VarGenius executes cohort-level DNA-seq variant calling and annotation and allows to manage the resulting data through a PostgreSQL database.

BACKGROUND: Targeted resequencing has become the most used and cost-effective approach for identifying causative mutations of Mendelian diseases both for diagnostics and research purposes. Due to very rapid technological progress, NGS laboratories are expanding their capabilities to address the increasing number of analyses. Several open source tools are available to build a generic variant calling pipeline, but a tool able to simultaneously execute multiple analyses, organize, and categorize the samples is still missing. RESULTS: Here we describe VarGenius, a Linux based command line software able to execute customizable pipelines for the analysis of multiple targeted resequencing data using parallel computing. VarGenius provides a database to store the output of the analysis (calling quality statistics, variant annotations, internal allelic variant frequencies) and sample information (personal data, genotypes, phenotypes). VarGenius can also perform the "joint analysis" of hundreds of samples with a single command, drastically reducing the time for the configuration and execution of the analysis. VarGenius executes the standard pipeline of the Genome Analysis Tool-Kit (GATK) best practices (GBP) for germinal variant calling, annotates the variants using Annovar, and generates a user-friendly output displaying the results through a web page. VarGenius has been tested on a parallel computing cluster with 52 machines with 120GB of RAM each. Under this configuration, a 50 M whole exome sequencing (WES) analysis for a family was executed in about 7 h (trio or quartet); a joint analysis of 30 WES in about 24 h and the parallel analysis of 34 single samples from a 1 M panel in about 2 h. CONCLUSIONS: We developed VarGenius, a "master" tool that faces the increasing demand of heterogeneous NGS analyses and allows maximum flexibility for downstream analyses. It paves the way to a different kind of analysis, centered on cohorts rather than on singleton. Patient and variant information are stored into the database and any output file can be accessed programmatically. VarGenius can be used for routine analyses by biomedical researchers with basic Linux skills providing additional flexibility for computational biologists to develop their own algorithms for the comparison and analysis of data. The software is freely available at: https://github.com/frankMusacchia/VarGenius.

Helper-dependent adenoviral vectors for liver-directed gene therapy of primary hyperoxaluria type 1.

Primary hyperoxaluria type 1 (PH1) is an inborn error of liver metabolism due to deficiency of the peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT), which catalyzes conversion of glyoxylate into glycine. AGT deficiency results in overproduction of oxalate that ultimately leads to end-stage renal disease and death. Organ transplantation as either preemptive liver transplantation or combined liver/kidney transplantation is the only available therapy to prevent disease progression. Gene therapy is an attractive option to provide an alternative treatment for PH1. Toward this goal, we investigated helper-dependent adenoviral (HDAd) vectors for liver-directed gene therapy of PH1. Compared with saline controls, AGT-deficient mice injected with an HDAd encoding the AGT under the control of a liver-specific promoter showed a significant reduction of hyperoxaluria and less increase of urinary oxalate following challenge with ethylene glycol, a precursor of glyoxylate. These studies may thus pave the way to clinical application of HDAd for PH1 gene therapy.

Growth hormone treatment of adolescents with growth hormone deficiency (GHD) during the transition period: results of a survey among adult and paediatric endocrinologists from Italy. Endorsed by SIEDP/ISPED, AME, SIE, SIMA.

Treatment of adolescents with growth hormone deficiency (GHD) during the transition period is a controversial issue. This paper is a contribution from the Italian community of paediatric and adult endocrinologists surveyed in a Delphi panel. The Delphi method is a structured communication technique, originally developed as a systematic, interactive forecasting method that relies on a panel of experts. The experts answer questionnaires in two or more rounds. There was substantial agreement on the definition of the problems associated with the diagnosis and treatment of adolescents with GHD in the transition period, as well as on the identification of the controversial issues which need further studies. There is general consensus on the need of re-testing all isolated idiopathic GHD after at least 30-day withdrawn from treatment, while in patients with multiple pituitary deficiency and low IGF-I levels there is generally no need to re-test. In patients with permanent or confirmed GHD, a starting low rhGH dose (0.01-0.03 mg per day) to be adjusted according to IGF-I concentrations is also widely accepted. For those continuing treatment, the optimal therapeutic schedule to obtain full somatic maturation, normalization of body composition and bone density, cardiovascular function and Quality of Life, need to be evaluated.

