Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder.

The study of monozygotic twins discordant for attention deficit hyperactivity disorder can elucidate mechanisms that contribute to the disorder, which affects ~7% of children. First, using in vivo neuroanatomic imaging on 14 pairs of monozygotic twins (mean age 9.7, s.d. 1.9 years), we found that discordance for the disorder is mirrored by differing dimensions of deep brain structures (the striatum and cerebellum), but not the cerebral cortex. Next, using whole-blood DNA from the same twins, we found a significant enrichment of epigenetic differences in genes expressed in these 'discordant' brain structures. Specifically, there is differential methylation of probes lying in the shore and shelf and enhancer regions of striatal and cerebellar genes. Notably, gene sets pertaining to the cerebral cortex (which did not differ in volume between affected and unaffected twins) were not enriched by differentially methylated probes. Genotypic differences between the twin pairs-such as copy number and rare, single-nucleotide variants-did not contribute to phenotypic discordance. Pathway analyses of the genes implicated by the most differentially methylated probes implicated γ-aminobutyric acid (GABA), dopamine and serotonin neurotransmitter systems. The study illustrates how neuroimaging can help guide the search for epigenomic mechanisms in neurodevelopmental disorders.

Coronary artery disease detected by coronary computed tomography angiography in adult survivors of childhood Hodgkin lymphoma.

BACKGROUND: Survivors of Hodgkin lymphoma (HL) have significant cardiovascular risk and require long-term surveillance. The current study assessed the prevalence of coronary artery disease (CAD) by coronary computed tomography angiography (CCTA) in adult survivors of childhood HL. METHODS: Thirty-one survivors of HL, 13 of whom (42%) were treated with radiotherapy (RT) only and 18 of whom (58%) were treated with multimodal therapy, underwent CCTA, echocardiography, electrocardiography (ECG), and treadmill stress testing. Obstructive CAD was defined as ≥50% occlusion of the left main or ≥70% occlusion of the left anterior descending, left circumflex, or right coronary arteries on CCTA. Echocardiograms with resting wall motion abnormalities or an ejection fraction <50%; ECGs with Q waves, ST abnormalities without Q waves, or T-wave abnormalities without Q waves; and a J-point depression of ≥1 mm with a horizontal or downsloping ST segment on stress testing were considered abnormal. RESULTS: The prevalence of disease in participants (median age, 40 years [range, 26 years-55 years]; median time from cancer diagnosis, 24 years [range, 17 years-39 years]) was 39%, with 39 plaques detected among 12 survivors. Three participants (10%) treated with RT only had 4 obstructive lesions; 9 patients (29%; 5 of whom were treated with RT only and 4 of whom were treated with multimodal therapy) had nonobstructive lesions. Approximately 15% of lesions involved the left main, 21% involved the proximal left anterior descending, 18% involved the proximal right coronary, and 13% involved the proximal left circumflex arteries. Of the 12 participants found to have CAD by CCTA, 7 had a positive ECG, 1 had a positive echocardiogram, and 1 had a positive stress test. CONCLUSIONS: CCTA identified CAD in a substantial percentage of survivors of HL and may be an effective screening modality for this population.

Successful endovascular coil embolization of large pseudoaneurysm of ductus arteriosus diverticulum.

