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Biomedical subjects

J N Weinstein

Publications and source records attributed to J N Weinstein.

At least 109 records · Page 6Linked to original sources
PubMed1994

Lumbar spinal stenosis and diabetes. Outcome of surgical decompression.

We reviewed 25 diabetic (mean age 68 years) and 25 non-diabetic patients (mean age 71 years) who had undergone decompression for lumbar spinal stenosis at a mean of 3.4 years after operation to determine whether diabetes affected the outcome of surgery. The preoperative symptoms were similar in the two groups except that an abrupt onset of symptoms, the presence of night pain and the absence of any posture-related pain relief were recorded only by diabetic patients. Nerve-conduction velocity was slowed in 80% of the diabetic and in 25% of the non-diabetic patients. Peripheral vascular deficiency was diagnosed in 20% of patients with diabetes and in 4% of non-diabetics. The outcome of surgery was similarly successful in the two groups. Mistaken preoperative diagnosis was the cause of failure in three diabetic patients, two with diabetic neuropathy and one with diabetic angiopathy.

Adult↗
PubMed1993

Morphometric model of normal rabbit dorsal root ganglia.

The rabbit dorsal root ganglion is an important model of pain mechanisms in the human spine. A morphometric model of the normal rabbit dorsal root ganglion was constructed to provide quantitative comparisons with injured ganglia. Lumbar ganglia were studied under light and electron microscopy using simple stereologic methods. Neuronal diameter ranged from 18 to 85 microns, with 60% between 30 and 50 microns. Neurons constituted approximately 30% of dorsal root ganglion volume, and neuronal nuclei accounted for 14% of neuronal volume and 4% of dorsal root ganglion volume. Contributions from organelles to dorsal root ganglion volume were: mitochondria, 1.5%; rough endoplasmic reticulum, 9.4%; lysosomes, 0.2%; golgi, 0.5%. This morphometric model facilitates quantitative analysis of ganglia exposed to direct or indirect stimuli, providing important information on the structural changes that influence pain production.

Animals↗
PubMed1993

Efficacy of flexion and extension treatments incorporating braces for low-back pain patients with retrodisplacement, spondylolisthesis, or normal sagittal translation.

Radiographic instability seemingly enjoys the status of a well-defined clinical syndrome. The concept is widely used, and specific treatments, usually spinal fusion, are routinely performed based on the diagnosis. The minimum standards necessary to establish radiographic instability as a legitimate clinical syndrome have not been established, however. The primary purpose of this study was to determine if treatment involving bracing, exercise, and education controlling either flexion or extension postures, would result in a distinctive pattern of favorable or unfavorable results, depending on the type of radiographic instability (retrodisplacement or spondylolisthesis). Fifty-six patients meeting strict study inclusion and radiographic evaluation criteria were assigned signed to a bracing treatment (flexion, extension, placebo-control) according to a randomization scheme, designed to ensure equal representation of translation categories (retro, normal, spondy) across treatment groups, and assessed at admission and 1-month follow-up. The sample was relatively evenly divided between men (46%) and women (54%), and by age. Translation classification was related to both gender and age, with men more likely classified as retro and women more likely spondy and patients in their 20s having lower incidence of spondy and higher incidence of normal translation. Translation classification was not related to selected indices of low-back pain history. Brace treatments were not shown to reduce patient range of motion or lessen trunk strength. A significant treatment by time interaction for the modified pain interference (VAS) scale indicated improvement for patients in extension compared with patients in flexion and control-placebo treatments. In conjunction with no significant three-way interaction between treatment, translation classification, and time, it was hypothesized that radiographic instability might more appropriately be considered a corroborative sign of advanced discogenic problems. Improvement in extension treatment, regardless of the type of radiographic abnormality, suggests that the treating clinician might consider extension treatment for chronic low-back pain patients. Causes and implications for the failure of this study to provide support for considering radiographic instability as a clinical syndrome are considered and future directions for this area of research suggested.

Adult↗
PubMed1993

A combined finite element and optimization investigation of lumbar spine mechanics with and without muscles.