The impact of real practice inappropriateness and devices' inefficiency to variability in growth hormone consumption.

INTRODUCTION: Growth hormone (GH) consumption is the object of a particular attention by regulatory bodies, due to its financial impact; nevertheless, GH treatment has been demonstrated to be cost-effective and is, therefore, usually reimbursed by public health service systems. In Italy, significant differences in GH consumption between regions have been recorded. Different appropriateness in real practice is a possible explanation, but the proportion of drug wasted due to different combinations of therapeutic regimes and types of devices used in drug administration is a complementary explanation. Aim of the study is, therefore, to determine how much of the variability in GH consumption is actually due to differences in clinical practice, and how much to waste. MATERIALS AND METHODS: A model was settled to estimate the population with indication for GH administration, separately for children, transition subjects and adults, based on both the scientific evidence available and directly collected clinical evaluations. A systematic literature search was conducted using Cochrane Library (HTA and NHSEE) databases, Medline via Ovid, Econlit via Ovid, Embase. CONCLUSION: The model applied to the Italian population showed that there was apparently unexplainable over-prescription and potential under-prescription in various regions, ranging from 20 to 40 % less than the estimated theoretical consumption to over 200 %. Wastage, at level of single device, could amount to as much as 15 % of the consumption, demonstrating that price per mg is not in general a good proxy of the cost per mg of therapy. Our estimates of the wastage shows a significant potential gap in the model assessment of the HTA bodies, as far as they do not explicitly take into account the issue of wastage and, consequently, the actual variability in local clinical practice.

[Topical anaesthesia in cataract surgery]. / Topische Anästhesie in der Kataraktchirurgie.

Topical anaesthesia was introduced together with the establishment of modern cataract surgery as an operation in a closed system. Superficial anaesthesia by itself leads to a good analgesia in most cases. However, up to 30% of the patients feel uncomfortable or even experience pain during surgery. Superficial anaesthesia can be intensified with subconjunctival infiltration or by modifying the application forms such as sponges or gel. With the introduction of the intracameral anaesthesia in the 1990 s primarily with unpreserved lidocaine 1%, the efficacy of the topical anaesthesia was improved significantly. The combined topical anaesthesia plus intracameral lidocaine administration can be used as a routine method. A general anaesthesia care for premedication and monitoring during cataract surgery is useful since most cataract patients are of advanced age and frequently suffer from cardiovascular diseases. In almost 10% of the patients changes in cardiopulmonal comorbidities were observed and in 2.6% anaesthesia intervention was required.

Abnormal serum alanine aminotransferase levels are associated with impaired insulin sensitivity in young women with polycystic ovary syndrome.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) are both associated with insulin resistance.We assessed whether NAFLD is associated with impaired insulin sensitivity in PCOS women independently of age and total adiposity. SUBJECTS AND METHODS: We enrolled 14 young PCOS women with NAFLD, 14 women with PCOS alone and 14 healthy controls, who were matched for age, body mass index, and total body fat (by bio-impedance analyzer). NAFLD was diagnosed by the surrogate measure of abnormal serum alanine aminotransferase (ALT) concentrations (defined as ALT>19 U/l) after excluding other secondary causes of liver disease (alcohol, virus, and medications). Insulin sensitivity was measured by euglycemic hyperinsulinemic clamp. RESULTS: Insulin sensitivity was markedly decreased (p<0.001) in PCOS women with abnormal ALT levels, whereas it was similar between PCOS women with normal ALT levels andmatched healthy controls (8.3+/-2.5 vs 12.1+/-1.7 vs 13.2+/-1.8 mg/min x kg of fat-free mass, respectively). PCOS women with abnormal ALT levels also had higher plasma triglycerides and lower HDLcholesterol concentrations than those with PCOS alone. There was a strong inverse association between serum ALT levels and insulin sensitivity in the whole group of PCOS women (r=-0.59, p=0.0013). CONCLUSIONS: Abnormal serum ALT levels, as surrogate measure of NAFLD, are closely associated with impaired insulin sensitivity in young PCOS women in a manner that is independent from the contribution of age and total adiposity. Early recognition of NAFLD by radiological imaging tests in this group of young patients is warranted.

Laboratory alteration of gypsiferous materials below a landfill.

