Two missense mutations in SALL4 in a patient with microphthalmia, coloboma, and optic nerve hypoplasia.

To investigate the genetic etiology of anophthalmia and microphthalmia, we used exome sequencing in a Caucasian female with unilateral microphthalmia and coloboma, bilateral optic nerve hypoplasia, ventricular and atrial septal defects, and growth delays. We found two sequence variants in SALL4 - c.[575C>A], predicting p.(Ala192Glu), that was paternally inherited, and c.[2053G>C], predicting p.(Asp685His), that was maternally inherited. Haploinsufficiency for SALL4 due to nonsense or frameshift mutations has been associated with acro-renal ocular syndrome that is characterized by eye defects including Duane anomaly and coloboma, in addition to radial ray malformations and renal abnormalities. Our report is the first description of structural eye defects associated with two missense variants in SALL4 inherited in trans; the absence of reported findings in both parents suggests that both sequence variants are hypomorphic mutations and that both are needed for the ocular phenotype. SALL4 is expressed in the developing lens and regulates BMP4, leading us to speculate that altered BMP4 expression was responsible for the eye defects, but we could not demonstrate altered BMP4 expression in vitro after using small interfering RNAs (siRNAs) to reduce SALL4 expression. We conclude that SALL4 hypomorphic variants may influence eye development.

Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects.

Anophthalmia/microphthalmia (A/M) is a genetically heterogeneous birth defect for which the etiology is unknown in more than 50% of patients. We used exome sequencing with the ACE Exome(TM) (Personalis, Inc; 18 cases) and UCSF Genomics Core (21 cases) to sequence 28 patients with A/M and four patients with varied developmental eye defects. In the 28 patients with A/M, we identified de novo mutations in three patients (OTX2, p.(Gln91His), RARB, p.Arg387Cys and GDF6, p.Ala249Glu) and inherited mutations in STRA6 in two patients. In patients with developmental eye defects, a female with cataracts and cardiomyopathy had a de novo COL4A1 mutation, p.(Gly773Arg), expanding the phenotype associated with COL4A1 to include cardiomyopathy. A male with a chorioretinal defect, microcephaly, seizures and sensorineural deafness had two PNPT1 mutations, p.(Ala507Ser) and c.401-1G>A, and we describe eye defects associated with this gene for the first time. Exome sequencing was efficient for identifying mutations in pathogenic genes for which there is no clinical testing available and for identifying cases that expand phenotypic spectra, such as the PNPT1 and COL4A1-associated disorders described here.

Spurious dynamics in somatosensory cortex.

Cortical networks are dynamical systems whose task is to process information. However, in addition to 'intended' dynamical behaviors, the sheer complexity of a cortical network's structure-regardless of its precise details-should generate additional 'unintended' dynamical behaviors. Dynamics observed in cortical network models and in the somatosensory cortex suggest that such spurious dynamical behaviors are likely to be pervasive but relatively simple, contributing to-rather than dominating-a network's response to stimuli. Spurious dynamics may be responsible for a variety of experimentally observed intriguing features of cortical dynamics. Because of their distributed origins and emergent nature, such dynamical features, while clearly identifiable, will resist attempts at identifying specific mechanisms to explain them. We describe some of the spurious dynamical phenomena associated with somatosensory cortical response to brushing stimulation, to illustrate how spurious dynamics can affect neurons' functional properties, cortical stimulus representation and, ultimately, perception.

Analysis of polycyclic aromatic hydrocarbons in sediment reference materials by microwave-assisted extraction.

The microwave-assisted extraction (MAE) of polycyclic aromatic hydrocarbons (PAHs) from harbor sediment reference material EC-1, marine sediment reference material HS-2 and PAH-spiked river bed soil was conducted. The extraction conditions for EC-1 were carried out at 70 degrees C and 100 degrees C under pressure in closed vessels with cyclohexane acetone (1:1), cyclohexane-water (3:1), hexane acetone (1:1), and hexane-water (3:1) for 10 min. A comparison between MAE and a 16-h Soxhlet extraction (SX) method showed that both techniques gave comparable results with certified values. MAE has advantages over the currently used Soxhlet technique due to a faster extraction time and lower quantity of solvent used. The consumption of organic solvent of the microwave method was less than one-tenth compared to Soxhlet.

