Biomedical subjects
Publications and source records attributed to F R Brown.
The combination of neurodevelopmental regression and adrenal insufficiency should alert practitioners or emergency room physicians about ALD. Although still unproven, early medical intervention with either gene therapy or bone marrow transplantation may offer more promise to these patients.
The peroxisomal disorders represent a group of inherited metabolic disorders that derive from defects of peroxisomal biogenesis and/or from dysfunction of single or multiple peroxisomal enzymes. Because peroxisomes are involved in the metabolism of lipids critical to the functioning of the nervous system, many of the peroxisomal disorders manifest with significant degrees of progressive psychomotor dysfunction. These disorders should be considered in the differential diagnosis of the infant with hypotonia and psychomotor delay (especially if accompanied by facial dysmorphisms, hepatomegaly, cataracts and/or retinitis, calcific stippling, short limbs, or combinations of these features), in the school-aged child with progressive neurologic dysfunction, and in adults with slowly progressive motor dysfunction. Current knowledge of peroxisomal biochemical and enzymatic processes permits precise identification of particular disorders within the peroxisomal disorder grouping. An effort should be made to identify the specific peroxisomal disorder to provide a precise explanation for neurodevelopmental deficits, to potentially prevent recurrence through genetic counseling, and to provide appropriate therapies when available.
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The purpose of this descriptive pilot study was to discover and correct problems with data collection in the identification of variables that are the strongest predictors of the occurrence of four nosocomial infections in cardiac patients. Data from 29 subjects who were admitted to a critical care unit (CCU) were tracked at a health care facility located in upstate New York. Data were obtained from daily care flow sheets and patients' charts. Although most results were not statistically significant, trends were identified in the data. The 7 patients who developed nosocomial infections were men who were older than 50 years, underwent a cardiac surgical or other invasive procedure, had more than one intravenous catheter, experienced a significant event in the CCU, and received prophylactic antibiotics. It is recommended that the number of independent variables tracked be reduced to 20. In addition, readmission of subjects whose data are being tracked should be included.
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The transport efficiency of the particle beam liquid chromatography/mass spectrometer interface is influenced by analyte concentration contributing to a widely reported non-linearity. In this work, coeluting, isotope-labeled internal standards were investigated as 'carriers' to improve the transport efficiency and linearity. Three styrene metabolites--mandelic, phenylglyoxylic and hippuric acids--and their pentadeutero analogs were separated by reversed-phase liquid chromatography (LC) with an ammonium acetate-acetonitrile mobile phase. Selected positive ions produced by electron ionization were monitored to generate particle beam LC/MS calibration curves. The present study demonstrates that particle beam LC/MS not only is non-linear, but also is subject to a matrix effect presumably by the same mechanism responsible for non-linearity. Coeluting, isotope-labeled internal standards were ineffective at linearizing the particle beam liquid chromatograph/mass spectrometer detector response. Isotope dilution quantification, however, compensates for variable transport efficiencies, linearizes calibration and compensates for the matrix effect, affording reliable quantification of the styrene metabolites.
Williams syndrome is characterized by cardiac defects, varying degrees of physical and developmental delay, stellate eye pattern, possible elevated serum calcium level, and elfin/pixie facial features. A problem perhaps unique to these children is hyperacusis that can be severe enough to disrupt many routine daily activities. Parental questionnaires were used to determine the prevalence of hyperacusis and otitis media in individuals with Williams syndrome. Prevalences of 95% for hyperacusis and 61% for otitis media were found. This was significantly higher than in the general population. Despite the prevalence of hyperacusis, parents of these children were not counseled about management of the problem. The audiologist may become involved with Williams syndrome patients through hearing assessment and management, parental counseling, and research.
The cognitive and adaptive capacities of 130 individuals with Down syndrome were investigated as a function of age and environmental placement. Intellectual deterioration occurred whether individuals resided at home or in an institutional setting. Social/adaptive deterioration also occurred but with the least decline for those individuals who resided in institutional settings.
