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Biomedical subjects

J N Weinstein

Publications and source records attributed to J N Weinstein.

At least 73 records · Page 4Linked to original sources
PubMed1996

Chordoma of the spine above the sacrum. Treatment and outcome in 21 cases.

STUDY DESIGN: Twenty-one cases of chordoma arising in the mobile spine were retrospectively reviewed. OBJECTIVES: All the cases were submitted to oncologic and surgical staging to correlate treatment and outcome. SUMMARY OF BACKGROUND DATA: Excluding plasmacytomas, chordoma is the most frequent primary malignant tumor of the spine, occurring mainly in elderly men. The course of the disease is slow, metastases occur late, and death can result from complications related to local extension of the disease. Complete excision of the tumor according to oncologic criteria can be hampered by extension of the tumor and by anatomic constraints in the mobile spine. METHODS: All charts, radiographs, and images were reviewed. The composite information provided by this review allowed for oncologic and surgical staging of these cases. Treatment was defined according to Ennekings criteria. All the patients were followed for determination of their status clinically and radiographically. RESULTS: Ten patients died (1 to 137 months after treatment, mean 65 months); four patients are alive with the disease; only seven patients (33%) are symptom free at the final follow-up (39 to 112 months after treatment, mean 65 months). Conventional radiation therapy was not effective in eradicating the tumor, even if associated with palliative or debulking surgery: of 15 cases, 12 were associated with recurrence or progression. Intralesional surgery also was not effective (two recurrences in two cases, 18 to 41 months later). En bloc excision of the lesion, sometimes combined with radiation therapy as an adjuvant, obtained the best results (four patients disease free at 39 to 112 months, mean 77 months). CONCLUSIONS: En bloc excision--even if marginal--is the treatment of choice of chordomas of the spine. Early diagnosis and careful surgical staging and planning are necessary. Megavoltage radiation can be administered as an adjuvant.

Adult↗
PubMed1996

An approach to rapid estimation of relative binding affinities of enzyme inhibitors: application to peptidomimetic inhibitors of the human immunodeficiency virus type 1 protease.

This report describes a method for rapid assessment of the binding affinities of a series of analogous ligands to an enzyme. This approach is based on two variables (scores), representing (i) the enthalpy of binding and (ii) the strength of hydrophobic interaction. The method is then used to evaluate the binding of 11 different peptidomimetic inhibitors to the HIV-1 protease. Three-dimensional structures of these enzyme-inhibitor complexes are modeled based on the crystal structures of HIV-1 protease complexes with the known inhibitors. These structures are minimized using the AMBER force field, and the scores of binding enthalpy for each of the ligands are calculated. A second score to represent the hydrophobic interaction between a pair of atoms uses an exponential function of distance between the atoms and the product of their atomic hydrophobicity constants. This exponential function is used to assess the hydrophobic interaction energy between an enzyme and its inhibitor and also to compute and display a 'molecular hydrophobicity map' as a 3D visualization tool. These methods are then applied to obtain trends in relative binding affinities of pairs of analogous inhibitors. Calculated scores agree well with corresponding results from thermodynamic cycle perturbation (TCP) simulations as well as experimental binding data. Since the proposed calculations are computationally cheaper and faster than TCP calculations, it is suggested that these scores can form the basis for rapid, preliminary theoretical screening of proposed derivatives of an inhibitor prior to TCP analysis, synthesis, and testing.

HIV Protease↗
PubMed1996

Classics in Spine. Surgery literature revisited.

STUDY DESIGN: This article reviews the criteria for evaluating the quality of clinical trials. OBJECTIVES: To outline the current methodologic standards by which the validity of controlled trials need to be evaluated. SUMMARY OF BACKGROUND DATA: Weber's study, published in 1983 in Spine, is the only randomized trial comparing surgery and conservative management of sciatica in herniated lumbar discs. METHODS: Weber's article is revisited to illustrate basic principles in the design of clinical trials. RESULTS: Weber's study is a classic in spine surgery and has changed thinking regarding the benefit of surgery in sciatica related to herniated lumbar discs. However, the authors found potentially critical flaws in this study: a large number of crossovers, inadequate sample size, and insensitive outcome measurements. CONCLUSIONS: A randomized, controlled trial is the most rigorous way to evaluate health intervention. Despite the difficulties of performing such studies, investigators should use the most appropriate scientific methodology.

Clinical Trials as Topic↗
PubMed1996

European Spine Society--the AcroMed Prize for Spinal Research 1995. Unexpected load and asymmetric posture as etiologic factors in low back pain.

