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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
PubMed2005

Colonisation rates of Streptococcus pyogenes and Staphylococcus aureus in the oropharynx of a young adult population.

There are very few reports on the rates of oropharyngeal colonisation by Streptococcus pyogenes and Staphylococcus aureus in young adults. The present study found colonisation rates of 9.6% and 26.2%, respectively. These rates are two-fold higher than historical rates, indicating that these organisms may be more prevalent than thought previously. This finding may have important clinical consequences in certain populations, and requires further investigation.

Adolescent↗
PubMed2001

Performance feedback deficit in geriatric depression.

BACKGROUND: The orbital frontal cortex is involved with processing of performance feedback. This study tests the hypothesis that older depressed subjects, compared with elderly control subjects, commit more subsequent errors after receiving feedback from an initial error. METHODS: We administered 116 older depressed patients and 139 control subjects the Trail Making Test Part B (TRAILS-B). Subjects who committed an error on TRAILS-B were immediately given feedback on performance. We then measured the frequency of making an error on the subsequent three tries. The likelihood of making any subsequent error was examined. RESULTS: After controlling for the overall initial error rate, more depressed patients than control subjects made subsequent errors. This association remained significant in later regression models. When the depressed group was examined in additional models, severity of depression was not associated with increased subsequent errors. CONCLUSIONS: These results extend previous findings suggesting a performance feedback deficit in geriatric depression. The findings support previous studies linking the orbital frontal cortex and depression.

Aged↗
PubMed2001

Protein structural motif recognition via NMR residual dipolar couplings.

NMR residual dipolar couplings have great potential to provide rapid structural information for proteins in the solution state. This information even at low resolution may be used to advantage in proteomics projects that seek to annotate large numbers of gene products for entire genomes. In this paper, we describe a novel approach to the structural interpretation of dipolar couplings which is based on structural motif pattern recognition, where a predefined gapless structural template for a motif is used to search a set of residual dipolar couplings for good matches. We demonstrate the applicability of the method using synthetic and experimental data. We also provide an analysis of the statistical power of the method and the effects of order tensor frame orientation, motif size, and structural complexity on motif detection. Finally, we discuss remaining problems that must be overcome before the method can be used routinely to identify protein homologies.

Nuclear Magnetic Resonance, Biomolecular↗
PubMed2001

Protein backbone structure determination using only residual dipolar couplings from one ordering medium.

Residual dipolar couplings provide significant structural information for proteins in the solution state, which makes them attractive for the rapid determination of protein folds. Unfortunately, dipolar couplings contain inherent structural ambiguities which make them difficult to use in the absence of additional information. In this paper, we describe an approach to the construction of protein backbone folds using experimental dipolar couplings based on a bounded tree search through a structural database. We filter out false positives via an overlap similarity measure that insists that protein fragments assigned to overlapping regions of the sequence must have self-consistent structures. This allows us to determine a backbone fold (including the correct Calpha-Cbeta bond orientations) using only residual dipolar coupling data obtained from one ordering medium. We demonstrate the applicability of the method using experimental data for ubiquitin.

Algorithms↗
PubMed2001

Convection-enhanced intraparenchymal delivery (CEID) of cytosine arabinoside (AraC) for the treatment of HIV-related progressive multifocal leukoencephalopathy (PML).

AIDS-related PML continues to be a relatively common and rapidly fatal infection in patients with AIDS, and no effective therapy has been established to alleviate the effects of this disease. Through the years, isolated reports and small case studies have shown somewhat encouraging results using cytosine arabinoside (AraC) in the treatment of PML. The optimism behind the use AraC for this disease began to fade with ACTG trial 243, which suggested that AraC had no benefit in patients with HIV-related PML. In this article, we provide evidence that suggests that the failure of AraC in the ACTG trial may have been due to insufficient delivery of the drug through traditional intravenous and intrathecal routes. Furthermore, we provide evidence that convection-enhanced intraparenchymal delivery of AraC may prove to be a safe and effective means of treating this infection, and we outline a clinical trial that we have recently undertaken to test this hypothesis.

