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We report on the development of transient parkinsonism after progesterone injection in a pregnant patient with a risk of abortion. Etiological possibilities are discussed, including pregnancy itself, possible toxic effects of the dead fetus, and progesterone injection. Progesterone-induced parkinsonism seems the most likely diagnosis in this case.
Emissions of volatiles from apple fruits (Malus domestica Borkh.) were monitored in situ over the course of a growing season (from early June to mid September) for two apple varieties, Golden Delicious and Maigold. Results indicate a characteristic time-course of volatile emissions as the sampling date was a statistically significant factor for nine of the 13 compounds considered. The amounts of volatiles collected were greatest early and late in the season. The temporal effect on emissions was generally much larger than the effect of variety, which was significant for only four of the 13 compounds considered. The possible sources of variation which are not explained by the statistical models are discussed, and it is considered that they are most likely related to differences in the emissions from individual fruits.
The methyl ester of oleic acid, a plant oil derivative, can be used as an additive oil for pesticides. We compared the biodegradability in soil of this oil with that of a mineral oil by means of laboratory experiments using lysimeters of 70 cm height x 20 cm diameter. The migration in soil of the oils and of the metabolites of the plant ester over 120 days was examined by gas chromatography and liquid chromatography. The plant oil and its metabolites were completely degraded within 60 days, whereas degradation of the mineral oil required 90 days. The molecules did not migrate far into the soil and therefore presented no risk of contaminating groundwater.
Electrospray ionization (ESI) mass spectrometry was employed to obtain both molecular weight confirmation and structural information for a series of novel alkenyldiarylmethane (ADAM) analogs. The mass spectral data were intended for use during the structure elucidation of ester hydrolysis products formed during an in vitro metabolism study of a series of novel ADAM analogs. The data on the precursor molecules show the presence of the molecular ion peak, [M+H](+), as well as a peak consistent with the hydrolysis product of the original ester ([MH-ROH+H(2)O](+)). However, chemical ionization mass spectrometry, elemental analysis and (1)H NMR data indicated the presence of only the intact diester compounds, suggesting that the formation of the hydrolysis product was an instrumental artifact, i.e., in-beam hydrolysis during ESI or a result of longer ion residence times of the ion trap mass analyzer.
We report an electrospray ionisation multistage mass spectrometry (ESI-MSn) method that utilises molecular mass information for determination of sequence distribution and chemical structure of mass-selected macromolecules of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) biopolyester, PHBH. On the basis of ESI-MSn studies of PHBH oligomers obtained by partial alkaline depolymerisation of natural PHBH containing 13-14 mol% of hydroxyhexanoate (HH) units, the microstructure of this bacterial copolyester was assessed up to the level of 28 repeat units. The subtle structural details of the PHBH were evaluated based on sequencing of individual macromolecular ions thus showing the utility of this technique for the analysis of biological copolyester macromolecules. It was confirmed that both HH and hydroxybutyrate (HB) units of the PHBH copolymer are randomly distributed.
We report matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) and off-line coupling of size-exclusion chromatography with MALDI-TOFMS analysis (SEC/MALDI-TOFMS) methods for the detailed characterization of poly[(R,S)-3-hydroxybutyrate-co-L-lactic acid], P[(R,S)-3HB-co-LA], and poly[(R,S)-3-hydroxybutyrate-co-epsilon-caprolactone], P[(R,S)-3HB-co-CL], copolymer samples which are expected to be used in special medical application as scaffolds for cartilage and soft tissue engineering. The novel copolyesters contained randomly distributed (R,S)-3-hydroxybutyrate structural units, were synthesized by transesterification of the corresponding homopolymers, i.e. atactic poly[(R,S)-3-hydroxybutyrate], a-PHB, and poly(L-Lactide) (PLLA) or poly(epsilon-caprolactone) (PCL), respectively. The MS methods used for the characterization of the resulting polydisperse copolyester samples were supported by classical methods (NMR, SEC). The structures of individual copolyester macromolecules, including end-group chemical structures, were established using initially MALDI-TOFMS and then SEC/MALDI-TOFMS. The compositions of the copolyesters were determined by two methods, namely based on 1H NMR and MALDI-TOF spectra. The two sets of values showed good agreement. The sequence distribution was determined using the signal intensities of individual copolyester macromolecules, which appeared in MALDI-TOF mass spectra. Furthermore, sequence analysis gave information about the degree of transesterification. The copolyesters synthesized, with only one exception, were demonstrated to be almost random, which implies that the ester-ester exchange was close to completion.