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This paper describes the characterization of glucuronide and sulfuric acid conjugates and alkyl phosphates by thermospray tandem mass spectrometry (MS/MS). Primary thermospray mass spectra were generated using ammonium acetate buffer and filament-on ionization with both positive and negative ion detection. In positive ion mode molecular weight information was obtained for glucuronic, phosphoric and other weak acids. Under these conditions, however, spectra were not obtained for the sulfate adducts or phosphate salts. Negative ion thermospray mass spectrometry was more versatile, providing spectra of all metabolic structures examined. Positive and negative ion mass spectra provided complementary information for glucuronic acids. Collisionally activated dissociation (CAD) mass spectra of the glucuronide [M + NH4]+ or [M - H]- ions exhibited characteristic glucuronide 'fingerprints' as well as prominent aglycone ions. The aryl sulfates were hydrolyzed to the corresponding phenols under buffer/thermospray conditions and for these analytes CAD mass spectra were obtained from [phenate]- or [phenol + acetate]- parent ions. The M- of dimethyl thiophosphate underwent sequential loss of alkyl and alkoxy radicals and formaldehyde with collisional activation. MS/MS greatly enhances the power of the thermospray interface by providing fragmentation information useful both in the identification of unknowns and for improved mass spectrometry specificity.
To examine the proposal that myelin proteolipid protein underlies the adhesion of neighboring membranes in central nervous system (CNS) myelin, we carried out X-ray diffraction studies on the structure and interactions of model bilayers composed of total myelin lipids plus proteolipid apoprotein (PLP). Total myelin lipids were used because their heterogeneity was expected to provide an appropriate environment for the integral membrane protein to achieve its native conformation and establish appropriate contacts with the apposed bilayer. We found that incorporation of PLP into myelin lipid bilayers, whether organized into multilamellar vesicles or oriented multilayers, did not appreciably affect the lamellar period, which ranged from 65-71 A. In oriented multilayers, the wide-angle spacing at approximately 4.8 A, which arises from the lateral packing of lipid chains and is perpendicular to the lamellar diffraction, was less oriented and weaker in bilayers containing the protein. These results indicate that PLP was incorporated into the bilayers and had a disordering effect on the hydrocarbon chains but did not extend into the spaces between bilayers. Bilayer profiles calculated from the lamellar diffraction to about 15 A spacing did not show any major changes in the distribution of electron density, suggesting that to moderate resolution, the protein was distributed uniformly across the width of the lipid bilayer. Periodicities measured from osmotically stressed multilamellar vesicles did not depend on the presence of PLP, indicating that the protein did not form stabilizing contacts between bilayers.(ABSTRACT TRUNCATED AT 250 WORDS)
Herpes simplex viral encephalitis is a fairly common nonepidemic encephalitis which produces severe neurological sequelae in survivors. Most viral infections of the central nervous system produce diffuse damage, but the herpes simplex virus demonstrates a predilection for localization in the temporal and orbitofrontal regions of the brain. This case study illustrates the highly significant language difficulties, marked memory deficits, and propensity for physical aggression following temporal lobe damage brought about by herpes encephalitis, and presents the usefulness of a new diagnostic measure in delineating such a variable cognitive pattern.
We examined the oxidation of different chain length fatty acids in the leukocytes and the quantity of lipid peroxides in the plasma of two Reye syndrome patients. We have found that the oxidation of [1-14C] octanoic acid in homogenates of leukocytes from one of the Reye syndrome patients was only 38 percent of the control, whereas oxidation of [1-14C] palmitic and [1-14C] lignoceric acid was slightly increased. The level of lipid peroxides in the serum of both of the Reye Syndrome patients was 4.42 and 3.04 times higher than the control level. These results suggest that impaired oxidation of medium chain fatty acids (octanoic acid) and higher levels of lipid peroxides may contribute to the pathogenesis of cellular toxicity in Reye Syndrome. Reye Syndrome (RS) was first described by Reye et. al. in 1963 and is now recognized as an important cause of morbidity and mortality in infants and children. The clinical course in RS consists of an antecedent viral illness with subsequent encephalopathy and hepatic dysfunction. Laboratory findings in RS include hypoglycemia, hyperammonemia, free fatty acidemia, elevated organic acids and amino aciduria. The ultrastructural findings in RS patients include changes in mitochondria, smooth endoplasmic reticulum morphology, and an increase in the number of peroxisomes. The elevation of serum free fatty acids in RS and their decrease in patients who improve clinically suggests a disturbance in fatty acid metabolism. To understand the role of free fatty acids in the pathogenesis of RS, we examined the levels of lipid peroxides in plasma and catabolism of fatty acids of different chain lengths in leukocytes from RS patients.
