Lack of association of VEGF promoter polymorphisms with sporadic ALS.

The authors tested the association of three vascular endothelial growth factor (VEGF) promoter polymorphisms with sporadic ALS (SALS) to verify the results of a previous study and to investigate their modifier effects on the subphenotypes of SALS in a large family-based and case-control cohort of North American white subjects (N = 1,603). They did not find any association of the VEGF promoter polymorphisms with SALS or its subphenotypes, suggesting that they do not have a direct causal role in ALS.

Paraoxonase cluster polymorphisms are associated with sporadic ALS.

BACKGROUND: Paraoxonases (PONs) are involved in the detoxification of organophosphate pesticides and chemical nerve agents. Due to a reported possible twofold increased risk of ALS in Gulf War veterans and the associations of PON1 polymorphisms with the neurologic symptom complex of the Gulf War syndrome, the authors investigated the association between sporadic ALS (SALS) and PON gene cluster variants in a large North American Caucasian family-based and case-control cohort (N = 1,891). METHODS: Clinically definite and probable ALS was diagnosed according to the revised El Escorial criteria, exclusion of family history of ALS, and SOD1 mutation analysis. Single nucleotide polymorphism (SNP) genotyping was done using TaqMan assays on ABI7900HT. Data were analyzed using SPSS, Haploview, FBAT, and THESIAS. RESULTS: A haploblock of high linkage disequilibrium (LD) spanning PON2 and PON3 was associated with SALS. The SNPs rs10487132 and rs11981433 were in strong LD and associated with SALS in the trio (parents-affected child triad) model. The association of rs10487132 was replicated in 450 nuclear pedigrees comprising trios and discordant sibpairs. No association was found in case-control models, and their haplostructure was different from that of the trios with overall reduced LD. Resequencing identified an intronic variant (rs17876088) that differentiated between detrimental and protective SALS haplotypes. CONCLUSION: This study demonstrates evidence of significant association of variants in the Paraoxonase gene cluster with sporadic ALS and is compatible with the hypothesis that environmental toxicity in a susceptible host may precipitate ALS.

Nitric oxide-induced oxidative stress in autosomal recessive and dominant inclusion-body myopathies.

Autosomal-recessive and autosomal-dominant hereditary inclusion-body myopathies are severe, progressive muscle diseases, characterized pathologically by vacuolated muscle fibres containing paired helical filaments. We immunostained muscle biopsy specimens from quadriceps-sparing autosomal-recessive and autosomal-dominant inclusion-body myopathy subjects, disease-control subjects and normal patients, utilizing isoform-specific antibodies against the neuronal and inducible forms of nitric oxide synthase, and antibodies against nitrotyrosine. Approximately 75% of the vacuolated muscle fibres in all recessive and dominant inclusion-body myopathy patients contained inclusions strongly immunoreactive with antibodies against neuronal and inducible nitric oxide synthase which, by immunoelectron microscopy, were colocalized to clusters of tubulofilaments (previously shown, by us, to be paired helical filaments). Strong nitrotyrosine immunoreactivity was in the form of multiple dots and large granular patches, which ultrastructurally did not immunolocalize to tubulofilaments. Excess intracellular nitric oxide can combine with superoxide to produce highly toxic peroxynitrite, which can nitrate tyrosines of proteins. The presence of nitrotyrosine is indicative of nitric oxide-induced oxidative stress. Our data suggest that oxidative stress plays a role in the pathogenic cascade of hereditary inclusion-body myopathies.

Spinal cord venous infarction following endoscopic sclerotherapy for esophageal varices.

The authors report an unusual case of venous infarction of the spinal cord associated with endoscopic sclerotherapy for esophageal varices. MR imaging findings included signal abnormalities and abnormal enhancement of the affected spinal cord and T-8 vertebral body. A review of the hemodynamic changes associated with portal hypertension and the normal venous drainage of the spinal cord is presented.

