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Biomedical subjects

M J Nelson

Publications and source records attributed to M J Nelson.

At least 19 recordsLinked to original sources

Mössbauer and EPR studies of the photoactivation of nitrile hydratase.

The alphabeta dimer of active nitrile hydratase from Rhodococcus sp. R312 contains one low-spin ferric ion that is coordinated by three Cys residues, two N-amide groups from the protein backbone, and one OH(-). The enzyme isolated from bacteria grown in the dark is inactive and contains the iron site as a six-coordinate diamagnetic Fe-nitrosyl complex, called NH(dark). The active state can be obtained from the dark state by photolysis of the Fe-NO bond at room temperature. Activation is accompanied by the conversion of NH(dark) to a low-spin ferric complex, NH(light), exhibiting an S = (1)/(2) EPR signal with g values of 2.27, 2.13, and 1.97. We have characterized both NH(dark) and NH(light) with Mössbauer spectroscopy. The z-axis of the 57Fe magnetic hyperfine tensor, A, of NH(light) was found to be rotated by approximately 45 degrees relative to the z-axis of the g tensor (g(z) = 1.97). Comparison of the A tensor of NH(light) with the A tensors of low-spin ferric hemes indicates a substantially larger degree of covalency for nitrile hydratase. We have also performed photolysis experiments between 2 and 20 K and characterized the photolyzed products by EPR and Mössbauer spectroscopy. Photolysis at 4.2 K in the Mössbauer spectrometer yielded a five-coordinate low-spin ferric species, NH(A), which converted back into NH(dark) when the sample was briefly warmed to 77 K. We also describe preliminary EPR photolysis studies that have yielded new intermediates.

Darkness↗

Left lower quadrant pain of unusual cause.

The differential diagnosis of left lower quadrant abdominal pain in an adult man includes, among others, sigmoid diverticulitis; leaking abdominal aortic aneurysm; renal colic; epididymitis; incarcerated hernia; bowel obstruction; regional enteritis; psoas abscess; and in this rare instance, situs inversus with acute appendicitis. We report a case of situs inversus totalis with left-sided appendicitis and a brief review of the literature. There were several subtle indicators of total situs inversus present that were missed by the physicians and surgeons who initially evaluated the patient prior to surgery. Computed tomography scan with contrast, however, revealed the diagnosis immediately, and treatment was successfully initiated.

Abdominal Pain↗

The normal difference in bilateral indirect blood pressure recordings in normotensive individuals.

If there is a significant dichotomy between bilateral blood pressure determinations in both arms, it is often taken as a sign of some type of underlying pathology. We wished to evaluate what the normal variation might be for significant differences between blood pressures in both arms. Significant difference was arbitrarily chosen as a systolic blood pressure value greater than 10 mm Hg. Bilateral indirect blood pressure determinations were obtained in 100 subjects with no known history of hypertension in the sitting position. The blood pressure was obtained by 2 observers, one who recorded the systolic and diastolic blood pressure as announced by the person taking the blood pressures who was blinded to the actual values taken. The coefficient of variation in obtaining the blood pressures in each arm was determined in 5 of the 100 subjects. The age, sex, and handedness of each individual were recorded as demographic variables. The average left and right systolic blood pressures were 112.1 +/- 16.5 and 112.7 +/- 16.3 mm Hg, respectively. The average left and right diastolic pressures were 64.4 +/- 11.6 and 63.5 +/- 9.9 mm Hg, respectively. There was no significant difference between left minus right systolic or diastolic differences (Student's paired t-test). There were no significant differences in systolic or diastolic blood pressure between gender or between right and left handed individuals (non-paired t-test). The average coefficients of variation for right and left arm systolic blood pressures were 5.41% and 5.81%, respectively. Fifteen subjects had differences in systolic blood pressure between both arms exceeding 10 mm Hg (7% to 22%, 95% confidence interval). Differences of more than 10 mm Hg in indirect bilateral blood pressure recordings are frequent in normotensive individuals and probably do not per se indicate any abnormal pathology. In the right clinical situation, differences that are noted should probably be repeated and should be added to the total clinical picture when used to determine whether a pathologic condition is present.

