Showing papers by "Rush University Medical Center published in 1994"

Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. First International Vagus Nerve Stimulation Study Group.

Abstract: Vagus nerve stimulation (VNS) was shown to reduce seizure frequency in refractory epilepsy patients in two pilot studies. Based on these results, a multicenter, prospectively randomized, parallel, double-blind study of patients with refractory partial seizures was initiated. After a 12-week baseline period, identical vagus nerve stimulators were implanted and patients randomized to either a high or low 14-week VNS treatment paradigm. The primary objective was to demonstrate that high VNS (therapeutic parameters) was more effective in reducing partial seizure frequency than was low VNS (less or noneffective parameters). Patients continued receiving antiepileptic drugs (AEDs) with plasma concentrations held constant throughout the study. We report results of the first 67 patients to exit the 14-week acute phase. After 14 weeks of VNS, 31 patients receiving high VNS experienced a mean seizure frequency percentage reduction of 30.9%, which was statistically significant as compared with the mean seizure frequency percentage reduction of 11.3% in 36 patients receiving low VNS (p = 0.029, t test; p = 0.036, Wilcoxon rank-sum test). In addition to the significant intragroup p-values, mean seizure frequency percentage change reached statistical significance for high VNS (p < 0.001) but not low VNS (p = 0.072) as compared with baseline. Twelve of 31 (38.7%) patients receiving high VNS achieved at least 50% reduction in seizure frequency whereas 7 of 36 (19.4%) patients receiving low VNS experienced at least 50% reduction after 14 weeks. The implant procedure and VNS therapy were well tolerated. Our study confirmed the effectiveness of VNS as treatment for epilepsy patients with refractory partial seizures.

Phenotypic stability of bovine articular chondrocytes after long-term culture in alginate beads

Abstract: Articular chondrocytes embedded in alginate gel produce de novo a matrix rich in collagens and proteoglycans. A major advantage of this culture system is that the cells can be recovered by chelating the calcium, which otherwise maintains the alginate in its gel state. Chondrocytes thus released are surrounded by tightly bound cell-associated matrix, which seems to correspond to the pericellular and territorial matrices identified in cartilage by electron microscopy. The cells and their associated matrix can be easily separated by mild centrifugation from more soluble matrix components derived principally from the 'interterritorial' matrix. This new cell culture system thus makes it possible to study the assembly and turnover of molecules present in two distinct matrix pools. Importantly, a significant proportion of the aggrecan molecules in each of these two pools can be extracted using a non-denaturing solvent, thereby making possible studies of the metabolism and turnover of native proteoglycan aggregates. We show in this report that chondrocytes isolated from the full depth of adult bovine articular cartilage and maintained for 8 months in alginate gel are still metabolically active and continue to synthesize cartilage-specific type II collagen and aggrecan. The cells did not synthesize large amounts of type I collagen or of the small nonaggregating proteoglycans as usually occurs when chondrocytes lose their phenotypic stability. After this extended period of time in culture, the cells were present as two populations exhibiting differences in size, shape and amount of extracellular matrix surrounding them. The first population was found only near the surface of the bead: these cells were flattened and surrounded by a matrix sparse in proteoglycans and collagen fibrils. The second population was found throughout the remaining depth of the bead: the cells were more round and almost always surrounded by a basket-like meshwork consisting of densely packed fibrils running tangential to the surface.

