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Two and four-coil phased array detectors have been developed to increase the sensitivity of proton spectroscopic imaging of the human brain. These include a quadrature figure-8 coil for the study of the vertex, several arrays of 2-4 small overlapping (6-8 cm diameter) circular coils and a combination figure-8 coil plus circular coil. These were constructed in our laboratory and tested to assess their utility for brain spectroscopy. Methods for optimally combining the data from the independent receivers based on the analytical coil maps or measured signal to noise ratios (SNRs) of the data were investigated. High spatial resolution (0.2-0.4 cm3 voxel size) two- or three-dimensional chemical shift images of normal brain were obtained in 17-minute acquisitions. These spatial resolutions are comparable to those previously obtained with conventional small surface coils, but the specialized detectors allow this sensitivity to be achieved for a larger region or for previously inaccessible areas such as the top of the head. The coverage and SNR increases demonstrated are similar to those obtained in magnetic resonance phased array imaging.

A novel cyclodepsipeptide of fungal origin, PF1022A, recently was reported to have anthelmintic activity. To supplement published reports and determine potential utility of PF1022A as a ruminant anthelmintic, the compound was examined in in vitro and in vivo models. Assays used measured motility of Haemonchus contortus (intrinsic drug potency), ATP levels (parasite death), and activity against H. contortus, Ostertagia ostertagi, and Trichostrongylus colubriformis in the jird (spectrum, potency, and efficacy by various routes). The potency of PF1022A in reducing motility is greater than commercial anthelmintics. Examination of ATP levels in PF1022A-paralyzed H. contortus indicates that worms are not killed, suggesting the compound acts as a neurotoxin in nematodes. In the jird, PF1022A has activity orally against each of the parasites studied and at doses comparable to all commercial anthelmintics, except the macrocyclic lactones which are more potent. Unfortunately, for some nematode species, parenteral delivery is ineffective at realistic doses.

The stabilization bite splint is discussed with regard to design, delivery, and clinical procedures that contribute to conservative appliance therapy. Indications for stabilization bite splint therapy and a clinical case report are presented.

The UMLS knowledge sources provide detailed information about biomedical naming systems and databases. The Metathesaurus contains biomedical terminology from an increasing number of biomedical thesauri, and the Semantic Network provides a structure that encompasses and unifies the thesauri that are included in the Metathesaurus. This paper addresses some fundamental principles underlying the design and development of the Metathesaurus and Semantic Network. It begins with a description of the formal properties of thesauri, including the Metathesaurus, and the formal properties of the Semantic Network. It continues with consideration of the principle of semantic locality and how this is reflected in the UMLS knowledge sources. The paper concludes with a discussion of the issues involved in attempting to re-use knowledge and the potential for re-use of the UMLS knowledge sources.

Objectives: This study was designed to determine whether citrate levels detected by localized 1H spectroscopy could reliably discriminate regions of prostate adenocarcinoma from surrounding regions of normal peripheral zone and benign prostatic hyperplasia (BPH)., Methods: In 28 patients and 5 volunteers stimulated echo proton spectroscopy was used in conjunction with endorectal surface coils to obtain water-suppressed 1H spectra from regions of normal prostate peripheral zone, BPH, and prostate cancer. 1H spectra from prostate cancer patients were correlated with pathologic areas identified on T2-weighted endorectal coil magnetic resonance (MR) images and histologic study of the step-sectioned gland after surgery., Results: The major finding of in vivo studies was consistently lower citrate levels in prostate cancer compared with BPH and normal prostate peripheral zone. This was reflected by significantly (P < 0.05) lower mean citrate/(creatine plus choline) peak area ratio observed for regions of cancer (0.67 +/- 0.17) compared with BPH (1.21 +/- 0.29) and normal peripheral zone (1.46 +/- 0.28). Moreover, there was no overlap of individual cancer and normal peripheral zone citrate ratios and no significant difference between citrate ratios in regions of normal peripheral zone in young volunteers (1.28 +/- 0.14) and age-matched patients (1.46 +/- 0.28). The observed alterations in vivo citrate levels were supported by citrate concentration data obtained from extracts of histologically proven samples of normal, benign, and malignant prostatic tissues removed at surgery. In vitro citrate levels in the normal peripheral zone (30.9 +/- 8.5 mumol/g wet weight) and BPH (46.3 +/- 5.4 mumol/g wet weight) were significantly higher than those for prostate cancer (3.74 +/- 0.54 mumol/g wet weight)., Conclusions: These studies further demonstrate the potential of citrate as an in vivo marker for discriminating prostate cancer from surrounding regions of normal peripheral zone and BPH.

An analytic correction method was developed and applied to correct the signal intensity nonuniformity caused by the inhomogeneous reception profile of surface coils used--because of their higher sensitivity--for magnetic resonance imaging of the brain at 1.5 T. The reception profile was analytically modeled by using the Biot-Savart law. The correction considerably improved visual interpretation of the images by modeling and removing the dependence of signal intensity on distance from the coil. The method can be used for single or multiple coils of any planar geometry and in any orientation. Application of this technique allows imaging of the brain with surface coils, yielding increased resolution and signal-to-noise ratio, without the penalty of image nonuniformity.