Some urban solid waste landfill sites in Spain are located on geological substrates of gypsiferous lithology. Although this type of substrate is assumed to be of low permeability, it can develop secondary pores by dissolution and, under favourable environmental conditions, form a karstic system that may pose serious geotechnical problems in the medium and long term. The purpose of this work was to study alterations caused by selective tests in various sections of a gypsum lithological column obtained from the Colmenar de Oreja landfill site (Spain). The tests were used to assess the influence of individual environmental factors and involved the addition of milli-RO water, solutions containing a 1%, 5% or 10% concentration of landfill leachate, and 2, 5, 10 and 15mgl(-1) solutions of NaCl in successive immersion-drying cycles at -15, 20 or 60 degrees C. Differences in alterability between the six studied segments of the lithological column were found to be due to differences in lutite content, specific crystal habit and type of cement. Segments with specular gypsum were the strongest in the tests, while the segment with the highest amount of detrital materials was the most responsive to temperature and moisture changes. The treatments that produce greater alterations are those that contain only milli-RO water.

Explorative analysis of gender-specific characteristics in patients with heart failure in an Italian hospital.

Sex-related differences have been shown to deeply affect health-related aspects of patients. However, the lack of gender-specific analysis makes it difficult to advance personalized medicine in terms of a gender-based approach. The aim of the present study was to describe gender-specific features of patients diagnosed with heart failure (HF), with a focus on the clinical presentation. Data were collected from a properly designed database and referred to an Italian hospital. Patients aged ≥18 years with a primary or secondary diagnosis of HF between 1 January 2012 and 31 December 2016 were included, and their demographic and clinical characteristics were analyzed according to gender. Of the 719 HF patients included, 317 (44.1%) were male and 402 (55.9%) were female. Women tended to be older compared to men (82.4±8.8 years and 77.1±10.6 years, respectively). As for clinical presentation, 62.1% of female and 38.3% of male patients had preserved ejection fraction, and 56.1% of men and 58.2% of women suffered from atrial fibrillation. The left atrium was partially compromised in 62.4% of male and 63% of female patients, while right atrium dysfunction tended to be more frequent in male patients compared to female patients (29.1% and 25.5%, respectively). In conclusion, gender-specific features of a cohort of HF patients from a clinical setting were accurately described.

Multiple hormonal and metabolic deficiency syndrome in chronic heart failure: rationale, design, and demographic characteristics of the T.O.S.CA. Registry.

Recent evidence supports the concept that progression of chronic heart failure (CHF) depends upon an imbalance of catabolic forces over the anabolic drive. In this regard, multiple hormonal deficiency syndrome (MHDS) significantly has impacts upon CHF progression, and is associated with a worse clinical status and increased mortality. The T.O.S.CA. (Trattamento Ormonale nello Scompenso CArdiaco; Hormone Therapy in Heart Failure) Registry (clinicaltrial.gov = NCT02335801) tests the hypothesis that anabolic deficiencies reduce survival in a large population of mild-to-moderate CHF patients. The T.O.S.CA. Registry is a prospective multicenter observational study coordinated by "Federico II" University of Naples, and involves 19 centers situated throughout Italy. Thyroid hormones, insulin-like growth factor-1, total testosterone, dehydroepiandrosterone , and insulin are measured at baseline and every year for a patient-average follow-up of 3 years. Subjects with CHF are divided into two groups: patients with one or no anabolic deficiency, and patients with two or more anabolic deficiencies at baseline. The primary endpoint is the composite of all-cause mortality and cardiovascular hospitalization. Secondary endpoints include the composite of all-cause mortality and hospitalization, the composite of cardiovascular mortality and cardiovascular hospitalization, and change of VO2 peak. Patient enrollment started in April 2013, and was completed in July 2017. Demographics and main clinical characteristics of enrolled patients are provided in this article. Detailed cross-sectional results will be available in late 2018. The T.O.S.CA. Registry represents the most robust prospective observational trial on MHDS in the field of CHF. The study findings will advance our knowledge with regard to the intimate mechanisms of CHF progression and hopefully pave the way for future randomized clinical trials of single or multiple hormonal replacement therapies in CHF.

Definition of the upper reference limit for thyroglobulin antibodies according to the National Academy of Clinical Biochemistry guidelines: comparison of eleven different automated methods.