Regulation of vascular endothelial barrier function

Abstract: The increase in endothelial permeability in response to inflammatory mediators such as alpha-thrombin and histamine is accompanied by cell rounding and interendothelial gap formation, implicating that the predominant transport pathway is a diffusive one [i.e., via cellular junctions (paracellular transport)]. However, the possible contribution by vesicle-mediated transport (i.e., via albumin binding protein gp60) to the overall permeability increase needs investigation. Regulation of paracellular transport in endothelial cells is associated with modulation of actin-based systems which anchor the cell to its neighbor or extracellular matrix, thus maintaining endothelial integrity. At the cell-cell junctions, actin is linked indirectly to the plasma membrane by linking proteins (e.g., vinculin, catenins, alpha-actinin) to cadherins, which function in homophilic intercellular adhesion. Cadherins may also play a role in regulating the formation of tight junctions, which also may be associated with actin. At endothelial focal contacts, the transmembrane receptors (integrins) for matrix proteins are linked to actin via linking proteins (i.e., vinculin, talin, alpha-actinin). In response to inflammatory mediators, second messengers signal two regulatory pathways which modulate the actin-based systems, which may lead to impairment of the endothelial barrier integrity. One pathway is based on protein kinase C (PKC) isozyme-specific phosphorylation of linking proteins at the cell-cell and cell-matrix junctions. The increased phosphorylation is associated with actin reorganization, cell rounding, and increased paracellular transport. The other is the activation of myosin light-chain kinase, (MLCK), which causes an actin-myosin-based contraction that may lead to a centripetal retraction of endothelial cells. Current research is in the identification of protein substrates of PKC isozymes, the specific role of their phosphorylation in barrier function, and determining the precise role of MLCK in modulation of endothelial barrier function.

Febrile seizures : recognition and management

Abstract: The majority of all febrile seizures represent a benign syndrome that does not require extensive testing or long term medication. A careful history of the febrile seizure, family history, developmental history and physical examination can identify those infants and children with this syndrome. While one-third of this group will experience additional febrile seizures, there is no significant increase in the incidence of later epilepsy or neurological sequelae. The parents of these children need to be reassured and educated about this syndrome. They should understand the emergency treatment of seizures and aggressively treat fever. The more difficult task for the physician is to correctly identify those children who experience nonbenign seizures. Careful history and physical examination can accurately identify this group. Further evaluation including neuroimaging, electroencephalogram and developmental assessment may be necessary. In those children with a high risk of later epilepsy, treatment with an antiepileptic drug should be considered.

Summation priming and coarse semantic coding in the right hemisphere

Abstract: There are now numerous observations of subtle right hemisphere (RH) contributions to language comprehension. It has been suggested that these contributions reflect coarse semantic coding in the RH. That is, the RH weakly activates large semantic fields---including concepts distantly related to the input word---whereas the left hemisphere (LH) strongly activates small semantic fields---limited to concepts closely related to the input (Beeman, 1993a,b). This makes the RH less effective at interpreting single words, but more sensitive to semantic overlap of multiple words. To test this theory, subjects read target words preceded by either “Summation” primes (three words each weakly related to the target) or Unrelated primes (three unrelated words), and target exposure duration was manipulated so that subjects correctly named about half the target words in each hemifield. In Experiment 1, subjects benefited more from Summation primes when naming target words presented to the left visual field-RH (Ivf-RH) than when naming target words presented to the right visual field-LH (rvf-LH), suggesting a RH advantage in coarse semantic coding. In Experiment 2, with a low proportion of related prime-target trials, subjects benefited more from “Direct” primes (one strong associate flanked by two unrelated words) than from Summation primes for rvf-LH target words, indicating that the LH activates closely related information much more strongly than distantly related information. Subjects benefited equally from both prime types for Ivf-RH target words, indicating that the RH activates closely related information only slightly more strongly, at best, than distantly related information. This suggests that the RH processes words with relatively coarser coding than the LH, a conclusion consistent with a recent suggestion that the RH coarsely codes visual input (Kosslyn, Chabris, Mar-solek, & Koenig, 1992).

