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Biomedical subjects

R M Levy

Publications and source records attributed to R M Levy.

At least 19 recordsLinked to original sources
PubMed1996

Cytomorphology of progressive multifocal leukoencephalopathy (PML): review of sixteen cases occurring in HIV-positive patients.

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disorder of the central nervous system (CNS) resulting from infection of oligodendrocytes by JC virus. Although all patients immunocompromised by any congenital, acquired, or iatrogenic condition are at risk, the population which currently accounts for the majority of new cases is that infected with the human immunodeficiency virus (HIV). Though the clinical/radiologic presentation is characteristic, biopsy confirmation is necessary, as these patients are at risk for other primary CNS disorders which may produce similar clinical findings. Immediate assessment of tissue adequacy by cytologic smear is generally preferred in these specimens due to its relative reduced risk of disease transmission when compared to conventional frozen section. We report here the cytologic findings seen in touch imprints and squash preparations of 16 cases of PML, all occurring in HIV-positive patients and obtained by stereotactic guided needle biopsy. Typical cytomorphologic findings are described and correlated with histologic sections. In addition, features useful in the exclusion of other differential diagnostic possibilities are discussed.

Adult↗
PubMed1995

A relaxation-matrix analysis of distance-constraint ranges for NOEs in proteins at long mixing times.

Long-mixing-time data (tau m > 200 ms) from NOE spectra have largely been ignored as a source of protein structural information due to the effects of spin diffusion on calculated interproton distances when using the two-spin approximation. An effective approach for incorporating spin-diffusion effects in an average way into refinements is to choose distance bounds based on distributions of distances observed in NOE back calculations on homologous proteins from a protein structure database. We have determined distributions of interproton distances characteristic of newly observed NOE cross peaks for the proteins crambin, PTI, and echistatin at long mixing times. A relaxation-matrix analysis was used to model the effects of spin diffusion. Constraint ranges were constructed from the interproton distance distributions which can be used in standard protein-refinement programs based on the two-spin approximation. Back calculations are also used to analyze constraint ranges typically used for protein structure determinations based on NOE spectra at shorter mixing times.

Electron Spin Resonance Spectroscopy↗
PubMed1995

Crankshaft motions of the polypeptide backbone in molecular dynamics simulations of human type-alpha transforming growth factor.

Order parameters for the backbone N-H and C alpha-H bond vectors have been calculated from a 150 ps molecular dynamics (MD) simulation of human type-alpha transforming growth factor in H2O solvent. Two kinds of 'crankshaft motions' of the polypeptide backbone are observed in this MD trajectory. The first involves small-amplitude rocking of the rigid peptide bond due to correlated changes in the backbone dihedral angles psi i-1 and phi i. These high-frequency 'librational crankshaft' motions are correlated with systematically smaller values of motional order parameters for backbone N-H bond vectors compared to C alpha-H bond vectors. In addition, infrequent 'crankshaft flips' of the peptide bond from one local minimum to another are observed for several amino acid residues. These MD simulations demonstrate that comparisons of N-H and C alpha-H order parameters provide a useful approach for identifying crankshaft librational motions in proteins.

Amino Acid Sequence↗
PubMed1995

A comparison of intrathecally administered narcotic and nonnarcotic analgesics for experimental chronic neuropathic pain.

The antinociceptive actions of morphine and tizanidine (an alpha 2-adrenergic agonist) administered intrathecally in a rat model of mononeuropathic pain were investigated. Tizanidine increased to normal levels the intensity of a noxious pressure stimulus required to induce paw withdrawal (p < 0.01) and decreased the duration of limb withdrawal from both normal-temperature and cooled floors in a dose-dependent manner (p < 0.01). Tizanidine had virtually no effect on the latency of paw withdrawal from a noxious heat stimulus. In comparison, morphine significantly decreased, in a dose-dependent manner, limb withdrawal from the normal-temperature and cooled floors and increased to cutoff values the withdrawal latencies of both noxious heat and pressure stimuli (p < 0.01). The effect of tizanidine was limited to the hyperalgesic limb and served to normalize reactive latencies, whereas morphine affected both hindlimbs and increased latencies to supranormal cutoff values. These data suggest that intrathecal tizanidine may be more specific than morphine in reversing the allodynia and hyperpathia associated with neuropathic pain states and may be of value in the management of patients with these clinical syndromes.

Analgesics↗
PubMed1994

Intrinsic pKas of ionizable residues in proteins: an explicit solvent calculation for lysozyme.