Unexpected loads, which often occur in the working environment, can lead to high forces in the spine and, thus, may be a cause of low back injury. This paper discusses the effect of "sudden load" on the erector spine reaction and amplitude. Muscle responses were mediated by several factors, including fatigue, posture, expectation and rehabilitation, in chronic low back pain patients. The subjects were fatigued by holding a 20% maximum voluntary contraction for 1 min. A functional restoration program was tested for its efficacy in reducing reaction time and EMG amplitude in chronic low back pain patients. Reaction time was longer and EMG amplitude lower in patients than in their matched controls. EMG reaction time and magnitude decreased in patients after a 2-week rehabilitation program, including specific training of coordination and posture control. The results of the modelling showed higher spinal compressive load and lower shear forces when the load was expected than when the load was unexpected. The effect of sudden loads can be exacerbated if a worker is not standing on a flat surface or is fatigued. Chronic low back pain patients have less ability to protect themselves from sudden loads, but they can be trained to improve their response by means of an appropriate rehabilitation program.

Adult↗
PubMed1996

Application of the electrotopological state index to QSAR analysis of flavone derivatives as HIV-1 integrase inhibitors.

PURPOSE: A QSAR study based on electrotopological state (E-state) indices was conducted for a series of flavone HIV-1 integrase inhibitors to guide drug design. METHODS: E-state indices formulated to encode electronic and topological information for each skeletal atom in a molecule (Kier and Hall Pharm. Res. 7:801-807 (1990)) were calculated using the Molconn-X program, and partial least squares (PLS) multivariate regression was used to derive QSAR models. RESULTS: Predictive models with correlation coefficients (r2) of 0.98 (3 PLS components) and 0.99 (5 PLS components) and corresponding cross-validated correlation coefficients (c.v. r2) of 0.51 and 0.73, were obtained for inhibition of cleavage and integration, respectively, with one molecule omitted from the analysis. CONCLUSIONS: E-state indices at C6, C3', C5', C5, and O4 were found to be more important for prediction of activity than those for any of the other 12 flavone skeletal atoms that are common to the molecules in the data set.

Flavonoids↗
PubMed1996

Posterolateral approach for anterior resection and posterior stabilization of the upper cervical spine: a case report.

Surgical approaches to atlanto-axial lesions are generally accomplished by either anterior (transoral) or posterior approaches as dictated by the location of the lesion. In certain patients, these approaches are combined, either in a single or staged procedure. Mechanical stabilization is much more readily accomplished posteriorly, as this allows easy incorporation of the occiput. While the transoral approach allows excellent exposure of the bodies of C1 and C2, it entails substantial surgical trauma. We describe the case of a woman with destruction of the anterior portions of the C1 and C2 vertebrae by metastatic breast cancer addressed by simultaneous anterior tumor debulking and posterior instrumentation through a posterolateral approach to the upper cervical spine.

Aged↗
PubMed1995

Targeting cancer micrometastases with monoclonal antibodies: a binding-site barrier.

Monoclonal antibodies penetrate bulky tumors poorly after intravenous administration, in part because of specific binding to the target antigen. Experiments presented here demonstrate an analogous phenomenon in micrometastases; poor antibody penetration, attributable to a "binding-site barrier" phenomenon, can be seen in guinea pig micrometastases as small as 300 microns in diameter. Increasing the dose of antibody can partially overcome this limitation, but at a cost in specificity.

Animals↗
PubMed1995

The virtual hospital. Providing multimedia decision support tools via the Internet.

Physicians in the clinical setting remain isolated from important sources of medical information. The authors have created a multimedia database known as The Virtual Hospital that improves access to current medical data, which is used to improve patient care decisions. The Virtual Hospital is a digital health sciences library stored on a server (computer) at The University of Iowa and delivered via the Internet to inexpensive personal computers in the workplace. The emerging standard of the World Wide Web is used to provide cross-platform distribution.

Computer Communication Networks↗
PubMed1995

Clinical correlates of patient satisfaction after laminectomy for degenerative lumbar spinal stenosis.

STUDY DESIGN: Prospective multicenter observational study of the outcome of surgery for degenerative lumbar spinal stenosis. OBJECTIVES: To identify correlates of patient satisfaction with the results of surgery. SUMMARY OF BACKGROUND DATA: Little published information exists on correlates of patient satisfaction after surgery for spinal stenosis. METHODS: Preoperative and 6-month follow-up data for 194 patients were analyzed. Associations between preoperative variables and satisfaction with the results of surgery were examined in univariate and multivariate models. RESULTS: In multiple linear regression models that adjusted for the effects of age, gender, individual surgeon, number of interspaces decompressed, whether a fusion was performed, depression score, and overall level of pain, the predominance of back (as opposed to leg) pain, greater comorbidity, and worse preoperative functional status were associated with lower patient satisfaction. The regression model explained just 15% of the variance in patient satisfaction. CONCLUSIONS: Patients bothered predominantly by back pain preoperatively and those with greater medical comorbidity and functional disability are significantly less satisfied with the results of surgery for degenerative lumbar spinal stenosis.