Exercise renography in untreated subjects with essential hypertension.

UNLABELLED: Exercise induced renal dysfunction is reported to occur in treated hypertensive patients but not seen normotensive subjects. It is unclear if this phenomenon is related to the disease or to treatment. METHODS: Four normal volunteers and 15 hypertensive subjects (antihypertensive medications were discontinued for more than 4 wk) were studied with upright radionuclide renography at rest and during bicycle exercise. The amount of exercise was sufficient to increase the heart rate at least 20 bpm above the resting value. All subjects were healthy, without evidence of left ventricular hypertrophy renal disease or hypertensive retinal disease. BUN, serum creatinine concentration and urinalysis were normal in all subjects. Renograms were performed for 12-15 min after injection of either 1 mCi[123]orthoidohippurate (OIH) or 2-7 mCi 99mTc-mercaptoacetyltriglycine (MAG3). Visual analysis and mean transit time calculation were performed on the rest and exercise studies. RESULTS: Seven of 14 hypertensive subjects and none of the normal volunteers demonstrated abnormal prolongation in renal transit during exercise which was not seen on the resting renogram. Four of these seven subjects had a history of hypertension for 2 yr or less. CONCLUSION: About 50% of individuals with mild-to-moderate hypertension and normal renal function may have abnormal renal transit of renal excretion agents during exercise, although their baseline studies are normal. This finding is unassociated with therapy and appears to be related directly to the pathophysiology of essential hypertension.

Radiation safety in the central radiopharmacy.

The currently increasing number of new radiopharmaceuticals and the increase in individual patient-dose activity, particularly for single photon emission computer tomography imaging, coupled with the switch toward unit doses probably contribute to an increase in the radiation burden to radiopharmacy personnel. To meet this increased need of the nuclear medicine community, a medium-sized radiopharmacy may order seven to eight 3-Ci molybdenum-99/technetium-99M generators per week and may perform 10 to 15 elutions per day. The maximum radiation exposure to radiopharmacy personnel occurs during the generator elutions, compounding (kit preparation), and unit-dose dispensing. Additional sources of radiation exposure can occur during receipt of radioactive packages, transport of prepared doses, and the process of storage and disposal of radioactive waste. Recent reports have shown extremity radiation doses to the fingers and hands at 14 to 21 rem/year. Radiation exposure can be monitored by film badges, thermoluminescent detectors, or one of the analog or digital self-reading dosimeters. Each monitoring device has advantages and the choice depends upon the personnel involved (eg, visitors) and the particular needs of the radiopharmacy. Extremity dose reductions during radiopharmacy procedures can be achieved by a number of techniques, some as simple as the use of 8- to 9-inch forceps during transfers of radioactive vials and syringes and the use of a dose-drawing syringe shield during unit-dose dispensing procedures. In preparation of unsealed doses or capsules of radioactive iodine, there is a potential for a high internal dose because of inhalation of the volitile solution. Frequent monitoring in the form of bioassays and the use of strict threshold levels will ensure early detection of exposure to radioactive iodine and quick corrective action. In pharmacies and nuclear medicine departments handling fluorine-18 for use with Anger gamma cameras, the high levels of both beta and gamma radiation present an additional set of radiation safety problems.

Effects of continuous low-frequency pacing on immature canine diaphragm.

Although diaphragm pacing has been shown to be a practical method of supporting ventilation in children, its usefulness has been limited because of concern that continuous (24 h/day) diaphragm pacing would fatigue and damage the diaphragm. We examined the functional and structural effects of continuous low-frequency diaphragm pacing on the left hemidiaphragm of five immature dogs aged 65 +/- 2 (SD) days at onset of pacing. Stimulus parameters approximated those required to pace infants: frequency 11.1 Hz, inspiratory time 810 ms, and respiratory rate 20 breaths/min. Animals were paced 24 h/day for 24-28 days. Paced tidal volumes and airway occlusion pressures were unchanged at low (less than 15 Hz) stimulus frequencies but were reduced at high (greater than 20 Hz) stimulus frequencies. Although histologically the paced hemidiaphragms appeared normal, histochemical studies showed a conversion from a mixture of type I (54%) and type II (46%) fibers to a uniform population of type I fibers with high oxidative enzyme activity. Transformation of muscle type was also demonstrated by pyrophosphate gel electrophoresis; fast and slow isomyosin bands were noted in control specimens, whereas only slow isomyosin was identified in paced specimens. Thus, in immature dogs, continuous low-frequency pacing affects both function and structure of the diaphragm.