Macrophage/particle interactions: Effect of size, composition and surface area

Abstract: Particulate wear-debris are detected in histiocytes/macrophages of granulomatous tissues adjacent to loose joint prostheses. Such cell-particle interactions have been simulated in vitro by challenging macrophages with particles dosed according to weight percent, volume percent, and number of particles. Each of these dosage methods has inherent shortcomings due to varying size and density of challenging particles of different compositions. In this study we challenged P388D1 macrophages with titania and polystyrene particles (< 2 microns), with dosage based on the ratio of the surface area of the particles to the surface area of the cells. The effect of size and composition on (1) the bone resorbing activity, (2) fibroblast proliferation, and (3) secretion of IL-1 and PGE2 was determined. Macrophage response to particulate debris appears to be dependent on particle size, composition, and dose as given by surface area ratio. P388D1 macrophages challenged with titania particles released IL-1, but did not stimulate fibroblasts. Inhibition of macrophage DNA synthesis at higher surface area ratios suggests cell damage or death. Particle-stimulated cells increased bone resorption up to 125% of controls but released only basal levels of PGE2. Macrophages stimulated by wear particles are expected to synthesize numerous factors affecting events in the bone-implant interface. Using the concept of surface area ratio allows us to study and compare such cellular responses to wear particles in a standardized manner.

Composition and morphology of wear debris in failed uncemented total hip replacement

Abstract: Interfacial membranes collected at revision from 11 failed uncemented Ti-alloy total hip replacements were examined. Particles in the membranes were characterised by electron microscopy, microchemical spectroscopy and particle size analysis. Most were polyethylene and had a mean size of 0.53 micron +/- 0.3. They were similar to the particles seen in the base resin used in the manufacture of the acetabular implants. Relatively few titanium particles were seen. Fragments of bone, stainless steel and silicate were found in small amounts. Most of the polyethylene particles were too small to be seen by light microscopy. Electron microscopy and spectroscopic techniques are required to provide an accurate description of this debris.

Age and clinical decision making in oncology patients.

Abstract: Background Ageism is a cultural bias that might inappropriately steer oncologists away from recommending aggressive treatments for older patients. The extent to which older patients might prefer less aggressive cancer therapies is unknown. Our lack of knowledge about patients' personal preferences for therapy may perpetuate this bias. Purpose We conducted a study to determine 1) if age influences patient acceptance of cancer therapy and 2) if the older patients would be more or less likely to trade increased survival for maintaining quality of life than their younger counterparts. Methods Using an interview format, 244 cancer patients of all ages treated at a tertiary care cancer center read two sets of hypothetical vignettes. The first set consisted of four vignettes that varied in terms of stage of disease and treatment toxicity. Patients were asked to make hypothetical decisions about treatment given with respect to varying levels of either increasing cure or extending survival. The second set of vignettes presumed acceptance of cancer therapy. Within each vignette, two hypothetical treatments (mild versus severe) with different probabilities of 1-year survival were contrasted. The point at which patients shifted preferences from a treatment with mild versus severe side effects was the dependent measure. Mixed analysis of variance (ANOVA) procedures (F test) assessed the impact of age ( or = 65 years) and patient disease stage (early versus advanced) on hypothetical decisions about treatment. All P values are two sided. Results In the treatment-preference vignettes, there was no effect of either age [F(1,239) = 2.14; P = .14] or patient stage [F(1,239) = .40; P = .53] on treatment acceptance. Older adults were as likely as their younger counterparts to agree to chemotherapy for both curative and control purposes. In the switch-point vignettes, younger adults switched to a more toxic treatment to gain survival advantage at an earlier point than the older patients in both the early-disease vignette [F(1,232) = 3.88; P = .05] and the advanced-disease vignette [F(1,232) = 4.43; P = .036]. There was neither an effect of disease stage on treatment decisions nor an interaction between disease stage and age. Conclusions and implications In a tertiary care setting, older adults do not differ from their younger counterparts in terms of acceptance of chemotherapy. However, when treatment is presumed, they differ in terms of willingness to trade survival for current quality of life. Generalization of findings is limited by the relatively small sample of older adults (n = 43) and the referral population from which the sample was drawn. Replication with a larger older adult sample in a community setting is needed.

Migration of corrosion products from modular hip prostheses. Particle microanalysis and histopathological findings.