Adult↗

A stereoselective cobalt-containing nitrile hydratase.

Nitrile hydratase from Pseudomonas putida NRRL-18668 has been purified and characterized. The purified enzyme catalyzes the hydration of 2(S)-(4'-chlorophenyl)-3-methylbutyronitrile at least fifty times faster than that of 2(R)-(4'-chlorophenyl)-3-methylbutyronitrile. This enzyme is a member of the class of nitrile hydratase that contains cobalt. Visible absorption and CD spectra suggest the cobalt exists as a non-corrin low-spin Co3+ ion in a tetragonally-distorted octahedral ligand field. Chemical reduction of the native enzyme results in a species with the EPR signature of a low-spin Co2+ complex. Like the other cobalt-containing nitrile hydratases, this enzyme is relatively stable, maintaining its activity below 35 degrees C, and it shows a broad activity optimum between pH 7.2 and 7.8. The structural genes for this enzyme have been cloned and sequenced. The deduced amino acid sequences for the alpha and beta subunits show 48-63% and 35-41% homology, respectively, to other sequenced nitrile hydratases. In particular, the cysteine residues in the alpha subunit that have been suggested to coordinate the metal ion in the iron-containing nitrile hydratases [Brennan, B. A., Cummings, J. G., Chase, D. B., Turner, I. M., Jr., & Nelson, M. J. (1996) Biochemistry 35, 10068-10077] are conserved in this enzyme, suggesting that this nitrile hydratase, like the enzyme from Rhodococcus rhodochrous J1, is a member of a newly described class of metalloenzymes with Co3+-thiolate ligation [Brennan, B. A., Alms, G., Nelson, M. J., Durney, L. T., & Scarrow, R. C. (1996) J. Am. Chem. Soc. 118, 9194-9195].

Amino Acid Sequence↗

Incremental analysis of diagnostic peritoneal lavage fluid in adult abdominal trauma.

It is uncertain how much diagnostic peritoneal lavage (DPL) fluid must be recovered from abdominal trauma patients to avoid falsely low red blood cell (RBC) counts. A study was carried out to investigate this controversy. A convenience sample of adult abdominal trauma patients in a Level 1 university trauma center who were undergoing DPL with 1 L crystalloid was enrolled. Subjects with grossly positive or colorless effluent were excluded. A blinded prospective experimental design was used. Differences were evaluated among RBC counts collected at 200, 400, 600, and 800 mL of returned fluid using repeated-measures analysis of variance. In 11 patients, mean RBC counts collected at 200 and 400 mL were 24,600 (95% confidence interval [CI], 20,700 to 29,100) and 39,700 (95% CI, 33,200 to 47,100) cells/microL. These were substantially lower than the final mean count of 95,800 (95% CI, 80,000 to 115,800), measured at 800 mL (F = 23.7, P < .0001). Mean counts at 600 mL were less than those obtained at 800 mL but were not statistically different (P = .08). Two of the 11 subjects would have been misclassified (as not requiring surgery) had "early" sampling been used. In abdominal trauma patients, the RBC count of DPL fluid regularly increases as more fluid is recovered. It is important to collect >600 mL of effluent to avoid misleading, low RBC counts and misclassification of patients.

Abdominal Injuries↗

Factors favoring houseplant container infestation with Aedes aegypti larvae in Marília, São Paulo, Brazil.