Aged↗
PubMed1995

Long-term follow-up of patients with chronic back pain treated in a multidisciplinary rehabilitation program.

STUDY DESIGN: The study evaluated the long-term outcomes of 129 chronic low back pain patients who had completed a multidisciplinary rehabilitation program. OBJECTIVES: Two major outcome issues were addressed--one related to the effectiveness of the program as measured by return to work, use of the medical system, and sense of well being, and the other concerning the stability of the outcome effect over time. SUMMARY OF BACKGROUND DATA: Other outcome studies have established the short-term effectiveness of rehabilitation programs such as the present one with between 50% and 75% of patients. However, long-term follow-up--i.e., 1 1/2 to 2 years or more--has been lacking to determine what happens later. METHODS: Graduates of the program were contacted by telephone to complete a 23-item questionnaire. Every effort was made to include all who had completed the program. Many had moved away or were inaccessible, but few of those contacted refused to participate. RESULTS: An attempt was made to classify the job outcome into good, fair, and poor outcomes by weighting return to work, remaining at work, and continuing to look for work. Forty-nine percent of the sample attained a good job outcome, 13% a fair job outcome, and 38% a poor job outcome. Regarding general well-being, 53% reported doing better or much better, 27% reported being about the same, and 20% reported being worse or much worse at follow-up. CONCLUSIONS: The results provide support for the efficacy of programs such as this.

Adult↗
PubMed1995

Three-dimensional quantitative structure-activity relationship (QSAR) of HIV integrase inhibitors: a comparative molecular field analysis (CoMFA) study.

We present the results from a comparative molecular field analysis (CoMFA) of a set of flavone analogs that inhibit HIV-1 integrase-mediated cleavage (3'-processing step) and integration (strand transfer step) in vitro. The results indicate a strong correlation between the inhibitory activity of these flavones and the steric and electrostatic fields around them. CoMFA quantitative structure-activity relationship models with considerable predictive ability (cross-validated r2 as high as 0.8) were obtained.

Chemical Phenomena↗
PubMed1995

Neuropeptide changes in compressed spinal nerve roots.

STUDY DESIGN: Compression-induced changes in the concentration of substance P and VIP (vasoactive intestinal polypeptide), in spinal nerve roots and dorsal root ganglia were studied in an experimental nerve root compression model in pigs. OBJECTIVES: To analyze by radioimmunoassay the concentration of the neuropeptides substance P and VIP in a model for experimental chronic nerve root compression. SUMMARY OF BACKGROUND DATA: Neuropeptides such as substance P and VIP seem to be involved in the transmission of pain and changes in the levels of these neuropeptides have been described in models where peripheral or spinal nerve injury was induced. METHODS: An ameroid constrictor was applied on a spinal nerve root just cranial to the dorsal root ganglion. The inner diameter of this constrictor is gradually reduced. After 1 or 4 weeks, tissue samples were taken from the nerve root cranial to the constrictor and from the dorsal root ganglion for measurement of substance P and VIP concentrations. RESULTS: There was a statistically significant increase in substance P concentrations in the compressed dorsal root ganglia when compared to the noncompressed dorsal root ganglia at both 1 and 4 weeks. Substance P concentration was also significantly increased in the nerve root after 1 but not after 4 weeks. The VIP levels were not significantly changed in either tissue. CONCLUSIONS: The results of the study indicates an increase in substance P levels in the dorsal root ganglion (after 1 and 4 weeks) and in the nerve root (after 1 week) in a model for chronic nerve root compression in pigs. There were no significant differences in the VIP concentrations. The study thus indicates that changes in substance P are related to experimental chronic nerve root compression.

Animals↗
PubMed1995

Characterization of thermal hyperalgesia, c-fos expression, and alterations in neuropeptides after mechanical irritation of the dorsal root ganglion.

