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This paper briefly describes the Chemical Incident Screening Database currently used by the CSB to identify and evaluate chemical incidents for possible investigations, and summarizes descriptive statistics from this database that can potentially help to estimate the number, character, and consequences of chemical incidents in the US. The report compares some of the information in the CSB database to roughly similar information available from databases operated by EPA and the Agency for Toxic Substances and Disease Registry (ATSDR), and explores the possible implications of these comparisons with regard to the dimension of the chemical incident problem. Finally, the report explores in a preliminary way whether a system modeled after the existing CSB screening database could be developed to serve as a national surveillance tool for chemical incidents.

Soft metal gaskets (indium and silver) were used to reduce contact resistance between the wire and the electrode in an aluminum wire Z pinch by more than an order of magnitude over the best weighted contact case. Clamping a gasket over a Z-pinch wire compresses the wire to the electrode with a greater normal force than possible with wire weights. Average contact resistance was reduced from the range of 100-3000 Omega (depending on wire weight mass) to 1-10 Omega with soft metal gaskets. Single wire experiments (13 microm Al 5056) on a 16 kA, 100 kV Marx bank showed an increase in light emission (97%) and emission volume (100%) of the plasma for the reduced contact resistance cases. The measured increases in plasma volume and light emission indicate greater energy deposition in the ablated wire. Additionally, dual-wire experiments showed plasma edge effects were significantly decreased in the soft metal gasket contact case. The average height of the edge effects was reduced by 51% and the width of the edge effects was increased by 40%, thus the gasket contact case provided greater axial uniformity in the plasma expansion profile of an individual wire.

Seventeen elements, Al, Ca, Cd, Co, Cr, Cu, Fe, K, Li, Mg, Mn, Na, Ni, P, Pb, V, and Zn (macroelements and trace elements) were investigated by Atomic Spectrometries on a particular wild edible mushroom collected in the central region of Argentina during 2 different years in the same season. The metal content profile in Suillus granulatus samples is given. The found quantities of Na, K, Ca, Mg, Fe, P, V, and Al were 0.40, 10.84, 0.48, 0.30, 0.57, 4.24, 0.18, and 1.23 g/kg dry weight, respectively. The levels of Li, Cu, Zn, Cd, Co, Ni, Cr, and Mn were 0.98, 23.02, 22.30, 0.26, 0.16, 1.17, 0.90, and 28.75 mg/kg dry weight, respectively. Pb was not detected at the investigated levels. The results indicate that the levels of metals in the analyzed samples are not considered to be a health risk. In order to demonstrate the validity of our method, a recovery study was performed with acceptable results.

Four different phytopharmaceutical dosage forms for use in weight control programs were analyzed. Two different ground herbal blends and their correspondent infusions, a capsule and a tincture were investigated for the presence of compounds used as adulterants in these products. A capillary electrophoresis (CE) method was developed and validated. The optimized experimental conditions were: BGE, sodium tetraborate buffer 20mM, pH 9.2, voltage applied 30kV, capillary temperature 25°C, injection sample at 0.5Psi during 5s. Ephedrine, norephedrine, caffeine and furosemide were baseline separated in less than 7min; the migration times were found to be 2.65, 2.90, 3.75 and 6.58min, respectively. The analysis showed in sample 3 concentrations of 0.45±0.03mgg(-1) (ephedrine), 0.33±0.02mgg(-1) (norephedrine), 1.09±0.41mgg(-1) (caffeine) and 0.80±0.17mgg(-1) (furosemide). Caffeine content in samples 1, 2 and 4 was 0.61±0.06mgg(-1), 15.66±1.05mgg(-1) and 2.27±0.13mgml(-1), respectively. Linearity was obtained in the concentration range of 1-1000μgml(-1). Limits of detection (LOD) and quantification (LOQ) were determined as 0.42μgml(-1) and 1.40μgml(-1) (ephedrine), 0.47μgml(-1) and 1.40μgml(-1) (norephedrine), 0.12μgml(-1) and 0.48μgml(-1) (caffeine), 0.22μgml(-1) and 0.73μgml(-1) (furosemide). The common constituents of the samples did not interfere with the potential adulterants. Repeatability was better than 0.24% RSD for the retention time and 1.43% for the peak area. Intermediate precision was tested by changing the capillary, the day of operation and the operator, in all the cases the %RSD was better than 3.06., (Copyright © 2007 Elsevier Ltd. All rights reserved.)

The apparent electrophoretic mobilities of indomethacin in beta-cyclodextrin at a range of concentrations were measured directly by capillary electrophoresis. Three different linear plots and a non linear plot are proposed for the apparent binding constant calculations, based on the fact that the molar ratio of the inclusion complex was 1:1. K values obtained at 298 K were 421 M(-1) (double reciprocal fit), 488 M(-1) (x-reciprocal fit), 428 M(-1) (y-reciprocal fit) and 490 M(-1) (non linear fit). The corresponding K values at 313 K were 380 M(-1) (double reciprocal fit), 355 M(-1) (x-reciprocal fit), 366 M(-1) (y-reciprocal fit) and 339 M(-1) (non linear fit). Using the proposed methods, the binding constant of the indomethacin-beta-cyclodextrin inclusion complex can be obtained easily. The methods have been applied to obtain the values of the constant K under different experimental conditions. Under optimized conditions the K constant is temperature dependent and non-arrhenian behaviour was observed.