Utility of thallium-201 scintigraphy in detecting right ventricular dysfunction in pulmonary embolism.

Acute right ventricular dysfunction has been established both as a diagnostic and prognostic indicator in pulmonary embolism. This report illustrates the utility of thallium-201 scintigraphy as an adjunctive noninvasive test in the diagnosis of pulmonary embolism by demonstrating increases in regional right ventricular perfusion and its subsequent resolution with treatment presumably as a result of decreased pressure work.

Tissue harmonic imaging sonography: evaluation of image quality compared with conventional sonography.

OBJECTIVE: The purpose of this study was to determine if tissue harmonic imaging (THI) sonography produced higher quality images than did conventional sonography. SUBJECTS AND METHODS: A prospective study was performed on 89 patients to compare the image quality of THI sonography with that of conventional sonography. Each examination was performed using THI sonography (transmitted frequency, 2.0 MHz; received frequency, 4.0 MHz) and conventional sonography at 2.5 and 4.0 MHz. The pancreatic area was studied in 60 patients, and other anatomic areas were studied in 68 patients. The images were then graded for penetration, detail, and total image quality. Graders were unaware of the sonographic technique. RESULTS: Of the 60 pancreatic examinations, THI sonography was the best technique for penetration in 45, detail in 54, and total image quality in 50. For the pancreas, THI sonography was significantly better than 2.5-MHz conventional sonography for penetration (p = .0002), detail (p < .0001), and total image quality (p < .0001). THI sonography was significantly better than 4.0-MHz conventional sonography for penetration (p < .0001), detail (p < .0001), and total image quality (p < .0001). Of the 68 examinations of other anatomic areas, THI sonography was the best technique for penetration in 42, detail in 57, and total image quality in 58. For other anatomic areas, THI sonography was significantly better than 2.5-MHz conventional sonography for penetration (p = .05), detail (p < .0001), and total image quality (p < .0001). THI sonography was significantly better than 4.0-MHz conventional sonography for penetration (p < .0001), detail (p < .0001), and total image quality (p < .0001). CONCLUSION: The THI technique improved sonographic image quality.

Right ventricular dysfunction in obstructive sleep apnoea: reversal with nasal continuous positive airway pressure.

The incidence and pathogenesis of right ventricular dysfunction in obstructive sleep apnoea (OSA) remains controversial. Using nuclear ventriculography, the prevalence of right ventricular dysfunction (RVD) was therefore determined in obese patients with OSA, as well as their clinical characteristics, arterial blood gas values, spirometry and sleep parameters. The reversibility of RVD was evaluated after long-term use of nasal continuous positive airway pressure (nCPAP). We studied 112 obese patients with OSA by nuclear ventriculography, 35 with RVD (Group 1), 77 without RVD (Group 2), and 14 patients without OSA as controls (Group 3). Repeat nuclear ventriculography was performed in seven patients who used nCPAP nightly for 6-24 months. The mean right ventricular ejection fractions (RVEF) were 31%, 47% and 44% in Groups 1, 2 and 3, respectively. Group 1 also had a lower left ventricular ejection fraction (LVEF) of 55 vs 63% in Group 2. The OSA groups did not differ in mean spirometric or arterial blood gas values. Group 1 had a lower mean nocturnal arterial oxygen saturation (Sa,O2) of 82 vs 87% in Group 2, and a longer apnoea duration of 22.3 vs 19.2 s. All but two patients in Group 1 had either awake alveolar hypoventilation or an apnoea + hypopnoea index > 40 disordered breathing events.h-1. Repeat nuclear ventriculography after nCPAP revealed an increase in RVEF from 30 to 39%. In conclusion, right ventricular dysfunction is common in obstructive sleep apnoea, but it is reversible with nasal continuous positive airway pressure treatment and appears to be related to nocturnal oxygen desaturation.

Comparison of thallium-201 and gallium-67 citrate scintigraphy in the diagnosis of pulmonary disease.

