Identification of novel pathogenic copy number variations in Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is a hereditary sensory-motor neuropathy characterized by a strong clinical and genetic heterogeneity. Over the past few years, with the occurrence of whole-exome sequencing (WES) or whole-genome sequencing (WGS), the molecular diagnosis rate has been improved by allowing the screening of more than 80 genes at one time. In CMT, except the recurrent PMP22 duplication accounting for about 60% of pathogenic variations, pathogenic copy number variations (CNVs) are rarely reported and only a few studies screening specifically CNVs have been performed. The aim of the present study was to screen for CNVs in the most prevalent genes associated with CMT in a cohort of 200 patients negative for the PMP22 duplication. CNVs were screened using the Exome Depth software on next generation sequencing (NGS) data obtained by targeted capture and sequencing of a panel of 81 CMT associated genes. Deleterious CNVs were identified in four patients (2%), in four genes: GDAP1, LRSAM1, GAN, and FGD4. All CNVs were confirmed by high-resolution oligonucleotide array Comparative Genomic Hybridization (aCGH) and/or quantitative PCR. By identifying four new CNVs in four different genes, we demonstrate that, although they are rare mutational events in CMT, CNVs might contribute significantly to mutational spectrum of Charcot-Marie-Tooth disease and should be searched in routine NGS diagnosis. This strategy increases the molecular diagnosis rate of patients with neuropathy.

Novel CAPN3 variant associated with an autosomal dominant calpainopathy.

AIMS: The most common autosomal recessive limb girdle muscular dystrophy is associated with the CAPN3 gene. The exclusively recessive inheritance of this disorder has been recently challenged by the description of the recurrent variants, c.643_663del21 [p.(Ser215_Gly221del)] and c.598_612del15 [p.(Phe200_Leu204del)], associated with autosomal dominant inheritance. Our objective was to confirm the existence of autosomal dominant calpainopathies. METHODS: Through our activity as one of the reference centres for genetic diagnosis of calpainopathies in France and the resulting collaborations through the French National Network for Rare Neuromuscular Diseases (FILNEMUS), we identified four families harbouring the same CAPN3 heterozygous variant with supposedly autosomal dominant inheritance. RESULTS: We identified a novel dominantly inherited CAPN3 variant, c.1333G>A [p.(Gly445Arg)] in 14 affected patients from four unrelated families. The complementary phenotypic, functional and genetic findings correlate with an autosomal dominant inheritance in these families, emphasizing the existence of this novel transmission mode for calpainopathies. The mild phenotype associated with these autosomal dominant cases widens the phenotypic spectrum of calpainopathies and should therefore be considered in clinical practice. CONCLUSIONS: We confirm the existence of autosomal dominant calpainopathies as an entity beyond the cases related to the in-frame deletions c.643_663del21 and c.598_612del15, with the identification of a novel dominantly inherited and well-documented CAPN3 missense variant, c.1333G>A [p.(Gly445Arg)]. In addition to the consequences for genetic counselling, the confirmation of an autosomal dominant transmission mode for calpainopathies underlines the importance of re-assessing other myopathies for which the inheritance is considered as strictly autosomal recessive.

Análisis de la distribución del tiempo en materia de cuidado crítico por profesionales de enfermería mediante TISS-28 / Analysis of the distribution of time in critical care by nursing professionals using TISS-28 / Análise da distribuição do tempo em cuidados intensivos por profissionais de enfermagem usando o TISS-28

RESUMEN Introducción: Hoy en día, las intervenciones terapéuticas son más especializadas y complejas. Se ha identificado que el Therapeutic Intervention Scoring System-28 (TISS-28) es un instrumento adecuado para planear las actividades de enfermería. Objetivo: Determinar mediante la aplicación del instrumento TISS-28 el grado de complejidad de las intervenciones realizadas al brindar cuidados de enfermería a pacientes en estado crítico. Métodos: Estudio descriptivo, 270 pacientes (adultos, pediátricos y neonatales) en estado crítico; se recabó información sociodemográfica tanto del personal de enfermería como de los pacientes a través de un instrumento, se aplicó el TISS-28 para identificar el grado de complejidad de las intervenciones que se le brindaron al paciente. El análisis estadístico fue descriptivo para variables sociodemográficas y laborales, para las acciones realizadas por enfermería mediante niveles de grados de complejidad se hizo uso del análisis bivariado y la regresión logística. Resultados: Las intervenciones brindadas por el personal de enfermería en el servicio de medicina interna en el Grado II es de 9.8 veces más que en el resto de los pacientes, grado III aumenta 68 veces cuando el paciente tiene una sobre estancia hospitalaria. Discusión: Los pacientes que se encuentran en los servicios de cuidados intensivos o quirúrgicos requieren mayores cuidados. Conclusión: El TISS-28 permite predecir el estado del paciente crítico y su evolución. Determina el tiempo de atención requerido según la gravedad de este, además facilita la asignación idónea de enfermera-paciente.