PURPOSE: In the last two decades, thyroglobulin autoantibodies (TgAb) measurement has progressively switched from marker of thyroid autoimmunity to test associated with thyroglobulin (Tg) to verify the presence or absence of TgAb interference in the follow-up of patients with differentiated thyroid cancer. Of note, TgAb measurement is cumbersome: despite standardization against the International Reference Preparation MRC 65/93, several studies demonstrated high inter-method variability and wide variation in limits of detection and in reference intervals. Taking into account the above considerations, the main aim of the present study was the determination of TgAb upper reference limit (URL), according to the National Academy of Clinical Biochemistry guidelines, through the comparison of eleven commercial automated immunoassay platforms. METHODS: The sera of 120 healthy males, selected from a population survey in the province of Verona, Italy, were tested for TgAb concentration using eleven IMA applied on as many automated analyzers: AIA-2000 (AIA) and AIA-CL2400 (CL2), Tosoh Bioscience; Architect (ARC), Abbott Diagnostics; Advia Centaur XP (CEN) and Immulite 2000 XPi (IMM), Siemens Healthineers; Cobas 6000 (COB), Roche Diagnostics; Kryptor (KRY), Thermo Fisher Scientific BRAHMS, Liaison XL (LIA), Diasorin; Lumipulse G (LUM), Fujirebio; Maglumi 2000 Plus (MAG), Snibe and Phadia 250 (PHA), Phadia AB, Thermo Fisher Scientific. All assays were performed according to manufacturers' instructions in six different laboratories in Friuli-Venezia Giulia and Veneto regions of Italy [Lab 1 (AIA), Lab 2 (CL2), Lab 3 (ARC, COB and LUM), Lab 4 (CEN, IMM, KRY and MAG), Lab 5 (LIA) and Lab 6 (PHA)]. Since TgAb values were not normally distributed, the experimental URL (e-URL) was established at 97.5 percentile according to the non-parametric method. RESULTS: TgAb e-URLs showed a significant inter-method variability. Considering the same method, e-URL was much lower than that suggested by manufacturers (m-URL), except for ARC and MAG. Correlation and linear regression were unsatisfactory. Consequently, the agreement between methods was poor, with significant bias in Bland-Altman plot. CONCLUSIONS: Despite the efforts for harmonization, TgAb methods cannot be used interchangeably. Therefore, additional effort is required to improve analytical performance taking into consideration approved protocols and guidelines. Moreover, TgAb URL should be used with caution in the management of differentiated thyroid carcinoma patients since the presence and/or the degree of TgAb interference in Tg measurement has not yet been well defined.

Larval vomiting during a mission in Haïti.

Following an original case report of massive regurgitation of maggots and the difficulty of medical management, we return to the fecal contamination problem for troops in the field. The survey of maggots has allowed for the diagnosis of contamination by ingestion of house fly eggs as a major infection vector. The successive ingestion of anti-acid and gastric dressing can induce an important diminution of gastric acidity that can allow for the proliferation of germs. In an operational context or natural catastrophe andin addition to field hygiene rules that are very important, it can also be useful to propose exclusive field rationsfor few daysin order to limit the interhuman contamination.

Variability in the quantitation of mitral regurgitation by Doppler color flow mapping: comparison of transthoracic and transesophageal studies.

OBJECTIVES: This study was designed to assess the most accurate and reproducible methods to quantitate mitral regurgitation by color flow transthoracic and transesophageal echocardiography. BACKGROUND: Quantitative measurements of mitral regurgitant jets have resulted in an intraobserver and interobserver variability of up to 20%. Few data are available evaluating the various techniques by which mitral regurgitant jets are quantitated. METHODS: Forty patients who underwent cardiac catheterization and both transesophageal and transthoracic echocardiography within 1 week were studied. Two boundaries of the color regurgitant jet area were identified and quantitated: 1) the central aliased core of the regurgitant jet with the mosaic pattern excluding any swirling low velocity flow; and 2) the largest definable area of the regurgitant flow, including low velocity flow considered to be part of the regurgitant jet. RESULTS: The total regurgitant areas obtained by transthoracic and transesophageal studies did not differ (5.7 +/- 4.6 vs. 5.7 +/- 3.7 cm2; p = NS). However, the transesophageal mosaics were significantly larger than those obtained by transthoracic echocardiography (3.6 +/- 3.1 vs. 2.8 +/- 3.4 cm2; p less than 0.01). In transthoracic studies observer variability was higher when the mosaic aspect of the regurgitant jet rather than the total regurgitant area was measured (24 +/- 20 vs. 16 +/- 11%; p less than 0.05). In contrast, in transesophageal studies variability was lower when the mosaic area rather than the total regurgitant area was measured (11 +/- 12% vs. 18 +/- 18%; p less than 0.05). The best correlations with left ventriculography were obtained by using the absolute total regurgitant area (r = 0.72) for transthoracic studies and the mosaic area of the jets (r = 0.87) for transesophageal studies. CONCLUSIONS: Doppler color flow jet areas correlate closely with angiographic results in the evaluation of mitral regurgitation. The total regurgitant area (including the surrounding swirling flow) in transthoracic studies and the aliased core of the regurgitant jet (mosaic) in transesophageal studies appear to be the most accurate and reproducible measurements for evaluating mitral regurgitation.