The determination of trace elements in Hypericum perforatum leaves and flowers, their teas, tinctures and tablets was carried out by Electrothermal Atomic Absorption Spectrometry (ETAAS) and Ultrasonic Nebulization System coupled to Inductively Coupled Plasma Optical Emission Spectrometry (USN-ICP-OES). Hypericum perforatum (St. John's wort), is a phytomedicine used for the treatment of depression. Samples were collected from different sources in the argentinian market. Heavy metals contents in the investigated samples were found at different levels. Chromium and cobalt were undetectable above their limits of detection in both liquid and solid samples; while aluminum, cadmium, lead, iron and vanadium were present in the majority of samples. The analytical results obtained for all metals indicate that they were present at concentration well below the acceptable daily intake recommended by the World Health Organization. Based on the results obtained in the present work, it is concluded that the present techniques are suitable for the routine determination of heavy metals concentration in phytopharmaceuticals.

A high-performance capillary electrophoretic (CE) method has been developed for obtaining electropherograms of various extracts and the commercial formulation (fingerprints) of Hedera helix L used in Argentina as a cough's treatment. Also, a capillary zone electrophoresis (CZE) method was developed for the search, identification and determination of some possible adulterants. These likely adulterants are common synthetic drugs used in respiratory diseases (antitussive, decongestant and bronchodilator agents). Under optimum conditions, the analytes (ephedrine, codeine, diphenhydramine and constituents of H. helix formulations) were separated within less than 10 min in 20 mM sodium tetraborate buffer (pH 9.0). The present procedure was validated with respect to selectivity, linearity range, limits of detection (LOD) and quantification (LOQ), precision (repeatability and intermediate precision), solution stability and accuracy; the results obtained were satisfactory. Good linearity was obtained over two orders of magnitude and detection limits (S/N = 3) were better than 1.2 microg ml(-1) for all analytes. The CE methodology was successfully applied to the search and subsequent determination of ephedrine, codeine and diphenhydramine in H. helix extracts and its phytopharmaceutical products.

This study describes the development and validation of a method for quantification of the antiulcer experimental drug xanthatin in tablets by capillary electrophoresis (CE). Solid oral dosage forms based on xanthatin were designed and assayed on rats. A CE methodology was developed; the parameters evaluated were: background electrolyte composition, concentration and pH, applied voltage and sample preparation. The method was validated in terms of range of linearity, limits of detection (LOD) and quantification (LOQ), accuracy, precision and selectivity and then applied to the pharmaceutical dosage forms. Xanthatin determination was carried out in less than 3 min with a 20 mM sodium tetraborate buffer, pH 9.20. Drug concentration per tablet found was 2.97 +/- 0.2 mg. Calibration plots were linear over at least three orders of magnitude of analyte concentrations, LOD and LOQ were 7.6 and 26 microg mL(-1) respectively. For accuracy evaluation a recovery test was performed, the values being better than 98.6%. With respect to precision, the results obtained were better than 1.02 RSD% (repeatability) and 1.54% (intermediate precision). After the manufacturing process the resulting tablets were biologically active. The methodology developed is useful, simple and rapid for xanthatin determination in tablets.

Phytopharmaceuticals containing Valerian are used as mild sleep-inducing agents. The elemental composition of 3 different marks of Valeriana officinalis roots commercially available in the Argentinian market, their teas, and a commercial tincture have been studied. The content of Al, Ca, Cd, Co, Cr, Cu, Fe, Li, Mn, Ni, Pb, V, and Zn was determined in phytopharmaceuticals by flame atomic emission/absorption spectrometry, electrothermal atomic absorption spectrometry, and ultrasonic nebulization coupled to inductively coupled plasma-optical emission spectrometry. Prior to analyses of the samples, a digestion procedure was optimized. The analytical results obtained for Fe, Al, Ca, and V in the solid sample study were within the range 100-1000 mg/kg, and for Mn, Zn, and Pb within the range 10-100 mg/kg. Cadmium was found at levels up to 0.0125 mg/kg.

The present work describes a simple, accurate and rapid method for the separation and simultaneous determination of codeine, diphenhydramine, ephedrine and noscapine present in cough-cold syrup formulations by capillary zone electrophoresis. Factors affecting the separation were the buffer pH and concentration, applied voltage, and presence of additives. Separations were carried out in less than 10 min with a 20 mM sodium tetraborate buffer, pH 8.50. The carrier electrolyte gave baseline separation with good resolution, great reproducibility and accuracy. Calibration plots were linear over at least three orders of magnitude of analyte concentrations, the lower limits of detection being within the range 0.42-1.33 microg ml(-1). Detection was performed by UV absorbance at wavelengths of 205 and 250 nm. Quantification of the components in actual syrup formulations was calculated against the responses of freshly prepared external standard solutions. The method was validated and met all analysis requirements of quality assurance and quality control. The procedure was fast and reliable and commercial pharmaceuticals could be analyzed without prior sample clean-up procedure.