Since reinvasion of São Paulo State by the Aedes aegypti (L.) mosquito in 1985, flower pots and vases have been important larval habitats despite educational messages focusing on their control. The objectives of this study were to characterize flower pots and vases as larval habitats with respect to the quantities present and infested, the types of plants involved, and the specific locations of the mosquito larvae; to explore local names for houseplants; and to examine factors affecting acceptance of control measures. The results showed an average of more than four potential plant-related larval habitats per premises, of which only 0.4% were occupied by the vector. Plant-related containers represented 31% of all the containers with Aedes aegypti larvae. Although a sample of 126 respondents was able to list 105 different houseplant names, 49% of the positive plants were of two types: ferns and the ornamental plant Dieffenbachia avoena. The public's apparent unwillingness to accept recommended anti-aegypti control measures involving houseplants seems related to the relative rarity of aegypti larvae in the very common houseplant containers, the control program's poor credibility as a source of information about plants, and a perception that the recommended control measures are harmful to plants. An intervention currently being planned for dengue control will use educational material that refers specifically to those plants whose containers are most commonly found to harbor aegypti larvae; it will also utilize information sources such as botanists with greater credibility regarding plants; and it will set out alternative plant care recommendations that are more likely to appeal as beneficial to the plants and that will stand a better chance of being accepted.

Aedes↗

Resonance Raman spectroscopy of nitrile hydratase, a novel iron-sulfur enzyme.

Resonance Raman spectra of Rhodococcus sp. R312 (formerly Brevibacterium sp. R312) nitrile hydratase, a novel non-heme iron enzyme, have a large number of peaks in the 300-500 cm-1 region; observation of shifts in these peaks after labeling with 34S shows that they arise from cysteine coordinated to the ferric ion in the protein. The rich Raman spectra result from coupling of the Fe-S stretch with cysteine side chain deformation modes; the observation of 15N isotope shifts in most of these peaks suggests participation of N-donor metal ligands and peptide backbone amide nitrogens in these modes as well. The aggregate 34S isotope shift is too large to result from a single cysteine ligand, consistent with the analysis of EXAFS data that shows two or three S-donor ligands [Scarrow et al. (1996) Biochemistry 35, 10078-10088]. Widespread 2H isotope shifts seen after exchange of the protein into 2H2O suggest the presence of hydrogen bonds to the coordinated cysteine sulfurs. Comparison of the resonance Raman spectra of nitrile hydratase prepared at pH 7.3 and 9.0 shows a shift of intensity into the higher-energy peaks in the spectra of the latter sample. This is interpreted as resulting from an increase in Fe-S bond strength at the higher pH and is supported by observation of a small decrease in Fe-S bond length in the EXAFS analysis [Scarrow et al. (1996) Biochemistry 35, 10078-10088]. Such a decrease in Fe-S bond length is also consistent with pH dependent changes in EPR spectra and could reflect the loss of one or more hydrogen bonds to sulfur ligands.

Brevibacterium↗

X-ray spectroscopy of nitrile hydratase at pH 7 and 9.

The iron K-edge X-ray absorption spectrum of Rhodococcus sp. R312 (formerly Brevibacterium sp. R312) nitrile hydratase in frozen solutions at pH 7 and 9 has been analyzed to determine details of the iron coordination. EXAFS analysis implies two or three sulfur ligands per iron and overall six coordination; together with previous EPR and ENDOR results, this implies an N3S2O ligation sphere. The bond lengths from EXAFS analysis [rav(Fe-S) = 2.21 A at pH 7.3; rav(Fe-N/O) = 1.99 A] support cis coordination of two cysteine ligands and conclusively rule out nitric oxide coordination to the iron, a possibility proposed on the basis of an FTIR difference experiment [Noguchi, T., Honda, J., Nagamune, T., Sasabe, H., Inoue, Y., & Endo, I. (1995) FEBS Lett. 358, 9-12]. The higher-frequency EXAFS can be simulated well by inclusion of multiple scattering from two or three imidazole ligands; the fit to the data is improved if first-sphere multiple scattering pathways are also included. A slight shortening (by 0.02 +/- 0.01 A) of one or both Fe-S bonds when the pH is raised from 7.3 to 9.0 is consistent with shifts observed in the Raman spectrum [Brennan et al. (1996) Biochemistry 35, 10068-10077].

