Biomedical subjects
Publications and source records attributed to J H Miller.
A 16-year-old girl presented with widespread multiorgan involvement by Burkitt lymphoma including nodular infiltration of the breasts bilaterally. Although non-endemic Burkitt lymphoma rarely involves the breasts, their evaluation should be included when assessing a chest computed tomogram (CT).
Various mechanisms of injury have been hypothesized for each of the common elbow fractures, but few have been proved. This paper describes cadaveric experiments demonstrating some fracture mechanisms. Tests were performed at different angles of flexion, with impacts around the elbow or along the forearm bones. A range of fractures occurred. Radial head and coronoid fractures followed impact along the forearm up to 80 degrees flexion. Olecranon fractures occurred by direct impact around 90 degrees flexion. Distal humeral fractures mostly occurred above 110 degrees flexion. A flexion-extension 'arc of injury' is shown, which relates fracture types to elbow position at the moment of impact. The results confirmed some of the mechanism hypotheses, and cast doubt on others. Knowledge of these mechanisms can give greater understanding of the injury which has occurred, such as the abnormal bone excursions which occur during impact and likely patterns of soft tissue damage.
To determine the accuracy and reliability of a labeled leukocyte imaging technique in the early diagnosis of pediatric appendicitis, we prospectively studied patients presenting to the pediatric emergency department with abdominal pain suggestive of appendicitis. Patients scheduled for urgent laparotomy were excluded, as were postmenarchal females. Blinded interpretations by two independent radiologists were compared with surgical findings, if managed operatively, or with discharge diagnoses and three week follow-up, if managed medically. Twenty-three children underwent technetium-99m hexamethylpropylene amine oxime (HMPAO) leukocyte scintigraphy. Seven had pathologically proven appendicitis, with false negative interpretations made in three and five cases by the two radiologists. Sixteen patients had prompt resolution of symptoms; however, scintigraphic abnormalities were identified in 10 and seven cases by the two radiologists. Resulting sensitivity, depending on the individual reader, ranged from 29 to 57%, with specificity 38 to 56%, positive predictive value 22 to 29%, negative predictive value 64 to 67%, and accuracy 43 to 48%. Interrater reliability for agreement on the scintigraphic diagnosis of appendicitis was poor (kappa = 0.38). Technetium-99m HMPAO leukocyte scintigraphy was neither accurate nor reliable as a diagnostic tool in a subgroup of pediatric patients with an initial clinical presentation equivocal for appendicitis. This finding contradicts previously published experience using similar scintigraphic techniques.
OBJECTIVE: To describe the neuropathologic findings in four cases of meningeal melanocytoma, a rare benign melanocytic tumor of the central nervous system. DESIGN: Retrospective analysis of surgical pathology and autopsy material. RESULTS: Grossly, all four tumors were well-circumscribed pigmented lesions, and three of four were attached to dura. Microscopically, the neoplasms were composed of spindle cells with epithelioid foci. Mitoses were not seen and only one case exhibited minimal necrosis. Immunohistochemistry and electron microscopy demonstrated the melanocytic nature of the lesions; all four cases showed S100 protein and neuron-specific enolase staining, and three cases exhibited melanoma-specific antigen staining. Immunostaining for epithelial markers and vimentin was uniformly negative. The single case in which electron microscopy was performed demonstrated premelanosomes. CONCLUSIONS: Meningeal melanocytoma is a benign pigmented neoplasm that can easily be confused with melanoma, especially on frozen section analysis. Practicing surgical pathologists should be aware of this entity.
The lacZ gene encoding a beta-galactosidase (beta Gal) from the hyperthermophile Thermotoga maritima was cloned on an 11-kb fragment by complementation of an Escherichia coli lacZ deletion stain. The nucleotide sequence of the structural gene and two other ORFs found within a 6317-bp region were determined. The deduced amino acid (aa) sequence of the Tt. maritima beta Gal predicts a 1037-aa polypeptide with a calculated M(r) of 122,312. The translated sequence is 30% similar to nine other beta Gal sequences from bacteria and one yeast. Alignment of the Tt. maritima beta Gal with these other sequences reveals that the residues responsible for Mg2+ binding, catalysis and substrate recognition are conserved in the thermophilic enzyme. Sequence analysis also revealed the presence of a divergently transcribed operon containing at least two other genes 5' to lacZ. These ORFs encode proteins homologous to a second family of beta Gal found in Bacillus species and to an ATP-dependent family of bacterial oligopeptide transport proteins.