ABSTRACT Introduction: Currently, therapeutic interventions have become more complex and specialized, but the Therapeutic Intervention Scoring System-28 (TISS-28) has been identified as an adequate tool in the planning of the corresponding nursing activities. Objective: To estimate through the Therapeutic Intervention Scoring System-28 (TISS-28) the degree of complexity of the necessary nursing interventions to provide care to patients in critical status. Methods: This is a descriptive study on 270 adult, pediatric, and neonatal patients in critical status. The TISS-28, and nursing and patient sociodemographic instruments were used. A descriptive statistical analysis using the sociodemographic and work-related variables was carried out. Bi-variate analysis and logistic regression were calculated in order to analyze the nursing performance by levels of complexity. Results: The interventions provided by the nursing staff in the internal medicine service in Grade II is 9.8 times more than in the rest of the patients, grade III increases by 68 times when the patient has an excess hospital stay. Discussion: Patients in the intensive care or surgical services require more care. Conclusion: The TISS-28 offers an estimate on the evolution and attention time required by patients in critical status as well as the corresponding ideal nurse-patient ratios.

RESUMO Introdução: Atualmente as intervenções terapêuticas são mais especializadas e complexas, identificou-se que o Therapeutic Intervention Scoring System-28 (TISS-28) é um instrumento adequado para planejar as atividades de enfermagem. Objetivo: Determinar mediante a aplicação do instrumento TISS-28, o grau de complexidade das intervenções realizadas na assistência de cuidados de enfermagem a pacientes em estado crítico. Métodos: Estudo descritivo, 270 pacientes (adultos, pediátricos e neonatais) em estado crítico; foi coletada informação sociodemográfica tanto do pessoal de enfermagem quanto dos pacientes através de um instrumento, aplicou-se o TISS-28 para identificar o grau de complexidade das intervenções que foram prestadas ao paciente. A análise estatística foi descritiva para variáveis sociodemográficas e laborais; a análise bivariada e a regressão logística foi utilizada para as ações realizadas por enfermagem mediante níveis de graus de complexidade. Resultados: As intervenções realizadas pela equipe de enfermagem no serviço de clínica médica do Grau II são 9,8 vezes mais do que no restante dos pacientes, o grau III aumenta em 68 vezes quando o paciente tem um tempo de internação excessivo. Discussão: Os pacientes que se encontram nos serviços de cuidados intensivos ou cirúrgicos requerem maiores cuidados. Conclusão: O TISS-28 permite prever do estado do paciente crítico e sua evolução. Determina o tempo de atenção requerido conforme a gravidade deste, aliás facilita a atribuição idónea de enfermeira-paciente.

Assessment of sociolegal judgment of offenders.

While working with young male offenders the authors developed a scale to assess sociolegal judgment, i.e., the ability to evaluate the possible social and legal consequences of various choices of action in a given situation. They found that some inmates had committed crimes because of poor sociolegal judgment, whereas others understood the consequences of their actions but chose to act illegally despite this knowledge.

Prognostic implications of a negative dipyridamole-thallium scan: results in 360 patients.

PATIENTS AND METHODS: A total of 360 patients with either normal perfusion (314) or fixed defects (46) on dipyridamole-thallium scans were followed over an average period of 16 months. Of the 360 patients, 194 subsequently underwent major noncardiac surgery. RESULTS: There were a total of eight cardiac events including two postoperative complications (one fatal and one nonfatal myocardial infarction) and six cardiac events during long-term follow-up (one sudden death and five nonfatal infarctions). During the follow-up period, three patients underwent coronary artery bypass surgery. The low cardiac event rate could not be explained by a low pretest likelihood of coronary artery disease: 77% of the 360 patients had either typical angina pectoris, a previous myocardial infarction, or peripheral vascular disease, which is associated with a high prevalence of coronary artery disease. CONCLUSIONS: In patients with a high pretest likelihood of coronary artery disease, the absence of thallium redistribution on a dipyridamole-thallium scan denotes a very low (1%) cardiac risk for major noncardiac surgery as well as low long-term cardiac mortality (0.3%) and morbidity (1.4%) rates. The coronary death rate is comparable to that of patients with minimal (less than 50%) coronary stenoses.