Absorptiometry, Photon↗

Disposable containers as larval habitats for Aedes aegypti in a city with regular refuse collection: a study in Marília, São Paulo State, Brazil.

In Marília, Brazil, refuse is collected at least every other day, yet non-useful, non-returnable containers such as cans, plastic bottles and tires account for almost half of the container habitats found positive for the Aedes aegypti mosquito. A study was therefore conducted to investigate why these containers exist despite regular refuse collection and a high level of awareness of dengue prevention, and how the control program could most effectively respond. Differing community perceptions as to what constitutes refuse were found to lead people to store a variety of containers in their yard. Other dimensions of the problem include the presence of informal refuse collectors in search of saleable materials, and dumping of refuse in vacant lots and along roads. An intervention based on these data will involve the informal refuse collectors in implementation of a community-based recycling project.

Aedes↗

Forced air speeds rewarming in accidental hypothermia.

STUDY OBJECTIVE: To compare the rates of rewarming of forced-air and passive insulation as a treatment for accidental hypothermia. METHODS: We carried out a prospective, randomized clinical trial in two urban, university-affiliated emergency departments. Our subjects were 16 adult hypothermia victims with core temperatures less than 32 degrees C. A convective cover inflated with air at about 43 degrees C (forced-air group) or cotton blankets (control group) were applied until the patient's core temperature reached 35 degrees C. Members of both groups were given IV fluids warmed to 38 degrees C and warmed, humidified oxygen at 40 degrees C by inhalation. RESULTS: The mean +/- SD initial temperature was 28.8 degrees +/- 2.5 degrees C (range, 25.5 degrees C to 31.9 degrees C) in the patients who underwent forced-air rewarming and 29.8 degrees +/- 1.5 degrees C (range, 28.2 degrees C to 31.9 degrees C) in those given blankets. Core temperature increased about 1 degree C/hour faster in patients treated with forced-air rewarming (about 2.4 degrees C/hour) than in patients given only cotton blankets (about 1.4 degrees C/hour, P = .01). Core-temperature afterdrop was detected in neither group. CONCLUSION: Forced air accelerated the rate of rewarming without producing apparent complications in hypothermic patients.

Adult↗

Effects of topical administration of 0.5% apraclonidine on intraocular pressure, pupil size, and heart rate in clinically normal dogs.

OBJECTIVE: To evaluate the effect of 0.5% apraclonidine on intraocular pressure (IOP), pupil size, and heart rate in clinically normal dogs. DESIGN: Randomized masked saline-controlled case study. ANIMALS: Nine clinically normal conditioned adult dogs of either sex. PROCEDURE: Normal diurnal variation in IOP, pupil size, and resting heart rate were determined from 7 AM to 7 PM (day 1). These measurements were repeated on day 2 after topical application of 60 microliters of 0.5% apraclonidine to 1 randomly chosen eye of each dog. The contralateral eye received saline solution. RESULTS: Compared with the saline-treated fellow eye, mean IOP in the apraclonidine-treated eye was significantly reduced (3.0 mm of Hg, 16%) 8 hours after treatment. Because of mild day-to-day variations in IOP, however, IOP in the apraclonidine-treated eye on day 2 was not significantly different from day-1 baseline values obtained from the same eye. Significant mydriasis (2.1 mm, 29.7%), persisting for up to 8 hours, occurred in apraclonidine-treated eyes. Although apraclonidine did not significantly alter heart rate when all 9 dogs were viewed as a group, 4 dogs experienced a 9 to 19.5% reduction in heart rate 2 hours after treatment. Mild blanching of the conjunctiva occurred in apraclonidine-treated eyes. CONCLUSIONS: Apraclonidine lowered IOP and, in contrast to cats where it causes miosis, induced mydriasis in dogs. Although heart rate generally is unchanged, it may be reduced in select individuals. CLINICAL RELEVANCE: Topically applied 0.5% apraclonidine may be a useful adjunct to other antiglaucoma treatment modalities in dogs, but is unlikely to be effective as the sole agent in most forms of canine glaucoma.