One way to fulfill point-of-care knowledge needs is to present caregivers with a visual representation of the available "answers". Using such a representation, caregivers can recognize what they want, rather than have to recall what they need, and then navigate to an appropriate answer. Given selected pieces of information from a computer-based patient record, an interface can anticipate certain knowledge needs by initializing caregiver navigation in a semantic neighborhood of answers likely to be relevant to the patient at hand. These notions draw heavily on two collaborative projects--the U.S. National Library of Medicine Unified Medical Language System and the U.S. National Cancer Institute Knowledge Server. Both of these projects support navigation because they make the structure of medical knowledge explicit in a way that can be exploited by human interfaces.

Multicystic encephalomalacia (MCE) is a rare lesion that arises during the perinatal period. Although hypoxic-ischemic insults may be responsible for this lesion, recent evidence suggests that herpesviruses may represent another etiologic agent. To elucidate the pathogenesis of MCE, eight cases collected over a 34-year period were evaluated for destructive lesions in gray and white matter. Immunocytochemical methods, in situ hybridization and polymerase chain reaction (PCR) methodology were employed to search for herpes simplex viruses types 1 and 2 (HSV1 and HSV2), cytomegalovirus (CMV), varicella zoster virus (VZV), Epstein-Barr virus (EBV) and JC variant of papovavirus (JCV). Review of the clinical histories revealed that there had been a complicated labor and delivery in 6/7 cases. Neuropathological lesions consisted of extensive tissue destruction, neuronal loss and gliosis in hemispheric white matter, cerebral cortex, basal ganglia, thalamus, cerebellum and brainstem tegmentum. Only one case showed evidence of latent HSV infection by PCR. CMV, VZV, JCV and EBV were not detected. Arteriopathy was noted in one case. The widespread nature of the lesions and their association with perinatal ischemia suggest that severe hypoxia may be the more common etiology of MCE. Term infants appear especially susceptible to this type of cerebral damage.

The barrier word method of identifying nominal phrases in text, using a very long barrier word list, was evaluated in two different sets of text. In a sample of 10 paragraphs from the Medical Knowledge Self-Assessment Program of the American College of Physicians, the yield of nominal phrases as a percent of total chunks isolated was 66%. Some 500,000 chunks were isolated from Principles and Practice of Oncology (PPO). 38% of these chunk-occurrences were of chunks which matched to 10,000 concept names in Meta-1.4, the most recent version of the UMLS Metathesaurus. 50 paragraphs from PPO were chosen at random. Co-occurrences of concepts in those paragraphs were reviewed. 42 of the paragraphs had unique or infrequently occurring co-occurrences which described closely the major thrust of the paragraph.

Partial meniscectomies were performed on 32 fresh human meniscal autopsy specimens. The following laser systems were tested: carbon dioxide (CO2), neodymium:yttrium aluminum garnet (Nd:YAG), potassium titanyl phosphate (KTP), holmium:YAG (Ho:YAG), and excimer. Meniscectomies with these lasers were compared with scalpel, mechanical, and electrocautery meniscectomies. Lasers were applied to specimens in and out of normal saline. Routine hematoxylin and eosin and sirius red sections were prepared for each specimen, and the depths of thermal changes were analyzed. Scanning electron microscopy was used to visualize the meniscectomy interface. Among these specimens, the scalpel and mechanical meniscectomies showed the least extension of cellular changes (range, 10-15 nm). The excimer laser caused the least tissue changes of the lasers tested. Tissue changes were less extensive with the pulsed CO2 laser than with the holmium:YAG, neodymium:YAG, and KTP lasers. Scanning electron microscopy showed that use of the scalpel meniscectomy resulted in the smoothest meniscectomy edge, followed by use of the excimer, CO2, holmium:YAG, neodymium:YAG, and KTP lasers. The most surface disruption occurred with electrocautery. Meniscectomies under saline required more energy and took longer in each case, with the holmium:YAG, neodymium:YAG, and CO2 laser cutting the best. Saline meniscectomies showed less thermal change. The CO2 and KTP lasers cut best in air.

Oncologists' information needs arise at diverse times and settings. For example: "Is superior vena cava syndrome a medical emergency?" Our collaborative group is developing a system that supports an interface with combinations of spoken, gestural, and simulated three-dimensional manipulation to help an oncologist focus on the information need, not the system. The system requires a small amount of input from the oncologist, and then anticipates what information is pertinent to the patient at hand, based on the sources it has available. The system makes use of a "Knowledge Server" to find relevant information. The Knowledge Server uses selected data for the particular patient from a Computer-based Patient Record (CPR) to provide context for the information needs. The Knowledge Server leverages the Unified Medical Language System (UMLS) resources as well as relevant communications standards. A layered, interaction protocol is used to help manage the fulfillment of information needs. Each of the oncology knowledge sources is transformed into a uniform representation that utilizes both its formal schema (e.g., its table of contents) and its concepts and words indexed through the UMLS Metathesaurus. Our focus on the appropriate use of information from a CPR, and on anticipating oncologists' information needs, resulted from our study of several longitudinal patient scenarios. We believe that our use of scenario-based design techniques will help to ensure the system's success.