Metals have been investigated in different plant materials in order to establish their normal concentration range and consider their role in plants as part of human medicinal treatment. Metal monitoring as a pattern recognition method is a promising tool in the characterization and/or standardization of phytomedicines. In the present work measurable amounts of Ca, Cu, K, Li, Mg, Mn, Na, Ni, and Zn were detected in phytopharmaceutical derivatives of Hypericum perforatum by atomic techniques. Atomic methodologies like flame atomic absorption spectrometry (FAAS) and electrothermal atomic absorption spectrometry (ETAAS) allow reliable determination of mineral content in pharmaceutical quality control of medicinal plants. Additionally, capillary electrophoresis (CE) patterns of characteristic components (fingerprints) have been performed for the search of adulterants in phytopharmaceutical products.

The separation of basic nitrogenous compounds commonly used as active ingredients in cold medicine formulations by micellar electrokinetic capillary chromatography and capillary zone electrophoresis with direct absorptiometric detection was investigated. The type and composition of the background electrolyte (BGE) were investigated with respect to separation selectivity and BGE stability. BGE of 10 mM sodium dihydrogenphosphate-sodium tetraborate buffer containing 10 mM SDS and 10% acetonitrile, pH 9.0 was found to be optimal. Dextromethorphan hydrobhromide, diphenhydramine hydrochloride and phenylephrine hydrochloride were baseline-separated in less than 11 min, giving separation efficiencies of up to 494,000 theoretical plates, reproducibility of corrected peaks areas below 3% relative standard deviation and concentration detection limits from 2.5 to 5.5 microg ml(-1). Detection was performed at 196 and 214 nm., (Copyright 2002 Elsevier Science B.V.)

Nevirapine is an antiretroviral agent belonging to the class of non-nucleoside reverse transcriptase inhibitors. We describe a fast, simple isocratic reversed-phase high-performance liquid chromatography method with a 30-mm long column for assaying nevirapine in human serum. After deproteinization of 200 microl serum samples with 50% trichloroacetic acid, the supernatant was injected into a reversed-phase C18 column, using 10 mM phosphate buffer (pH 5)-acetonitrile (82:18, v/v) as the mobile phase. Peak detection was performed at 240 nm. Nevirapine retention time was 2 min. The method was validated over 0.1-10 microg/ml and the assay was linear over this concentration range (r2>0.998). Within- and between-day precisions were less than 5.4%. The lower limit of quantification was 0.1 microg/ml. Nevirapine in human serum samples was stable for 2 days at 20-25 degrees C, 15 days at 4 degrees C and 3 months at -20 degrees C.

At the recent tuberous sclerosis complex consensus conference, the clinical diagnostic criteria for tuberous sclerosis complex were simplified and revised to reflect both new clinical information about tuberous sclerosis complex and an improved understanding of the disorder derived from molecular genetic studies. Based on this new information, some clinical signs once regarded as pathognomonic for tuberous sclerosis complex are now known to be less specific. No single sign is present in all affected patients, and there is no proof that any single clinical or radiographic sign is absolutely specific for tuberous sclerosis complex. Accordingly, the clinical and radiographic features of tuberous sclerosis complex have now been divided into major and minor categories based on the apparent degree of specificity for tuberous sclerosis complex of each feature. A definitive diagnosis of tuberous sclerosis complex now requires two or more distinct types of lesions, rather than multiple lesions of the same type in the same organ system. Although diagnosis on purely clinical grounds can continue to be difficult in a few patients, there should be little doubt about the diagnosis for those individuals who fulfill these strict criteria. Couples with more than one child with tuberous sclerosis complex, no extended family history, and no clinical features of tuberous sclerosis complex are more likely to have germline mosaicism for tuberous sclerosis than nonexpression of the mutation. Germline mosaicism, while fortunately rare, will not be suspected from either diagnostic criteria or molecular testing until a couple has multiple affected children. Genetic counseling for families with one affected child should include a small (1% to 2%) possibility of recurrence, even for parents who have no evidence of tuberous sclerosis complex after a thorough diagnostic evaluation.

Background: Childhood presentation of polycystic kidney disease has been reported with tuberous sclerosis complex (TSC). Recently some such cases have been shown to be due to combined deletion of the PKD1 and TSC2 genes, which lie close together on chromosome 16. The phenomenon of anticipation, whereby disease presentation occurs at a progressively earlier age in each generation, has been suggested to occur in autosomal dominant polycystic kidney disease (ADPKD). We have carried out a genetic study of a family in which these issues became clinically relevant. Neonatal presentation of polycystic kidneys occurred in an individual with a maternal family history of epilepsy and features of TSC without renal cystic disease., Methods: Detailed historical and clinical profiles were gathered for three generations of the maternal and paternal families. Both parents underwent renal ultrasound scanning. Genomic DNA was obtained from affected and unaffected individuals from the maternal family and used for linkage analysis to gene loci for TSC., Results: Renal cysts were not present in the mother by ultrasound. Linkage to TSC2 was found for members of the maternal family with clinical features of TSC. While a diagnosis of TSC was confirmed in her mother the child was found not to have inherited the disease-related allele. The father was found to have asymptomatic bilateral polycystic kidneys consistent with ADPKD. The presence of ADPKD in other paternal relatives could not be confirmed., Conclusions: The index case was found to have paternally inherited ADPKD with unusually early presentation. While at risk for concomitant maternal inheritance of TSC this diagnosis was ruled out by linkage analysis studies. The ability to clarify the true nature of a complex inherited condition greatly facilitates future management and counselling. The mechanisms underlying phenotypic heterogeneity in ADPKD remain to be clearly defined and are the subject of ongoing investigation.