BACKGROUND: Pseudoaneurysm of the ductus arteriosus diverticulum, although rare in adults, may have catastrophic consequences if left untreated due to erosion and rupture of the pseudoaneurysm into adjacent thoracic structures. Although thoracic endovascular aortic repair (TEVAR) is the standard treatment method for aneurysm closure of the ductus arteriosus diverticulum, it was not possible in our patient secondary to marked aortoiliac access vessel tortuosity, significant vascular calcific burden, and an abdominal aortic aneurysm. We describe the first reported case of endovascular coil embolization being successfully used as the definite repair of a ductus arteriosus diverticulum pseudoaneurysm. CASE PRESENTATION: An 85-year-old man with history of severe coronary arterial disease presented with an enlarging pseudoaneurysm of a ductus arteriosus diverticulum. The diverticulum and thoracic aortic junction demonstrated the typical obtuse angles and wide neck, differentiating it from otherwise similar-appearing diagnostic considerations. Repair was attempted with conventional aortic stent graft but the patient's infrarenal abdominal aortic aneurysm and his heavily calcified, tortuous iliac vessels could not accommodate the 24Fr introducer sheath necessary for stent graft placement. Therefore, endovascular coil embolization was successfully completed through a 4Fr directional catheter. The patient tolerated the procedure well and was discharged from the hospital in good condition on post-embolization day six. CONCLUSIONS: Endovascular coil embolization is an alternative treatment for ductus arteriosus diverticulum pseudoaneurysm closure in cases where the standard TEVAR method is unsuccessful. Instead of the wide entry point at the aorta we used the junction of the diverticulum and pseudoaneurysm as the "neck" for satisfactory and stable coil placement. Endovascular coil embolization alone may be a viable definitive therapy for occlusion of the ductus pseudoaneurysm component of the diverticulum in cases where complex anatomy or extensive vascular disease makes stent graft repair impractical if not impossible.

Matrix metalloproteinase-9/gelatinase B is required for process outgrowth by oligodendrocytes.

Oligodendrocytes (OLs) extend processes to contact axons as a prerequisite step in myelin formation. As the OL processes migrate toward their axonal targets, they modify adhesion to their substrate, an event that may be regulated by matrix metalloproteinases (MMPs). In the mouse optic nerve, MMP-9/gelatinase B increases during myelin formation. Although tissue inhibitor of metalloproteinase (TIMP)-3 also increases in parallel, the developing optic nerve has focally active MMPs demonstrable by in situ zymography. The distribution of proteolytic activity is similar to that of myelin basic protein, a marker of myelin formation. OLs in culture secrete MMP-9 and express active cell-associated metalloproteinases at the growing tips of their processes. TIMP-1 and a function-perturbing anti-MMP-9 antibody attenuate outgrowth of processes by OLs, indicating a requirement for MMP-9 in process outgrowth. Process reformation is retarded significantly in OLs cultured from MMP-9 null mice, as compared with controls, providing genetic evidence that MMP-9 is necessary for process outgrowth. These data show that MMP-9 facilitates process outgrowth by OLs in vivo and in culture.

Enhanced cardiac thermal dilution analysis for cardiac output, volumes, stroke volumes, and regurgitation rates--sensitivity analysis using digital simulation.

Cardiac output is measured by placing a double lumen catheter with a thermistor on the tip through the right ventricle into the pulmonary artery, injecting cold saline into the right atrium, and integrating the resulting pulmonary artery temperature profile. If a similar procedure is performed with thermistors located in the right atrium, right ventricle, and pulmonary artery, the resulting temperature curves are determined by the known or easily measured quantities: injectate temperature, injectate volume, heart rate, systolic time interval, body temperature, and time in the cardiac cycle at which injection begins and the unknown quantities: right atrial, right ventricular, pulmonary artery mean and stroke volumes, inflow and outflow valve regurgitation rates, and cardiac output. A digital computer program using a lumped parameter model has been developed to use these quantities to produce thermal dilution curves and optimize the fit of the model curves to the temperature curves from the thermal dilution measurement to determine the unknown quantities. The program is used to investigate the effects of measuring system time constant, heat transfer, and noise on the accuracy of these measurements. The results indicate that the method is practical.

Vascular events after spinal cord injury: contribution to secondary pathogenesis.

Traumatic spinal cord injury results in the disruption of neural and vascular structures (primary injury) and is characterized by an evolution of secondary pathogenic events that collectively define the extent of functional recovery. This article reviews the vascular responses to spinal cord injury, focusing on both early and delayed events, including intraparenchymal hemorrhage, inflammation, disruption of the blood-spinal cord barrier, and angiogenesis. These vascular-related events not only influence the evolution of secondary tissue damage but also define an environment that fosters neural plasticity in the chronically injured spinal cord.

Per-urethral transvesical first-trimester amniocentesis.