A terminology is a systematic, authoritative collection of concept names, or terms, in some domain. No single terminology names all the important concepts in biomedicine. One approach to creating a more comprehensive biomedical terminology is to merge existing biomedical terminologies, as the UMLS( Metathesaurus( has done for the last six years. Because existing terminologies may overlap--for example, one terminology may name a concept also named by another terminologyQthe terminologies in the Metathesaurus must be merged. Some terminologies suggest merges through their structure or content e.g., they suggest synonyms or connections to other terminologies; other merges can be suggested by algorithm. Regardless, all merges in the Metathesaurus must be approved by a human editor with appropriate domain knowledge. By the time Meta-U96 is released early in 1996, one prototype and seven released versions of the Metathesaurus will have been produced by a sequence of four qualitatively different methods, named for the way in which they merge terms: #1 "Term Rewrite Rules, #2 "Transitive Closure on Facts," #3 "Fact-at-a-Time Concept Merging," and #4 "Action-at-a-Time Object Processing." The development of each method has been constrained by the annual Metathesaurus release schedule. The first two methods made the best use of limited computational resources, and the last two make better use of human editing resources.

For sequential studies of patients with brain tumors, the authors have designed an automated registration procedure for intra- and interexamination alignment of magnetic resonance images. This was evaluated with artificially misregistered data and data from repeat studies of six healthy volunteers and six brain tumor patients. In a subset of cases, a manual procedure based on matching of neuroanatomic landmarks was also applied for comparison. The results showed that the technique is robust and reproducible, giving an accuracy in the range of 1-2 mm, which corresponded to the spatial resolution of the images. Subject motion between imaging sequences within the same study was negligible, although adjustments (one to two section thicknesses) were required in the z direction to correlate multisection and volume images and to allow accurate image segmentation. For alignment between sequential volunteer and patient examinations, translations of up to 22 mm and rotations in the x, y, and z axes of up to 9 degrees were required. This alignment procedure may be valuable in numerous aspects of treatment planning and patient follow-up.

We examined the immunopathology and the expression of human immunodeficiency virus type 1 (HIV-1) in lumbosacral dorsal root ganglia (DRGs) from 16 patients with acquired immunodeficiency syndrome (AIDS) and 10 HIV-1-seronegative controls. Using in situ hybridization, we detected HIV-1 RNA in a few perivascular cells in DRGs from five of 16 AIDS patients (31%). In addition, using polymerase chain reaction, we detected HIV-1 DNA more frequently in DRGs from four of five AIDS patients (80%) examined. We detected interleukin-6 (IL-6) immunoreactivity in endothelial cells in DRGs from seven of 16 AIDS patients (44%) but from none of 10 HIV-1-seronegative controls (0%). We found more nodules of Nageotte, CD8+ T lymphocytes, and intercellular adhesion molecule-1 (ICAM-1)-positive endothelial cells and mononuclear cells in DRGs from AIDS patients than in DRGs from controls. Increased numbers of nodules of Nageotte in DRGs of AIDS patients were associated with detection of HIV-1 RNA by in situ hybridization and detection of IL-6 by immunohistochemistry. We conclude that low levels of replication of HIV-1, through cytotoxic T lymphocytes or expression of cytokines, may play a role in the subclinical degeneration of sensory neurons frequently observed in DRGs of AIDS patients.

The mechanisms by which human immunodeficiency virus (HIV) infection provokes progressive neurodegeneration and dementia in acquired immunodeficiency syndrome (AIDS) remain obscure. In HIV-infected (HIV+) individuals, we found that the brain cells preferentially infected by HIV, viz. the microglia, were abundant, activated, and intensely immunopositive for interleukin-1 alpha (IL-1 alpha), an immune response-generated cytokine that increases the synthesis and processing of beta-amyloid precursor proteins (beta-APP) and promotes proliferation and activation of astroglia. We also found an increase in the number of activated astroglia expressing elevated levels of S100 beta, a cytokine that increases intraneuronal calcium levels and promotes excessive growth of neuronal processes (neurites). These glial changes were accompanied by increased expression of beta-APP immunoreaction product in neurons and overgrown (dystrophic) neurites. In addition, some neurons contained monoclonal antibody Tau-2 immunopositive, neurofibrillary tangle-like structures. Our findings provide evidence that glial activation with increased expression of IL-1 alpha and S100 beta may be important in the neuropathogenesis of AIDS dementia. We propose that HIV infection promotes excessive microglial IL-1 alpha expression with consequent astrogliosis and increased expression of S100 beta. Overexpression of these two cytokines may then be involved in AIDS neuropathogenesis by inducing gliosis, growth of dystrophic neurites, and calcium-mediated neuronal cell loss in AIDS.

The Metathesaurus is a machine-created, human edited and enhanced synthesis of authoritative biomedical terminologies. Its formal properties permit it to be a) exploited by computers, and b) modified and enhanced without compromising that usage. If further constraints were imposed on the existence and identity of Metathesaurus relationships, i.e., if every Metathesaurus concept had a "genus" and a "differentia," then the Metathesaurus could be converted into an "Aristotelian Hierarchy." In this sense, a genus is a concept that classifies another concept, and a differentia is a concept that distinguishes the classified concept from all other concepts in the same class. Since, in principle, these constraints would make the Metathesaurus easier to leverage and maintain computationally, it is interesting to ask to what degree the maintenance and enhancement procedures now in place are producing a Metathesaurus that is also an "Aristotelian Hierarchy." Given a liberal interpretation of the current Metathesaurus schema, the proportion of the Metathesaurus that is "Aristotelian" in each annual version is increasing in spite of dramatic concurrent increases in the number of Metathesaurus concepts. Without formality there is no modifiability nor scalability. [1] We need formal methods and computer-based tools that can help us with the task [of controlled medical vocabulary construction]. We need research in which controlled vocabulary development is the focus rather than a stepping stone for work on other theories and applications. [2]

We will argue that 'sharing', 're-use', 're-purposing', and 'addition' of health care information is difficult, intrinsically; that the best way to overcome the difficulty is to start doing it, as soon as possible, and that the UMLS Knowledge Sources provide the best place to start. We recommend that the UMLS be used as a default source of biomedical concept names and relationships, as a comprehensive, data-based, 'reference model', and as an example of a large, ecumenical, evolving, continuously updated source of re-usable health care information.