AIDS-Related Opportunistic Infections↗
PubMed2001

Informant-rated cognitive symptoms in normal aging, mild cognitive impairment, and dementia. Initial development of an informant-rated screen (Brief Cognitive Scale) for mild cognitive impairment and dementia.

An informant-rated cognitive screen may have the potential to reliably help detect early dementia. A valuable scale should have good interitem associations and strong reliability when tested in groups with and without cognitive impairment. Our scale, the Brief Cognitive Scale (BCS), consists of 18 questions designed to assess cognitive function that affects everyday activities. Each question is coded with one of four levels, ranging from no impairment to severe impairment. We administered this screen to 120 subjects: 26 controls, 28 with a diagnosis of mild cognitive impairment (MCI), and 66 with a diagnosis of dementia. In addition, we administered a Folstein Mini-Mental Status Examination (MMSE) to each subject. Our results showed that the BCS scores were lowest in the control group and highest in the dementia group. In our sample, this scale was effective at discriminating between subjects with no cognitive impairment, MCI, and dementia. However, the scale needs further refinement before it can be employed in a clinical setting.

Aged↗
PubMed2000

Comparison of cytosine arabinoside delivery to rat brain by intravenous, intrathecal, intraventricular and intraparenchymal routes of administration.

We evaluated the delivery of 14C-cytosine arabinoside (AraC) to rat brain by: 1) intravenous (IV) bolus, by 2) intrathecal (IT) and 3) intraventricular (IVT) infusion, and by 4) convection-enhanced delivery (CED) into the caudate nucleus. Plasma and brain AraC metabolites were measured with HPLC, and distribution and concentration of 14C-AraC in brain sections were measured by quantitative autoradiography. After IV administration, the alpha and beta plasma half-lives were 1.9 and 46.5 min, respectively. The blood-to-brain transfer constant of AraC was 2.5+/-1.4 microliter g(-1) min(-1), compatible with high water solubility. After IT and IVT administration, tissue levels were high at the brain and ventricular surfaces, but declined exponentially into brain. After CED, maximum brain levels were up to 10,000 times higher than the IV group, and the distribution pattern was one of high 14C-AraC concentration in the convective component, with exponentially declining concentrations outside this region. The rate loss constant from brain was 0.002+/-0.0004 min(-1), suggesting that AraC was accumulating in brain cells. AraC was metabolized into uracil arabinoside within the brain. 14C-AraC was infused into 1 dog and distributed widely in the ipsilateral hemisphere. These studies suggest that delivery of AraC to brain parenchyma by the IV, IT or IVT routes will be subtherapeutic. Delivery by CED can achieve, and maintain, therapeutic levels of AraC in the brain, and should be further evaluated as a potential method of drug delivery.

Animals↗
PubMed2000

A Bayesian statistical method for the detection and quantification of rotational diffusion anisotropy from NMR relaxation data.

It has recently become more widely appreciated that the presence of rotational diffusional anisotropy in proteins and other macromolecules can have a significant affect on the interpretation of NMR relaxation data in terms of molecular motion. In this paper, we show how commonly used NMR relaxation data (R(1), R(2), and NOE) obtained at two spectrometer frequencies can be analyzed using a Bayesian statistical approach to reliably detect and quantify the degree of rotational diffusion anisotropy. Our approach differs from previous methods in that it does not make assumptions concerning the internal motions experienced by the residues which are used to quantify the diffusion anisotropy, but rather averages the results over all internal motions consistent with the data. We demonstrate our method using synthetic data corresponding to isotropic, axially symmetric anisotropic, and fully asymmetric anisotropic rotational diffusion, as well as experimental NMR data. We compare the Bayesian statistical approach with a widely used method for extracting tumbling parameters using both synthetic and experimental data. While it can be difficult to separate the effects of chemical exchange from rotational anisotropy using this "standard" method, these effects are readily separated using Bayesian statistics. In addition, we find that the Bayesian statistical approach requires considerably less CPU time than an equivalent standard analysis.

Algorithms↗
PubMed2000

Lipari-Szabo mapping: A graphical approach to Lipari-Szabo analysis of NMR relaxation data using reduced spectral density mapping.