Early amniocentesis (before 13 weeks' gestation) using a per-urethral transvesical route is studied. Eight samples were obtained in eight patients scheduled for elective termination of pregnancy. The volume of amniotic fluid averaged 12.5 +/- 7.8 ml. Culture was successful in all samples. In one case, culture was achieved with only 2 ml of amniotic fluid. The amniotic fluid can be easily obtained via the per-urethral transvesical route. We conclude that early per-urethral amniocentesis before 13 weeks amenorrhea may be an alternative to the transabdominal route. A clinical trial should be carried out in order to evaluate both techniques.

Life sciences flight hardware development for the International Space Station.

During the construction phase of the International Space Station (ISS), early flight opportunities have been identified (including designated Utilization Flights, UF) on which early science experiments may be performed. The focus of NASA's and other agencies' biological studies on the early flight opportunities is cell and molecular biology; with UF-1 scheduled to fly in fall 2001, followed by flights 8A and UF-3. Specific hardware is being developed to verify design concepts, e.g., the Avian Development Facility for incubation of small eggs and the Biomass Production System for plant cultivation. Other hardware concepts will utilize those early research opportunities onboard the ISS, e.g., an Incubator for sample cultivation, the European Modular Cultivation System for research with small plant systems, an Insect Habitat for support of insect species. Following the first Utilization Flights, additional equipment will be transported to the ISS to expand research opportunities and capabilities, e.g., a Cell Culture Unit, the Advanced Animal Habitat for rodents, an Aquatic Facility to support small fish and aquatic specimens, a Plant Research Unit for plant cultivation, and a specialized Egg Incubator for developmental biology studies. Host systems (Figure 1A, B: see text), e.g., a 2.5 m Centrifuge Rotor (g-levels from 0.01-g to 2-g) for direct comparisons between g and selectable g levels, the Life Sciences Glovebox for contained manipulations, and Habitat Holding Racks (Figure 1B: see text) will provide electrical power, communication links, and cooling to the habitats. Habitats will provide food, water, light, air and waste management as well as humidity and temperature control for a variety of research organisms. Operators on Earth and the crew on the ISS will be able to send commands to the laboratory equipment to monitor and control the environmental and experimental parameters inside specific habitats. Common laboratory equipment such as microscopes, cryo freezers, radiation dosimeters, and mass measurement devices are also currently in design stages by NASA and the ISS international partners.

Syndesmotic screw placement: a biomechanical analysis.

At the present time, syndesmotic screw fixation is recommended when there is a tibiofibular diastasis, a Maisonneuve fracture, or syndesmotic instability after fixation of distal tibia-fibula fractures. The aim/purpose of this study was to demonstrate the optimal level of syndesmotic screw placement before creation of a Maisonneuve fracture. Legs of 17 embalmed cadavers underwent knee disarticulation. The legs were then dissected to expose the syndesmosis/interosseous membrane. The paired cadaver legs were tested in two groups. In group I (10 pairs), the left legs were tested without any syndesmotic fixation and the right legs were tested with the syndesmosis fixed at 2.0 cm above the tibiotalar joint. In group II (7 pairs), the syndesmosis in each left leg was fixed at 3.5 cm above the tibiotalar joint and the right leg syndesmosis was fixed at 2.0 cm above the tibiotalar joint. After ligament section and syndesmosis fixation, each leg was then jig mounted with transfixing wires through the proximal tibia and calcaneus. The ankle was placed in neutral with 15 degrees of pronation and a load of 150 pounds and a strain gauge anchored medially and laterally. The proximal tibia was internally rotated while the ankle was held fixed until syndesmotic, bony, or hardware failure occurred. Torsional force, the degree of rotation and the amount of syndesmotic widening were quantitated. Two-tailed t-test comparing no fixation with fixation at 2.0 cm indicated less syndesmotic widening with screw placed at 2.0 cm (P = 0.04). Two-tailed t-test comparing screw fixation at 2.0 cm and 3.5 cm indicated less syndesmotic widening with screw placed at 2.0 cm (P = 0.07). It would seem reasonable to place a syndesmotic screw at 2.0 cm above tibiotalar joint.