Abstract: Migration of solid corrosion products from the modular head-neck junction of fifteen total hip replacements to the periprosthetic tissues was studied. The devices and tissues were recovered at the time of a revision procedure or at autopsy after a mean of sixty-four months (range, eight to ninety-seven months). The prostheses had a cobalt-chromium-alloy head coupled with a cobalt-chromium-alloy or a titanium-alloy stem. The solid corrosion product was identified by electron microprobe analysis and Fourier transform infrared microprobe spectroscopy as a chromium orthophosphate hydrate-rich material. The product was present at the junction of the modular head and neck and as particles within the periprosthetic tissues as early as eight months postoperatively. In several hips, it was also present on the polyethylene bearing surface. The particles in the tissues ranged in size from less than one to 500 micrometers. They were present within histiocytes or were surrounded by foreign-body giant cells in the pseudocapsule of the hip joint; in the membranes of the femoral bone-implant interface; and at sites of femoral endosteal erosions, with and without loosening of the femoral component.

TrkA-Immunoreactive Profiles in the Central Nervous System: Colocalization With Neurons Containing p75 Nerve Growth Factor Receptor, Choline Acetyltransferase, and Serotonin

Abstract: The present investigation used an antibody directed against the extracellular domain of the signal transducing nerve growth factor receptor, trkA, to reveal immunoreactive perikarya or fibers within the olfactory bulb and tubercle, cingulate cortex, nucleus accumbens, striatum, endopiriform nucleus, septal/diagonal band complex, nucleus basalis, hippocampal complex, thalamic paraventricular and reuniens nuclei, periventricular hypothalamus, interpeduncular nucleus, mesencephalic nucleus of the fifth nerve, dorsal nucleus of the lateral lemniscus, prepositus hypoglossal nucleus, ventral cochlear nucleus, ventral lateral tegmentum, medial vestibular nucleus, spinal trigeminal nucleus oralis, nucleus of the solitary tract, raphe nuclei, and spinal cord. Colocalization experiments revealed that virtually all striatal trkA-immunoreactive neurons (> 99%) coexpressed choline acetyltransferase (ChAT) but not p75 nerve growth factor receptor (NGFR). Within the septal/diagonal band complex virtually all trkA neurons (> 95%) coexpressed both ChAT and p75 NGFR. More caudally, dual stained sections revealed numerous trkA/ChAT (> 80%) and trkA/p75 NGFR (> 95%) immunoreactive neurons within the nucleus basalis. In the brainstem, raphe serotonergic neurons (45%) coexpressed trkA. Sections stained with a pan-trk antibody that recognizes primarily trkA, as well as trkB and trkC, labeled neurons within all of these regions as well as within the hypothalamic arcuate, supramammilary, and supraoptic nuclei, hippocampus, inferior and superior colliculus, substantia nigra, ventral tegmental area of T'sai, and cerebellular Purkinje cells. Virtually all of these other regions with the exception of the cerebellum also expressed pan-trk immunoreactivity in the monkey. The widespread expression of trkA throughout the central neural axis suggests that this receptor may play a role in signal transduction mechanisms linked to NGF-related substances in cholinergic basal forebrain and noncholinergic systems. These findings suggest that pharmacological use of ligands for trkA could have beneficial effects on the multiple neuronal systems that are affected in such disorders as Alzheimer's disease.

Utility of an objective dyskinesia rating scale for Parkinson's disease: inter- and intrarater reliability assessment.

Abstract: Although dyskinesia is a frequent and important problem in Parkinson's disease (PD), a reliable assessment measure has not been thoroughly developed and tested. We modified the Obeso dyskinesia scale to create an objective rating scale for dyskinesia assessment during activities of daily living. Thirteen physicians and 15 study coordinators involved in a clinical trial independently reviewed videotape segments of PD patients performing three tasks: walking, putting on a coat, and lifting a cup to the lips for drinking. Raters evaluated the severity of worst dyskinesia seen, the types of all dyskinesias seen, and the type of dyskinesia most associated with motoric disability. For all assessments, the total group showed statistically significant inter- and intrarater reliability. Physicians had a higher consistency than did coordinators, but for most measures the difference was not statistically significant. Physicians and coordinators found the scale easy to use and especially practical for rating dyskinesia severity and for identifying the most disabling dyskinesia. Dyskinesias can be assessed in clinical trials and warrant regular documentation.

Wear Debris in Total Joint Replacements.