Purpose: Image-guided, single-voxel, localized proton magnetic resonance (MR) spectroscopy was performed to assess white matter in childhood adrenoleukodystrophy (ALD)., Materials and Methods: Eleven X-linked ALD subjects, seven with neurologic symptoms or white matter lesions at MR imaging and four asymptomatic patients, were compared with nine aged-matched, healthy volunteers., Results: Compared with those from normal white matter, MR spectra from white matter lesions (n = 6) showed 65% reduction in the ratio of N-acetyl aspartate (NAA) to total creatine (tCr) (P < .01); 55% increase in the ratio of choline-containing compounds (Cho) to tCr (P < .02); substantial levels of tCr; 94% increase in the ratio of glutamate, glutamine, or inositol to tCr (P < .02); and lactate accumulation in four patients. Patients without brain lesions (n = 4) exhibited a 51% increase in Cho-to-tCr ratio (P < .01) and 11% nonsignificant increase in NAA-to-tCr ratio., Conclusion: Proton MR spectroscopy may prove a valuable technique for noninvasive diagnostic and prognostic assessment of ALD.

Children with AIDS frequently have neurological manifestations due to complications of immunodeficiency or intrinsic effects of human immunodeficiency virus type 1 (HIV-1) on the central nervous system (CNS). The most common neurological disorders not directly related to HIV-1 infection include cerebrovascular disease and lymphoma. Global anoxic-ischemic and necrotizing encephalopathies are frequent, while CNS hemorrhages and arteriopathies are less frequent. Opportunistic CNS infections are uncommon, limited predominantly to monilial and cytomegaloviral encephalitides. Only a few cases of CNS toxoplasmosis have been reported in children. CNS lymphomas often occur in the setting of systemic polymorphous, polyclonal B-cell proliferations that have been associated with Epstein-Barr virus infection. Intrinsic effects of HIV-1 on the CNS include microcephaly, diffuse gliosis, basal ganglia mineralization, HIV encephalitis, and corticospinal tract degeneration. Although viral antigens can be detected in microglia and multinucleated cells in HIV encephalitis, most of the CNS effects of HIV-1 infection cannot be attributed to detectable levels of viral antigen, suggesting that the pediatric CNS is unusually susceptible to low-level HIV-1 infection or to systemic effects of HIV-1 infection, possibly mediated by soluble factors, including the inflammatory cytokines, interleukin-1 beta, and tumor necrosis factor-alpha, which have been shown to be increased in serum and cerebrospinal fluid of children with AIDS.

Left ventricular (LV) volumes and mass were evaluated in 10 healthy volunteers with breath-hold cine magnetic resonance (MR) imaging. The results were compared with those obtained with conventional cine MR imaging. The breath-hold studies showed no ghosting artifact, and cardiac edges were clearly identified because of the reduced blurring. Measurements of LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV mass obtained with breath-hold cine MR imaging showed close correlation with those obtained with conventional cine MR imaging (r = .98, .97, and .99, respectively). The interobserver variabilities for LVEDV, LVESV, and LV mass determined with breath-hold cine MR imaging (4.0%, 8.0%, and 3.7%, respectively) were equal to or less than those determined with conventional cine MR imaging (4.0%, 8.6%, and 5.0%, respectively). The authors conclude that breath-hold cine MR imaging is highly useful because an accurate assessment of cardiac function is obtained in less than 5 minutes.

T1 relaxation times of PCr and beta-ATP in human cardiac and skeletal muscle were evaluated using a variable nutation method. This allows T1 measurements with a constant TR and a significant reduction in acquisition time compared with the partial saturation method. Four 1D CSI datasets were obtained using 30 degrees, 45 degrees, 60 degrees, and 90 degrees BIR-4 adiabatic RF pulses within 40 min. The T1 of the phosphate phantom obtained with this method agreed with values obtained with the partial saturation method. The T1s of PCr and beta-ATP in heart are 3.98 +/- 0.18 s and 1.86 +/- 0.16 s (mean +/- SE). Our results demonstrated that T1 values in heart and skeletal muscle are not significantly different.