Amber mutations have been constructed at 328 positions, corresponding to residues 2 to 329 in the E. coli lac repressor protein. Synthetic and naturally occurring nonsense suppressors have been used to insert, in series, 12-13 amino acids at positions specified by an amber (UAG) codon in the lacI mRNA. The resulting set of over 4000 single amino acid replacements in the lac repressor protein allows a detailed analysis of its substitution tolerance along the linear array of residues, and reveals structure-function relationships in lac repressor and in proteins in general. (1) There are two main regions in the repressor which are extremely sensitive to amino acid replacements. One, the amino-terminal 59 residues, has been implicated in DNA and operator binding by a large body of work. The second, extending from approximately residues 239 to 289/292, forms the repressor core and shares the most homology with other repressor and DNA binding proteins. (2) Throughout the rest of the protein, segments of 6 to 14 amino acids, which are highly tolerant to single amino acid replacements, appear to act as "spacers" between one or several hydrophobic residues that are relatively intolerant to substitutions. (3) We have replaced the amino acids in these tolerant regions with spans of alanine residues, from 5 to 13 amino acids. In all five of the regions tested, alanine replacements, sometimes of up to 8 amino acids, still allowed functional repressor, while deletion of the same residues destroyed repressor function. This reinforces the view that many regions of a protein do not require a specific sequence to serve as spacers between more important residues. (4) A distinct pattern of substitutions leading to the I(s) phenotype suggests the location of residues involved in inducer binding. (5) A number of general substitution patterns can be recognized. For instance, proline is not tolerated at over 40 sites which tolerate all the other amino acid replacements. Another set of sites tolerates only non-polar amino acids, whereas a third set tolerates a subset of the smallest amino acids, (serine, alanine, glycine and cysteine, and sometimes threonine and valine). (5) Overall, 93 of 328 sites (28%) tolerate all 13 amino acids tested, and 144 of 328 (44%) tolerate 12/13 or all 13 substitutions. We judge that 192 of 328 sites (59%) are generally tolerant to substitutions.
Target size determinations from radiation inactivation of proteins is dependent on the physical and chemical environment of the sample during radiation exposure. Effects of temperature and physical state have already been described. Buffers, the effects of protein concentration, and the addition of small molecules are examined for several enzymes. Phosphate buffer is found to have major effects on the rate of inactivation of certain, but not all, proteins. The amount of protein in irradiated samples is significant for all enzymes studied; the nature of the specific protein used is unimportant. Neither sucrose nor other glycitols could substitute for protein in target size determinations. Certain small molecules, especially cysteamine, were effective in sparing the need for high protein levels in radiation inactivation studies of four enzyme systems.
Several technical advances over the years have allowed microsurgery to be successful. However, thrombosis, particularly at the anastomosis site, remains a complication of microvascular surgery. Various preventive measures, including drugs, have been used to improve microvascular surgical anastomotic patency rates. The purpose of this article is to review the literature and the current status of topical antithrombotic agents. From this review along with laboratory investigations it is concluded that a combination of topical as well as systemic agents offers the best patency rates. However, the "ideal" antithrombotic agent is yet to be discovered and investigations need to be continued in order to improve or eliminate the complication of microvascular thrombosis. But the importance of atraumatic technique cannot be overemphasized.
Renal cell carcinoma is a rare pediatric malignancy that appears to have a similar clinical outcome in children and adults. We review the experience of Childrens Hospital Los Angeles and compare it with the published pediatric series, reporting on seven cases from 1954 to the present. As in earlier pediatric series, we find that Stage I/II patients do well (five of five complete responses with prolonged disease-free survival) with surgical resection. As in other pediatric series, our only Stage III patient died of disease. We also report on a recent case of renal cell carcinoma, metastatic to lymph nodes and lung parenchyma at diagnosis (Stage IV). This patient was treated with high dose continuous infusion recombinant interleukin-2 and had a partial response. The patient attained a complete response following a second laparotomy and two subsequent cycles of recombinant interleukin-2. He is presently well, without evidence of disease, 3 1/2 years after diagnosis. The significance of this form of therapy to advanced renal cell carcinoma in childhood is discussed.
The hyperthermophilic archaeum Pyrobaculum aerophilum grows optimally at 100 degrees C and pH 7.0. Cell homogenates exhibit strong proteolytic activity within a temperature range of 80-130 degrees C. During an analysis of cDNA and genomic sequence tags, a genomic clone was recovered showing strong sequence homology to alkaline subtilisins of Bacillus sp. The total DNA sequence of the gene encoding the protease (named "aerolysin") was determined. Multiple sequence alignment with 15 different serine-type proteases showed greatest homology with subtilisins from gram-positive bacteria rather than archaeal or eukaryal serine proteases. Models of secondary and tertiary structure based on sequence alignments and the tertiary structures of subtilisin Carlsberg, BPN', thermitase, and protease K were generated for P. aerophilum subtilisin. This allowed identification of sites potentially contributing to the thermostability of the protein. One common transition put alanines at the beginning and end of surface alpha-helices. Aspartic acids were found at the N-terminus of several surface helices, possibly increasing stability by interacting with the helix dipole. Several of the substitutions in regions expected to form surface loops were adjacent to each other in the tertiary structure model.
Most of the energy absorbed in the cell nucleus from a radiation field goes into the aqueous medium that surrounds macromolecules, like DNA, which are critical to the normal function of cells. This part of the energy deposition produces numerous reactive species that can diffuse to DNA sequences and induce chemical changes. The average diffusion distance of the free radicals that mediate this indirect mode of DNA damage is only a few nanometers because the cellular medium contains a high concentration of molecules that rapidly scavenge the radiation-induced species. Under these conditions, direct interaction of the radiation field with the DNA can not be neglected as a potential mode of damage induction. Two aspects of the direct effect will be discussed in this paper: (1) screening of the interaction between DNA and charged particles by the dielectric response of the aqueous medium and (2) the impact-parameter dependence of these interactions.