Transient mitral regurgitation: an adjunctive sign of myocardial ischemia during dipyridamole-thallium imaging.

A patient developed transient exacerbation of a mitral insufficiency murmur and a reversible posterior wall perfusion defect during dipyridamole-thallium imaging. Coronary angiography showed significant stenoses of both the right and the circumflex coronary arteries that supply the posterior papillary muscle. Cardiac auscultation for transient mitral incompetence, a sign of reversible papillary muscle dysfunction, is a simple and practical adjunctive test for myocardial ischemia during dipyridamole-thallium imaging. It may confirm that an isolated reversible posterior wall myocardial perfusion defect is truly ischemic in nature as opposed to an artifact resulting from attenuation by the diaphragm.

Preoperative coronary artery disease risk stratification based on dipyridamole imaging and a simple three-step, three-segment model for patients undergoing noncardiac vascular surgery or major general surgery.

A 3-step, 3-segment scintigraphic model was developed to improve the accuracy of dipyridamole-thallium imaging for preoperative cardiac risk assessment and to simplify the prognostic interpretation of the images. The model was developed in a pilot study of 60 patients and validated in a group of 355 patients referred for vascular and major general surgery. Study end points included myocardial infarction and cardiac death. Step 1: The postoperative cardiac event rate was 1.3% in 225 patients with normal anterior, inferio- and posterolateral segment perfusion and without transient left ventricular dipyridamole-induced cavitary dilation. Step 2: The physiologic rationale for step 2 consists of identifying patients who are most likely to have left main, 3-vessel or high-risk 2-vessel coronary artery disease or a significant amount of jeopardized myocardium in the territory of a critical coronary stenosis. Of 29 patients with either reversible defects of all 3 segments, transient cavitary dilation, or at least 1 severe grade 3/3 reversible defect, 52% (15 of 29) sustained a postoperative cardiac event. Step 3: The remaining 101 patients were stratified according to age greater than 70 years (p = 0.01), presence of diabetes (p = 0.0004) and the number of segments displaying reversible defects (1 or 2) with cardiac event rates ranging from 5 to 36%. The 3-step, 3-segment model is a useful alternative to the conventional interpretation of dipyridamole myocardial perfusion images for the purpose of quick and efficient preoperative risk stratification based on the rationale of correlating surgical risk with the amount of potentially ischemic myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Transient left ventricular cavitary dilation during dipyridamole-thallium imaging as an indicator of severe coronary artery disease.

Transient left ventricular (LV) cavitary dilation during dipyridamole-thallium imaging was reported in 45 of 510 (9%) consecutive patients referred for dipyridamole-thallium imaging. Clinical and hemodynamic effects observed during dipyridamole infusion were not predictive of transient cavitary dilation on the thallium images. Coronary angiography was performed in 32 of the 45 patients: 75% had either left main, 3-vessel or "high-risk" 2-vessel coronary artery disease. Although 25 of 45 patients (56%) with transient cavitary dilation were either asymptomatic or had only grade 1/4 effort angina, 16 of 25 patients (64%) not referred for coronary revascularization sustained a cardiac event during a mean follow-up of 12 months. Most events were cardiac deaths (75%) and 87% of events occurred within 4 months of the test. Noncardiac surgery was performed in 187 of the 510 patients. The postoperative cardiac event rate was 2% in the 101 patients with normal scans or fixed defects, 19% in 75 patients with reversible perfusion defects and 58% in 12 patients with reversible cavitary dilation (p less than 0.0001). Thus, transient LV dilation during dipyridamole-thallium imaging is a marker of severe underlying coronary artery disease, denotes a poor prognosis and predicts a high risk of postoperative cardiac complications in patients who undergo noncardiac surgery.

Usefulness of the severity and extent of reversible perfusion defects during thallium-dipyridamole imaging for cardiac risk assessment before noncardiac surgery.

Thallium-dipyridamole imaging is a very sensitive test for predicting cardiac events after noncardiac surgery, but it lacks specificity. To improve specificity, a semiquantitative scoring system was developed that combined dipyridamole-induced reversible left ventricular dilatation with scintigraphic indexes for severity and extent of reversible perfusion defects. Using this scoring system, patients were classified into low, intermediate and high risk subgroups. Thallium-dipyridamole imaging was performed in 66 patients before major general and vascular surgery. Thirty-nine patients classified as low risk (30 with normal scans and 9 with fixed defects) underwent surgery uneventfully. Surgery was cancelled in 6 patients with extensive thallium redistribution and coronary angiography was performed because of severe coronary artery disease in 5 and idiopathic dilated cardiomyopathy in 1. In the remaining 21 patients with thallium redistribution, a positive statistical correlation (p = 0.001) between scintigraphic indexes of severity and extent, and cardiac events was noted. Using cutoff values for the scintigraphic indexes, patients with reversible defects could be classified into intermediate and high risk subgroups. Only 1 of 11 patients at intermediate risk developed a complication, whereas 8 of 10 patients at high risk had a postoperative event (7 deaths and 1 myocardial infarction). Thus, using scintigraphic indexes for severity and extent, patients with reversible defects can be stratified into an intermediate risk subgroup that can safely undergo surgery and a high risk subgroup that requires coronary angiography.