The milk protein alpha-lactalbumin was isolated from bovine whey protein concentrate solution by immobilized metal ion affinity chromatography (IMAC) using Cu(II)-Chelating Sepharose Fast Flow. Stepwise pH (5.5-3.8) changes in sodium acetate buffer were used to elute the protein selectively, at which time it was concentrated and reapplied to an uncharged Chelating Sepharose Fast Flow column to remove the contaminating Cu(II) ions. A purity of 90% and recovery of 80% was achieved. The described method appears to be suitable for isolation of alpha-lactalbumin in a form adequate for milk formula engineering.

We reviewed the records of all children (younger than 16 years of age) who presented with a diagnosis of optic neuritis (ON) identified through the comprehensive records-linkage system at the Mayo Clinic and identified 94 cases between 1950 and 1988 with a documented history of idiopathic ON. Detailed follow-up information was available on 79 patients, with a median length of follow-up of 19.4 years. Life-table analysis showed that 13% of the 79 patients with isolated ON had progressed to clinically or laboratory-supported definite multiple sclerosis (MS) by 10 years of follow-up, 19% by 20 years, 22% by 30 years, and 26% by 40 years. Gender, age, funduscopic findings, visual acuity, or family history of either ON or MS did not predict the development of MS. The presence of bilateral sequential or recurrent ON increased the risk of developing MS (p = 0.002; hazard ratio = 5.09), whereas the presence of infection within 2 weeks before the onset of ON decreased the risk of developing MS (p = 0.060; hazard ratio = 0.24). This study of childhood ON supports the lower risk of recurrence and progression to MS compared with adults.

The authors designed a low-deadspace system to deliver inhaled nitric oxide from a high-concentration (10%) source. Nitric oxide, nitrogen dioxide, and O2 concentrations were compared under simulated inhaled nitric oxide therapy (in vitro) from low (0.08%, 800 ppm) and high (10%, 100,000 ppm) sources of nitric oxide in nitrogen. O2 concentrations remained above 99% and nitrogen dioxide below 3 ppm for nitric oxide delivered at dosages up to 180 ppm from the 10% source. An acute toxicity trial (in vivo) was also performed in nine rabbits mechanically ventilated with 100% O2 for four hours. Six rabbits received 80 ppm nitric oxide from a 10% source and three control rabbits received only O2. Nitric oxide, nitrogen dioxide, and O2 concentrations were monitored in the ventilator circuit. Methemoglobin, arterial blood gases, arterial blood pressure, and heart rate were sampled every hour. At the 80-ppm nitric oxide dose, an average of 1.1 +/- 0.2 ppm of nitrogen dioxide was produced within the ventilator circuit. Arterial methemoglobin in rabbits that received nitric oxide rose by 0.5% from baseline, compared with a 0.2% rise for controls (p = 0.001). The authors conclude that inhaled nitric oxide therapy can be provided from a high-concentration source. Because this system does not reduce inspired O2 fraction, it may be more appropriate than low-source-concentration nitric oxide delivery systems for testing the efficacy of inhaled nitric oxide as an adjunct to optimal conventional medical therapy.

We describe here four sibs, born to consanguineous, healthy, asymptomatic parents. Three of these infants had a rapidly fatal course in the neonatal period; death was attributed to congestive heart failure with radiographic evidence of cardiomegaly in all of them. Necropsy was done in only one of them and showed the typical findings of tuberous sclerosis complex (TSC) in the central nervous system (CNS), kidneys, heart, and liver. The fourth sib, currently 2 years old, also has typical signs of TSC, namely hypomelanotic skin macules and calcified subependymal nodules. Both parents and a living maternal grandmother had appropriate examination, which included skin inspection under Wood's lamp, dental examination, fundoscopy, echocardiography, abdominal and renal ultrasound, and head CT and MRI scans, and no signs of TSC were found in either parent or in the only living grandmother. By history alone there is no other relative with signs or symptoms suggestive of TSC. Linkage analysis and loss of heterozygosity (LOH) investigations on a variety of lesions obtained from postmortem and tissue or blood specimens from all available family members studied failed to identify a microdeletion in the chromosomal regions where TSC genes are located. It is very unusual that in a single TSC family there were three consecutive neonatal deaths, and very likely that all had cardiac rhabdomyomas. Moreover, to the best of our knowledge, there are no previous reports of TSC families with more than one affected sib, unusually severe manifestations of the disease, and completely normal, consanguineous parents.