The role of endogenous opioids in respiratory control in the pentobarbital anaesthetised rat was investigated using a rebreathing technique to generate a progressively increasing hypercapnic stimulus to the respiratory centers following administration of an opioid antagonist or agonist. Respiratory output was measured by intraesophageal pressure (IEP) changes, and a ventilatory equivalent (VEq) was calculated by multiplying IEP by respiratory rate (mmHg.min-1). A non-selective opioid antagonist, naloxone (0.4 mg/kg i.v.), significantly enhanced the slope of the CO2 response curve for VEq (20 +/- 3 mmHg.min-1.%CO2-1) compared with the control (14 +/- 2 mmHg.min-1.%CO2(-1)) (P < 0.05; n = 14). A similar enhancement of the hypercapnic response by naloxone was found in rats anaesthetised with urethane (n = 5). The mu receptor agonist dermorphin (1 mg/kg i.v.) significantly depressed the slope of the CO2 response curve for IEP (-0.01 +/- 0.03) compared with the control (0.10 +/- 0.03) in pentobarbital anaesthetised rats (P < 0.05; n = 5) but had no significant effect on respiratory rate. These results suggest a role of endogenous opioids in the modulation of respiration during hypercapnia.
The relation between the site of energy deposition and the site of its biological action is an important question in radiobiology. Even at 77 degrees K, evidence is clear that these two sites must be separated since energy deposition is random but specific products are formed. Several processes that may contribute to this separation are: 1) hole migration and stabilization through deprotonation to give neutral oxidation product radicals; 2) electron trapping and transfer to form specific radical anions, possibly followed by protonation to give neutral reduction product radicals; and 3) recombination of spatially separated charges or radicals. These microscopic processes will be reviewed critically in an analysis using electron paramagnetic resonance spectroscopy (EPR) evidence for and against long-range transfer of energy and/or charge in frozen, hydrated DNA.
PURPOSE: A review of upper extremity arterial injuries managed at the Royal Adelaide Hospital between 1969 and 1991 was undertaken because the optimal management of complex upper extremity trauma, particularly in proximal injuries, remains unclear. METHODS: Patients were identified from the computer registry of patients treated by the vascular unit at the Royal Adelaide Hospital. They were studied in three groups: (1) subclavian and axillary artery, (2) brachial artery, and (3) radial and ulnar artery injuries. The mechanism of injury, associated injuries, treatment and outcome were reviewed. RESULTS: There were 114 patients with upper extremity arterial injuries: 28 with subclavian and axillary, 62 with brachial, and 24 with radial and ulnar artery injuries. Good upper limb function was obtained in 32% of subclavian and axillary artery injuries, 79% of brachial artery injuries, and all radial and ulnar artery injuries. Amputation was performed in 14% of the proximal injuries and 8% of the brachial artery injuries. Three deaths occurred in this study group. CONCLUSION: Blunt proximal injuries were usually associated with neurologic, soft tissue, and bony damage, which was responsible for the poor functional outcome. Critical limb ischemia or severe hemorrhage rarely occurred. Complete brachial plexus lesions resulted in uniformly poor outcomes. More distal injuries were associated with fewer nerve and soft tissue injuries, resulting in a more satisfactory outcome.
Radiation-induced electron migration along DNA is a mechanism by which randomly produced stochastic energy deposition events can lead to non-random types of damage along DNA manifested distal to the sites of the initial energy deposition. Radiation-induced electron migration in nucleic acids has been examined using oligonucleotides containing 5-bromouracil (5-BrU). Interaction of 5-BrU with solvated electrons results in release of bromide ions and formation or uracil-5-yl radicals. Monitoring either bromide ion release or uracil formation provides an opportunity to study electron migration processes in model nucleic acid systems. Using this approach we have discovered that electron migration along oligonucleotides is significantly influenced by the base sequence and strandedness. Migration along 7 base pairs in oligonucleotides containing guanine bases was observed for oligonucleotides irradiated in solution, which compares with mean migration distances of 6-10 bp for Escherichia coli DNA irradiated in solution and 5.5 bp for E. coli DNA irradiated in cells. Evidence also suggests that electron migration can occur preferentially in the 5' to 3' direction along a double-stranded oligonucleotide containing a region of purine bases adjacent to the 5-BrU moiety. Our continued efforts will provide information regarding the contribution of electron transfer along DNA to formation of locally multiply damaged sites created in DNA by exposure to ionizing radiation.
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Post-transplant hypertension can be a diagnostic dilemma. In a select population of pediatric patients, in whom other diagnostic methods failed to reveal an abnormality, renal cortical SPECT imaging, using either Tc-99m GH or Tc-99m DMSA, revealed information that was not apparent on conventional planar renal scintigraphy. Abnormalities detected by this methodology included unsuspected renal infarct and areas of segmental perfusion deficit. The authors conclude that this methodology is a valuable tool in the evaluation of post renal transplantation hypertension in pediatric patients.