Abstract: In vivo degradation of prosthetic implant materials is increasingly recognized as a major factor limiting the durability of total joint arthroplasty. In vivo degradation occurs primarily by means of wear processes that can generate large quantities of particulate debris. This debris can stimulate an adverse local host response leading to periprosthetic bone loss, which can compromise implant fixation and bone stock. The authors review the basic mechanisms of implant degradation and the host response to particulate degradation products, particularly in the context of the pathogenesis of osteolysis. Submicron polyethylene particles (mean size, 0.5 um) are the dominant type of wear particle present in periprosthetic tissues associated with uncemented hip replacements. Polyethylene wear can be minimized by improving the quality of the polyethylene, avoiding use of large-diameter (greater than 28 mm) femoral heads in total hip arthroplasty, and improving the design and fabrication of modular connections, which can be important sources of three-body wear particles. Advances in the understanding of the basic mechanisms of osteolysis are critical to the development of preventive measures that will minimize the clinical impact of this phenomenon.

Physical therapy and Parkinson's disease A controlled clinical trial

Abstract: In a randomized, single-blind, crossover study, we evaluated physical disability in moderately advanced Parkinson's disease (PD) patients after 4 weeks of normal physical activity and 4 weeks of an intensive physical rehabilitation program. We used a timed motor task and a standard assessment of PD severity (the Unified Parkinson's Disease Rating Scale [UPDRS] with subscales for mentation, activities of daily living [ADL], and motor function) completed by an investigator blinded to the physical rehabilitation status of the patient. Following physical rehabilitation, there was significant improvement in the UPDRS ADL and motor scores, but no change in mentation score. During the 6 months following physical rehabilitation, patients did not regularly exercise, and the UPDRS scores returned to baseline. We conclude that physical disability in moderately advanced PD objectively improves with a regular physical rehabilitation program, but this improvement is not sustained when normal activity is resumed.

HIV-Specific T-Helper Activity in Seronegative Health Care Workers Exposed to Contaminated Blood

Abstract: Objective. —To evaluate human immunodeficiency virus (HIV) type 1—specific cellular immune responses in HIV-seronegative health care workers with occupational high-risk exposures to HIV-infected (HIV-positive) patients. Design. —Peripheral blood mononuclear cells (PBMCs) were obtained after occupational exposures to HIV, and PBMCs from health care workers exposed to HIV-negative patients served as controls. The PBMCs were stimulated in vitro with HIV envelope synthetic peptides. Interleukin 2 (IL-2) production was measured in a bioassay. The HIV antibody status was determined by standard enzyme-linked immunosorbent assays. Exposed individuals were also evaluated for HIV proviral DNA by polymerase chain reaction techniques. Participants. —The PBMCs from eight health care workers with high-risk exposures and nine control health care workers were studied. Results. —The PBMCs from all individuals showed strong IL-2 production to control antigens, indicating intact T-helper function. Interleukin 2 production to HIV peptides was detected in PBMCs from six of eight HIV-exposed individuals, but in only one of the nine health care workers exposed to HIV-negative body fluids ( P Conclusion. —Human immunodeficiency virus—specific T-helper activity was detected in six (75%) of eight HIV-negative health care workers with exposure to HIV-positive body fluids. Potent HIV-specific T-helper activity was detectable 4 to 8 weeks after the exposure and was lost in individuals followed up for 8 to 64 weeks. Three health care workers remained responsive at 8,19, and 24 weeks. Exposure to HIV without evidence of subsequent infection appears to result in activation of cellular immunity without activation of antibody production. ( JAMA . 1994;271:42-46)

Vagus Nerve Stimulation for Treatment of Partial Seizures: 3. Long‐Term Follow‐Up on First 67 Patients Exiting a Controlled Study