In this paper, we explore connections between the Lipari-Szabo formalism and reduced spectral density mapping, and show how spectral density estimates can be associated with Lipari-Szabo parameters via a simple geometric construction which we call Lipari-Szabo mapping. This relationship can be used to estimate Lipari-Szabo parameters from spectral density estimates without the need for nonlinear optimization, and to perform 'model selection' in a graphical manner. The Lipari-Szabo map also provides insight into the Lipari-Szabo model, and allows us to determine when a given set of experimental spectral densities are inconsistent with the Lipari-Szabo formalism. Practical applications of Lipari-Szabo mapping in conjunction with more traditional analysis methods are discussed.

Anisotropy↗
PubMed2000

Iterative sequence/secondary structure search for protein homologs: comparison with amino acid sequence alignments and application to fold recognition in genome databases.

MOTIVATION: Sequence alignment techniques have been developed into extremely powerful tools for identifying the folding families and function of proteins in newly sequenced genomes. For a sufficiently low sequence identity it is necessary to incorporate additional structural information to positively detect homologous proteins. We have carried out an extensive analysis of the effectiveness of incorporating secondary structure information directly into the alignments for fold recognition and identification of distant protein homologs. A secondary structure similarity matrix based on a database of three-dimensionally aligned proteins was first constructed. An iterative application of dynamic programming was used which incorporates linear combinations of amino acid and secondary structure sequence similarity scores. Initially, only primary sequence information is used. Subsequently contributions from secondary structure are phased in and new homologous proteins are positively identified if their scores are consistent with the predetermined error rate. RESULTS: We used the SCOP40 database, where only PDB sequences that have 40% homology or less are included, to calibrate homology detection by the combined amino acid and secondary structure sequence alignments. Combining predicted secondary structure with sequence information results in a 8-15% increase in homology detection within SCOP40 relative to the pairwise alignments using only amino acid sequence data at an error rate of 0.01 errors per query; a 35% increase is observed when the actual secondary structure sequences are used. Incorporating predicted secondary structure information in the analysis of six small genomes yields an improvement in the homology detection of approximately 20% over SSEARCH pairwise alignments, but no improvement in the total number of homologs detected over PSI-BLAST, at an error rate of 0.01 errors per query. However, because the pairwise alignments based on combinations of amino acid and secondary structure similarity are different from those produced by PSI-BLAST and the error rates can be calibrated, it is possible to combine the results of both searches. An additional 25% relative improvement in the number of genes identified at an error rate of 0.01 is observed when the data is pooled in this way. Similarly for the SCOP40 dataset, PSI-BLAST detected 15% of all possible homologs, whereas the pooled results increased the total number of homologs detected to 19%. These results are compared with recent reports of homology detection using sequence profiling methods. AVAILABILITY: Secondary structure alignment homepage at http://lutece.rutgers.edu/ssas CONTACT: anders@rutchem.rutgers.edu; ronlevy@lutece.rutgers.edu SUPPLEMENTARY INFORMATION: Genome sequence/structure alignment results at http://lutece.rutgers.edu/ss_fold_predictions.

Algorithms↗
PubMed2000

Simplified amino acid alphabets for protein fold recognition and implications for folding.

Protein design experiments have shown that the use of specific subsets of amino acids can produce foldable proteins. This prompts the question of whether there is a minimal amino acid alphabet which could be used to fold all proteins. In this work we make an analogy between sequence patterns which produce foldable sequences and those which make it possible to detect structural homologs by aligning sequences, and use it to suggest the possible size of such a reduced alphabet. We estimate that reduced alphabets containing 10-12 letters can be used to design foldable sequences for a large number of protein families. This estimate is based on the observation that there is little loss of the information necessary to pick out structural homologs in a clustered protein sequence database when a suitable reduction of the amino acid alphabet from 20 to 10 letters is made, but that this information is rapidly degraded when further reductions in the alphabet are made.