Increased muscular beta-hydroxyacyl CoA dehydrogenase with McArdle's disease.

Enzymes of energy production were measured in muscle homogenates and in individual muscle fibers from 5 patients with McArdle's disease. Individual fibers were investigated to determine whether fibers of all types were completely devoid of glycogen phosphorylase activity and whether the involved fibers might be biochemically altered in a fiber type dependent manner to enhance the energy-generating capabilities of the cells through other metabolic pathways. Using highly sensitive biochemical assays, a complete absence of glycogen phosphorylase, a and b, activity was found in fibers of all types in the McArdle's patients. Levels of enzymes representing glycolysis, the Krebs cycle, and high energy phosphate metabolism were essentially normal in each fiber type, indicating an apparent lack in metabolic adaptation of these energy pathways to the absence of glycogen utilization. However, a key enzyme in the beta-oxidation of fatty acids (beta-hydroxyacyl CoA dehydrogenase, beta OAC) was elevated in all patients, and substantially in 4 of the 5. This suggested that lipid substrates can provide support for oxidative endurance capacity in some patients. Individual fiber analyses indicated that the compensation involved fibers of all types.

Exercise and recovery ventilatory and VO2 responses of patients with McArdle's disease.

This study was designed to determine whether patients with McArdle's disease, who do not increase their blood lactate levels during and after maximal exercise, have a slow "lactacid" component to their recovery O2 consumption (VO2) response after high-intensity exercise. VO2 was measured breath by breath during 6 min of rest before exercise, a progressive maximal cycle ergometer test, and 15 min of recovery in five McArdle's patients, six age-matched control subjects, and six maximal O2 consumption- (VO2 max) matched control subjects. The McArdle's patients' ventilatory threshold occurred at the same relative exercise intensity [71 +/- 7% (SD) VO2max] as in the control groups (60 +/- 13 and 70 +/- 10% VO2max) despite no increase and a 20% decrease in the McArdle's patients' arterialized blood lactate and H+ levels, respectively. The recovery VO2 responses of all three groups were better fit by a two-, than a one-, component exponential model, and the parameters of the slow component of the recovery VO2 response were the same in the three groups. The presence of the same slow component of the recovery VO2 response in the McArdle's patients and the control subjects, despite the lack of an increase in blood lactate or H+ levels during maximal exercise and recovery in the patients, provides evidence that this portion of the recovery VO2 response is not the result of a lactacid mechanism. In addition, it appears that the hyperventilation that accompanies high-intensity exercise may be the result of some mechanism other than acidosis or lung CO2 flux.

2,4-Dinitrophenol, muscle biopsy, and McArdle's disease.

Exercise is simulated in muscle biopsy preparations by using low concentrations of 2,4-dinitrophenol (DNP), which do not produce contracture or anatomic damage. The validity of this simulation is supported by (1) the biochemical effects of simultaneous muscle contraction and DNP are not additive, suggesting that exercise and DNP stress the same pathways; (2) the effects of increasing concentrations of DNP and increasing levels of stimulation are similar with an early drop in phosphocreatine, increasing lactate and inosine monophosphate (IMP), and a late fall in ATP levels; and (3) DNP provocation in a patient with McArdle's disease demonstrated an absence of lactate and high levels of IMP correlating with clinical findings. DNP provocation may be a simple way of studying metabolic pathways in neuromuscular diseases.