Molecular dynamics simulations of triclinic hen egg white lysozyme in aqueous solution were performed to calculate the intrinsic pKas of 14 ionizable residues. An all-atom model was used for both solvent and solute, and a single 180 ps simulation in conjunction with a Gaussian fluctuation analysis method was used. An advantage of the Gaussian fluctuation method is that it only requires a single simulation of the system in a reference state to calculate all the pKas in the protein, in contrast to multiple simulations for the free energy perturbation method. pKint shifts with respect to reference titratable residues were evaluated and compared to results obtained using a finite difference Poisson-Boltzmann (FDPB) method with a continuum solvent model; overall agreement with the direction of the shifts was generally observed, though the magnitude of the shifts was typically larger with the explicit solvent model. The contribution of the first solvation shell to the total charging free energies of the titratable groups was explicitly evaluated and found to be significant. Dielectric shielding between pairs of titratable groups was examined and found to be smaller than expected. The effect of the approximations used to treat the long-range interactions on the pKint shifts is discussed.

Amino Acids↗
PubMed1994

Three-dimensional structure of echistatin and dynamics of the active site.

The snake venom protein echistatin contains the cell recognition sequence Arg-Gly-Asp and is a potent inhibitor of platelet aggregation. The three-dimensional structure of echistatin and the dynamics of the active RGD site are presented. A set of structures was determined using the Distance Geometry method and subsequently refined by Molecular Dynamics and energy minimization. Disulfide pairings are suggested, based on violations of experimental constraints. The structures satisfy 230 interresidue distance constraints, derived from nuclear Overhauser effect measurements, five hydrogen-bonding constraints, and 21 torsional constraints from vicinal spin-spin coupling constants. The segment from Gly5 to Cys20 and from Asp30 to Asn42 has a well-defined conformation and the Arg-Gly-Asp sequence, which adopts a turn-like structure, is located at the apex of a nine-residue loop connecting the two strands of a distorted beta-sheet. The mobility of the Arg-Gly-Asp site has been quantitatively characterized by 15N relaxation measurements. The overall correlation time of echistatin was determined from fluorescence measurements, and was used in a model-free analysis to determine internal motional parameters. The active site has order parameters of 0.3-0.5, i.e., among the smallest values ever observed at the active site of a protein. Correlation of the flexible region of the protein as characterized by relaxation experiments and the NMR solution structures was made by calculating generalized order parameters from the ensemble of three-dimensional structures. The motion of the RGD site detected experimentally is more extensive than a simple RGD loop 'wagging' motional model, suggested by an examination of superposed solution structures.

Amino Acid Sequence↗
PubMed1994

Molecular mechanics and electrostatic effects.

Continuum solvent models predict a quadratic charge dependence (linear response) of the free energy of a system of charged solutes. The relation between this prediction and the structure of the solvation shell around the solutes is discussed. Studies of the derivative of the free energy with respect to the charges for different reference states are shown to be a convenient way of testing the linear response assumption without resorting to the standard free energy perturbation method. We illustrate this with a system of two oppositely charged ions in aqueous solution, where nonlinearities are observed before the full charging process is completed. Since molecular mechanics (MM) simulations preserve the full nonlinearity of the problem, they are well suited to the investigation of the conditions under which linear response accurately reflects the behavior of the system. The error when using linear response theory to calculate the free energies of charging is estimated to be as large as 10-20%.

Chemical Phenomena↗
PubMed1994

Brain abscess and subdural empyema.

Notable contributions have been made recently in the diagnosis and management of brain abscesses and subdural empyema. Several articles present an international perspective, echoing much of the Western literature, including a profound decrease in mortality with the availability of computed tomography and early recognition and treatment. Diagnostic studies have highlighted the superiority of magnetic resonance imaging to computed tomography in the detection of subdural empyema and the potential value of positron emission tomography. Novel diagnostic tools, including 99mTc-hexamethylpropyleneamine oxime leukocyte scintigraphy and C-reactive protein levels, have been evaluated and show great promise. Surgical studies comparing stereotactic drainage with craniotomy for brain abscesses and burr hole versus craniotomy drainage of subdural empyema suggest the efficacy of these more limited procedures. Local instillation of antibiotics is a potentially effective adjunct for refractory brain abscesses. Recent studies suggest that the most significant predictors of poor outcome are the patient's level of consciousness and the rapidity of disease progression prior to the initiation of treatment.

