a pre-existing jet. Angiographic MR increased by 2 grades in 3 (8%) patients; new jets appeared in all 3, arising from the commissures in 2 and from a leaflet tear in 1 case. One patient with a leaflet tear sustained an increase of 3 grades in angiographic MR. The final degree of angiographic MR was nil in 13, mild in 15, moderate in 6 and severe in 2 patients. Leaflet tears were responsible for both cases of severe MR. BMC does not appear to affect pre-existing mitral regurgitation adversely in almost all patients. It may abolish trivial jets but in most cases it creates new jets alongside the old ones. Leaflet tears are responsible for severe mitral regurgitation after BMC and this is independent of pre-existing regurgitant jets.

Objectives: We sought to compare the myocardial velocity gradient (MVG) measured across the left ventricular (LV) posterior wall during the cardiac cycle between patients with hypertrophic cardiomyopathy (HCM), athletes and patients with LV hypertrophy due to systemic hypertension and to determine whether it might be used to discriminate these groups., Background: The MVG is a new ultrasound variable, based on the color Doppler technique, that quantifies the spatial distribution of transmyocardial velocities., Methods: A cohort of 158 subjects was subdivided by age into two groups: Group I (mean [+/-SD] 30 +/- 7 years) and Group II (58 +/- 8 years). Within each group there were three categories of subjects: Group Ia consisted of patients with HCM (n = 25), Group Ib consisted of athletes (n = 21), and Group Ic consisted of normal subjects; Group IIa consisted of patients with HCM (n = 19), Group IIb consisted of hypertensive patients (n = 27), and Group IIc consisted of normal subjects (n = 33)., Results: The MVG (mean [+/-SD] s-1) measured in systole was lower (p < 0.01) in patients with HCM (Group Ia 3.2 +/- 1.1; Group IIa 2.9 +/- 1.2) compared with athletes (Group Ib 4.6 +/- 1.1), hypertensive patients (Group IIb 4.2 +/- 1.8) and normal subjects (Group Ic 4.4 +/- 0.8; Group IIc 4.8 +/- 0.8). In early diastole, the MVG was lower (p < 0.05) in patients with HCM (Group Ia 3.7 +/- 1.5; Group IIa 2.6 +/- 0.9) than in athletes (Group Ib 9.9 +/- 1.9) and normal subjects (Group Ic 9.2 +/- 2.0; Group IIc 3.6 +/- 1.5), but not hypertensive patients (Group IIb 3.3 +/- 1.3). In late diastole, the MVG in patients with HCM (Group Ia 1.3 +/- 0.8; Group IIa 1.4 +/- 0.8) was lower (p < 0.01) than that in hypertensive patients (Group IIb 4.3 +/- 1.7) and normal subjects (Group IIc 3.8 +/- 0.9). An MVG < or = 7 s-1, as a single diagnostic approach, differentiated accurately (0.96 positive and 0.94 negative predictive value) between patients with HCM and athletes when the measurements were taken during early diastole., Conclusions: In both age groups, the MVG was lower in both systole and diastole in patients with HCM than in athletes, hypertensive patients or normal subjects. The MVG measured in early diastole in a group of subjects 18 to 45 years old would appear to be an accurate variable used to discriminate between HCM and hypertrophy in athletes.

Transthoracic and transoesophageal echocardiography (TTE, TEE) were performed in 130 consecutive patients referred for mitral balloon valvotomy. Atrial septal aneurysms were diagnosed by TTE and TEE in 2 and 3 patients, respectively. All 3 patients underwent mitral balloon valvotomy via the transseptal route. The foramen ovale was found to be patent in 2 of these patients, thus rendering puncture of the interatrial septum unnecessary. In the 3rd patient transseptal catheterisation was performed through the wall of the aneurysm itself. There were no significant complications in any of these patients. No left-to-right interatrial shunting could be demonstrated by oximetry in any of the 3 patients. Transoesophageal colour flow imaging showed trivial shunting in 2 patients and none in the 3rd. Transseptal mitral balloon valvotomy can be performed safely in patients with atrial septal aneurysms, especially in those with co-existent patent foramen ovale.