Algorithms↗
PubMed1999

Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

OBJECTIVE: Risedronate, a new pyridinyl bisphosphonate, is a potent antiresorptive bone agent. This study examines the safety and efficacy of daily, oral risedronate therapy for the prevention of corticosteroid-induced bone loss. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 224 men and women who were initiating long-term corticosteroid treatment. Patients received either risedronate (2.5 mg or 5 mg) or placebo daily for 12 months. Each patient also received 500 mg of elemental calcium daily. The primary outcome measure was the percentage of change in lumbar spine bone mineral density (BMD). Secondary measures included proximal femur BMD and incidence of vertebral fractures. RESULTS: After 12 months, the lumbar spine BMD (mean +/- SEM) did not change significantly compared with baseline in the 5-mg (0.6 +/- 0.5%) or the 2.5-mg (-0.1 +/- 0.7%) risedronate groups, while it decreased in the placebo group (-2.8 +/- 0.5%; P < 0.05). The mean differences in BMD between the 5-mg risedronate and the placebo groups were 3.8 +/- 0.8% at the lumbar spine (P < 0.001), 4.1 +/- 1.0% at the femoral neck (P < 0.001), and 4.6 +/- 0.8% at the femoral trochanter (P < 0.001). A trend toward a decrease in the incidence of vertebral fracture was observed in the 5-mg risedronate group compared with the placebo group (5.7% versus 17.3%; P = 0.072). Risedronate was well tolerated, and the incidence of upper gastrointestinal adverse events was comparable among the 3 groups. CONCLUSION: Risedronate therapy prevents bone loss in patients initiating long-term corticosteroid treatment.

Adolescent↗
PubMed1999

Estimation of dynamic parameters from NMR relaxation data using the Lipari-Szabo model-free approach and Bayesian statistical methods.

In order to analyze NMR relaxation data in terms of parameters which describe internal motion, one must first obtain a description of the overall tumbling of the macromolecule in solution. Methods currently used to estimate these global parameters may not always provide reliable estimates of their values and uncertainties. In this paper, we present a general data analysis formalism based on products of Bayesian marginal probability densities which can be used to efficiently combine the information content from multiple experiments, such as R(1), R(2), and NOE data collected at multiple magnetic field strengths, or data from cross-correlation or rotating frame relaxation dispersion experiments. Our approach allows the estimation of global tumbling and internal dynamical parameters and their uncertainties without some of the assumptions which are made in the commonly-used methods for model-selection and global parameter estimation. Compared to an equivalent classical statistical approach, the Bayesian method not only is more computationally efficient, but also provides greater insight into the information content of the data. We demonstrate that this approach can be used to estimate both the isotropic rotational correlation time in the context of the original and "extended" Lipari-Szabo formalisms [Lipari & Szabo, J. Am. Chem. Soc. 1982, 104, 4546; Clore et al., J. Am. Chem. Soc. 1990, 112, 4989], as well as the rotational diffusion coefficients for axially symmetric anisotropic tumbling.

Anisotropy↗
PubMed1999

Lymphoma of the central nervous system in AIDS.

Central nervous system (CNS) lymphoma is a common complication of patients with HIV infection occurring in as many as 20% of patients with AIDS. This article reviews current observations on primary CNS lymphoma and systemic AIDS-related lymphoma with CNS involvement. Clinical features, diagnosis, differential diagnosis, clinical course, and therapeutic options are herein reviewed.

Central Nervous System Neoplasms↗
PubMed1999

Comparison of 14C-sucrose delivery to the brain by intravenous, intraventricular, and convection-enhanced intracerebral infusion.