The relationship between the number of cortical tubers observed by magnetic resonance imaging (MRI) and the severity of cerebral dysfunction of tuberous sclerosis patients has been examined in a meta-analysis of the published literature. The literature review has identified five independent studies for examining the association. These studies consistently reveal that the cortical tuber count detected on MRI scans is increased among those with more severe cerebral disease. Severity of the cerebral dysfunction is measured by the seizure status and its control and by the developmental status and the level of mental retardation. Meta-analysis demonstrates that within a study population, the MRI-detected cortical tuber count is six times more likely to be above the median count for tuberous sclerosis patients with severe cerebral dysfunction (poor seizure control or moderate-severe retardation or both) than more mildly affected tuberous sclerosis patients. Similarly, across studies, moderately to severely affected patients are five times more likely to have greater than seven MRI-detected cortical tubers than those more mildly affected. These associations are both statistically significant and strong. The cortical tuber count is a biomarker that reasonably predicts the severity of cerebral dysfunction of tuberous sclerosis. Cortical tubers of tuberous sclerosis form in the early gestational period. The embryologic disruption determining the clinical severity of the cortical dysfunction of tuberous sclerosis is set in the early gestational period.

We undertook a clinical and surgical study with evaluation of the long-term results (average 5 years, range 1-9 years) of 193 stabilized posterior cemented total knee replacements (TKRs) type Insall-Burstein in patients with severe osteoarthritis (OA) and rheumatoid arthritis (RA), carried out consecutively by the same surgeon from January 1986 to January 1995, at our COT Unit at the Central Military Hospital "Gomez Ulla" in Madrid, in collaboration with the Departments of Traumatology and Morphological Sciences of the University of Alcala de Henares (Madrid). The principal purpose was to examine the success rate of this type of prothesis implanted during primary surgery, according to severity of the case. Six methodology protocols were produced in this study (exploratory, surgical technique in primary surgery, revision surgery, rehabilitation, evaluation and clinical revisions), and satisfactory statistical results (SPSS/PC+) were obtained with the three scales of evaluation: Harris Galante, The Hospital for Special Surgery and Knee Society. These were: 90.5% +/- 0.8% excellent and good results for the OA series, and 83.9% +/- 5% for the RA series. The analysis of survival after long-term monitoring was also statistically significant, with a 96.95% survival rate. Complications arose in 3.10% of cases (6 revisions: 4 aseptic loosenings and 2 loosenings due to infection), which were treated with a constrained prosthesis, and in cases of infection with an arthrodesis. After undertaking a comparative study with other series, we conclude that the Insall-Burnstein stabilized posterior total knee prosthesis, is an excellent Primary replacement associated with long-term survival in patients with a severe degree of articular destruction and functional incapacity, and we give some specific recommendations to reduce complications.

We compared in vitro rates of hemolysis for a recently developed centrifugal pump with a conventional roller pump (10-10-00; Stöckert, Munich, Germany). Flow rates of 0.3 L/min and 1 L/min and a pressure of 200 mm Hg were chosen to simulate conditions during neonatal extracorporeal membrane oxygenation (ECMO). There was no significant difference in hemolysis rates between centrifugal and roller pumps (p = 0.57) nor between high and low flow (p = 0.86). The centrifugal pump caused no more blood trauma than the roller pump at the low-flow/high-pressure conditions required for neonatal ECMO. The Nikkiso pump is superior to roller pumps in size and priming volume (25 ml) and may permit development of a smaller and simpler ECMO system.

Parenteral nutrition has been used in the nutritional management of low-birth-weight infants for the past 25 years. Nonetheless, many aspects of the technique still are not completely understood. Further, Other aspects that are reasonably well understood frequently are not applied in clinical practice. As a result, infants requiring this therapy frequently do not benefit maximally from it. Some of the important issues concerning this technique are discussed, and some of the important questions that need to be addressed are identified. Answers to many of these important questions are necessary to further enhance the benefits and diminish the undesired consequences of this therapy for infants who require it.

We conclude that echocardiographically detected cardiac rhabdomyomata are common in patients with tuberous sclerosis complex, and are more prevalent and prominent in the younger patient. Tumors regress in size or number, or both, in most patients aged < 4 years, and less so in older patients. Cardiac rhabdomyomata are associated with a higher incidence of preexcitation and may increase the risk for arrhythmia.

Objective: To describe the clinical manifestations, imaging findings, and histologic features of extrapulmonary lymphangioleiomyomatosis (LAM) in the tuberous sclerosis complex (TSC)., Design: We retrospectively reviewed institutional medical records since 1940 to identify patients with TSC and extrapulmonary LAM., Material and Methods: Of 403 patients with TSC, 3 had pulmonary and extrapulmonary LAM and retroperitoneal lymphangiomatous cysts. The clinical, imaging, and histologic features of these three patients were summarized, including analysis of biopsy specimens by conventional histology, immunohistology, radiolabeled ligand-binding assays, and tissue culture., Results: The three young women had characteristic dermatologic findings of TSC and pulmonary LAM. Two patients were of normal intelligence, and one had a recent history of contraceptive use. All three patients had intra-abdominal lymphangiomatous cysts, uterine LAM, and renal angiomyolipomas. Renal and uterine biopsy specimens demonstrated positive immunostaining for melanoma-related antigens and expression of estrogen and progesterone receptors by ligand-binding assay and immunohistology. Cells cultured from LAM tissue of one of the patients exhibited a mitogenic response to estradiol., Conclusion: Clinically significant extrapulmonary LAM is a rare manifestation of TSC and may occur in women with this disease who also have pulmonary LAM. The clinical features of these patients confirm the importance of sex steroids in the development of these lesions. Immunohistochemical findings suggest that LAM and angiomyolipomas have a neuroectodermal origin. The development of lymphangiomatous cysts in these patients is probably due to smooth muscle proliferation in lymph vessels, which can result in lymphatic obstruction.