Doppler myocardial imaging (DMI) is a new ultrasound imaging modality in which colour Doppler algorithms are adapted to visualise the myocardium. It allows measurement of regional intramyocardial velocities and quantification of intramural left ventricular function. However promising the technique is, to date the accuracy of endocardial boundary detection by DMI has not been validated. As Doppler velocity estimation is based on measurement of phase shift rather than signal strength, the technique is relatively independent of chest wall attenuation. In the current study, a series of in vitro and in vivo studies was performed to compare standard B-mode grey-scale imaging (GSI) and DMI techniques in endocardial boundary detection. In vitro, the minimum and maximum volumes of a single-chamber tissue-mimicking phantom were calculated using both imaging techniques. In vivo, left ventricular end-diastolic (ED) volume and end-systolic (ES) volume indices were measured from GSI and DMI images in a group of 40 volunteers. All images were obtained in the freeze-frame mode with the Doppler display turned on and off so that simultaneous DMI and GSI information was obtained. In vitro, the limits of agreement between the minimum volume of the phantom and the minimum volume measured by GSI and DMI was 4% and 3%, respectively. For maximum volumes, limits of agreement were 3% for GSI and 2% for DMI. In vivo, the limits of agreement between the two imaging techniques in volume measurements were 6 mL (9%) for ED and 4 mL (11%) for ES. The comparison of the endocardial boundary detection by GSI vs. DMI showed DMI to be significantly superior: ED (72 +/- 16% vs. 85 +/- 8%, respectively; p < 0.05) and ES (71 +/- 13% vs. 88 +/- 7%, respectively; p < 0.05). The results of the study show that: (1) in vitro, based on two-dimensional algorithms, DMI provides as accurate volume measurements as GSI; and (2) in vivo, there is a very good agreement of left ventricular volume measurements between GSI and DMI. However, the endocardial boundary is more reliably displayed and visually easier to detect using DMI than GSI.

Nonuniform rotation of mechanical intravascular ultrasound transducers may give rise to a geometric distortion of the ultrasound image known as the rotation angle artefact. This investigation studied the influence of different degrees and combinations of catheter shaft angulation on image morphology and the quantitative impact of the artefact using a circular perspex phantom and 3.5 F, 30 MHz Boston Scientific "Sonicath" catheters connected to a Hewlett Packard Sonos intravascular scanner. Major and minor diameters, cross-sectional area and circumference of the phantom lumen were measured and a "distortion index" calculated. Visually apparent geometric distortion was graded from 1 (absent) to 4 (severe). As expected, eccentric transducer location was associated much more frequently with identifiable distortion (70%) than was a concentric location (6%). Greater distortion occurred with increasing degrees of catheter shaft angulation, and was more pronounced in images from older catheters. The lumen area measurements in images in which no artefact was identified were accurate to within +/- 10% in 97% of cases, compared to only 81% of cases when an artefact was noted. The quantitative accuracy of an image in which geometric distortion is identified is thus not reliable. The direction of the quantitative error cannot be confidently predicted in any given case, although the mean lumen area tends to increase as the grade of distortion increases.

Intravascular ultrasound is widely used to guide coronary stent implantation. The key quantitative criterion for successful implantation is the demonstration of adequate expansion of the stented lumen relative to that of the adjacent reference vessel segments. In this study we aimed to establish the reproducibility of intravascular ultrasound measurements of the reference segments in lesions undergoing coronary stenting. Measurements of the reference segment lumen dimensions warn made in a blinded fashion by two experienced observers, and reproducibility was assessed by calculating the mean difference and standard deviation of the paired measurements. The unselected intraobserver random variability of the mean reference lumen area measured 0.6 mm2. The interobserver random variability was 0.94 mm2. The intraobserver and interobserver variability of minimum lumen area within the stent was smaller, measuring 0.30 mm2 and 0.52 mm2, respectively. There was 91% intraobserver agreement, and 75% interobserver agreement, in identifying adequate stent expansion as defined by a stent-to-mean reference lumen area ratio of > 0.8. The potentially significant level of variability inherent in selecting and measuring the reference segments, and its impact on clinical decision-making, should be remembered when this method of assessing the acute quantitative outcome of stent implantation is applied.