Evaluation of pulmonary venous flow by transesophageal echocardiography in subjects with a normal heart: comparison with transthoracic echocardiography.

Nineteen normal subjects and five patients with atrial fibrillation underwent transesophageal and transthoracic echocardiographic studies to evaluate the normal pulmonary venous flow pattern, compare right and left pulmonary venous flow and assess the effect of sample volume location on pulmonary venous flow velocities. Best quality tracings were obtained by transesophageal echocardiography. Anterograde flow during systole and diastole was observed in all patients by both techniques. Reversed flow during atrial contraction was observed with transesophageal echocardiography in 18 of the 19 subjects in normal sinus rhythm, but in only 7 subjects with transthoracic echocardiography. Two forward peaks during ventricular systole were clearly identified in 14 subjects (73%) with transesophageal echocardiography, but in none with the transthoracic technique. The early systolic wave immediately followed the reversed flow during atrial contraction and was strongly related to the timing of atrial contraction (r = 0.78; p less than 0.001), but not to the timing of ventricular contraction, and appeared to be secondary to atrial relaxation. Conversely, the late systolic wave was temporally related to ventricular ejection (r = 0.66; p less than 0.001), peaking 100 ms before the end of the aortic valve closure and was unrelated to atrial contraction time. Quantitatively, significantly higher peak systolic flow velocities were obtained in the left upper pulmonary vein compared with the right upper pulmonary vein (60 +/- 17 vs. 52 +/- 15 cm/s; p less than 0.05) and by transesophageal echocardiography compared with transthoracic studies (60 +/- 17 vs. 50 +/- 14 cm/s; p less than 0.05). Increasing depth of interrogation beyond 1 cm from the vein orifice resulted in a significant decrease in the number of interpretable tracings.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of mitral regurgitation on pulmonary venous velocities derived from transesophageal echocardiography color-guided pulsed Doppler imaging.

The effect of mitral regurgitation on pulmonary venous flow velocity was studied in 66 patients undergoing transesophageal echocardiography. Nine patients were studied intraoperatively before and after surgery, so that 75 pulmonary venous flow tracings were analyzed. Fifty-four patients had no significant (0 to 1+) mitral regurgitation and 21 had significant (2 to 3+) mitral regurgitation. Comparison of both groups revealed significant differences in the pulmonary venous flow pattern. In patients with no significant mitral regurgitation, the peak systolic velocity was higher (55 +/- 16 vs. -4 +/- 16 cm/s; p less than 0.0001) and the peak diastolic velocity was lower (43 +/- 13 vs. 59 +/- 17 cm/s; p less than 0.01) when compared with values in patients with significant mitral regurgitation. Consequently, the peak systolic/diastolic velocity ratio was significantly higher in the patients without significant mitral regurgitation (1.4 +/- 0.5 vs. 0.4 +/- 1.3; p less than 0.0001). The same trend was noted with respect to the systolic and diastolic velocity integrals. As the degree of mitral regurgitation increased, the peak diastolic velocity and diastolic velocity integral increased, whereas the peak systolic velocity and systolic velocity integral decreased. In patients with severe mitral regurgitation, the systolic flow became reversed (retrograde). The sensitivity of reversed systolic flow for severe mitral regurgitation was 90% (9 of 10), the specificity was 100% (65 of 65), the positive predictive value was 100% (9 of 9), the negative predictive value was 98% (65 of 66) and the predictive accuracy was 99% (74 of 75).(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitation of mitral regurgitation by transesophageal echocardiography with Doppler color flow mapping: correlation with cardiac catheterization.

