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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. more...

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. more...

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. more...

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.) more...

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.) more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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 more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

Objective: To assess the value of Doppler colour flow imaging for diagnosing and guiding non-surgical treatment of pseudoaneurysm of the femoral artery complicating cardiac catheterisation., Design: A prospective study., Setting: Cardiac department in a teaching hospital., Patients: 9 patients (8 female, 1 male) who presented with pseudoaneurysm 1-15 days after cardiac catheterisation., Interventions: The femoral arterial communication to the false aneurysm was localised by Doppler colour flow imaging. Manual pressure was then applied to the ultrasound transducer which was positioned directly over the site of the arterial communication. Pressure was progressively increased until it was sufficient to prevent colour flow from the artery into the false aneurysm cavity while allowing Doppler flow to continue within the arterial lumen., Main Outcome Measures: Characteristics of pseudoaneurysm, duration of manual compression, success rate, follow up., Results: The pseudoaneurysms ranged from 1.3 to 5.5 cm in length. Six pseudoaneurysms were 1.3-2.0 cm away from the arterial puncture. The pseudoaneurysm was closed in 8/9 patients by compression exerted manually through the transducer for 25-40 minutes (3 successful cases required two or three periods of compression within 48 hours). No pseudoaneurysm recurred during 14-61 days of follow up., Conclusions: Most pseudoaneurysms of the femoral artery can be treated by a period of manual pressure applied with an ultrasound transducer and guided by Doppler colour flow. more...

Objective: Assessment of an anterior staircase modification to the standard atrial transseptal technique., Design: Retrospective report on patients undergoing atrial transseptal puncture., Setting: A regional cardiac centre., Patients: A series of 658 patients catheterised between 1975 and 1991., Results: Needle entry to the left atrium was obtained in 647 (98.3%) patients with needle and catheter entry to the left atrial cavity in 637 patients (96.8%). Sustained atrial arrhythmia occurred in six patients (0.9%) and pronounced bradycardia in one. Cardiac perforation occurred in three patients (0.5%) but did not cause cardiac tamponade. There were no deaths or embolic complications caused by the transseptal puncture. The anterior staircase manoeuvre was particularly useful in patients with problem septa--that is, when the septum bulged into the right atrial cavity, lacked a detectable limbic edge, was tough or tender, or when the right atrium was considerably enlarged., Conclusion: The anterior staircase technique is a useful modification to the atrial transseptal puncture technique because it allows repeated passage down the atrial septum without the need for guidewire and needle exchanges for repositioning in the superior vena cava. more...