Brain Abscess↗
PubMed1994

Consensus conference on the neurosurgical management of pain.

On the recommendation of the American Association of Neurological Surgeons Section on Pain, a satellite conference was organized for the 1993 annual meeting to work toward a consensus regarding the indications, expected outcomes, and potential complications of neurosurgical procedures for intractable pain. Twenty-two experts in the field attended this 2-day conference to consolidate our understanding of the role of neurosurgical procedures in pain management and to review critically the methodologies for clinical studies. With the support of the Section on Pain, this consensus development process will continue in order to refine the application and study of neurosurgical procedures for pain.

Algorithms↗
PubMed1993

The neurologic complications of human immunodeficiency virus infection.

The physician caring for HIV-1-infected patients must have a good working knowledge of the broad spectrum of neurologic diseases that occur in association with this infection. As with any other neurologic disorder, the site of the neuraxis that is affected must be properly identified. In HIV-1-infected persons, more than one site may be involved simultaneously, such as the coexistence of myelopathy and peripheral neuropathy, often resulting in a confusing array of neurologic signs and symptoms. The frequent occurrence of two or more diseases affecting the neuraxis, such as progressive multifocal leukoencephalopathy and toxoplasmosis, further complicates the picture. With the AIDS patient, the physician cannot rely on the clinical adage that all attempts should be made to ascribe the patient's problems to one disease. Often, it is not the case. As with other illnesses, the approach to the HIV-1-infected person with neurologic disease needs to be thorough and fluid. After rendering a diagnosis and embarking on therapy, the physician needs to be open minded about the possibility of an incorrect or additional diagnosis not previously considered. Lastly, despite all the knowledge that has been accumulated in the first decade of the AIDS epidemic, new illnesses occurring with HIV-1 infection are recognized with regularity. The physician must always bear in mind that the illness with which he or she is confronted may be one that has not been previously described.

AIDS-Related Opportunistic Infections↗
PubMed1993

Global folding of proteins using a limited number of distance constraints.

A Monte Carlo method is presented which can obtain the correct tertiary fold of a protein given the secondary structure and as few as three interactions between each secondary structure unit. This method was used to fold hemerythrin, flavodoxin, bovine pancreatic trypsin inhibitor and a variable light domain from an immunoglobulin using the known secondary structures of these proteins. Each of the proteins was successfully folded to obtain a structure resembling the initial X-ray structure. Reasonable success was also achieved when using a secondary structure prediction algorithm to assign secondary structure. The r.m.s. deviations between the folded proteins and the crystal structures are in the order of 3-5 A for the backbone coordinates. Evaluation of the r.m.s. deviations between members of the globin family indicates that two equivalent overall folds may have r.m.s. deviations of this or even larger magnitude. The limiting number of constraints necessary to achieve the correct fold is discussed.

Algorithms↗
PubMed1993

Neuromodulation techniques for medically refractory chronic pain.

Advances in our knowledge of the physiology of pain transmission and modulation have created new surgical options for the control of chronic pain. The pain modulation network can be activated by administration of spinal opiates or by electrical stimulation of the nervous system with transcutaneous, peripheral nerve, spinal cord, and deep brain stimulation. The theoretical basis and the clinical applications of neurostimulation for the treatment of medically intractable chronic pain are reviewed.

Chronic Disease↗
PubMed1993

Systemic T-cell lymphoma presenting with isolated neurological dysfunction and intraparenchymal brain lesions. Case report.

Secondary non-Hodgkin's lymphoma of the central nervous system is typically a late manifestation of systemic T-cell lymphoma, with a 2-month median survival time after the development of neurological disease. Of the reported patients with this late complication, only 1% manifest spread of the disease to the brain parenchyma. The authors report a patient with an unusual initial neurological presentation of systemic T-cell lymphoproliferative disorder and associated space-occupying lesions of the brain parenchyma. The diagnosis was supported by extensive molecular, immunological, and histopathological analysis. Neurological symptoms appeared early in the course of systemic disease and were characterized by spontaneous exacerbations and remissions. The patient has survived for more than 5 years since the onset of his neurological symptoms. Histopathological characterization including immunoperoxidase staining for T-cell markers, DNA content, and cell-cycle analysis of brain tissue obtained at stereotactic biopsy were compared to those of atypical lymphoid cells of peripheral blood, bone marrow, and liver. The neurological manifestations and possible etiologies of T-cell lymphoma are discussed.