Eighty consecutive patients who underwent both left ventriculography and single-plane transesophageal echocardiography with Doppler color flow mapping were studied to compare the two techniques in the assessment of mitral regurgitation. Only the mosaic aspect of the regurgitant jet was included in the measurements. Values for inter- and intraobserver variability for the maximal regurgitant area measurements were 10 +/- 9% and 9 +/- 8%, respectively. The best correlation between angiography and Doppler color flow imaging was obtained with the maximal regurgitant area (r = 0.90). A maximal regurgitant area less than 3 cm2 predicted mild mitral regurgitation with a sensitivity of 96%, specificity of 100% and a predictive accuracy of 98%, whereas a maximal regurgitant area greater than 6 cm2 predicted severe mitral regurgitation with a sensitivity of 91%, a specificity of 100% and a predictive accuracy of 98%. A strong, although inferior, correlation was found for the maximal regurgitant area/left atrial area ratio (r = 0.81). A ratio less than 20% predicted mild mitral regurgitation with 94% accuracy, whereas a ratio greater than 35% predicted severe mitral regurgitation with 85% accuracy. Thus, single-plane transesophageal echocardiography with Doppler color flow mapping is an exquisitely sensitive technique for the diagnosis of mitral regurgitation. Minimal degrees of mitral regurgitation can be detected in approximately 62% of patients in whom no mitral regurgitation is detected by angiography. The mosaic maximal regurgitant area is a simple and easily obtainable Doppler echocardiographic index that provides an accurate estimation of mitral regurgitation severity.

Diastolic function in patients undergoing coronary angioplasty: influence of degree of revascularization.

To assess the early effects of successful coronary angioplasty on Doppler-derived left ventricular filling patterns and the significance of the extent of revascularization on these variables, 31 patients undergoing coronary angioplasty were examined within 24 h before and after the revascularization procedure. After angioplasty, the peak early to late velocity ratio increased from 0.89 +/- 0.2 to 1.05 +/- 0.3 (p less than 0.0001) and the one-third filling fraction increased from 42 +/- 10% to 48 +/- 10% (p less than 0.0001). The percent atrial contribution to filling decreased from 45 +/- 7% to 41 +/- 8% (p less than 0.01), and the pressure half-time and the isovolumetric relaxation time shortened from 55 +/- 15 to 43 +/- 13 ms (p less than 0.001) and from 100 +/- 14 to 82 +/- 17 ms (p less than 0.0001), respectively. When comparing patients with complete (n = 23) and incomplete (n = 8) revascularization, the same changes in the Doppler variables were observed. However, the mean rate of acceleration of early filling increased significantly after angioplasty only in those patients with complete revascularization. These data indicate that the left ventricular diastolic filling pattern is modified significantly as early as 24 h after successful coronary angioplasty. Improvement in impaired relaxation appears to be the most likely explanation for these changes, although increased myocardial stiffness in patients with incomplete revascularization is an alternative hypothesis.

Mobile aortic atheroma and systemic emboli: efficacy of anticoagulation and influence of plaque morphology on recurrent stroke.

OBJECTIVES: We sought to determine the influence of plaque morphology and warfarin anticoagulation on the risk of recurrent emboli in patients with mobile aortic atheroma. BACKGROUND: An epidemiologic link between aortic atheroma and systemic emboli has been described both in pathologic and transesophageal studies. Likewise, a few studies have found an increased incidence of recurrent emboli in these patients. The therapeutic implications of these findings has not been studied. METHODS: Thirty-one patients presenting with a systemic embolic event and found to have mobile aortic atheroma were studied. The height, width and area of both immobile and mobile portions of atheroma were quantitated. The dimensions of the mobile component was used to define three groups: small, intermediate and large mobile atheroma. The patients were followed up by means of telephone interview and clinical records, with emphasis on anticoagulant use and recurrent embolic or vascular events. RESULTS: Patients not receiving warfarin had a higher incidence of vascular events (45% vs. 5%, p = 0.006). Stroke occurred in 27% of these patients and in none of those treated with warfarin. The annual incidence of stroke in patients not taking warfarin was 0.32. Myocardial infarction occurred in 18% of patients also in this group. Taken together, the risk of myocardial infarction or stroke was significantly increased in this group (p = 0.001). Forty-seven percent of patients with small, mobile atheroma did not receive warfarin. Recurrent stroke occurred in 38% of these patients, representing an annual incidence of 0.61. There were no strokes in patients with small, mobile atheroma treated with warfarin (p = 0.04). Likewise, none of the patients with intermediate or large mobile atheroma had a stroke during follow-up. Only three of these patients had not been taking warfarin. CONCLUSIONS: Patients presenting with systemic emboli and found to have mobile aortic atheroma on transesophageal echocardiography have a high incidence of recurrent vascular events. Warfarin is efficacious in preventing stroke in this population. The dimension of the mobile component of atheroma should not be used to determine the need for anticoagulation.