It is hypothesized that the teratogen di(2-ethylhexyl) phthalate (DEHP) acts by in vivo hydrolysis to 2-ethylhexanol (2-EHXO), which in turn is metabolized to 2-ethylhexanoic acid (2-EHXA), the proximate teratogen. Teratological studies were conducted with Wistar rats, with administration of these agents on day 12 of gestation. On an equimolar basis DEHP was least potent, 2-EHXO was intermediate, and 2-EXHA was the most potent of the three agents, which is consistent with the hypothesis. Similarity in the types of defects found with these agents also suggests a common mechanism, with 2-EHXA as the proximate teratogen. All three agents were potentiated by caffeine. Valproic acid, which is an isomer of 2-EXHA, also produced similar defects, and was approximately twice as potent as 2-EHXA.
A modified FETAX (Frog Embryo Teratogenesis Assay: Xenopus) protocol was used to assess the joint action of ten aliphatic carboxylic acids on Xenopus embryo development. Stock solutions of each acid alone, made up at twice the EC50 of the individual acids, were prepared for testing alone and in a mixture with an equal volume of each acid stock solution. For each treatment, five concentrations and a control dish, each with 25 embryos, were tested for 96 h, with solution renewal every 24 h. The embryos were then fixed and evaluated for gross malformations. For each dish, the number and types of malformations were recorded. An EC50 was calculated for each acid alone and this value was defined as 1.0 toxic unit (TU) for malformation induced by the acid. An EC50 was also calculated for the mixture. The concentration of each acid at the mixture EC50 and the TU values corresponding to these concentrations were then determined. A TU value of 0.990 (0.923-1.060) was obtained for the mixture by adding the TU values for each acid in the mixture. This represents a concentration additive rate of malformation. Microcephaly, TU = 1.09 (1.01-1.18), was the primary malformation, but did not completely account for the response. The concentration additive rate of malformation indicates that all ten acids are likely to induce malformation in Xenopus embryos in a similar manner. Quantitative structure-activity relationship (QSAR) analysis revealed developmental malformation induced by the acids was highly correlated (r2 = 0.979) with hydrophobicity and molar refractivity (r2 = 0.949). The approach has potential application in determining compounds that induce developmental malformations in a similar manner, when metabolism and pharmacokinetic factors are considered.
3-Hydroxy-5,5-dimethylhexanoic acid (HDH) is an analogue of carnitine which differs only in the substitution of a quaternary carbon atom for the quaternary ammonium nitrogen. Thus HDH is isosteric with carnitine but lacks the quaternary ammonium positive charge. Racemic HDH, each of its enantiomers, and the O-acetyl derivative (Ac-HDH) were evaluated as alternate substrates and inhibitors for several carnitine acyltransferases. HDH and Ac-HDH are not substrates for carnitine acetyltransferase (CAT) at concentrations up to 10 mM, suggesting that the positive quaternary ammonium charge on carnitine is essential for CAT catalysis. However, HDH competitively inhibits CAT (Ki = 8.3 mM), carnitine palmitoyltransferase-I (CPT-I) (Ki = 3.6 mM), and CPT-II (Ki = 2.8 mM). Ac-HDH is also a competitive inhibitor of CAT when assayed in the reverse direction (Ki = 4.1 mM). Similarly, R-(+)-HDH and S-(-)-HDH are not substrates for CAT, but they are stereoselective competitive inhibitors (Ki = 20.3 and 7.5 mM for the R and S enantiomers, respectively). Stereoselective inhibition by HDH is even more dramatic with CPT-I, since S-(-)-HDH inhibits CPT-I (Ki = 1.4 mM) but R-(+)-HDH has no effect in concentrations up to 5 mM. As with CAT, HDH is a stereoselective inhibitor of CPT-II, and the Ki values for S-(-)- and R-(+)-HDH are 2.2 and 6.7 mM, respectively. Since the observed Ki values are significantly larger than the Km for carnitine, the positive charge on carnitine must also be important, but not essential, for binding to the carnitine site on carnitine acyltransferases.
Isocaproaldehyde (4-methylpentanal) is a product of the side-chain cleavage of cholesterol, the first step of steroid biosynthesis. Here, we report the characterization of enzymes responsible for the oxidoreduction of isocaproaldehyde in human, monkey, dog, and rabbit adrenal glands. NADPH-linked isocaproaldehyde reductase activity in the adrenal extracts of the four species was much higher than the NADH-linked reductase and NAD(P)(+)-linked dehydrogenase activities and was potently inhibited by aldose reductase inhibitors. The major species of isocaproaldehyde reductase purified from the four mammalian adrenal glands were biochemically identical with aldose reductase, and exhibited Km values of 1 microM. The contents of aldose reductase in adrenal glands of the four mammals were relatively high, and its localization in canine adrenal cortex was immunohistochemically demonstrated. In addition, the purified aldose reductases and recombinant human aldose reductase reduced other alkanals and alkenals at low Km values of 2-61 microM, and their catalytic efficiencies were higher than that of human aldehyde reductase. Thus, aldose reductase acts not only as a major reductase for isocaproaldehyde formed from steroidogenesis but also as a scavenger of aldehydes derived from lipid peroxidation in mammalian adrenal glands.