STUDY DESIGN: This study analyzed hypersensitization in sensory systems after mechanical irritation of the dorsal root ganglion. OBJECTIVES: To develop a reliable and reproducible animal model of hyperalgesia arising from the dorsal root ganglion and to understand the unique contributions of the dorsal root ganglion to clinical manifestations of sciatica. SUMMARY OF BACKGROUND DATA: The dorsal root ganglion likely plays an important role in disorders of sciatica. However, no previous study has analyzed sciatica after irritation of the dorsal root ganglion. Thermal hyperalgesia indicates a decrease in thermal nociceptive threshold and hypersensitization in sensory systems. METHODS: The left L4 and L5 dorsal root ganglia in rats (n = 22) were exposed circumferentially. Other rats (n = 22) also had the left L4 and L5 dorsal root ganglia ligated loosely with two 4-0 chromic gut sutures. Changes in thermal withdrawal latency were examined in the hindpaws across time. Substance P and vasoactive intestinal polypeptide contents were quantified in the dorsal root ganglion and spinal cord. Substance P, calcitonin gene-related peptide, and c-fos expression also were examined in the spinal cord by immunohistochemistry. In addition, histologic changes in myelinated nerve content were examined in the dorsal root ganglion. RESULTS: Thermal hyperalgesia occurred in rats with exposure of the dorsal root ganglion and in rats with loose ligation of the dorsal root ganglion, and was accompanied by an increase in c-fos expression and spontaneous pain-related behaviors. CONCLUSIONS: This experimental model reliably produced a disorder resembling an acute phase sciatica and should help further advance the understanding of pathomechanisms of spinal pain after irritation of the dorsal root ganglion in humans.

Animals↗
PubMed1995

In vitro anti-HIV-1 activity of HIV protease inhibitor KNI-272 in resting and activated cells: implications for its combined use with AZT or ddI.

KNI-272, a conformationally constrained human immunodeficiency virus (HIV) protease inhibitor containing a P1 allophenylnorstatine (Apns) ((2S,3S)- 3-amino-2-hydroxy-4-phenylbutyric acid), has been shown to be a selective and potent inhibitor of the replication of a wide spectrum of HIV strains in vitro. When KNI-272 was tested in combination with 3'-azido-2',3'-dideoxythymidine (AZT) or 2',3'-dideoxyinosine (ddI) against a primary HIV-1 isolate in phytohemagglutin-activated peripheral blood mononuclear cells (PHA-PBM), its activity was identified to be additive, but not synergistic or antagonistic, as analyzed with the COMBO program package. When tested alone for anti-HIV-1 activity in resting PBM (R-PBM) and PHA-PBM, KNI-272 was found to be comparably potent against the virus in both target cell populations, whereas AZT was more potent in PHA-PBM than in R-PBM and ddI was more potent in R-PBM. These data suggest a potential clinical application of KNI-272 and its analogs.

Antiviral Agents↗
PubMed1994

Growth and chemotherapeutic response of cells in a hollow-fiber in vitro solid tumor model.

BACKGROUND: Cancer treatments that appear promising in tissue culture are often less effective in solid tumors, in part because of the proliferative and microenvironmental heterogeneity that develops in these tumors as they grow. Heterogeneous tumor models are thus needed for drug screening. PURPOSE: Our goal was to develop and test for drug evaluation a solid tumor model based on cell growth inside biocompatible hollow fibers. METHODS: Building on the experience of Hollingshead and co-workers with a sparse-cell, hollow-fiber tumor model, we tested six human tumor cell lines for in vitro growth inside 450-microns internal-diameter polyvinylidine fluoride fibers and examined them histologically. Human SW620 colon carcinoma cells grown in hollow fibers were also examined using electron microscopy, and their doxorubicin sensitivity was assessed. A colorimetric assay based on sulforhodamine B was adopted to replace the more cumbersome clonogenic cell survival assay. RESULTS: Five of the human tumor cell lines tested grew to confluence, forming heterogeneous in vitro tumors with subpopulations of viable and necrotic cells. For SW620 hollow-fiber tumors, maximum viable cell populations in excess of 10(8) cells/mL were obtained after 8 days of growth. This viable cell density remained roughly constant for 3-4 days, permitting dose-response experiments over this time interval. Tumor cells in hollow fibers were much more resistant to a 4-hour doxorubicin exposure than were tumor cells in monolayers: LC50 values (i.e., the drug concentrations at which the plating efficiency equals one-half the plating efficiency of untreated cells) of 3.5 microM and 0.16 microM were obtained for hollow-fiber tumors and monolayers, respectively. LC50 values decreased when drug exposure time was increased. Results from the colorimetric assay were in agreement with those from the clonogenic assay. CONCLUSION: The successful growth of tumor cells to confluence in hollow fibers and the feasibility of performing in vitro drug dose-response experiments with a relatively easy colorimetric assay demonstrate the potential of the hollow-fiber solid tumor model as a tool for experimental therapeutic research. IMPLICATION: Hollow-fiber solid tumors may prove useful for experimental drug evaluation.

Antineoplastic Agents↗