Administration, Topical↗

Abnormal cerebral glucose metabolism in HIV-1 seropositive subjects with and without dementia.

UNLABELLED: This study was undertaken in order to extend our previous finding of relative basal ganglia hypermetabolism in AIDS dementia complex (ADC) and to develop clinically useful metabolic indices of CNS involvement in HIV-seropositive (HIV+) subjects. METHODS: Twenty-one HIV+ subjects (11 with AIDS) underwent FDG-PET scanning; 12 had a follow-up scan at 6 mo and 4 had a third scan at 12 mo. Forty-three age-matched heterosexual volunteers served as controls. FDG-PET scanning was performed with arterial blood sampling, and scan data were analyzed using the Scaled Subprofile Model (SSM) with principal component analysis. RESULTS: SSM/principal component analysis of the combined (HIV+ and controls) FDG-PET dataset extracted two major disease-related metabolic components: (a) a nonspecific indicator of cerebral dysfunction, which was significantly correlated with age, cerebral atrophy and ADC stage and (b) the striatum, which was heavily weighted (relatively hypermetabolic) and appeared to provide a disease-specific measure of early CNS involvement. CONCLUSION: FDG-PET scans provide quantitative measures of abnormal functional connectivity in HIV-seropositives-with or without AIDS or ADC. These measures, which are robust across centers with respect to instrumentation, scanning technique and disease severity, appear to track the progression of CNS involvement in patients with subclinical neurologic or neuropsychologic dysfunction.

AIDS Dementia Complex↗

Structure and kinetics of formation of catechol complexes of ferric soybean lipoxygenase-1.

Ferric soybean lipoxygenase forms stable complexes with 4-substituted catechols. The structure of the complex between the enzyme and 3,4-dihydroxybenzonitrile has been studied by resonance Raman, electron paramagnetic resonance, visible, and X-ray spectroscopies. It is a bidentate iron-catecholate complex with at least one water ligand. The kinetics of formation of complexes between lipoxygenase and 3,4-dihydroxybenzonitrile and 3,4-dihydroxyacetophenone have been studied by stopped-flow spectroscopy. The data are consistent with two kinetically distinct, reversible steps. The pH dependence of the first step suggests that the substrate for the reaction is the catechol monoanion. When these results are combined, plausible mechanisms for the complexation reaction are suggested.

Catechols↗

Photolysis of "purple" lipoxygenase: implications for the structure of the chromophore.

Treatment of soybean lipoxygenase isozyme 1 with its substrates, linoleic acid and oxygen, or product, 13(S)-hydroperoxy-9,11(Z,E)-octadecadienoic acid (13-HPOD), leads to the appearance of a purple color. Although the structure of the chromophore has not been determined, we present strong evidence that it is an Fe(3+)-OOR complex between the enzyme and 13-HPOD. Irradiation of frozen purple solutions of lipoxygenase causes the reversible production of a radical, shown by the effects of 2H and 17O enrichment on its EPR spectrum to be derived from 13-HPOD. The action spectrum of the photolysis reaction corresponds to the visible spectrum of the purple species, strongly implying that the purple chromophore contains 13-HPOD (or a product thereof) as part of its structure. Concomitant with the production of this radical there is a decrease in the intensity of an EPR signal corresponding to enzyme-bound Fe3+ and characteristic of the purple species. Taken together, these observations support the suggestion that the purple species is a complex between ferric lipoxygenase and 13-HPOD, likely the ferric peroxide.

Chromogenic Compounds↗

X-ray spectroscopy of the iron site in soybean lipoxygenase-1: changes in coordination upon oxidation or addition of methanol.