Background: The flow convergence region (FCR), a zone of progressive laminar velocity acceleration, can be imaged by color Doppler proximal to stenotic and regurgitant orifices. Theoretically, FCR proximal to a discrete circular and planar orifice consists of concentric hemispheric shells of equal and accelerating velocities centered at the orifice. According to the continuity principle, flow rate across any of these isovelocity surfaces equals flow rate through the orifice. The aim of this study was to investigate whether these principles could be applied to quantify left-to-right shunting and the size of atrial septal defects after balloon mitral commissurotomy., Methods and Results: Biplane transesophageal echocardiography (TEE) with color flow imaging was performed on 36 consecutive patients (mean age, 57 +/- 16 years; range, 14-78 years) immediately before and within 24 hours of balloon (Inoue, n = 33; Mansfield, n = 3) mitral commissurotomy. Left-to-right atrial shunting was detected by TEE in 33 patients (92%) and by oximetry in 11 patients (31%). The radius r of FCR was measured from the first aliasing limit, at a Nyquist velocity reduced to 11 cm/sec by zero-shifting, to the orifice in the atrial septum. FCR was assumed to be hemispherical. Hence, flow rate (Q) was calculated as 2 pi r2 Vr, where Vr is the velocity at a radial distance r. The velocity profile of transatrial flow was assessed by means of high pulse repetition frequency, from which the maximum flow velocity (Vp) and the velocity-time integral (VTI) were obtained. The flow area of the atrial septal defect was calculated as Qm, the maximal flow rate, divided by Vp. Hence, shunt flow was calculated as flow area x VTI x heart rate. FCR was analyzed in two orthogonal planes. Mean Qm (38.1 +/- 26.5 versus 5.3 +/- 2.7 mL/sec), flow area (22.1 +/- 11.2 versus 4.4 +/- 2.0 mm2), and shunt flow (1,590 +/- 1,070 versus 200 +/- 130 mL/min) on transverse plane imaging were all significantly higher in patients with shunts detected by oximetry than in those without. Similar results were obtained from longitudinal plane imaging. Qm correlated well with oximetric shunt flow (r = 0.89-0.94, p < 0.001) and shunt ratio (r = 0.91-0.94, p < 0.001). Flow area correlated closely (r = 0.93-0.94, p < 0.001) with area determined by direct measurement from two-dimensional echocardiography. Shunt flow determined by FCR also correlated closely (r = 0.94-0.98, p < 0.001) with that determined by oximetry and that derived from two-dimensional echocardiography and pulsed Doppler (r = 0.96, p < 0.001)., Conclusions: The flow convergence region imaged by TEE color flow mapping provides new and accurate quantitative information on atrial shunt flow and defect size after balloon mitral valvotomy. It is a quick, reliable, and fairly simple method that can be readily incorporated into routine clinical practice. more...

Objective: To assess the effects on haemodynamic function and symptoms of percutaneous balloon dilatation of mitral stenosis in patients unable to undergo surgical treatment because of associated medical/cardiac problems., Design: A review of clinical outcome in 28 patients (of 108 undergoing balloon dilatation of the mitral valve) who were unsuitable for surgery., Setting: A tertiary cardiac referral centre: some patients referred were from other cardiac centres in Scotland., Patients: 28 patients judged by cardiac surgeons to be unsuitable for valve replacement or valvotomy because of respiratory disease (15 patients), nonmitral cardiac disease (6), multi-organ impairment (5), psychiatric problems (1) or dense intrathoracic adhesions (1)., Interventions: Percutaneous anterograde balloon dilatation of the mitral valve with polyethylene/polyvinyl balloons in 20 patients and the Inoue balloon in eight patients., Main Outcome Measures: Haemodynamic variables were measured before and immediately after mitral valve dilatation. Patient survival and symptom class (New York Heart Association) were followed for a year after the procedure., Results: Dilatation at the mitral orifice was achieved in all cases. The mean (SD) pressure drop across the valve fell from 13.9 (5.3) to 5.6 (2.5) mm Hg, cardiac output rose from 3.18 (1.02) to 3.96 (2.5) l/min, and valve area increased from 0.78 (0.32) to 1.58 (0.56) cm2. The procedure was well tolerated by most patients, even those with metabolic/electrolyte disturbance, severe obstructive airways disease, myocardial impairment, and coronary disease. In three patients a small shunt developed at the atrial level: none developed severe mitral reflux. The two patients who required assisted ventilation died soon after the procedure and in one patient with severe coronary artery disease myocardial infarction developed and she died in cardiogenic shock. Early symptomatic improvement was reported by 23 of the 25 survivors, though the increase in exercise capacity was often limited by their non-mitral disease. At one year follow up a further 6 patients had died because of their additional disease: 15 continued to show symptomatic improvement., Conclusions: Percutaneous balloon dilatation of the mitral valve is a useful new option in patients who are too ill to undergo cardiac surgery; but longer term benefit can be limited by the associated disease. more...