Gallium is presently used in the diagnosis of inflammatory, granulomatous, and neoplastic lung disease despite its many logistical problems. In contrast, thallium-201 scintigraphy, which was initially developed for myocardial imaging, offers the principal advantage of immediate imaging and diagnosis although it had not been investigated previously for use in pulmonary disease. In this study, thallium and gallium were prospectively compared with each other for the diagnosis of a variety of lung diseases. The overall concordance rate was 75%. Thallium was found to be significantly more sensitive than gallium for the entire group studied (N = 51, p < 0.006). In a subset of patients in whom a firm diagnosis was established, thallium was also found to be more sensitive, 86% vs 64%. The greater sensitivity of thallium-201 and its several inherent advantages suggest that thallium-201 should replace gallium-67 citrate as the radioisotope of choice for nuclear imaging of the chest.

Stem cell factor amplifies newborn and sickle erythropoiesis in liquid cultures.

A two-phase liquid-culture system was used to substantially amplify and differentiate erythroblasts, starting with mononuclear cells from the blood of normal adults, newborn infants, and patients with sickle cell anemia. After the first 7 days (phase 1), in medium plus fetal bovine serum (FBS) alone, or in combination with stem cell factor (SCF) or conditioned medium (CM), the cell number was unchanged, and the cells all looked like lymphocytes. These cells were then diluted into medium with erythropoietin (Ep) alone, with Ep and either SCF or CM, or in methylcellulose with the same factors (phase 2). After 14 days in liquid phase 2 with SCF and Ep, the cell numbers increased an average of 30-fold in the sickle, 24-fold in the newborn, and 4-fold in the normal adult cultures; almost all the cells were erythroblasts and erythrocytes. SCF in phase 1 increased the number of late progenitors (CFU-E) assayed in methylcellulose, with the largest number in sickle, followed by newborn cultures and then adult cultures. We conclude that erythroid progenitor cells survive for at least 7 days without Ep (but with FBS). Progenitor cells are amplified, particularly with SCF. Later in culture, SCF with Ep increases the final number of differentiated erythroid cells. Both the early and the late effects of SCF are most effective in sickle, followed by newborn cultures and then adult cultures.

Collateral pathways in superior vena caval obstruction as seen on gamma images.

The collateral pathways, known from contrast studies to take over the drainage of blood from the various parts of the body when the superior vena cava or its major tributaries are occluded because of disease, can easily be demonstrated with equal clarity (except for the vertebral plexus pathway) by radionuclides. The failure to delineate the vertebral plexus pathway is felt to lie in the close anatomical relationship between the vertebral plexus and the vertebrae, which cause attenuation of the emerging photons. Because of the existing anastomotic channels and their anatomical direction, location and distribution of the individual collateral pathways are individually identifiable. The site/level, extent, degree, and probable duration of occlusion directly affect the degree and extent of the collaterals that subsequently develop. In 20 of 49 abnormal radionuclide superior venacavograms, incidental but abnormal imaging features not ascribable to caval obstruction or syndrome were noted. These included persistent left superior vena cava, aortic aneurysm, pericardial effusion, and disparity in pulmonary perfusion.

Scintigraphic features of superior vena cava obstruction due to substernal non-toxic goitre.

Four men with clinical features of superior vena caval syndrome due to large substernal non-toxic multinodular goitre have undergone radionuclide superior vena caval studies. In all cases the dynamic scintigraphs showed a characteristic thyroidal configuration attributed to the definition of stretched thyroidal veins and their tributaries. Radiocontrast studies of two patients demonstrated the characteristic thyroid configuration. A radionuclide superior venacavogram taken post-thyroid lobectomy in one case showed the features had reverted to normal.

Mercury vapor as a contaminant of hospital environment.

Surveys for airborne mercury in two Ottawa hospitals have been conducted. Two different analytical methods were used. Although the concentrations of mercury vapor were below the TLV, all samples analyzed showed measureable amounts of mercury to be present. Predominant sources of mercury contamination are broken thermometers and sphygmomanometers.

Bone scan evidence of renal osteodystrophy in undialyzed uremic patients.