Adult↗
PubMed1992

Molecular dynamics simulation of solvated protein at high pressure.

We have completed a molecular dynamics simulation of protein (bovine pancreatic trypsin inhibitor, BPTI) in solution at high pressure (10 kbar). The structural and energetic effects of the application of high pressure to solvated protein are analyzed by comparing the results of the high-pressure simulation with a corresponding simulation at low pressure. The volume of the simulation cell containing one protein molecule plus 2943 water molecules decreases by 24.7% at high pressure. This corresponds to a compressibility for the protein solution of beta = 1.8 x 10(-2) kbar-1. The compressibility of the protein is estimated to be about one-tenth that of bulk water, while the protein hydration layer water is found to have a greater compressibility as compared to the bulk, especially for water associated with hydrophobic groups. The radius of gyration of BPTI decreases by 2% and there is a one third decrease in the protein backbone atomic fluctuations at high pressure. We have analyzed pressure effects on the hydration energy of the protein. The total hydration energy is slightly (4%) more favorable at high pressure even though the surface accessibility of the protein has decreased by a corresponding amount. Large pressure-induced changes in the structure of the hydration shell are observed. Overall, the solvation shell waters appear more ordered at high pressure; the pressure-induced ordering is greatest for nonpolar surface groups. We do not observe evidence of pressure-induced unfolding of the protein over the 100-ps duration of the high-pressure simulation. This is consistent with the results of high-pressure optical experiments on BPTI.(ABSTRACT TRUNCATED AT 250 WORDS)

Aprotinin↗
PubMed1992

The efficacy of image-guided stereotactic brain biopsy in neurologically symptomatic acquired immunodeficiency syndrome patients.

A prospective series of 50 neurologically symptomatic human immunodeficiency infected patients with intracranial lesions who underwent image-guided stereotactic brain biopsy is presented. Patients were diagnosed with primary central nervous system lymphoma (14 patients), progressive multifocal leukoencephalopathy (14 patients), toxoplasmosis (13 patients), human immunodeficiency virus encephalitis (3 patients), infarction (2 patients), and 1 patient each with metastatic adenocarcinoma, metastatic melanoma, cryptococcoma, and atypical mycobacterial infection. Two of the patients with toxoplasmosis had a second intracranial abnormality. Two biopsies resulted in either descriptive diagnosis only or were nondiagnostic; the definitive diagnostic efficacy of image-guided stereotactic biopsy was thus 96%. No deaths were incurred as a result of biopsy. Four intraoperative or postoperative hemorrhages occurred; in only 1 patient was there a residual neurological deficit related to the surgery. Image-guided stereotactic biopsy may thus be considered both safe and effective in this patient population.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Progressive multifocal leukoencephalopathy in patients with HIV infection: lack of impact of early diagnosis by stereotactic brain biopsy.

Thirteen patients with HIV-related progressive multifocal leukoencephalopathy (PML), representing an institutional incidence of 4.2%, are reported. All cases were diagnosed by image guided stereotactic brain biopsy shortly after their presentation for neurologic complaints. All patients were males; risk factors included homosexual or bisexual activity or intravenous drug use. At the time of presentation with PML, the mean T4 count was 85 (range 9-240 cells/mm3). The most common neurologic symptoms were cognitive dysfunction and aphasia, whereas gait abnormalities and disordered cognition were the most common neurologic signs. Cerebrospinal fluid analysis was helpful only to rule out other causes of CNS disease. Magnetic resonance imaging, more sensitive than computed tomography (CT) scanning, typically revealed multiple areas of increased intensity on T2 weighted images although unifocal disease was seen in 23% of patients. Despite early stereotactic biopsy and aggressive symptomatic therapy, survival of these patients was poor with a mean of 2.6 months after the onset of neurological symptoms and 2.0 months after biopsy.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Neurosurgical aspects of human immunodeficiency virus infection.

The spectrum of neurologic disease that complicates human immunodeficiency virus (HIV) is extremely broad. This article deals with those HIV-related diseases that may occur with a frequency of more than 1% and are of potential neurosurgical importance: those that result from a direct involvement of the nervous system by HIV and those that result either directly or indirectly from the concomitant immunosuppression. Infectious complications are the most common but not the sole cause of neurologic disability in the latter category. Other causes of neurologic disease seen in association with HIV infection include neoplasms, metabolic-nutritional disorders, and vascular complications.

AIDS Dementia Complex↗