SPECT instrumentation: performance, lesion detection, and recent innovations.

The use of a gamma camera for single photon emission computed tomography (SPECT) imaging places greater demand on camera performance than does planar imaging, since camera specifications that are adequate for planar imaging may produce serious image artifacts in SPECT. Manufacturers have responded to the challenge with improvements in both hardware and software, but the user must pay careful attention to quality control procedures. Field nonuniformity is caused mainly by spatial distortion, which may vary during rotation; some cameras incorporate a means of automatically correcting for angular changes. The purpose of performing SPECT is to improve lesion detection, ie, to improve contrast, which is influenced by many factors. Attenuation corrections may be applied either before or after reconstruction. For Tc-99m an attenuation coefficient less than that for water, ie, either 0.11 or 0.12, would appear to give better results; the visual appearance is improved but the effect on contrast is minimal. Scattered photons are the major cause of loss of contrast in SPECT images. Recent developments in on-line energy corrections allow the use of narrower photopeak windows as well as asymmetric energy windows. Offpeak energy windows have demonstrated significant improvements in contrast; however, the increase in nonuniformity can cause artifacts which may limit their use. Simultaneous collection of separate images, one in the photopeak region and the other in the scatter region (92 to 125 keV) may enable a transaxial scatter image to be subtracted from the transaxial photopeak image. This may permit quantification of the true radioactivity distribution. New collimator designs introduced to improve SPECT resolution include cast collimators which can be made with more uniform hole construction than the lead-foil type; for brain imaging, long bore parallel hole and converging fan beam collimators as well as astigmatic collimators which converge in both planes with different lines of focus. Some of these improve both sensitivity and resolution compared to parallel hole collimators. Noncircular orbits have also been introduced in order to improve resolution, but their use presents many problems which require careful monitoring. Transaxial multicrystal systems have been developed over many years, but have not been widely used, primarily because of their inherent complexity, high costs, and limited applicability. Some of these drawbacks may be overcome by a new type of SPECT camera currently under development by several different groups.(ABSTRACT TRUNCATED AT 400 WORDS)

McArdle's disease with myoadenylate deaminase deficiency: observations in a combined enzyme deficiency.

Exercise and work potential of a patient with coexistent myophosphorylase and myoadenylate deaminase (AMPDA) deficiency was compared with that of three patients with myophosphorylase deficiency alone. The patient with the combined defect failed to produce an abnormal rise in serum ammonia or hypoxanthine as seen in the other patients after forearm exercise. Maximum oxygen consumption and work rates during cycle ergometer testing were similar in all patients, but well below controls. The occurrence of two defects involving short-term energy metabolism in muscle presents an opportunity to define further the metabolic role of AMPDA.

The implications of decreased performance of new generation gamma-cameras on the interpretation of 131I-Hippuran renal images.

Several patients with renal failure in whom the kidneys were more clearly imaged with 99Tcm-DTPA than 131I-Hippuran were recently observed. We have postulated that our newer generation gamma-cameras have a reduced capacity to image 131I in comparison to older generation cameras. This hypothesis was tested by comparing representative older and newer imaging systems. Full-width tenth-maximum 99Tcm linespread functions were 1.20 and 1.55 cm for the older and newer cameras, respectively. The 99Tcm count rate on the newer camera was 111% that of the older camera, and the observed kidney to background count ratios in a phantom model were virtually identical for the two cameras imaging a number of simulated 99Tcm count distributions. Full-width tenth-maximum 131I linespreads were 1.55 and 4.78 cm, respectively, on the older and newer cameras and the 131I count rate on the newer camera was 27% of the count rate on the older system. The phantom model demonstrated a consistently lower 131I perceived kidney to background count ratio on the newer gamma-camera compared to the older system. These findings should be considered in the interpretation of 131I-Hippuran studies on newer-generation equipment until revised criteria of interpretation have been established. Non-visualization of the kidney may not have the same prognostic implication using modern cameras as has been reported from studies with older generation detector systems.