A combined finite element and optimization approach to study the effects of muscles on the biomechanics of the lumbar spine was initiated. Briefly, a three-dimensional, nonlinear, finite element model of a ligamentous L3-4 motion segment was formulated (LIG model) for the predictions of stresses, etc., in the motion segment. A separate, biomechanical optimization-based force model with experimental input was developed to predict the forces in muscles and disc across the L3-4 segment in response to a person holding 90 N in his hands with spine flexed 30 degrees, and knees straight. The predicted muscle forces from the optimization model were then incorporated into the L3-4 finite element model as nodal forces to simulate the muscle action (MUS model). The predicted responses from the muscles active (MUS) finite element model were compared to the corresponding results from the ligamentous (LIG) finite element model subjected to an equivalent load. The biomechanical parameters compared were: translation and rotation of L3, disc bulge, intervertebral foramen gap, intradiscal pressure, facet loading, ligament tension, compressive disc load, and stresses in the vertebral body. The addition of muscular forces in the MUS model led to a decrease in the anteroposterior translation and flexion rotation (displacements in the sagittal plane) of the segment compared to the corresponding LIG model predictions. Thus, the muscles imparted stability to the ligamentous segment. The presence of muscles also led to a decrease in stresses in the vertebral body, the intradiscal pressure and other mechanical parameters of importance. However, the load bearing of the facets increased compared to the ligamentous model. Thus, facets play a significant role in transmitting loads in a normal intact spine. These results, for the first time, provide quantitative data on the stabilizing effects of muscles on the mechanics of a ligamentous spine. The results also provide a scientific explanation in support of the "degenerative cascade" concept proposed in the literature. The model predictions, in conjunction with the degenerative cascade concept, also support the observation that the osteoarthritis of facets may follow disc degeneration. Future research directions based on the current model are presented.

Biomechanical Phenomena↗
PubMed1993

Thoracolumbar burst fractures. The clinical efficacy and outcome of nonoperative management.

There continues to be considerable controversy regarding the management of thoracolumbar burst fractures. Most feel that failure of the middle osteoligamentous complex, particularly with retropulsion of fragments into the spinal canal, is an indication for operative management. Others advocate postural reduction and prolonged bedrest for such injuries. The purpose of this study was to 1) review the clinical outcome and efficacy of closed management of thoracolumbar burst fractures; and 2) quantify what, if any, remodeling occurs in the bony canal as measured by serial CT. Forty-one patients who presented with a burst fracture of the thoracolumbar spine without neurologic deficit were reviewed clinically and radiographically following nonoperative management. At injury, canal compromise averaged 37% (range, 16-66%); 26 patients had at least 30% canal compromise. During treatment, one patient developed neurologic deterioration that prompted surgery; all other patients remained neurologically intact. At average follow-up of 2 years, an overall outcome evaluation indicated that 49% of the patients had excellent outcomes relative to pain and function; 17%, good; 22%, fair; and 12%, poor. Approximately 90% of the patients had a satisfactory work status relative to factors associated with their burst fracture. Serial roentgenograms documented significant progression in body collapse, which averaged 8% (P < 0.0001) from injury to follow-up. On the other hand, serial CTs documented significant improvement from injury to follow-up for canal compromise and midsagittal diameter. Average improvements in canal compromise and midsagittal diameter were 22% (P < 0.0001) and 11% (P < 0.0001), respectively. Only three patients had canal compromise greater than 30%, no patients had canal compromise greater than 40%, and no patients experienced canal area deterioration over time. On average, nearly two-thirds of the fragment occluding the canal resorbed, with most remodeling complete within one year. For patients with burst fractures presenting neurologically intact, we obtained the following findings: 1) nonoperative management yields acceptable results; 2) following nonoperative management, bony deformity (i.e., kyphosis and body collapse) progresses marginally relative to the rate of canal area remodeling; 3) incidence of subsequent neurologic deficits is quite low; and 4) initial radiographic severity of injury or residual deformity following closed management does not correlate with symptoms at follow-up. This pattern of results suggests nonoperative management as the preferred treatment in these circumstances.

Adult↗
PubMed1993

A simple method for affinity purification of radiolabeled monoclonal antibodies.

A simple method is described for affinity purification of radiolabeled antibodies using glutaraldehyde-fixed tumor target cells. The cell-bound antibody fraction is removed from the cells by an acid wash and then immediately subjected to buffer-exchange chromatography. The method was applied to the D3 murine monoclonal antibody which binds to a 290 kDa antigen on the surface of Line 10 guinea pig carcinoma cells. No alteration in the molecular size profile was detected after acid washing. Purification resulted in a significant increase in immunoreactivity by an average of 14 +/- 47% (SD; range 4-30%).