The Inoue balloon was used for dilatation of tricuspid stenosis in a 74 year old woman. The valve was reached by an over-the-wire approach with a 0.025 exchange length guide wire. The Inoue stylet would not reach the tricuspid orifice because the right atrium was so large. The Inoue balloon's special dilatation characteristics allowed good positioning at the tricuspid orifice. After dilatation to 27.5 mm, the pressure drop across the valve was reduced from 12 to 5 mm Hg. Further dilatation at 30 mm, however, created moderately severe tricuspid reflux without a further reduction of gradient. The Inoue balloon is suitable for dilatation of tricuspid stenosis but small increments in dilatation size may be required for optimal reduction in gradient without creating significant reflux. more...

Objective: To determine the effect of watching a game of Scottish football on heart rate and blood pressure., Design: Prospective study., Setting: Two Scottish Premier League football grounds., Subjects: 10 healthy men, each a supporter of one of two clubs., Main Outcome Measures: Systolic and diastolic blood pressure and heart rate at home, while walking, and during the match., Results: Systolic blood pressure and heart rate were significantly higher when the men were watching the match than when they were at home. While they were watching the match, heart rate was maximal immediately after a goal had been scored by the supported team., Conclusion: The emotional stress invoked by Scottish football is associated with significant increases in heart rate and systolic blood pressure. more...

Objective: To establish and compare the characteristics of older (greater than or equal to 70 years) and younger patients with chest pain selected to undergo coronary angiography and by analysis of their subsequent management to assess the value of coronary angiography for older patients with chest pain., Design: Retrospective analysis of clinical case notes and coronary angiography reports., Setting: Cardiology department with referral population of one million in an Edinburgh hospital., Patients: 134 consecutive patients with chest pain aged 70 years or over investigated by coronary angiography between 1978 and 1988; 134 randomly selected patients aged under 70 investigated over the same period., Main Outcome Measures: Clinical and angiographic features at time of angiography and management after angiography., Results: Older patients represented a small, but increasing, proportion of those investigated. Older patients had more severe symptoms at the time of angiography, were taking more antianginal drugs, and had had their symptoms for longer than younger patients. At angiography more older patients had triple vessel coronary disease, left main stem stenosis, or left ventricular impairment. After angiography similar proportions of older and younger patients underwent coronary artery surgery, with more elderly patients requiring urgent operation; although operative mortality was higher for elderly patients, symptomatic benefit was similar to that in younger patients., Conclusions: Older patients with angina selected to undergo coronary angiography and subsequent coronary surgery have more severe symptoms and underlying cardiac disease. Earlier referral and investigation might yield a population with lower operative risk. Selection of patients for coronary angiography and coronary artery surgery should be based on the potential for benefit and should avoid "agism." more...

Audible cardiac murmurs are uncommon and may indicate severe native valve dysfunction. In six patients with bioprosthetic mitral valves audible honking systolic murmurs suddenly developed. Doppler echocardiography showed characteristic striated regurgitant signals. At operation each prosthesis had torn cusps. New audible murmurs and striated Doppler signals originating from mitral bioprosthetic valves are indicators of cusp tears. Recognition of this is important because early detection of prosthetic valve dysfunction may improve subsequent surgical outcome. more...

Five cases are described in which embolised catheters were removed percutaneously from the right side of the heart. Flexible endoscopy biopsy forceps were used in four cases and achieved removal in two: in the two other cases the catheter lay in a position which could not be reached by the biopsy forceps mouth, and retrieval was made with a helical wire basket after dislodgment of the proximal end of the catheter. In a fifth case a catheter fragment was removed from the pulmonary artery with endoscopy grasping forceps. Flexible endoscopy forceps provide a very firm grip and with a Teflon sleeve they can be negotiated around curves. They have limited manoeuvrability but W-shape "grasping" forceps have a large mouth, which helps to overcome this limitation. more...