IMP response: an indicator of metabolic stress in working muscle.

An in vitro system for the combined biochemical and physiologic analysis of striated muscle has been developed. It is hoped that its eventual application will be to the evaluation of human muscle disease. To test the method's usefulness in evaluating metabolic defects, we used iodoacetate to induce a glycolytic defect in animal muscle. This produced the expected effects of precipitous fatigue on repetitive stimulation, increased inosine monophosphate (IMP) and decreased adenosine triphosphate (ATP) and phosphocreatine; in addition, the severity of the glycolytic block was directly related to the amount of IMP produced per gram twitch tension.

Controlled trial of thyrotropin releasing hormone in amyotrophic lateral sclerosis.

A double-blind controlled trial of thyrotropin releasing hormone (TRH) 150 mg IM daily in 30 patients with amyotrophic lateral sclerosis is reported. The drug/placebo was administered for 2 months, followed by a 2-month "wash-out". Evaluation of strength, functional ability, and respiratory functions was performed. A temporary increase in the strength of some muscles was detected following the administration of TRH, but no change in functional performance was noted. Neither the patients nor the investigators believed the effects were of any marked clinical significance. The course of the illness was not altered.

Cinematic display of respiratory organ motion with impedance techniques.

A technique is described for the recording of individual images during discrete phases of the respiratory cycle, i.e., isovolume images. The method is based on the observation that transthoracic impedance is related approximately linearly to lung volume. This impedance signal can be converted to an FM signal to stimulate a Z pulse, then added in parallel to the Z pulse from the gamma camera. Simulated X and Y position signals locate simulated Z at the periphery of the computer field of view. Summation of the images with coinciding simulated Z counts produces isovolume images, one for each phase of respiration. These images then can be displayed in cinematic mode or as motion-corrected images. This new technique offers a potential for improved image resolution, temporal separation of organs that exhibit different motion patterns, and estimation of regional pulmonary function.

A dual collimator design for beat-to-beat measurement of cardiac performance with an Anger camera.

A dual collimator was designed for an Anger camera to permit measurement of cardiac performance on a beat-to-beat basis. Special all-purpose (SAP) and special high-sensitivity (SHS) collimator sections can be interchanged without movement of the patient. Thus, left-ventricular regions of interest delineated on SAP multigated images can be transferred to SHS dynamic images to generate beat-to-beat volume curves. Preliminary balloon studies demonstrated an excellent correlation between ejection fractions calculated with the two collimators: r greater than 0.99, n = 17, p less than 0.001. Varying the volume of an adjacent "right ventricle" balloon failed to alter significantly the count rate from the "left ventricle" balloon's region of interest. Preliminary results on 12 patients, comparing standard-camera ejection fractions with average beat-to-beat ejection fractions, showed that is is possible to measure cardiac function on a beat-to-beat basis with a single-crystal gamma camera. There was minimal difference between the ejection fractions calculated by the dual-collimator method and a standard gated technique (r = 0.98, n = 12, p less than 0.001).

Deadtime measurements with a multihole phantom: concise communication.

The performance characteristics of any Anger camera are defined by that camera's spatial and temoral resolutions. Procedures using first-past techniques--such as ejection fraction or left-to-right shunt determinations--require that deadtimes be minimal. We have evaluated a simplified method for measuring a camera's deadtime; it uses a multihole phantom consisting of a lead sheet with 196 holes, 7/16 in. diameter, arranged in a 14 X 14 matrix. Each hole can be filled with a removable lead plug. Count rates are determined following incremental removal of the plugs. Deadtime curves were generated for each of three cameras by this and standard techniques. For each camera, the three curves were virtually identical. Using the phantom, deadtimes could be determined in 15 to 20 min. This phantom provides a simple, rapid, and accurate means of determining camera deadtime and minimizing personnel radiation exposure.