Animals↗
PubMed1993

Fc-receptor-mediated targeting of antibody-bearing liposomes containing dideoxycytidine triphosphate to human monocyte/macrophages.

Liposomes bearing surface-attached antibody (L-Ab) molecules can be used for various purposes including the immunospecific delivery of drugs or other materials to antigenic target cells. In this study, L-Ab were prepared to deliver an anti-human immunodeficiency virus (HIV) drug, dideoxycytidine triphosphate (ddCTP) to human monocyte/macrophages. Cells of the monocyte/macrophage lineage are an important reservoir of HIV-1. A mouse monoclonal antibody IgG2a was labelled with 125I and modified using N succinimidyl-3-(2-pyridyldithio)propionate (SPDP) as a heterobifunctional reagent in order to conjugate with liposomes to produce a covalent bond (thioether). SPDP-modified antibody was incubated with liposomes containing 5 mol% of maleimido phenyl butyrate phosphatidylethanolamine (MPB-PE) at room temperature (21 degrees C) for 24 h. L-Ab were separated from free and aggregated antibodies by centrifugation. L-Ab were characterized by measuring particle size and binding to anti-mouse IgG-sepharose. Ninety five per cent of the liposomal (L-Ab) lipid label was bound to anti-mouse IgG-sepharose, whereas only 7% of plain liposomes were bound, indicating non-specific binding. Uptake of L-Ab was measured in human monocyte/macrophages as a function of time and compared with that of plain liposomes. The uptake increased with time and it was 4-6 times greater than that of plain liposomes although part of that effect may have been due to unreacted MPB groups.

Antibodies, Monoclonal↗
PubMed1993

A distributed pharmacokinetic model of two-step imaging and treatment protocols: application to streptavidin-conjugated monoclonal antibodies and radiolabeled biotin.

Two-step imaging and treatment protocols involve injecting a suitably prepared monoclonal antibody that can bind both to a specific tumor antigen and to a second reagent which carries a drug or radionuclide. The second component is injected later, after the antibody has distributed throughout the target tumors and been largely cleared from the plasma and normal tissues. We introduce a mathematical model for the analysis of such protocols and apply it to the case of a streptavidinylated monoclonal antibody and radiolabeled biotin diffusing into small, prevascular, densely cellular nodules that represent either primary or metastatic tumors. We examine the distribution of streptavidinylated antibody and radiolabeled biotin within a tumor nodule and compare the two-step protocol to a one-step protocol using radiolabeled antibody. Our analysis predicts that (1) streptavidinylation reduces both the amount of antibody that distributes into the tumor nodule and the homogeneity of that distribution; (2) streptavidinylated antibody in the nodule can be saturated by initial plasma concentrations of free radiolabeled biotin substantially lower than the initial plasma concentration of free streptavidinylated antibody; (3) radiolabeled biotin diffuses rapidly, but binds so quickly that it will not penetrate deeply into the nodule if too low a dose is given. Hence, nonuniform localization of radiolabel may result from a "binding site barrier" to diffusion of either or both components; and (4) the two-step protocol permits imaging sooner after injection of radiolabeled material than the one-step protocol and produces a higher exposure in tumor relative to plasma, even in the presence of antigen turnover.

Bacterial Proteins↗
PubMed1992

Neural computing in cancer drug development: predicting mechanism of action.

Described here are neural networks capable of predicting a drug's mechanism of action from its pattern of activity against a panel of 60 malignant cell lines in the National Cancer Institute's drug screening program. Given six possible classes of mechanism, the network misses the correct category for only 12 out of 141 agents (8.5 percent), whereas linear discriminant analysis, a standard statistical technique, misses 20 out of 141 (14.2 percent). The success of the neural net indicates several things. (i) The cell line response patterns are rich in information about mechanism. (ii) Appropriately designed neural networks can make effective use of that information. (iii) Trained networks can be used to classify prospectively the more than 10,000 agents per year tested by the screening program. Related networks, in combination with classical statistical tools, will help in a variety of ways to move new anticancer agents through the pipeline from in vitro studies to clinical application.

Alkylating Agents↗
PubMed1992

Micropharmacology of monoclonal antibodies in solid tumors: direct experimental evidence for a binding site barrier.