Most care-giver "knowledge" needs arise at the point of care and are "patient-centered." Many of these knowledge needs can be met using existing on-line knowledge sources, but the process is too time-consuming, currently, for even the computer-proficient. We are developing a set of public domain standards aimed at bringing potentially relevant knowledge to the point of care in a straight-forward and timely fashion. The standards will a) make use of selected items from a Computer-based Patient Record (CPR), e.g., a diagnosis and measure of severity, b) anticipate certain care-giver knowledge needs, e.g., "therapy," "protocols," "complications," and c) try to satisfy those needs from available knowledge sources, e.g., knowledge-bases, citation databases, practice guidelines, and on-line textbooks. The standards will use templates, i.e., fill-in-the-blank structures, to anticipate knowledge needs and UMLS Metathesaurus enhancements to represent the content of knowledge sources. Together, the standards will form the specification for a "Knowledge-Server" (KS) designed to be accessed from any CPR system. Plans are in place to test an interim version of this specification in the context of medical oncology. We are accumulating anecdotal evidence that a KS operating in conjunction with a CPR is much more compelling to users than either a CPR or a KS operating alone.

Can new medical knowledge be recognized computationally? We know knowledge is changing, and our knowledge-based systems will need to accommodate that change in knowledge on a regular basis if they are to stay successful. Computational recognition of these changes seems desirable. It is unlikely that low level objects in the computational universe, bits and characters, will change much over time, higher level objects of language, where meaning begins to emerge, may show change. An analysis of ten arbitrarily selected paragraphs from the Medical Knowledge Self-Assessment Program of the American College of Physicians was used as a test bed for nominal phrase recognition. While there were words not known to Meta-1.2, only 8 of the 32 concepts new to the primary author were pointed to by new words. Use of a barrier word method was successful in identifying 23 of the 32 new concepts. Use of co-occurrence (in sentences) of putative nominal phrases may reduce the amount of human effort involved in recognizing the emergence of new relationships.

Objective: The presence of HIV-1 in postmortem brain tissue from 31 patients with AIDS and 12 HIV-1-negative controls was investigated., Design: Most laboratories have access to the methods used. We readily applied in situ hybridization and immunohistochemistry to archival formalin-fixed paraffin-embedded (FFPE) brain specimens., Methods: The techniques used to detect HIV-1 were explant culture, in situ hybridization with 35S-labeled polymerase (pol) gene riboprobes and immunohistochemistry with monoclonal antibody to gp41., Results: HIV-1 was isolated from explant cultures in 13 out of 20 (65%) patients, whereas HIV-1-infected cells were detected in FFPE brain tissue from nine out of 26 (35%) patients examined by in situ hybridization and in seven out of 26 (27%) patients examined by immunohistochemistry., Conclusions: Although the isolation technique was the most sensitive of the three techniques tested, infected cells may be identified with in situ hybridization in conjunction with immunohistochemistry.

Two-dimensional phosphorus chemical shift imaging (2D-31P-CSI) was used to investigate macroscopic heterogeneity within the flexor digitorum profundus (FDP) muscle of the human forearm during exercise. Subjects performed low-frequency steady-state finger flexion exercise at submaximal work levels using a bulb ergometer. The number of fingers actively involved in finger flexion exercise was varied in a total of 12 experiments. Active muscles could be determined by the increase of Pi and decrease of phosphocreatine observed in the localized spectra. Within the FDP, regions of active and inactive fibers were significantly different in levels of Pi and phosphocreatine (P less than 0.01) during flexion of individual fingers. Individual flexion of the index finger was found to involve only fibers in the deep region of the FDP. Fibers in the central region were found to be involved in flexion of the middle finger, and fibers in the superficial region were involved in flexion of the ring and little fingers. The results of this study demonstrate the potential of 2D-31P-CSI for in vivo investigation of intramuscular heterogeneity in human skeletal muscle.

Dioxapyrrolomycin, pyrrolomycin C, pyrrolomycin D, and piericidin C2 produced by UC 11065 were evaluated as anthelmintics. Assays used to examine these compounds included effects on the free-living nematode Caenorhabditis elegans, ability to clear target nematodes (Haemonchus contortus and Trichostrongylus colubriformis) from jirds, and clearance of Haemonchus contortus from lambs. A crude extract of UC 11065 containing dioxapyrrolomycin, pyrrolomycin C, pyrrolomycin D, and piericidin C2 was active against C. elegans and against H. contortus in the jird. Purified and/or synthetic samples of dioxapyrrolomycin, pyrrolomycin C, pyrrolomycin D, and piericidin C2 were tested in the jird model; only dioxapyrrolomycin exhibited appreciable activity against H. contortus (greater than or equal to 90.9% clearance at 0.33 mg/jird), while none of the compounds showed appreciable activity against T. colubriformis. Dioxapyrrolomycin cleared 99.9% of H. contortus from lambs at 12.5 mg/kg. An in vitro migration study using susceptible and closantel-resistant H. contortus showed there is cross-resistance between dioxapyrrolomycin and closantel. Dioxapyrrolomycin appears to be a narrow-spectrum anthelmintic which works through a closantel-like mode-of-action.

The application of spectroscopy techniques to the study of normal and pathological tissue is currently limited by the difficulties of acquiring precisely localized spectra and analyzing the resulting, relatively low signal-to-noise data. Interpretation of multivoxel spectroscopy data is greatly facilitated by estimating peak parameters and representing their spatial distribution as metabolite images. We present here the new algorithm MIMSTATS, which performs an analysis of these images and determines whether the variations in the images are statistically significant. The algorithm has been developed and tested by application to 31P CSI data from the human forearm and brain. Our results demonstrate that MIMSTATS can detect signal at a very low signal-to-noise ratio in a reliable and reproducible fashion and provides a sound basis for testing hypotheses concerning differences in distribution of metabolites.