Doppler myocardial imaging is a new cardiac ultrasound technique based on the principles of colour Doppler imaging which can determine myocardial velocities by detecting the changes of phase-shift of the ultrasound signal returning directly from the myocardium. To determine the normal range of transmural velocities in healthy hearts a prospective study was carried out involving 42 normal subjects (age from 21 to 78, mean 47 +/- 16 years). Using M-mode Doppler myocardial imaging the peak values of the mean velocity and velocity gradient across the left ventricular posterior wall were measured during standardized phases of the cardiac cycle. Peak mean velocities had the following values during the cardiac cycle: isovolumic contraction - 1.3 +/- 1.2 cm. s-1, early ventricular ejection 4.2 +/- 1.2 cm. s-1, late ventricular ejection 1.8 +/- 1.1 cm. s-1, isovolumic relaxation -2.0 +/- 0.8 cm. s-1, rapid ventricular filling -6.6 +/- 2.2 cm. s-1, atrial contraction -2.8 +/- 1.8 cm. s-1, atrial relaxation 1.2 +/- 1.1 cm. s-1. Peak velocity gradients were: isovolumic contraction 1.3 +/- 1.9 s-1, early ventricular contraction 4.7 +/- 1.9 s-1, late ventricular contraction 1.1 +/- 1.0 s-1, isovolumic relaxation -0.6 +/- 0.5 s-1, rapid ventricular filling 6.1 +/- 3.4 s-1, atrial contraction 2.6 +/- 1.7 s-1, atrial relaxation 0.0 +/- 0.3 s-1. Linear regression analysis showed that with the increase of age, peak velocity gradient decreases during rapid ventricular filling (r = 0.83; P < 0.0001) and increases during atrial contraction (r = 0.86; P < 0.0001) while peak mean velocity increases only during atrial contraction (r = 0.80, P < 0.0001). Thus, there was no correlation between increasing age and systolic peak mean velocity and peak velocity gradient but both diastolic filling phases rapid ventricular filling and atrial contraction demonstrated age-related changes. In summary, this study has determined the age-related range of normal transmural myocardial velocities within the left ventricular posterior wall in healthy hearts during the cardiac cycle. We conclude that these measurements of peak mean velocities and peak velocity gradients, should form the baseline for subsequent Doppler myocardial imaging clinical studies on myocardial diseases processes.

The following recommendations are made: 1 Existing centres undertaking angioplasty should increase their activity, and the target figure of 400 PTCA procedures per million of the United Kingdom population should be achieved by the end of 1996-97, or immediately thereafter. 2 Angioplasty centres should be appropriately equipped to undertake PTCA safely and effectively and provide a reliable emergency service. They should have a minimum of two trained PTCA operators jointly undertaking a minimum of 200 procedures per year at that centre, and have regular meetings to share experience. 3 Angioplasty operators should ensure that where the need arises patients undergoing PTCA can receive immediate attention from a trained operator at any time until discharge from hospital. 4 Trained operators should undertake at least 1-2 PTCA procedures per week (> 60 procedures per year) to maintain competence, and those undertaking so few procedures should increase their activity over the next three years to more than 100 a year. 5 Trainers should have performed at least 500 procedures before formally training others and should undertake a minimum of 125 procedures a year to maintain accreditation as a trainer. 6 Surgical cover for PTCA procedures should be mandatory and on site cover remains the strongly preferred option. Where surgical cover is provided off site, this should be at a centre less than 30 minutes away by road. Whether provided on or off-site it should be possible to establish cardiopulmonary bypass within 90 minutes of the decision being made to refer the patient for surgery. 7 All operators and interventional centres should audit their activity and results, review these data locally with colleagues, and provide regular audit returns to the national database run by BCIS. This will allow future recommendations concerning standards to take more account of risk stratification and actual outcomes, and not place such emphasis merely on volumes of activity. 8 These recommendations should be reviewed in three years.

Morgagni hernias most commonly present in infancy or childhood with gastrointestinal or respiratory symptoms, resulting from visceral herniation into the thorax. They are much rarer in the adult, and may be misdiagnosed as pericardial masses. We report a case of a Morgagni hernia containing liver, which hindered cardiac imaging with echocardiography and angiography, and was best demonstrated with MRI.

Objective: To assess the value of an open access echocardiography service., Design: Study of new open access service for general practitioners, who were invited to refer patients taking diuretics for suspected heart failure, untreated patients with symptoms of possible heart failure, and asymptomatic patients with risk factors for left ventricular systolic dysfunction., Setting: Regional cardiology centre., Subjects: 259 consecutive patients., Main Outcome Measures: Presence or absence of left ventricular systolic dysfunction and consequent changes in clinical management., Results: 119 treated patients, 99 untreated patients, and nine asymptomatic patients were referred over five months. 32 were considered to be inappropriately referred. Among the treated patients, 31 had impaired left ventricular systolic function and five had valvular disease; angiotensin converting enzyme inhibitors were recommended for 34 of these patients. In addition, 53 were thought not to need diuretics. Eight untreated patients had impaired systolic function and six valvular disease., Conclusions: The service was well used by general practitioners and led to advice to change management in more than two thirds of patients.