OBJECT: The authors evaluated convection-enhanced delivery (CED) of 14C-sucrose to the rat brain as a method of enhancing cerebral drug delivery and compared it with intravenous (i.v.) and intraventricular (i.v.t.) routes of administration. METHODS: Groups of rats received 14C-sucrose by bolus i.v. infusion, i.v.t. infusion for 1, 2, or 7 days at 0.17 microl/minute, or CED at rates from 0.01 to 0.5 microl/minute for periods from 1 hour to 7 days. Radioisotope distribution and concentration in tissue were analyzed using quantitative autoradiography. Intravenously administered sucrose reached the entire brain, but levels in tissue were low. After i.v.t. administration, sucrose levels in tissue were high at, and declined exponentially away from, the ventricular surface. Chronic CED administration maintained high levels of sucrose in tissue that focally were up to 10,000 times higher than in the i.v. group. The isotope distribution pattern after chronic CED infusions indicated a central component that resulted from convention and a peripheral component in gray matter that was the result of diffusion. The brain influx (0.42 microl/g/min) and diffusion constants of sucrose (2.8 x 10(-6) cm2/second) were similar to reported values. The total brain efflux constant was 0.0044 minute, whereas the blood-brain barrier (BBB) efflux constant was 0.0016 minute. There were no pathological changes in the brains after CED except those associated with cannula insertion. Sucrose, which was thought to be inert, was found to interact with brain tissue; up to 25% was bound to an unidentified tissue component. CONCLUSIONS: Chronic CED appears to be a potentially useful method for significantly circumventing the BBB and increasing delivery of water-soluble drugs to the brain.

Animals↗
PubMed1999

The short-term effect of apically repositioned flap surgery on the composition of the subgingival microbiota.

The purpose of this investigation was to examine the short-term effect of apically repositioned flap surgery on clinical and microbiologic parameters in patients with adult periodontitis. A total of 11 patients with moderate to advanced periodontitis received apically repositioned flap surgery. Subjects were monitored during a 3-month pretreatment phase, the baseline surgical phase, and for 3 months post-surgery. Clinical assessments including plaque accumulation, gingival redness, suppuration, bleeding on probing, pocket depth, and attachment level were made at 6 sites per tooth. Subgingival plaque samples were taken from the mesial aspect of each tooth and the presence and levels of 29 subgingival taxa were determined using whole genomic DNA probes and checkerboard DNA-DNA hybridization. The mean levels and percentage of sites colonized by each species (prevalence) were computed for each subject at each visit. After surgery, there was a significant decrease in mean pocket depth and percentage of sites exhibiting gingival redness. Significant decreases were seen in the percentage of sites that had attachment levels < 4 mm, with a significant increase in the percentage of sites with attachment levels of 4 to 6 mm after therapy. The mean total DNA probe count for all bacterial species was significantly decreased by both scaling and root planing and surgical therapy. P gingivalis and B forsythus, 2 bacteria previously shown to be susceptible to mechanical therapy, exhibited statistically significant decreases in mean total DNA probe count. Because surgical therapy decreased levels of the suspected periodontal pathogens C rectus, P nigrescens, and C gracilis, it may be speculated that there was a potential added beneficial effect of surgery on the periodontal microbiota.

Actinomyces↗
PubMed1998

Changes in blood-brain barrier permeability associated with insertion of brain cannulas and microdialysis probes.

Blood-brain barrier (BBB) transcapillary transport was studied after insertion of cannulas and microdialysis probes into the brains of three groups of rats. Quantitative autoradiography was used to measure changes in BBB permeability around the insertion site. In the first group, BBB function was measured with 14C-sucrose at times from immediately, and up to 28 days, after insertion of a microdialysis probe. BBB function was disrupted biphasically: a 19-fold increase in the influx constant (K1) of sucrose occurred immediately after insertion with a second 17-fold increase at 2 days, followed by a slow decline to 5 times normal values at 28 days. In the second group, 14C-dextran (70 kDa) was used to measure BBB transcapillary transport; K1 was increased 90-fold after probe insertion. In the 3rd group, 14C-AIB (alpha-aminoisobutyric acid) was used to evaluate BBB transport after insertion of a 27 gauge cannula, which was used to infuse 1 microliter of saline over 5 min. The K1 of AIB was increased 25 times control values. We conclude that BBB transcapillary transport function is disturbed in response to insertion of brain cannulas and/or microdialysis probes, that BBB dysfunction is maximal at the cannula or probe tip, varies with time after insertion, may persist for at least 28 days after insertion, and occurs over a wide molecular range of solutes. These results suggest caution when using microdialysis as a method to study normal BBB function, and suggest that microdialysis may overestimate the rate of transfer into and out of the brain.

Animals↗