Disseminated histoplasmosis (DH) and progressive multifocal leukoencephalopathy occur in acquired immunodeficiency syndrome (AIDS). At autopsy, DH patients with central nervous system involvement almost always show extensive involvement of the lungs and reticuloendothelial system in addition to the brain, and progressive multifocal leukoencephalopathy is manifest as multiple demyelinating lesions in several locations in the brain. We describe an AIDS patient with a long history of aggressively treated DH who died with DH in the brain only; fungus was not found elsewhere at autopsy. In addition, there was a papovavirus infection restricted to the cerebellum with predominant involvement of the internal granular cell layer; again, demyelinating lesions were not found elsewhere in the brain. Each of these patterns of brain involvement is rare. As the incidence of AIDS increases and patients are treated aggressively, the frequency of unusual neuropathologic patterns of opportunistic infections may be expected to increase.

Plasma membrane vesicles, purified by aqueous two-phase partitioning, were used to investigate the presence of sugar and amino acid carriers in cotyledons and roots of Ricinus communis L. and in roots of red beet (Beta vulgaris L.). Artificial pH and electrical gradients were generated across the plasma membrane, and [(14)C]acetate and [(14)C]tetraphenylphosphonium were used to demonstrate the presence of an internal alkaline pH gradient and an internal negative membrane potential, respectively. In Ricinus cotyledons, uptake of sucrose was more strongly inhibited than that of glutamine by p-chloromercuribenzenesulphonic acid, phlorizin and phenylglyoxal. The sucrose transport system showed a high degree of substrate specificity with only the presence of maltose and phenyl-α-glucoside significantly affecting sucrose uptake; in contrast, the glutamine transport system was inhibited by a number of other amino acids. ΔpH+gDψ-driven glutamine uptake showed saturation kinetics with a K m of 0.35 mol · m(-3). Sucrose and glutamine Δψ-driven uptake was pH dependent with an optimum in the acidic range (pH 6.25) and a decrease at higher pH values. Vesicles obtained from cotyledons and roots of Ricinus showed different transport properties. In the cotyledons, gDH+gDψ-driven transport for both sucrose and glutamine were observed at similar levels; however, in the root tissue, δpH-Δψ-driven glutamine transport was the dominant uptake process. Uptake rates for glucose and fructose were low in the cotyledons whereas, in the roots, glucose and sucrose transport were slightly higher than that of fructose. In vesicles from red beet tissue there was a different uptake profile, with evidence of proton-coupled cotransport systems for sucrose and glucose, but lower uptake of glutamine and fructose. The results are discussed in relation to the reported different pathways for loading and unloading of solutes in these tissues.

Meta-1.1, the UMLS metathesaurus, represents medical knowledge in the forms of names of concepts and links between those concepts. The representations of the semantic neighborhood of a concept can be thought of as dimensions of the property of semantic locality and include term information (broader, narrower, or otherwise related), the contextual information (parent-child, siblings in a hierarchy), the semantic types, and the co-occurrence data (links discovered empirically from concepts used to index the medical literature.) The degree of redundancy of each of these dimensions was investigated by reviewing the extent of multiple presentations of concepts which appear as related to a given concept. The degree of overlap was surprisingly small. While the co-occurrence data finds some of the links represented by other dimensions, those links are but minute fractions of the vast amount of co-occurrence derived links. Because parent-child relationships are often subsumptive (or categorical) in nature, it might be expected that siblings usually share the same semantic types. While true in the aggregate, the wide variance in percent of types shared may reflect the intended usages of the source vocabularies. Noun phrases were extracted from the definitions of 40 concepts in Meta-1 in order to assess systematically the coverage of important concepts by Meta-1, and to assess whether the links between these definitional concepts, which may have special value, and the concept being defined were indeed present. Out of 161 of these definitional concepts, 29 were not represented in Meta-1, and 37 of those represented in Meta-1 had no direct link to the concept they were defining.(ABSTRACT TRUNCATED AT 250 WORDS)

In the ten year period 1980-1989, 97 patients were treated for tropical pyomyositis at Hospital Vozandes Oriente in eastern Ecuador, accounting for 2.2% of surgical admissions. Operation records from an affiliated hospital in Quito showed that, high on the Andean plateau, pyomyositis accounted for only 0.1% of surgical admissions. Among the patient population of Ecuador's eastern tropical rain forest, persons who were members of an indigenous ethnic group were affected with pyomyositis twice as often as would be expected from their representation in the general population.

Using ferritin as a marker of reactive microglia, we demonstrated a close association between proliferation of reactive microglia and expression of human immunodeficiency virus type 1 (HIV-1) in brain tissue from autopsied cases of acquired immunodeficiency syndrome (AIDS). An increased number of ferritin-positive reactive microglia was observed in formalin-fixed paraffin-embedded brain sections from all 13 AIDS cases examined. Similar findings were observed in brain tissue from other neurological diseases (subacute sclerosing panencephalitis, herpes simplex encephalitis and multiple sclerosis). Multinucleated giant cells were found in 7 of the AIDS cases which were also intensely labeled for ferritin. Dual-label immunohistochemistry using anti-ferritin and cell-specific markers showed that ferritin-positive cells were distinct from astrocytes, neurons and endothelia using anti-glial fibrillary acidic protein (anti-GFAP), anti-neurofilament protein and Ulex europaeus agglutinin 1, respectively. In 5 AIDS brains, only ferritin-positive cells were shown to contain HIV-1 gp41 antigen using dual-label immunohistochemistry. In addition, HIV-1 RNA was localized in ferritin-positive reactive microglia but not in GFAP-positive astrocytes using immunohistochemistry combined with in situ hybridization. Ferritin-positive reactive microglia and multinucleated giant cells were co-labeled with the microglial marker, Ricinus communis agglutinin 1 (RCA-1). However, RCA-1 also extensively stained resting microglia only a few of which were co-labeled for ferritin. The density of ferritin-positive cells was correlated with the presence of HIV-1 RNA-positive cells in AIDS brain. Thus, ferritin immunoreactivity can be used as an activation marker of microglia in archival paraffin sections and reflects the extent of inflammation in HIV-1-infected brain.