Severe bronchospasm followed by respiratory arrest during thallium-dipyridamole imaging.

We describe the occurrence of sudden severe bronchospasm and respiratory arrest following dipyridamole infusion in a patient with chronic obstructive pulmonary disease predominantly of the emphysematous type. The severe reaction was unexpected because the patient had tolerated well withdrawal of aminophylline derivatives for 48 hours and was receiving chronic prednisone 20 mg qd. Although the diagnostic and prognostic gains from dipyridamole imaging far outweigh the small risk associated with the test, patients with chronic pulmonary obstructive disease must be closely monitored during thallium-dipyridamole imaging.

Superiority of dipyridamole over exercise testing when exercise thallium imaging is limited by angina.

The extent of jeopardized myocardium can be underestimated on stress thallium myocardial perfusion images when exercise tolerance is limited by angina pectoris. A patient's tolerance for pain can influence the degree of myocardial ischemia observed on myocardial perfusion images during effort angina. A case is reported of a patient with angina pectoris showing mild ischemia limited to one myocardial segment on exercise thallium images, but severe and extensive reversible perfusion defects during dipyridamole-thallium imaging, and a 70% stenosis of the left main coronary artery on coronary angiography.

Apical hypertrophic cardiomyopathy with spontaneous post partum coronary artery dissection.

Primary coronary dissection is usually a catastrophic event with a fatal outcome; less than 20 cases of long term survival have been reported. A 32-year-old woman with apical hypertrophic cardiomyopathy who survived a spontaneous dissection of the left anterior descending coronary artery and acute anterior wall infarction two days postpartum is described. To the authors' knowledge, the simultaneous occurrence of these two rare conditions has never been previously reported. Thallium-dipyridamole imaging was performed to estimate the amount of residual viable myocardium in the infarcted area and to evaluate the hemodynamic significance of the residual luminal narrowing. Myocardial perfusion imaging can be useful to decide on surgical versus conservative treatment of these patients.

Dipyridamole-thallium imaging: minimum dose requirements.

A total of 372 consecutive dipyridamole-thallium studies were reviewed to determine if a relationship existed between the dose of dipyridamole administered and the likelihood that thallium images would show reversible defects. Men who received a dose of less than 31 mg were less likely to have thallium redistribution (P = 0.0001). Until the ideal study involving repeat testing with incremental dipyridamole doses on different days is carried out, the authors recommend that a minimal dose of 31 mg be administered for dipyridamole-thallium imaging.

Prognostic implications of transient left ventricular cavitary dilation during exercise and dipyridamole-thallium imaging.

OBJECTIVE: To determine the prognostic implication of exercise and dipyridamole-induced transient left ventricular cavitary dilation (TLVD). DESIGN: TLVD was observed and a follow-up obtained in 61 patients after exercise and in 62 patients following dipyridamole infusion. PATIENTS: There was no statistical difference between groups in terms of sex, history of hypertension, diabetes, renal failure, previous myocardial infarction, severity of angina syndrome, congestive heart failure, resting electrocardiographic (ECG) abnormalities, clinical or ECG signs of ischemia during stress, number of reversible perfusion defects on thallium images or duration of follow-up (21 months). RESULTS: Dipyridamole patients were slightly older (64 versus 57 years) and displayed more thallium redistribution (P = 0.002). After a mean follow-up of 21 months, both fatal and nonfatal (myocardial infarction or cardiac death) cardiac events were more frequent in the dipyridamole group (50% versus 9%, P = 0.0001). CONCLUSIONS: Patients with dipyridamole-induced TLVD are at greater risk than those with exercise-induced TLVD at the authors' institution.

Artificial intelligence versus logistic regression statistical modelling to predict cardiac complications after noncardiac surgery.