Plasma free captopril concentrations and haemodynamic response to captopril were studied in 20 patients with severe chronic heart failure. A 25 mg oral dose of captopril produced a 36% reduction in systemic vascular resistance, with individual responses varying from 13% to 64%. Mean systemic pressure fell by 20% and cardiac output rose 28%. The absorption of captopril was rapid. Peak plasma free captopril concentration occurred at 45 minutes after the dose and was followed by a smaller second peak. Peak plasma free captopril concentrations varied more than 20-fold but did not correlate with the maximal reduction in systemic vascular resistance. Elimination half life was seven hours. Fourteen patients were restudied after 1-2 months of captopril treatment and 12 showed symptomatic benefit. There was a sustained improvement in haemodynamic state and in non-invasive indices of myocardial function. During long term treatment the predose plasma free captopril concentration correlated well with dosage, but steady state captopril concentrations did not show a significant relation with haemodynamic response. On a dosage regimen of 25-50 mg three times daily the morning predose plasma free captopril concentration and plasma renin activity were relatively low and suggested that maximal inhibition of the renin-angiotensin system was not maintained throughout the dosage interval. more...

Cross sectional echocardiograms were recorded within one week of death in seven patients with valvular heart disease, four with coronary artery disease, and nine with congenital heart disease. Regional echo amplitude was measured from the cross sectional display by constructing histograms of pixel intensity. Parietal pericardium was used as an internal standard for setting the gain of the instrument. At necropsy myocardium was taken from the free wall of the left ventricle, the papillary muscles, and the septum. Fibrosis was assessed histologically and biochemically as hydroxyproline content. In individual samples histological and biochemical estimates were correlated. In all regions other than the septum in patients with left ventricular hypertrophy, log [collagen] correlated with median pixel intensity. The amplitude of reflected echoes from the hypertrophied septum was significantly higher than that from other samples but was similarly correlated with collagen content. Agreement between echo amplitude and histological grade was significantly less good. Thus in chronic left ventricular disease myocardial collagen content appears to be the major determinant of regional echo intensity. Reproducibility of measurements and more rigorous definition of tissue abnormalities will, however, require further study. more...

An obese man, with an attack of myocardial ischaemia, developed arrhythmias only when he was asleep. Episodes of sinus bradycardia occurred progressing to arterioventricular block and sinus arrest. These changes in the cardiac rhythm coincided with periods of sleep apnoea. more...

The effect of intravenous captopril was studied in 26 patients with severe chronic heart failure. Fourteen patients received a 25 mg intravenous bolus dose and 12 patients were given a series of incremental intravenous doses over the range 0.3125-45 mg. After the 25 mg bolus dose there was a rapid reduction in systemic vascular resistance and systemic blood pressure. The effect was greatest five minutes after the dose when cardiac output was increased by 20%. Mean right atrial pressure and pulmonary end diastolic pressure fell more slowly and reached their nadir 60 minutes after administration. Plasma free captopril concentration was significantly correlated with percentage reduction in systemic vascular resistance 15 minutes after the bolus injection, but was not correlated with either changes in right atrial or pulmonary artery pressures. With the series of incremental doses there was a progressive fall in systemic vascular resistance until a cumulative dose of 5.0 mg was reached; beyond this there was no further significant change. The rapid response to intravenous captopril indicates that it may be useful in the treatment of patients with severe heart failure who require intensive treatment. After intravenous injection of captopril haemodynamic responses in patients with heart failure were greatest at plasma concentrations of 100 g/ml to 150 ng/ml. This is considerably higher than the plasma free captopril concentrations found after conventional oral doses of captopril. more...

1 The plasma elimination half-life of mexiletine was measured in four subjects when the urine was rendered (a) acidic and (b) alkaline. 2 Urinary acidification (pH 5.0) was associated with a plasma elimination half-life of 2.8 h and 57.5% of the intravenous dose was excreted in the urine within 48 hours. When the urine was alkaline (pH 8.0) the half-life increased to 8.6 h with negligible amounts of drug appearing in the urine. 3 Urinary pH varies widely in cardiac patients and should be controlled or monitored to provide better therapeutic precision with mexiletine. more...