We describe the clinical presentation, pulmonary function tests, chest radiograph, and computed tomography findings, response to hormonal treatment, and duration of survival of nine patients with pulmonary involvement in tuberous sclerosis complex with follow-up over an average of 17 years (range, 1 to 35 years) since diagnosis. All patients were female, and the average age at onset of symptoms was 16 years (range, 3 months to 39 years); pulmonary symptoms did not develop until an average age of 33 years (range, 22 to 46 years). There was an average delay of 8 years before the correct diagnosis was made. The most common presenting clinical features were seizures, pneumothorax, bleeding into a renal angiomyolipoma, dyspnea, and typical skin changes. Pulmonary function tests commonly demonstrated obstruction to airflow and reduced single-breath diffusing capacity. Chest radiograph and computed tomography characteristically demonstrated diffuse interstitial infiltrates with cystic changes. Two asymptomatic patients with mild pulmonary involvement have remained in stable condition without hormonal therapy. The remaining seven patients had moderate to severe airflow obstruction; of these, five underwent hormonal therapy. Three patients had a clinical response to treatment. Two patients who did not receive hormonal treatment died of progressive respiratory failure. Most patients with pulmonary involvement in tuberous sclerosis have a slowly declining clinical course. Although the available data are limited, they suggest that a trial of hormonal therapy is recommended both for symptomatic patients and for those with declining pulmonary function. Tuberous sclerosis complex should be suspected in all patients with the diagnosis of lymphangioleiomyomatosis.

Purpose: To correlate the findings on MR scans of the brain in patients with tuberous sclerosis complex with mental disability and the type and age at onset of the first seizure., Methods: Patients with tuberous sclerosis complex who had MR brain scans were identified. The diagnosis was confirmed, and the clinical information on each patient was updated. The number, site, and area of abnormal signals were recorded on each scan. The presence of sulcal islands, gyral cores, and migration lines or wedges was recorded., Results: Seventy-five patients were studied. Twenty-nine patients who had infantile spasms had more tubers than the 26 who presented with other types of generalized seizures. These patients had more tubers than the 15 patients with partial seizures. Significantly more tubers were found in patients with seizure onset before 1 year of age and mental disability. Gyral cores, sulcal islands, and radial migration lines or wedges were more common in patients with infantile spasms who had an early seizure onset and were mentally disabled. Patients who did not have seizures had no mental disability., Conclusions: A greater number of tubers occurred in patients who had infantile spasms, had their first seizure before 1 year of age, or had a mental disability. These features reflect the degree of cerebral dysfunction caused by the tubers. Gyral cores, sulcal islands, and migration lines or wedges also reflect cerebral dysfunction. MR scans correlate well with the clinical features and are valuable in assessing patients with tuberous sclerosis complex.

A job exposure matrix combining features to increase the accuracy of exposure assessment was developed to evaluate cancer risks from workplace exposures to six chlorinated aliphatic hydrocarbons (CAHs). A detailed description of the matrix is provided to satisfy the need for more in-depth discussion of exposure assessment methods than is typical in today's epidemiologic literature. The matrix assigns semiquantitative estimates of the probability and intensity of exposure to each four-digit Standard Industrial Classification (SIC) and Standard Occupational Classification (SOC) code potentially associated with exposure to each CAH. The matrix also accounts for the changing patterns of use of the CAHs by decade from the 1920s to the 1980s. An algorithm combines these parameters to assign each study subject a unique lifetime probability of exposure and an estimated score of cumulative exposure for each CAH. These assignments can then become the subjects of analyses. The ability of the matrix to reduce the number of false positive exposure assessments is discussed and illustrated. A companion paper describes the detailed epidemiologic findings of this application of the matrix.

Total parenteral nutrition (TPN) is used both to prevent necrotizing enterocolitis (NEC) and to treat infants who develop the disease. Evidence for the efficacy of the technique in both settings is discussed. Several practical aspects of TPN also are discussed, as are a variety of theoretical considerations relevant to use of TPN either to prevent NEC or as an adjunct to treatment of the infant with the disease.