The traditional approach to developing models predictive of cardiac events has been to perform logistic regression (LR) analysis on a variety of potential predictors. An alternative to use an artificial intelligence system called a neural network (NN) which simulates biological intelligence. To evaluate the potential applicability of the latter method, we compared the ability of LR and NN techniques to predict cardiac events after noncardiac surgery. A total of 200 patients (training group) underwent cardiac risk assessment before major noncardiac surgery using 17 clinical parameters and 7 quantitative indices based on dipyridamole-thallium imaging. There were 21 post-operative myocardial infarctions and/or cardiac deaths. Data from the training group were used to develop two predictive models: one based on backward stepwise LR multivariate statistical analysis and the other one using a neural network. Both models were then validated on a second group of 160 consecutive patients also referred for preoperative risk stratification (validation group). The NN consisted of 14 input, 29 hidden, and 1 output neurons and used a back-propagation algorithm (learning rate 0.2, training tolerance 0.5, sigmoid transfer function). The sensitivity, specificity, positive and negative predictive accuracies for the prediction of postoperative events in the validation group of 160 patients were, respectively, 67% (6/9), 82% (124/151), 18% (6/33), and 98% (124/127) for LR, and 67% (6/9), 96% (145/151), 50% (6/12), and 98% (145/148) for the NN, with a difference in specificity which attained statistical significance (p < 0.01). Artificial intelligence may provide a useful alternative to conventional LR statistical analysis for the purpose of preoperative cardiac risk assessment.

In vivo glomerular filtration rate measurement based solely on image processing.

A simple and reliable technique was developed to measure split renal glomerular filtration (GFR) based solely on image processing of the standard 20-minute Tc-99m DTPA renogram. It requires neither syringe counting nor blood or urine sampling. Using three sequential blood samples in 36 patients, GFR values correlated well (r = 0.92) with in vitro GFR measurements.

Is cardiac migraine a clinical entity?

Chest pain because of a disorder of the coronary circulation is assumed to be ischemic in nature. Irrespective of the underlying pathophysiological mechanism, it is accepted that all routes lead to myocardial ischemia in the pathway to anginal pain. The authors describe a patient with a history of vasoactive disorders including migraine, asthma, documented variant angina with prolonged episodes of chest pain, and scintigraphic evidence of inferior and posterior wall ischemia during exercise and ergonovine testing in the absence of significant underlying stenoses. Remarkably, severe retrosternal chest pain, ST segment depression in multiple leads, and relative increased uptake in the inferior and posterior walls on Tc-99m sestamibi tomographic images developed during pharmacologic coronary vasodilatation with dipyridamole, leading the authors to speculate as to the possible existence of a nonischemic chest pain syndrome caused by coronary vasodilatation either in association with variant angina or as a separate entity.

Normal qualitative and quantitative Tc-99m sestamibi myocardial SPECT: spectrum of intramyocardial distribution during exercise and at rest.

Exercise myocardial perfusion imaging with Tc-99m sestaMIBI is routinely used to detect underlying coronary stenoses. Ischemia is diagnosed in regions that display decreased tracer uptake during exercise as compared to rest. Tc-99m sestaMIBI SPECT images of 42 healthy volunteers were assessed both qualitatively (tomographic slices) and quantitatively (sectored polar map) for potential sources of misinterpretation. On the myocardial tomographic slices, the most common culprit artifacts were diaphragmatic attenuation and bowel interposition, which caused fixed or reversible "perfusion defects" in the inferior and posterior regions (in 19/35 abnormal segments), and artifacts related to the presence and shift of hot spots (observed in 11/28 men; in women, they were more difficult to demonstrate because of the overriding effect of breast attenuation). Hot spots shifts between exercise and rest usually resulted in pseudo-reversible defects in the anterolateral and lateral walls. The quantified polar map display of the myocardium showed a physiologic decrease in sestaMIBI activity in the basal anterolateral and basal posterolateral areas in men during exercise. There are many normal variants that may mimic coronary artery disease on tomographic sestaMIBI images. Before reporting an area of decreased activity as either a fixed or reversible perfusion defect, the interpreter should ensure that it does not represent an artifact or a normal variation in the intramyocardial distribution of sestaMIBI during exercise.

Bone imaging after cementless press fit total hip arthroplasty.

In view of the high rate of loosening of conventional cemented hip prostheses, cementless implants are gaining popularity in Europe and North America. Smooth-surfaced "press fit" prostheses are designed for autolocking in the femoral canal at the time of installation. Fifteen patients were prospectively followed by bone imaging with Tc-99m MDP at three-month intervals after cementless "press fit" hip arthroplasty to define the "normal" distribution of mechanical stress to the surrounding bone, as well as the incorporation of bone allografts used for reconstruction of resorption sites in cases of revision surgery.