Monoclonal antibodies (MAbs) often distribute nonuniformly in tumors. In part, that observation reflects intrinsic heterogeneity within the tumor; in part, it reflects poor penetration through tumor substance. Several years ago, we proposed the "binding site barrier" hypothesis (J.N. Weinstein, R.R. Eger, D.G. Covell, C.D.V. Black, J. Mulshine, J.A. Carrasquillo, S.M. Larson, and A.M. Keenan, Ann. NY Acad. Sci., 507: 199-210, 1987; K. Fujimori, D.C. Covell, J.E. Fletcher, and J.N. Weinstein, Cancer Res., 49: 5656-5663, 1989), the idea that antibodies (and other ligands) could be prevented from penetrating tumors by the very fact of their successful binding to target antigen. Calculations suggested that this might be a significant factor in the therapy of even microscopic nodules. The higher the affinity and the higher the antigen density, the greater the barrier. Here, we provide direct experimental evidence of such a barrier to the percolation of D3 MAb through intradermally implanted line 10 carcinoma of guinea pigs. After affinity purification using glutaraldehyde-fixed line 10 cells, the D3 had an average immunoreactivity of 88%, a binding constant of 1.6 +/- 0.3 (SEM) x 10(10) M-1, and saturation binding of 355,000 +/- 15,000 molecules/cell. Using a combination of double-label autoradiography and double-chromagen immunohistochemistry, we determined simultaneously the distribution of (a) i.v. injected D3 MAb; (b) coinjected isotype-matched control IgG (BL3); (c) D3 antigen; (d) blood vessels. The previously developed mathematical models aided in the design of these experiments. Double immunochemical staining of the tumors showed antigen-rich patches 100-800 microns across, surrounded by blood vessels. At a low MAb dose (30 micrograms), binding to antigen severely hindered penetration into antigenic patches as small as 200 microns, even at 72 h. Explanation of this finding by a physical barrier was ruled out by the observation that BL3 distributed uniformly in the same patches. At a higher dose (1000 micrograms), the binding site barrier could be partially overcome. The same general principles of micropharmacology may apply to biological ligands other than antibodies, including those secreted by genetically modified cells.

Adenoma, Bile Duct↗
PubMed1992

Nuclear clefting in dorsal root ganglion neurons: a response to whole body vibration.

Normal adult rabbits were studied in a whole body vibration model which simulates the type of environmental exposure associated with vibration-induced low back pain. This model has previously been shown to induce changes in pain-related neuropeptides in the dorsal root ganglion. Following two weeks of daily exposure to whole body vibration, dorsal root ganglia were excised from control and vibrated rabbits and prepared for ultrastructural evaluation. Of over 1,200 cells sampled, 190 appropriately sectioned cells were analyzed: 32 from immobilized controls, 44 from normal controls, and 114 from vibrated animals. Analysis of nuclear contours revealed more prevalent and more extensive clefting of the nuclear membrane in vibrated cells. The membrane lining these clefts was traversed by numerous pores; density of these pores was 46% greater than in adjacent nonclefted segments (p less than .001). Number of clefts per nucleus was increased by 39% in vibrated animals. Cleft area represented 1.19% of nuclear area in vibrated cells compared to 0.74% in controls (p less than .001). Numerous mitochondria and free ribosomes and abundant rough endoplasmic reticulum were located within the cleft spaces of vibrated cells. Pores in the cleft membrane appeared normal, supporting the conclusion that the clefts are structural alterations rather than fixation or sectioning artifacts. Changes in dorsal root ganglion neuropeptides seen in previous studies of vibrated animals may result from increased or redirected cellular synthesis. Ultrastructural changes seen in these vibrated dorsal root ganglion neurons are consistent with such an alteration in metabolism and could reflect increased synthesis of pain-related neuropeptides.

Animals↗
PubMed1992

Early intervention in cancer using monoclonal antibodies and other biological ligands: micropharmacology and the "binding site barrier".