A general procedure is described to determine the common free D-amino acids except D-proline in mixtures that also contain L-amino acids. The system employs exogenous pure bacterial D-amino acid transaminase coupled with 2-oxohexanoate, which accepts the amino group from D-amino acids to form D-norleucine. This amino acid is readily quantified by amino acid analysis since it elutes in a position not occupied by any of the common amino acids. Formation of norleucine denotes the presence of some D-amino acid(s) whose identity can be established by a corresponding decrease in the susceptible amino acid(s) after treatment. The utility of the procedure is demonstrated by determination of the amounts of free D-alanine and free D-glutamate in extracts of Escherichia coli JM-103 grown on minimal medium; D-alanine was the major D-amino acid. By the same principle, 2-oxohexanoate through coupling with endogenous bacterial D-amino acid transaminase is shown to be capable of inhibiting the growth of E. coli by depleting it of the D-alanine and D-glutamate.
Transport of alpha-ketoisocaproate (KIC), a ketoacid originating from leucine and proposed to be involved in the buffering of glutamate in neurones, was studied in neuroblastoma NB-2a cells. The accumulated KIC was mostly transaminated to leucine, while free keto-acid was detectable either only after prolonged times or after inhibiting transaminase with aminooxyacetate. Accumulation of KIC was found to be inhibited by other branched-chain ketoacids, while lactate and beta-hydroxybutyrate were ineffective. The transport of KIC, resembling a facilitated diffusion, was decreased by phloretin, alpha-cyano-4-hydroxycinnamate, 4,4'-diisothiocyano-2,2'-stilbenedisulphonate, and p-chlorimercuribenzoate. The process of accumulation did not resemble a symport with protons; therefore an involvement of the known proton-coupled monocarboxylate transporters (MCT) was excluded. Distribution of KIC suggests a mechanism involving a cotransport with 2 [Na+].
The monoclonal antibody to N(epsilon)-(hexanonyl)lysine (HEL), a novel adduct formed by the reaction of linoleic acid hydroperoxide and lysine, has been prepared and characterized. The obtained antibody specifically recognized the HEL moiety. Using the monoclonal antibody, we evaluated the protective effects of feeding eriocitrin, which is one of flavonoids in lemon fruit, on oxidative modification induced by exercise in rats. The supplementation of eriocitrin significantly suppressed the increase in HEL in the skeletal muscle by exercise. The result suggests that the determination of HEL may be a good method for evaluation of the protective effect of beneficial food factors against oxidative stress.
In islets from adult rats injected with streptozotocin during the neonatal period, both a nonmetabolized analog of L-leucine and 3-phenylpyruvate augmented 14CO2 output from islets either prelabeled with L-[U-14C]glutamine or exposed to D-[2-14C]glucose and D-[6-14C]glucose, in a manner qualitatively comparable to that found in islets from control rats. The islets of diabetic rats differed, however, from those of control rats by their unresponsiveness to both the L-leucine analog and a high concentration of D-glucose in terms of increasing 3HOH generation from [2-3H]glycerol, an impaired sparing action of the hexose upon 14CO2 output from islets prelabeled with [U-14C]palmitate, and, most importantly, by a decreased rate of D-[2-14C]glucose and D-[6-14C]glucose oxidation when either incubated at a high concentration of the hexose (16.7 mM) or stimulated by nonglucidic nutrient secretagogues at a low concentration of D-glucose (2.8 mM). In islet homogenates, the activity of glyceraldehyde phosphate dehydrogenase, glutamate decarboxylase, and NADP-malate dehydrogenase was lower in diabetic than control islets. Such was not the case for glutamate-alanine transaminase, glutamate-aspartate transaminase, or glutamate dehydrogenase. The neonatal injection of streptozotocin thus affected, in the adult rats, the activity of several islet enzymes. Nevertheless, the metabolic data suggest that an impaired circulation in the glycerol phosphate shuttle, as observed in response to stimulation of the islets by either a high concentration of D-glucose or nonglucidic nutrient secretagogues, represents an essential determinant of the preferential impairment of glucose-induced insulin release in this model of non-insulin-dependent diabetes.