Cystosarcoma phyllodes metastatic to the mandible: report of a rare case and literature review.

Cystosarcoma phyllodes is a rare breast tumor with variable malignant potential. Metastasis has been reported in a small percentage of cases. We describe the case of a 52-year-old woman who developed a large facial tumor 1 year after she had undergone a mastectomy for a rapidly enlarging breast neoplasm. The facial lesion was found to be a malignant cystosarcoma phyllodes metastatic to the mandible, and the patient died shortly after diagnosis. To our knowledge, this patient represents only the third reported case of a phyllodes tumor metastatic to the mandible.

Self poisoning: admission to intensive care over a one year period.

The charts of all cases of self-poisoning admitted to an intensive care unit over one year are reviewed Two distinct groups are seen, according to the substances ingested The group who took prescription medications tended to be younger, and had a better outcome Those poisoned with household or industrial products were older, had a longer stay in intensive care, needed more intensive therapy and organ support and had a higher mortality.

Enhanced cardiac thermal dilution measurement of cardiac output, volumes, regurgitation, valve effective diameters, ventricular power and efficiency -- Feasibility analysis using digital simulation.

Cardiac output is measured by the thermal dilution method which uses a quadruple lumen catheter, with a thermistor on the tip, through the right atrium, right ventricle and into the pulmonary artery. Cold saline is injected into the right atrium and the resulting pulmonary artery temperature profile is integrated. The same procedure performed with three thermistors and three pressure sensors located on the catheter to measure temperature and pressure in the atrium, ventricle and artery respectively will produce a set of temperature and pressure curves with shapes determined by injectate temperature, injectate volume, heart rate, systolic time interval, body temperature, cardiac output, volumes, flow rates and valve openings. A digital computer program has been developed to optimize the fit of a lumped parameter model to the thermodilution curves in order to determine heart rate, systolic time as a fraction of cardiac cycle, right atrial systolic and diastolic volumes, ventricular systolic and diastolic volumes, cardiac output, inflow valve forward and reverse flow rates and effective diameters, outflow valve forward and reverse flow rates and effective diameters, ventricular power and efficiency. The program has been tested over a range of operating conditions including noise in the temperature and pressure signals, randomly varying heart rate and cardiac cycle. All of the data for the tests were produced by a digital computer simulation of a pulsatile artificial heart. The results of these tests indicate that the enhanced thermal dilution analysis method is feasible.

[Ambulatory monitoring and telephone transmission of uterine activity. Preliminary study on the evaluation of the TOKOS system]. / Monitorage ambulatoire et transmission téléphonique de l'activité utérine. Etude préliminaire sur l'évaluation du système TOKOS.

The authors compare 100 tracings of uterine contractions, recorded using a mobile monitoring apparatus with telephone output TOKOS System), with 100 tracings recorded using static equipment. The TOKOS system is useful in diagnosis of uterine contraction, being equivalent to the reference system. The TOKOS system is superior to the reference system in that it allows the intensity of the contractions to be evaluated. The TOKOS system is an original approach to maternal perception of uterine activity. Overall, 28% of contractions are identified by the patient. The authors conclude that the tracings produced by the TOKOS system are more reliable than maternal perception of uterine contractions.

[Sports and pregnancy. A review of the literature]. / Sport et grossesse. Revue de la littérature.

A review of the literature concerning sport during pregnancy is presented. The mother's heart rate, arterial blood pressure, systolic ejection fraction and cardiac output undergo the same changes during exercise in the pregnant and non-pregnant patient. The increase in the fetal heart rate during maternal physical exercise does not adversely affect the fetal outcome. The uterine blood flow is diminished during exercise. The respiratory rate increases equally in pregnant and non-pregnant women. The maternal response to effort is also modified by weight gain during pregnancy, by changes in the musculo-skeletal system, and by maternal temperature control during exercise. Weight gain, uterine contractility, duration of pregnancy, labour and neo-natal conditions are not altered by sport during pregnancy. Contra-indications to sport during pregnancy include threatened premature labour, and conditions associated with an increased risk of prematurity. A previous history of fetal growth retardation, acute fetal distress, or the presence of diabetes or arterial hypertension is a contra-indication to sport during pregnancy. The advice which should be given to a pregnant woman wishing to continue her sporting activities during pregnancy is outlined.