Atrial septal aneurysm and stroke: a transesophageal echocardiographic study.

The prevalence and morphologic characteristics of atrial septal aneurysms identified by transesophageal echocardiography in 410 consecutive patients are described. Two groups of patients were compared: Group I consisted of 133 patients referred for evaluation of the potential source of an embolus and Group II consisted of 277 patients referred for other reasons. An atrial septal aneurysm was diagnosed by transesophageal echocardiography in 32 (8%) of the 410 patients. Surface echocardiography identified only 12 of these aneurysms. Atrial septal aneurysm was significantly more common in patients with stroke (20 [15%] of 133 vs. 12 [4%] of 277) (p less than 0.05); right to left shunting at the atrial level was demonstrated in 70% of patients in Group I and 75% of patients in Group II by saline contrast echocardiography. Four patients in Group I had an atrial septal defect with additional left to right flow. There was no difference between the two groups in aneurysm base width, total excursion or left atrial or right atrial excursion. However, Group I patients had a thinner atrial septal aneurysm than did Group II patients. It is concluded that an atrial septal aneurysm occurs commonly in patients with unexplained stroke, is more frequently detected by transesophageal echocardiography than by surface echocardiography and is usually associated with right to left atrial shunting. Treatment (anticoagulant therapy vs. surgery) of atrial septal aneurysm identified in stroke patients can be determined only by long-term follow-up studies.

Analysis of coronary blood flow velocity dynamics in angiographically normal and stenosed arteries before and after endolumen enlargement by angioplasty.

OBJECTIVES: This study was designed to assess whether the spectral waveform of coronary velocity on Doppler study is characteristically altered in the presence of significant stenosis with normalization of the spectral waveform after relief of endolumen obstruction. BACKGROUND: Although coronary flow reserve determinations have provided physiologic information complementary to the angiographic percent diameter narrowing, flow velocity measurements have been limited to proximal arteries with inconsistent results after angioplasty. A 12-MHz Doppler guide wire permits flow velocity determination in the proximal and distal coronary artery with fast Fourier spectral analysis. METHODS: With the Doppler guide wire, proximal arterial flow velocity and flow reserve measurements in 17 angiographically normal arteries were compared with measurements in 29 significantly stenosed arteries. Proximal and distal flow velocity measurements were also obtained before and after angioplasty of the 29 abnormal arteries. Velocity spectrum was digitized to compute peak diastolic velocity, peak systolic velocity, mean velocity, diastolic/systolic velocity ratio and first third and first half flow fraction. RESULTS: Compared with proximal stenosed arteries, proximal normal arteries had significantly higher peak diastolic velocity (64 +/- 26 cm/s vs. 41 +/- 26 cm/s) and higher coronary vasodilator reserve (2.3 +/- 0.8 vs. 1.6 +/- 0.7). Normal arteries had higher flows in the first third and first half of the coronary cycle (46 +/- 3% vs. 39 +/- 7% and 65 +/- 2% vs. 56 +/- 10%, respectively). Before angioplasty, coronary velocity variables were significantly lower distal than proximal to the stenosis. After angioplasty, there was a greater mean increase in distal velocities (200% vs. 90% for the proximal arteries) that resulted in near equalization of proximal and distal mean velocity and a significant reduction in proximal/distal mean velocity ratio (2.4 +/- 1.7 vs. 1.2 +/- 0.4). CONCLUSIONS: Before angioplasty, abnormal coronary flow velocity dynamics are more marked distal than proximal to the stenosis. Greater increase in coronary flow velocities in the distal circulation after relief of endolumen obstruction results in a significant reduction in the proximal/distal flow velocity ratio. Thus, normalization of Doppler-derived flow velocity variables with marked reduction of the proximal/distal flow velocity ratios parallels angiographic success and may prove useful as an additional end point measurement in interventional cases with questionable angiographic findings.