The peroxisomal disorders are a group of inherited metabolic diseases with serious clinical sequelae. The number of recognized peroxisomal disorders has increased substantially since 1973, when an absence of peroxisomes was observed in patients with the cerebro-hepato-renal (Zellweger's) syndrome. More subtle peroxisomal dysfunction is now recognized, including that deriving from single peroxisomal enzymes. Peroxisomal disorders are relatively rare. However, these disorders assume importance because of our growing ability to relate clinical sequelae to specific enzymatic and biochemical deficits, because some of these disorders can now be identified prenatally and their recurrence can be prevented, and because therapies are rapidly evolving. We reviewed these disorders in light of increasing understanding of the biochemistry of the peroxisome.
To understand the possible role of salicylic acid in the pathogenesis of Reye's syndrome, we examined its effect on the oxidative metabolism of fatty acids in the rat liver mitochondrial-peroxisomal fraction. Fatty acids of different chain lengths are oxidized in different organelles. Octanoic acid is oxidized in mitochondria, lignoceric acid in peroxisomes, and palmitic acid in both mitochondria and peroxisomes. Salicylic acid (up to 1 mM concentration) had no effect on the oxidation of [1-14C]lignoceric acid. However, at the same concentration it inhibited the oxidation of [1-14C]palmitic acid by 26% and [1-14C] octanoic acid by 42%. The apparent Ki for the oxidation of [1-14C] octanoic acid, [1-14C]palmitic acid and [1-14C]lignoceric acid were 0.27, 6.0, and 14.8 mM, respectively. This selective inhibition of mitochondrial oxidation of medium-chain (octanoic acid) and long-chain (palmitic acid) fatty acids by salicylic acid may potentiate the accumulation of fatty acids in plasma in Reye's syndrome patients.
Testicular and adrenal function were evaluated in 12 patients with adrenoleukodystrophy and 2 patients with adrenomyeloneuropathy. Although only 5 subjects had clinical symptoms suggesting adrenal insufficiency, an additional 5 showed laboratory evidence of reduced adrenal reserve. 9 of the 14 patients developed neurological deficits prior to the onset of clinical or biological adrenal insufficiency. In the remaining 5 patients, adrenal insufficiency antedated the appearance of neurological symptoms; 2 of these 5 patients had only laboratory evidence of hypoadrenocorticism, and 3 had both clinical and laboratory abnormalities. None of the prepubertal patients had detectable signs of testicular insufficiency, while 3 of the 7 pubertal/adult patients had elevated serum LH or FSH levels. This mild testicular deficiency was seen only in association with clinical adrenal insufficiency and significant neurological impairment.
The effect which intrinsic (proteolipid) protein has on fluidity of central nervous system myelin membrane was measured through differences in temperature-dependent anisotropy of the lipid-soluble fluorescence probe, 1,6-diphenyl-1,3,5-hexatriene (DPH), in multilamellar vesicles (MLV) prepared from total myelin lipids in the presence and absence of proteolipid protein. Very little difference was observed in the anisotropies of DPH incorporated into intact myelin membrane vesicles compared with MLV reconstituted from total myelin lipid plus proteolipid protein but excluding myelin basic protein. In contrast, a significant decrease (P less than 0.01) in anisotropy was observed when MLV prepared from total myelin lipids depleted of proteolipid protein were compared with vesicles containing proteolipid protein. Given the different distributions of myelin basic protein and proteolipid protein suggested by freeze-fracture, neutron and X-ray diffraction studies, and the fact that the hydrophobic DPH probe is known to distribute in the non-polar regions of lipid bilayers, we interpret the marked decrease in anisotropy when proteolipid protein is excluded from MLV to suggest that at least part of the proteolipid is distributed in the hydrocarbon region of the MLV. These findings are consistent with the earlier physical studies and recent postulations that extensive hydrophobic segments exist in proteolipid protein and that these hydrophobic segments are buried in the myelin lipid bilayer and alternate with hydrophilic extra-membrane segments.
Adrenoleukodystrophy (ALD) must be considered in the diagnosis of men with progressive nervous system disease. We found the biochemical defect characteristic of ALD in two brothers with spastic paraparesis of late adult onset. Family study then revealed other affected men and asymptomatic heterozygotes in a pattern that conformed to an X-linked pattern of inheritance.