Monoclonal antibodies and other biological ligands tend to distribute nonuniformly in bulky tumors after systemic administration. In part, that observation reflects intrinsic heterogeneity of the tumor; in part, it represents poor percolation through tumor substance. Theoretical considerations led us several years ago to formulate the "binding site barrier" hypothesis, the idea that macromolecular ligands could be prevented from penetrating tumors by the very fact of their successful binding to the target receptor. All else being equal, the higher the density of target moieties (e.g., antigens) and the higher the affinity, the greater the barrier. Experimental evidence for this hypothesis remained circumstantial until we recently obtained direct experimental verification in an animal tumor system. As shown by calculations in the present study, metabolism of ligand in free form or once it has bound to the target can also limit dramatically the extent of penetration. The PERC program package, developed to examine these issues in the case of monoclonal antibodies, has now been applied to other types of ligands as well. We speculate that the same microscopic factors have influenced the evolution of biological ligands, such as the autocrine-paracrine and chemotactic factors. Micropharmacological issues (binding sites, molecular size, and charge) should be taken into account as we design the next generation of biological ligands for systemic administration. The same issues are, perhaps, even more important with respect to molecular design of biological factors to be secreted by genetically modified cells in the treatment of cancer and in cancer vaccines. Since the PERC calculations and experiments relate to aggregates of tumor cells no more than a few hundred micron across, the ideas appear relevant to the problems of early detection and intervention. However, barriers associated with organized epithelial cell layers and basement membrane in the case of early carcinomas and carcinomatous change remain to be understood.

Animals↗
PubMed1992

The macroscopic and microscopic pharmacology of monoclonal antibodies.

When monoclonal antibodies directed against tumor-associated antigens are injected intravenously, they sometimes fail to distribute uniformly in the substance of a tumor. To understand the possible reasons, it is necessary to consider both macroscopic and microscopic features of the pharmacology. We have analyzed antibody penetration into microscopic primary tumors and metastases by melding together information on the global pharmacokinetics, convective and diffusive transport across the blood capillary wall, diffusion through the tumor interstitial space, antigen - antibody interaction, metabolism, and lymphatic outflow. This analysis predicts that the very fact of successful binding will decrease the homogeneity of distribution. We believe that this "binding site barrier" constitutes major challenges to the molecular design of next-generation antibodies and also to the design of many other types of ligands for use in treatment of solid tumors.

Animals↗
PubMed1992

Isolated L4-L5 fusions using the variable screw placement system: unilateral versus bilateral.

Thirty-six patients were retrospectively followed an average of 25.1 months to evaluate the relative effectiveness of unilateral (16 patients) versus bilateral (20 patients) variable screw placement (VSP) instrumentation in isolate L4-L5 fusions. Demographic variables and preoperative diagnoses were similar between treatment groups. Outcome was assessed primarily through evaluation of plain roentgenograms and self-report questionnaires. Use of VSP instrumentation at the L4-L5 level with autogenous posterolateral grafting achieved a successful fusion rate of 97% with minimal complications. Fusion results with unilateral instrumentation were nearly identical to those of bilateral; in both cases, results were better than most historical controls for noninstrumented fusions in situ. Clinical outcome, as obtained through standardized measurement techniques of pain and function, demonstrated 69% excellent and good results. Clinical outcome was similar between treatment groups yet was not significantly related to the fusion status obtained at follow-up.

Adult↗
PubMed1992

In vitro inhibition of human immunodeficiency virus (HIV) type 1 replication by C2 symmetry-based HIV protease inhibitors as single agents or in combinations.

C2 symmetry-based human immunodeficiency virus (HIV) protease inhibitors were examined in vitro as single agents or in combination with 3'-azido-2',3'-dideoxythymidine (AZT) or 2',3'-dideoxyinosine for activity against HIV type 1 (HIV-1). Ten C2 symmetry-based or pseudo-C2 symmetry-based HIV protease inhibitors were active against a laboratory strain (HIV-1IIIB) in the HIV-1 cytopathic effect inhibition assay. Three inhibitors, A75925, A76928, and A77003, selected to represent a range of aqueous solubility and antiviral activity, were active against four different HIV-1 strains tested. These three inhibitors exhibited a significant inhibition of the cytopathic effect of HIV-1 against the CD4+ ATH8 cell line, with 90% inhibitory concentrations ranging from 0.1 to 4 microM. Cellular toxicity was negligible at up to 20 microM. Furthermore, they completely inhibited the replication of monocytotropic strain HIV-1Ba-L in purified monocytes and macrophages at 0.75 to 2 microM. Potent inhibitory activity against a primary HIV-1 isolate and an AZT-resistant HIV-1 variant was also observed for all three inhibitors in phytohemagglutinin-activated peripheral blood mononuclear cells. When these three HIV protease inhibitors and AZT or 2',3'-dideoxyinosine were used in combinations against a primary HIV isolate in phytohemagglutinin-activated peripheral blood mononuclear cells and the results were analyzed with the COMBO program package, their antiviral activities were identified to be synergistic in some cases and additive in others. The present data warrant further investigations of these compounds as potential antiviral agents for the therapy of HIV infections.

Didanosine↗