Objectives: To compare the use of cylindrical balloons and the Inoue balloon for percutaneous mitral valvotomy in patients in the United Kingdom., Design: Comparison of the haemodynamic results, complications, and symptomatic outcome of balloon dilatation for mitral stenosis in consecutive patients treated by cylindrical balloons and a second consecutive series of patients treated by the Inoue balloon., Setting: A tertiary cardiac referral centre in Scotland., Patients: 70 patients (mean age 60.6 years) treated by the single or double cylindrical balloon technique and 70 patients (mean age 58.9 years) treated with the Inoue balloon method., Main Outcome Measures: Success in obtaining dilatation at the mitral orifice, procedure and screening times, increase in valve area, complications, and early symptomatic outcome., Results: Dilatation of the mitral valve was obtained in 91% of patients when cylindrical balloons were used and in 99% of patients treated with the Inoue balloon. Use of the Inoue balloon gave significantly shorter procedure and screening times. Technical problems in obtaining and maintaining the position at the mitral orifice were more common with cylindrical balloons. Improvements in valve area and symptoms were not significantly different with use of the two types of balloon. The Inoue balloon avoided cardiac tamponade and the creation of larger atrial septal defects, but had a higher incidence of increase in mitral reflux., Conclusions: In these elderly patients, the Inoue balloon method was safer and faster for percutaneous mitral valvotomy, with a higher success rate for dilatation within the valve orifice. Haemodynamic and symptomatic improvement was similar with the two techniques.

The aim of this study was to determine the clinical, echocardiographic, and hemodynamic predictors of left atrial spontaneous echo contrast (SEC) and thrombus, respectively, in patients referred for balloon dilation of the mitral valve and to establish the relationship between the two phenomena in this group of patients. One hundred consecutive patients (mean age 57 +/- 14 years) referred for mitral balloon (Inoue) dilation were studied prospectively with transthoracic and transesophageal (83 biplane and 17 single plane) echocardiography (TEE) combined with spectral and color Doppler modalities, immediately before the procedure. TEE was repeated within 24 hours of valvotomy in the first 55 patients. All patients also underwent comprehensive left- and right-sided heart catheterization. TEE was performed successfully in 96 patients. SEC was detected in all 65 patients in atrial fibrillation and in 14 (45%) of 31 patients in sinus rhythm. Patients with SEC were significantly older (61 +/- 13 vs 45 +/- 12 years; p < 0.001) and had larger left atrial volume (98 +/- 48 vs 64 +/- 24 ml; p < 0.001), higher mitral valve echocardiographic scores (7.4 +/- 3.2 vs 5.3 +/- 2.6; p = 0.016), lower cardiac output (3.5 +/- 1.1 versus 4.6 +/- 0.9 L/min; p < 0.001), lower peak systolic pulmonary vein flow velocity (SVm) (24 +/- 12 versus 45 +/- 11 cm/sec; p < 0.001), and correspondingly lower systolic velocity-time integral (4.0 +/- 2.6 vs 7.9 +/- 2.9 cm; p < 0.001) than had patients without SEC. There were no significant associations between SEC and either mitral valve area or anticoagulant therapy. SVm and atrial fibrillation were found to be independent predictors of SEC. In patients in sinus rhythm, SVm was the only independent predictor of SEC. After mitral balloon dilation, SEC disappeared in only two of 35 patients in atrial fibrillation and in five of eight patients in sinus rhythm. Significant mitral regurgitation occurred in the two patients in atrial fibrillation. TEE detected left atrial thrombus in 14 patients. Thrombus was significantly associated with age, mitral valve area, and the severity of SEC. The latter was found to be an independent predictor of thrombus. Two patients in sinus rhythm had evidence of left atrial mechanical dysfunction. Both patients had left atrial SEC and one had thrombus in the appendage. It is concluded that SEC in patients with severe mitral stenosis is dependent on left atrial systolic function and peak systolic pulmonary vein velocity. It is not related to mitral valve area or anticoagulant therapy.(ABSTRACT TRUNCATED AT 400 WORDS)