Scintigraphy with the 99m-Tc complexes offers serveral distinct advantages to the nephrologist. The procedure is both easily performed and readily available, there have been no reports of toxicity, and the radiation exposure to the patient is lower than that of conventional radiography. We suggest that scintigraphic evidence of metabolic bone disease is present at the onset of terminal uremia with much higher frequency than is detectable by radiographs, and that unsuspected soft tissue calcification may also be detected on occasion. Therefore, 99m-Tc scans may be a valuable addition to the diagnostic regimen of the uremic, and should be thoroughly evaluated with more extensive studies, including quantitative analyses.

[99mTc] pertechnetate radionuclide venography--large-volume injection without tourniquet.

Radionuclide venography was performed in patients who were suspected clinically to have thromboembolic disease of the lower extremities and/or pelvis. A moderately large volume of pertechnetate was administered in the dorsal vein of each foot without the benefit of applied tourniquets at the time of injection. Sixty-five (27.2%) of 242 studies were abnormal; the majority revealed defect(s) and collaterals, some collaterals only, and a few defects only. In 140 normal patients only the deep venous system was outlined in 74.5%, while the remainder defined one or both sides of the superficial venous system (great saphenous vein). The merits and apparent advantages derived from radionuclide venographic procedure are discussed. The method is simple, reproducible, and useful in assessing thromboembolic disease, particularly in the deep venous system of the lower extremities and pelvis.

Occlusion of inferior vena cava--features by radionuclide venography.

Six adults with inferior vena caval obstruction are presented. Three were the results of surgical intervention, two were secondary to large thrombi, and one was due to pressure from a large renal-cell carcinoma and adjacent nodes. All underwent a modified approach of radionuclide venography, using a moderately large volume of sodium pertechnetate. Features characteristic of inferior vena caval obstruction were demonstrated in five of the six patients, and these various features are described and discussed.

Unusual bone images in hyperparathyroidism.

Whole-body scans with 99Tcm-Sn polyphosphate were performed on four patients suffering from hyperparathyroidism. Two of the patients were investigated twice, at intervals of five and eight months. A variety of unusual but symmetrical images were obtained, not always confined to the skeleton. It is suggested that in conditions of renal failure the radiopharmaceutical may be avidly accumulated on first passage by calcifying areas in the soft tissues. Deteriorating blood supply to the bones reduces uptake of 99Tcm in the the skeleton.

Improved methods for sampling and analysis of vinyl chloride.

An analytical scheme was developed for vinyl chloride, which is applicable to ambient and in-plant atmospheres. Using computerized gas chromatographs equipped with automatic injection system and flow rate control, high reproducibilities are achieved in the ppb range. Samples from various sources have been analyzed.

Is internal-external control an age-related variable?

Following the suggestion proposed by Duke, Shaheen, and Nowicki, this study was designed to test the basic hypothesis that the meaning of internal-external control (I-E) may differ with age. Such variables as age, educational level, socioeconomic status, self-confidence, etc., which have consistently been found to relate to I-E for children through college age Ss, were examined to see if these bear a relationship to I-E for a group of parents (95 fathers and 107 mothers) of college students (father mean age 48, mother mean age 46). Results indicated that with the exception of father education, there was no significant relationship between I-E and all other variables. Thus, these findings support the notion that I-E is an age-related variable, that generalizations from previous studies to older people should be re-evaluated, and that future research should study the meaning and dynamics of I-E for older people.

Computerized gas chromatographic-mass spectrometric analysis of polycyclic aromatic hydrocarbons in environmental samples.

Substantial progress has been made in the last few years in the development of a rapid method for determining polycyclic aromatic hydrocarbons (PAH) in environmental samples. The three-step method consists of (i) a preliminary separation of PAH by solvent and/or column chromatography, (ii) identification by a combination of gas chromatography with quadrupole mass spectrometry and computer, and (iii) measurement by computerized gas chromatography using internal standards. Samples of industrial effluents, coke oven emissions, coal tar and airborne particulates have been investigated. The efficiencies of different gas chromatographic columns were evaluated during these investigations.