The effect of choline deficiency on the composition and biosynthesis of the major membrane phospholipids was examined in adrenal medullary cells maintained in suspension cultures. The amount and proportions of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in these cells were not affected by the removal of choline from the culture media. However, the rate of biosynthesis of choline at the phosphatide level by the stepwise methylation of PE increased twofold within 24 h after choline was removed from the culture media, while ethanolamine incorporation into PE was increased by 50%. In contrast, the rate of incorporation of labeled choline into PC, presumably via CDP-choline, was virtually identical in cells that had been preincubated in the presence or absence of 1 mM choline. These results demonstrate that cultured cells of neural origin are capable of compensating for lack of exogenous choline by forming choline at the phosphatide level through the sequential methylation of PE. The hypolipidemic drug, DH-990, when added to the culture media, inhibited conversion of phosphatidylmonomethylethanolamine (PME) to PC, but had no effect on the N-methylation of PE. This differential effect indicates that the initial N-methylation of PE is catalyzed by an enzyme that is distinguishable from the enzyme(s) catalyzing the conversion of PME to PC.
This study was carried out to assess the developmental toxicity of orally administered 2-ethylhexanoic acid (2-EHA) throughout organogenesis in the rat and the rabbit. Treatment of Fischer 344 inbred rats with doses of 100 to 1000 mg 2-EHA/kg/day on (Gestation Days) (GD) 6-15 in a range-finding and a definitive study resulted in a high level of maternal death at 1000 mg/kg/day. Clinical signs of maternal toxicity, including increased liver weight, as well as increased resorptions, dead fetuses, and growth retardation, but no malformations, were observed at 500 mg/kg/day. Slight developmental toxicity, manifested as a reduction in skeletal ossification, occurred in fetuses exposed to 250 mg/kg/day. No adverse effects of treatment were associated with the lower 2-EHA doses (100 and 125 mg/kg/day). Maternal toxicity was also observed in range-finding and definitive studies in New Zealand white rabbits exposed to 25 to 1000 mg 2-EHA/kg/day on GD 6-18 with excessive mortality observed at the highest doses (500 and 1000 mg/kg/day). A low incidence of maternal death as well as abortion occurred following treatment with 125 and 250 mg 2-EHA/kg/day. Less severe clinical signs (reduced weight and food consumption and hypoactivity) were also observed in the 250 mg/kg/day group. There were no adverse effects on fetal viability, growth, or morphology at any dose level. Thus, exposure to 2-EHA during the entire period of organogenesis caused developmental toxicity only at maternally toxic doses in the rat or adverse maternal effects in the absence of developmental toxicity in the rabbit. No evidence of teratogenicity was associated with 2-EHA in this classical safety assessment regimen in either species. The no observed adverse effect levels (NOAELs) for maternal and developmental toxicities in rats are 250 and 100 mg/kg/day, respectively; the corresponding NOAELs for rabbits are 25 mg/kg/day (maternal) and > or = 250 mg/kg/day (developmental).
Reproductive toxicity of 2-ethylhexanoic acid (2-EHA) was studied in Wistar rats. The animals (24 animals per sex per group) were given 2-EHA as a sodium salt in drinking water at daily doses of 100, 300, or 600 mg/kg. Control animals received plain water. Male rats were exposed to 2-EHA for 10 weeks and females for 2 weeks prior to mating, both sexes during the mating period and females during the entire gestation and lactation period. 2-EHA caused a slight but dose-dependent decrease in fertility; time to mating increased at 300 and 600 mg/kg and even total infertility ensued. 2-EHA slightly decreased sperm quality in males. The spermatozoa were significantly less motile at 100 and 600 mg/kg and abnormal sperm occurred more frequently at the two highest dose levels. The average litter size was reduced by 16% in the dose group receiving 600 mg/kg. The birth weights of the pups were unaffected but the body weight gain was transiently slower during lactation at 600 mg/kg. Several pups appeared abnormal (kinky tail, lethargic, slightly paralyzed legs) and the physical development assessed by several landmarks (opening of eyes, eruption of teeth, hair growth) and reflexes (grip reflex, cliff avoidance) was delayed at 300 and 600 mg/kg. In another experiment, a single dose of 600 mg/kg 2-EHA was given to pregnant females by gavage on Gestational Day 4, 5, 6, or 7 and the number of implantations were counted on Gestational Day 10. Administration on Day 6 decreased the number of implantations and caused resorptions.(ABSTRACT TRUNCATED AT 250 WORDS)
The aim of this work was to develop an in vitro model suitable for studying insulin secretion in amphibians and for identifying agents capable of either blocking or stimulating such a process in this group. For this purpose, pancreases from the toad Bufo arenarum were incubated for 60 min at 25 degrees with several insulin secretagogues and blockers, and the immunoreactive insulin released into the medium was measured by radioimmunoassay. Under these experimental conditions, metabolic (glucose, ketoisocaproic acid, and arginine) and nonmetabolic (K+ and tolbutamide) agents as well as glucagon and acetylcholine significantly stimulated the release of immunoreactive insulin. Conversely, somatostatin and nifedipine blocked its secretion. All these agents exerted similar effects on the mammalian pancreas. These results prove that our model is a useful tool with which to study in vitro insulin secretion in amphibians and to identify agents which affect hormone release in this group.