[Criteria of recovery from caudal anesthesia in children]. / Critères de sortie après anesthésie caudale chez l'enfant.

The authors evaluated the return of sensory, motor, and sympathetic nervous system function following caudal block in children. Twenty children, ASA PS I, aged 5 +/- 4 yr (mean +/- SD), weighing 22 +/- 9 kg, scheduled for lower abdominal and urologic surgical procedures were studied. Anaesthesia was induced and maintained by halothane, N2O and oxygen. A caudal block was performed with 1 ml/kg of 0.25% bupivacaine. Analgesia assessed by Broadman's score was efficient in 18 out of the 20 children during the first 4 hours after the block. Upper level of cutaneous analgesia was T10 +/- 2 after the block. Two hours after the caudal injection an incomplete motor blockade was found in 14 of 20 children, and at 4 hours no block was found in any child. Heart rate was significantly increased in the upright position (122 +/- 12 to 131 +/- 26 bpm at 2 hours, and 110 +/- 21 to 118 +/- 28 bpm at 4 hours), whereas arterial blood pressure was unchanged in the upright position.

Exome Sequencing and High-Density Microarray Testing in Monozygotic Twin Pairs Discordant for Features of VACTERL Association.

Exome sequencing offers an efficient and affordable method to interrogate genetic factors involved in human disease. Performing exome sequencing of monozygotic twins discordant for VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities) association-type congenital malformations was hypothesized to potentially reveal discordant variants that could demonstrate disease cause(s). After demonstrating monozygosity, we applied high-density microarrays and exome sequencing to 2 twin pairs in which 1 twin had features of VACTERL association while the other was phenotypically normal (demonstrated through comprehensive clinical and radiological evaluation). No obvious discordant genotypic results were found that would explain phenotypic discordance. We conclude that VACTERL association is a complex disease, and while performing microarray analysis and exome sequencing on phenotypically discordant monozygotic twins may hypothetically reveal genetic causes of disorders, challenges remain in applying these methods in this circumstance.

Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic resonance imaging.

PURPOSE: To compare two-dimensional (2D) echocardiography, the current method of screening for treatment-related cardiomyopathy recommended by the Children's Oncology Group Guidelines, to cardiac magnetic resonance (CMR) imaging, the reference standard for left ventricular (LV) function. PATIENTS AND METHODS: Cross-sectional, contemporaneous evaluation of LV structure and function by 2D and three-dimensional (3D) echocardiography and CMR imaging in 114 adult survivors of childhood cancer currently median age 39 years (range, 22 to 53 years) exposed to anthracycline chemotherapy and/or chest-directed radiation therapy. RESULTS: In this survivor population, 14% (n = 16) had an ejection fraction (EF) less than 50% by CMR. Survivors previously undiagnosed with cardiotoxicity (n = 108) had a high prevalence of EF (32%) and cardiac mass (48%) that were more than two standard deviations below the mean of normative CMR data. 2D echocardiography overestimated the mean EF of this population by 5%. Compared with CMR, 2D echocardiography (biplane method) had a sensitivity of 25% and a false-negative rate of 75% for detection of EF less than 50%, although 3D echocardiography had 53% and 47%, respectively. Twelve survivors (11%) had an EF less than 50% by CMR but were misclassified as ≥ 50% (range, 50% to 68%) by 2D echocardiography (biplane method). Detection of cardiomyopathy was improved (sensitivity, 75%) by using a higher 2D echocardiography cutoff (EF < 60%) to detect an EF less than 50% by the reference standard CMR. CONCLUSION: CMR identified a high prevalence of cardiomyopathy among adult survivors previously undiagnosed with cardiac disease. 2D echocardiography demonstrated limited screening performance. In this high-risk population, survivors with an EF 50% to 59% by 2D echocardiography should be considered for comprehensive cardiac assessment, which may include CMR.