Iron K-edge X-ray spectroscopy (XANES and EXAFS) was used to study iron coordination in frozen solutions of soybean lipoxygenase-1 (SLO). The intensity of the 1s-->3d pre-edge transition of native iron(II) lipoxygenase is greater than what was found for six-coordinate high-spin iron(II) model complexes, but comparable to that of a five-coordinate model. This and a relatively short average bond length determined by EXAFS (2.13 A) indicate that the native lipoxygenase in our frozen samples is five-coordinate, excluding possible bonds longer than 2.5 A. The coordination of the iron(II) in native lipoxygenase changes when methanol (as low as 0.1%) or glycerol (20%) is added to the buffer prior to freezing. The addition of methanol diminishes the pre-edge transition and increases EXAFS-derived bond lengths by 0.04 A, indicating a change to six-coordination. The small pre-edge feature in active iron(III) lipoxygenase suggests six-coordination. EXAFS indicates a short, 1.88 A Fe-O bond, which, given other spectroscopic and crystallographic evidence, is assigned to coordinated hydroxide. The average of the remaining bond lengths is 2.11 A. The iron coordination in iron(III) lipoxygenase is less affected by the presence of alcohols than is the site in the iron(II) enzyme. Bond valence sums indicate that the bond lengths for lipoxygenase derived from our EXAFS analyses are comparable to those of crystallographically characterized model complexes. The flexibility of the coordination number in SLON (native SLO) and the presence of an [FeIIIOH]2+ unit in SLOA (active SLO) are of possible mechanistic importance.

Ferric Compounds↗

Structural characterization of alkyl and peroxyl radicals in solutions of purple lipoxygenase.

Soybean lipoxygenase isozyme 1 catalyzes the addition of dioxygen to fatty acid substrates that contain a 1,4-diene, generating allylic hydroperoxides. EPR spectra of purple enzyme solutions, formed by addition of saturating amounts of substrates or product to the enzyme, reveal the existence of fatty acid alkyl and peroxyl radicals that are bound to the enzyme and may be intermediates of the catalytic reaction [Nelson, M. J., Seitz, S. P., & Cowling, R. A. (1990) Biochemistry 29, 6897-6903]. We have analyzed the spectra of the radicals formed from the hydroperoxide products of four specifically deuterated linoleic acids and [per-2H]linoleic acid. The alkyl radical is an allyl radical, delocalized over C9 through C11 of linoleic acid. The data are consistent with delocalization of some of the spin over an unknown substituent at C12. The peroxyl radical is a 9-peroxyl derivative of linoleic acid. From the data we propose a novel mechanism for the lipoxygenase reaction: (1) oxidation of the 1,4-diene by the active-site Fe3+ to a delta 12-[9,10,11]-allyl radical; (2) activation of dioxygen at the Fe2+; (3) electrophilic attack by Fe(2+)-O2 on the 12-ene to form a 12,13-perepoxy-[9,10,11]-allyl radical; (4) opening of the perepoxide to the Fe(3+)-allylic hydroperoxide complex; (5) protonation to yield the 13-hydroperoxide. Addition of dioxygen to the allyl radical is proposed to form the 9-peroxyl, ultimately to yield the minor 9-hydroperoxide lipoxygenase product.

Color↗

The structure and function of lipoxygenase.

Lipoxygenases are non-heme iron enzymes that catalyze the dioxygenation of polyunsaturated fatty acids, yielding hydroperoxides. The first crystal structures have recently been published, revealing an unusual iron site. There have also been substantial developments in the analysis of the kinetics of the reaction, including the observation of uniquely large primary deuterium isotope effects. Exploitation of these results should enable substantial progress in understanding what appears to be a complicated and fascinating chemical mechanism.

Amino Acid Sequence↗

The role of sampling in vector control.

In most disease vector control programs of the world, little attention is given to sampling methodology for surveillance against importation of vectors, determination of vector distribution, vector incrimination, monitoring of entomologic risk factors, and evaluation of control. This paper discusses briefly the appropriate attractant and nonattractant collecting methods for each situation, the importance of using more than one collecting method, examples of entomologic indicators, basic sampling strategies (distribution, number, and frequency of samples), and guidelines for analysis of sampling data from vector programs.

Animals↗