The third version of the UMLS Metathesaurus, Meta-1.2, to be released in October 1992, will have a simpler schema and simpler distribution formats than the first two versions, Meta-1.0 and Meta-1.1 released in October 1990 and 1991, respectively. For one thing, it will have only a single kind of entry (Concept), rather than three (Concept, Related, and Synonym). Further, the Relational Format, will consist of four logical relations, or tables, instead of the nearly three score different tables used to represent the same kind of information in Meta-1.1. These four tables will contain, respectively, (1) the names of each concept, (2) the relationships between concepts, (3) attributes of the concepts, and (4) a word-based index into the concept names. We argue that the new schema and formats provide a better conceptual model of the Metathesaurus, and represent the information contained there more uniformly. Even though these changes are incremental and evolutionary, both users and software developers should find the Meta-1.2 significantly easier to understand, and the information contained in it significantly easier to use.

Localized variations in metabolites in resting and exercising skeletal muscle have been studied using Chemical Shift Imaging (CSI) techniques to obtain 2-D arrays of 31P NMR spectra from a slice through the human forearm. The excitation profile of the coil resulted in a slice thickness of ca 80 mm and the planar resolution of the CSI data corresponded to either 7, 10 or 14 mm. The metabolite information was represented both as 2-D arrays of spectra and by constructing images of the spatial distribution of different metabolites. Correlation with the anatomy was clearly visualized by overlaying the metabolite images on the appropriate region of the corresponding proton images. At rest, significant variations in the intensity of Pi, phosphocreatine (PCr) and ATP were observed in different regions of the arm. Our planar spatial and temporal (1-9 min) resolution was also sufficient to follow changes in Pi, PCr and pH in response to exercise. These changes were restricted to the exercising muscle and demonstrated heterogeneity both in the kinetics and magnitude of response between different muscles.

We describe a system for stereotactic radiosurgery with a linear accelerator. This technique allows treatment of small (less than 40 mm diameter) intracranial lesions, including vascular malformations, and primary and metastatic tumors that are deep within the brain or in areas not amenable to open surgery. A beam of ionizing radiation (1800 to 2500 cGy) is focused on the center of the lesion, which is determined by stereotactic localization. "Dynamic rotation" of the linac gantry and table continuously about this predetermined point ensures that only the lesion receives the full radiation dose, while the normal structures in the head receive minimal amounts of radiation. The system combines, for the first time in one place, elements of radiosurgical technique developed at various centers. Testing for accuracy compares favorably with results at other centers using linac-based systems as well as comparing favorably with the gamma knife.

We have studied a series of normal subjects and patients with brain tumors, by using 31P three-dimensional chemical shift imaging to obtain localized 31P spectra of the brain. A significant proportion of brain cytosolic ATP in normal brain is not complexed to Mg2+, as indicated by the chemical shift delta of the beta-P resonance of ATP. The ATP beta-P resonance position in brain thus is sensitive to changes in intracellular free Mg2+ concentration and in the proportion of ATP complexed with Mg because this shift lies on the rising portion of the delta vs. Mg2+ titration curve for ATP. We have measured the ATP beta-P shift and compared intracellular free Mg2+ concentration and fractions of free ATP for normal individuals (n = 6) and a limited series of patients with brain tumors (n = 5). In four of the five spectra obtained from brain tissue containing a substantial proportion of tumor, intracellular free Mg2+ was increased, and the fraction of free ATP was decreased, compared with normal brain.

A computer-assisted procedure has been developed to apply the main chain directed (MCD) assignment strategy to the analysis of 1H NMR spectra of proteins. The underlying mathematical foundation of this procedure, termed MCDPAT, is presented. MCDPAT is based upon the expanded library of MCD patterns defined previously (A.J. Wand and S.J. Nelson. 1991. Biophys. J. 59:1101-1112), and has been evaluated with both simulated and experimental data from the protein ubiquitin. The influence of the precision, spectral variation, and inherent degeneracy upon the design of the procedure is explored. Several approaches have been taken to overcome the uncertainty introduced by these variables. These include a hierarchical approach to both primary pattern recognition and subsequent construction of MCD-defined units of secondary structure. It is shown that the MCDPAT procedure, in conjunction with automated statistically based spectral analysis, leads to the successful MCD assignment of the protein ubiquitin. The implications and limitations of this approach are discussed.