A substantial fraction of the cysteine added to total parenteral nutrition (TPN) solutions is converted to the corresponding thiazolidine derivative, while in solution with relatively large concentrations of glucose typical of TPN (700 mM and higher). It was recently reported (Roberts et al. (1987) J. Med. Chem. 30, 1891-1896) that this thiazolidine, D-glucose-L-cysteine (DGC), offered no significant protection against the hepatic injury caused by 5 mmol/kg of acetaminophen in mice, suggesting that the cysteine present as DGC is poorly bioavailable in vivo. In the present study, fasted male ICR mice given 1.6 or 2.6 mmol/kg of acetaminophen sustained hepatic injury, estimated by elevations in plasma alanine aminotransferase (ALT) activities. Administration of 2.5 mmol/kg of N-acetylcysteine (NAC) 1 h before acetaminophen given i.p. prevented the rise in plasma ALT activities, apparently through support of glutathione (GSH) synthesis. Administration of 2.5 mmol/kg of DGC prior to acetaminophen resulted in slightly lower mean plasma ALT activities than were observed in animals given saline before acetaminophen, but the effect was not statistically significant. When DGC was given 1 h before p.o. administration of 1.6 or 2.6 mmol/kg of acetaminophen, the protective effects of DGC were statistically significant (P < 0.01, 0.025, respectively), although NAC afforded significantly greater protection than did DGC at the higher dose of acetaminophen. Given 4 h before acetaminophen, DGC attenuated acetaminophen-induced increases in plasma ALT activities significantly, whereas NAC was without effect. These results indicate that the cysteine in DGC is at least partially bioavailable in vivo and, further, that DGC may function as a slow release formulation of cysteine.

The impact of three features of a job-exposure matrix has been tested in a case-control study that evaluated the association of occupational exposure to dichloromethane and astrocytic brain cancer. These features were probability of exposure, an exposure assessment by decades, and the use of a more specific coding system of industries and occupations. The introduction of each feature had a striking effect on the estimate of relative risk. The odds ratio increased from 1.47 with none of these features, to 2.47 with high probability of exposure, to 4.15 with high probability of exposure and the specific coding system, to 6.08 with all features combined. These results indicate that job-exposure matrices efficacy in reducing the degree of exposure misclassification may be greatly improved by the introduction of these features.

Tuberous sclerosis (TS) is an autosomal dominant hamartiosis and hamartomatosis with variable expression that is commonly associated with medically intractable seizures. Patients with TS complex (TSC) frequently have multiple brain lesions that can give rise to seizure activity. We report 9 patients with TSC who underwent epilepsy surgery at the Mayo Clinic between 1986 and 1990. Surgical procedures performed included cortical resection (n = 2) and stereotaxic lesionectomy (n = 7). Neuropathologic diagnoses were cortical tubers (n = 7) and glioneural hamartomas (n = 2). Three of 9 patients had multifocal interictal scalp epileptiform EEG activity; however, ictal recordings identified the focus of seizure activity, which in all cases corresponded to a prominent neuroimaging abnormality. Our patients have been followed for 10-72 months (mean 35 months). Four patients are seizure-free with medication, 2 are seizure-free without medication, 2 had > 80% reduction in seizure frequency, and 1 experienced only an initial temporary reduction in seizure frequency. Postoperative EEG recordings showed absence of epileptiform abnormalities in the 5 patients who are seizure-free; the other 4 patients continue to have multifocal abnormalities. These data suggest that epilepsy surgery may be beneficial in selected patients with TSC despite multifocal EEG and neuroimaging abnormalities.

CT and MR have permitted radiology to play a greater, but not definitive, role in detecting the pathologic components of tuberous sclerosis. SEN may be identified in only 80% of patients. Tubers are more ubiquitous and readily identified by MR in children and adults when the brain is myelinated. Since tubers are predominantly peripheral hypomyelinated lesions, the detection of small lesions may be delayed until an infant is over 16-18 months of age when the myelin will have extended to the junction between the cortical white and gray matter. SEGA typically evolve later during the first and second decades of life. Successful genetic counseling implies a need to detect tuberous sclerosis at a stage during infancy when imaging may fail to confirm the diagnosis, so tuberous sclerosis remains a clinical diagnosis.

For the low birth weight (LBW) infant, energy balance during the first several days of life usually is equated to absorption of sufficient energy to match energy expenditure. Most studies show that energy expenditure of nongrowing LBW infants is 45 to 55 kcal/kg/day. Hence, for energy equilibrium, energy intake minus energy losses (i.e., metabolizable energy intake) must be at least 50 kcal/kg/day. Intakes above this amount result in energy storage or positive energy balance, whereas lesser intakes necessitate mobilization of endogenous energy stores (negative energy balance). Some of the problems of achieving positive energy balance in LBW infants (e.g., feeding intolerance and fear of necrotizing enterocolitis) can be circumvented by use of parenterally delivered nutrients. On balance, virtually all LBW infants will tolerate parenteral amino acid, glucose, and lipid intakes, respectively, of 2, 5, and 1 gm/kg/day or an energy intake of about 40 kcal/kg/day. It usually is possible to increase energy intake of most infants by an additional 10 kcal/kg/day. Whether this is achieved with enterally delivered nutrients or additional parenteral glucose or lipid intake, including the necessary modifications to enhance tolerance (e.g., insulin, 20% vs 10% lipid emulsions, and lipid emulsions containing medium-chain fatty acids), must be decided for each infant based on his or her underlying condition, likelihood of tolerating either substrate, and the impact of intolerance on the underlying condition. The consequences of not providing an essential nutrient during the immediate postnatal period also must be considered. The fact that essential fatty acid deficiency develops more rapidly in infants receiving isocaloric (60 kcal/kg/day) parenteral intakes with versus without amino acids, the likelihood that brain growth continues despite negative energy balance, and the possibility that LBW infants may not be able to desaturate/elongate linoleic and linolenic acids to the more unsaturated, longer-chain fatty acids that are deposited in the developing brain suggest that these infants may require exogenous intakes of specific fatty acids.