The underlying basis of the main chain directed (MCD) resonance assignment strategy for the analysis of 1H NMR spectra of proteins is reexamined. The criteria used in the construction of the patterns used in the MCD method have been extended to increase the robustness of the approach to the presence of variable protein secondary structure and significant spectral degeneracy. These criteria have led to the development of several dozen patterns exclusively involving the short distance relationships between main chain amide NH-C alpha-H-C beta H (NAB) J-coupled subspin systems of the amino acid residues. The MCD patterns have been examined for fidelity and frequency of occurrence in a database composed of the high resolution crystal structures of 39 proteins. The analysis has identified several extremely robust patterns, suitable for initiating a hierarchical construction of units of secondary structure based upon a systematic analysis of two-dimensional nuclear Overhauser effect spectra. A formal procedure, suitable for the computer assisted application of the MCD strategy, is developed. This procedure, termed MCDPAT, has been applied to the analysis of the crystal structures of human ubiquitin, T4 lysozyme, and ribonuclease A. It has been found that the MCDPAT procedure is conservative producing no significant errors and is globally successful in correctly identifying the appropriate units of secondary structure contained in these three proteins.

Mechanical analyses supporting various and prevailing stomatognathic concepts of occlusal function are sparse. This study, using a mechanical model, simulates a system in function and provides a vectorial analysis based on a static equilibrium of forces generated in a mandible at 10 different positions. The positions analyzed were one in centric occlusion and nine in eccentric positions. Four eccentric positions were in a balanced occlusal relationship and five were in group function. Among other conclusions that were drawn, the most relevant seems to be the finding that cusp inclines and condylar path inclination have a profound influence on the forces acting within the joints and dentition.

Members of the herpesvirus family, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and herpes simplex virus (HSV), have been recognized as causal agents of chorioretinal inflammatory diseases. We investigated the use of the polymerase chain reaction for the detection of CMV, HSV, and EBV genomes in aqueous, subretinal fluid, and vitreous specimens in patients with clinically diagnosed CMV retinitis. Cytomegalovirus but not HSV or EBV genomic sequences were detected in all of these clinical specimens. We also investigated 18 normal aqueous and eight normal vitreous specimens obtained from patients undergoing cataract or vitrectomy surgery. Cytomegalovirus, HSV, and EBV DNA were not detected in any of the normal aqueous specimens. There was one weakly positive CMV normal vitreous, but none was HSV or EBV positive by the polymerase chain reaction. These results indicate that the polymerase chain reaction may be useful as a rapid and sensitive diagnostic technique to aid in the confirmation of clinical observations.

The National Library of Medicine's Unified Medical Language System [1] Metathesaurus contains the richest single corpus of biomedical names in existence. Yet, developers wishing to make use of the Metathesaurus will be confronted by users who want to add local terminology and relationships not already represented there. We urge developers to fill those needs, while, at the same time, they plan for the many consequences of unilateral Metathesaurus enhancement. Foremost among these consequences is the need to maintain local enhancements across subsequent releases of the Metathesaurus. These problems are illustrated via examples of candidate Metathesaurus enhancement terms in use at the Columbia-Presbyterian Medical Center (CPMC), at the Mayo Clinic, and in Current Disease Descriptions (CDD). Sharing and reuse of Metathesaurus enhancement methods may permit local enhancements to be used at other sites, and it may permit the global Metathesaurus utilization effort to benefit from economies of scale.

The Unified Medical Language System Metathesaurus represents the results of a synthesis of existing biomedical naming systems (thesauri). The naming and other information about the meanings in the Metathesaurus can be used to find the preferred naming of that meaning in the source chosen by the user, by exploiting the property of semantic locality. The aspects of semantic locality in the Metathesaurus which can be thus exploited are the terms, the semantic types, the use of that term in a source context, and the co-occurrence of terms in MEDLINE. To find how a meaning is named in the source of choice, a user must exploit one of these aspects of semantic locality, entering a term somehow related to the term being sought, and navigating to the preferred term. While the first three of these aspects of semantic locality are normative, the last is empirical. Testing of the utility of the aspects of semantic locality in information retrieval would require a uniform interface with 1, no Metathesaurus, 2, the Metathesaurus without the aspects in question, and 3, the Metathesaurus including all the aspects. Other potential uses of empirically derived semantic locality include defining or suggesting potentially relevant concepts in a given situation.

The linkage of disparate biomedical databases is an important goal of the Unified Medical Language (UMLS) Project. We conducted an experiment to investigate the feasibility of using UMLS resources to link databases in clinical genetics and molecular biology. References from MIM ("Mendelian Inheritance in Man") were lexically mapped to the equivalent citations in MEDLINE. The MeSH major subject headings by which the citations in a particular MIM entry had been indexed were used to develop a "genetic-disorder-centered view of the world" in Meta-1 (the first official version of the UMLS Metathesaurus). Our hypothesis was that these MeSH subject headings could provide access to a "semantic neighborhood" in Meta-1 that would be relevant to a particular genetic disorder. By browsing in this "semantic neighborhood," a user could select various combinations of terms with which to search MEDLINE through an interface between Meta-1 and Grateful Med. Such searches might retrieve citations that were more recent than those in MIM or that provided useful supplementary information. Since some MEDLINE records contain pointers to entries in GENBANK, information about genetic sequences related to a particular clinical genetic disorder could also be retrieved. This scenario was implemented for a small number of MIM entries, providing a concrete demonstration that linking disparate electronic databases in an important subdomain of biomedicine is relatively straightforward.