A 14-year-old girl with nevoid basal cell carcinoma syndrome presented with intermittent headache and nausea. Magnetic resonance imaging and a computed tomographic scan of the head revealed a colloid cyst of the third ventricle and mild dilatation of the lateral ventricle. The cyst was successfully removed by stereotaxic surgery. The occurrence of two rare disorders in the same patient could be a coincidence. Other similar patients must be found before it is established that the colloid cyst is part of the nevoid basal cell carcinoma syndrome.

Of the 355 patients with tuberous sclerosis complex (TSC) examined at the Mayo Clinic, 49 had died (9 of causes other than TSC). We attempted to determine what pattern of organ involvement occurred most often in the 40 patients who died of TSC. One baby died of cardiac failure due to cardiac rhabdomyomas, and one child died of rupture of an aneurysm of the thoracic aorta. Eleven patients died of renal disease, which was the commonest cause of death. Ten patients died as a result of brain tumors, and four patients (who were 40 years of age or older) died of lymphangiomyomatosis of the lung. Thirteen patients with severe mental handicaps died of either status epilepticus or bronchopneumonia; in all but one of these patients, the only source of information was the death certificate. Survival curves show a decreased survival for patients with TSC in comparison with that for the general population. Patients with TSC need lifelong follow-up for early detection of potentially life-threatening complications.

Of 345 patients with tuberous sclerosis complex evaluated at the Mayo Clinic from 1950 to 1989, 23 were identified as having brain tumors. In 20 of the 23, histological or clinical evidence showed the tumor to be a subependymal giant cell astrocytoma. A search of the Mayo Clinic tissue registry yielded 73 giant cell-containing astrocytomas and intraventricular gliomas exclusive of ependymomas. Reexamination revealed no further examples of subependymal giant cell astrocytoma in patients without features of the tuberous sclerosis complex. Considerable histological variation was observed in the 15 subependymal giant cell astrocytomas subjected to critical microscopic review. It is of note that no correlation was noted between either the histological features, such as atypia, mitoses, endothelial proliferations, necrosis, or the flow cytometric characteristics and the clinical course or the survival time of the patients.

The incidence of tuberous sclerosis complex in Olmsted County, Minnesota, was 0.28 per 100,000 person-years from 1950 through 1989, the point prevalence on December 31, 1989, was 6.9 per 100,000 persons, and the incidence at birth was 6.0 per 100,000 live births. The incidence was 0.13 per 100,000 person-years from 1950 through 1974 and 0.46 per 100,000 person-years from 1975 through 1989. The higher rate of diagnosis during the later period is believed to be due to the use of computed tomography. Of the 12 patients considered in this study, one patient presented with seizures and severe intellectual disability, six patients presented with seizures, three patients presented with multiple facial angiofibroma, and two patients were asymptomatic.

We studied 60 patients with multiple system atrophy and autonomic failure and 60 control subjects matched for age, sex and race. Their psychosocial history, pedigree and occupation were obtained by personal interview. An inventory of autonomic and neurologic symptoms was obtained from 148 first-degree relatives of the patients and 80 controls by a self-administered questionnaire. Patients with multiple system atrophy had significantly more potential exposures to metal dusts and fumes, plastic monomers and additives, organic solvents, and pesticides than the control population. The potential exposures were determined in most subjects by their reported usual occupation. Clinical symptoms of multiple system atrophy were reported by a significantly larger group of patients' relatives than controls. These findings are possibly consistent with the hypothesis that multiple system atrophy develops as a result of a genetically determined selective vulnerability in the nervous system. Specific neuronal systems may become targets for environmental insults or toxins, and the disease state may occur when ageing neuronal systems can no longer sustain functional capacity. This preliminary study supports the need to further explore possible environmental, occupational, and familial contributions to the aetiology of multiple system atrophy.

Subependymal giant-cell astrocytomas (SEGA) are rare brain tumors. They occur typically in the walls of the lateral ventricles and very seldom in the wall of the third ventricle. In our experience, all patients with SEGA have had tuberous sclerosis. Between January 1950 and May 1990, of our 345 patients with tuberous sclerosis 22 were found to have SEGA. The diagnosis being made histologically in symptomatic cases or by clinical or neuroradiologic methods. The histological, immunohistochemical and ultrastructural features of this unique tumor are discussed. To date, histopathologic methods have not resolved the issue of whether these tumors are exclusively astrocytic or neuronal in nature, or show features of both. Modern immunohistochemical and/or molecular-biological techniques will no doubt elucidate the histogenesis of this highly characteristic, albeit polymorphous tumor.