Abstract: Vagus nerve stimulation (VNS) has demonstrated a significant anticonvulsant effect in preclinical studies, in pilot studies in humans, and in the acute phase of a multicenter, double-blinded, randomized study. After completion of a 14-week, blinded, randomized study, with 31 receiving high (therapeutic) VNS and 36 receiving low (less or noneffective) VNS, 67 patients elected to continue in an open extension phase. During the extension phase, all 67 patients received high VNS. Seizure frequency during the 3-month treatment blocks was compared with a 12-week baseline. For both groups, all periods of high VNS demonstrated a significant decrease in seizure frequency (p < 0.01 level) as compared with baseline. For the 16-18-month period of VNS, data were available for 26 of the 31 patients randomized to high VNS. This group achieved a 52.0% mean seizure frequency percentage reduction as compared with baseline. For those converted from low to high VNS, data were available for 24 of the 36 patients at the 16-18-month time period. This group reported a mean seizure frequency percentage reduction of 38.1% as compared with baseline. No significant change in the safety/side effect profile was reported during long-term follow-up. The previously reported side effects of hoarseness/voice change, coughing, and paresthesia (sensation in neck and jaw) continued to occur during VNS. These side effects were well tolerated. During the follow-up period, 1 patient died of thrombotic thrombocytopenic purpura (TTP) and 5 patients discontinued treatment because of unsatisfactory efficacy.

Can sensory and motor collateral sprouting be induced from intact peripheral nerve by end-to-side anastomosis?

Abstract: The possibility that collateral sprouting could occur from intact axons in an undamaged sciatic nerve was studied in the rat by suturing either a 7-day predegenerated or a fresh nerve segment in an end-to-side fashion to the sciatic nerve proper. Following a 14- or 35-day recovery period, the pinch reflex test was performed on the transplanted segment to demonstrate the presence of sensory axons. The majority of cases, using a predegenerated nerve segment but not a fresh segment, responded positively. Neurofilament staining and histological examination confirmed the presence of axons in the attached nerve segment. In another series of experiments, the proximal peroneal fascicle was ligated and cut. Following a 7-day predegeneration period the distal stump was sutured end-to-side to the ipsilateral tibial fascicle. After 90 days, stimulation of the tibial nerve proximal to the attached site induced substantial contraction in both the native gastrocnemius muscle and the foreign tibialis anterior muscle. These findings suggest that collateral sprouting may occur from intact axons, perhaps induced by factors emanating from the attached nerve segment, and subsequently make functional peripheral connections.

Arthroscopy-assisted Anterior Cruciate Ligament Reconstruction Using Patellar Tendon Substitution Two- to Four-year Follow-up Results

Abstract: The purpose of this retrospective study was to evaluate clinically, functionally, and objectively our initial experience using free, autogenous middle third patellar tendon for anterior cruciate ligament reconstruction without extraarticular augmentation in 62 of 75 patients (80% followup) who were available for clinical review at a minimum 2-year followup. Subjective, clinical, functional, Cybex dynamometer, and KT-1000 arthrometer tests were performed along with modified tests of the Hospital for Special Surgery, Noyes Cincinnati, Tegner, and Lysholm knee rating scales. Ninety-two percent had a negative pivot shift at followup. The mean Cybex dynamometer extension deficits postoperatively were 9% and 7% at 180 and 240 deg/sec. Mild patellar pain symptoms were noted in 18%. The reoperation rate was 10% with a mild flexion contracture as the most common reason. The Hospital for Special Surgery scoring scale postoperatively was 88; Noyes, 86; Lysholm, 88; and Tegner, 6. Mean postoperative single-legged and vertical jump indices were 88% and 87%, respectively. The KT-1000 arthrometric evaluation postoperatively revealed a mean maximum manual difference of 0.3 mm; 92% of the patients had a maximum manual difference of < or = 3 mm. Subjectively, 95% indicated that they would undergo the procedure again. Early results demonstrate excellent stability, preservation of motion, and encouraging evaluations by scoring scales and arthrometric evaluation.

Embolization of experimentally created aneurysms with intravascular stent devices.

Abstract: PURPOSE To assess the effectiveness of self-expanding, cobalt-alloy stents in the treatment of aneurysms in a canine model and to observe the pattern of blood flow and formation of fibrotic scar tissue. METHODS Porous metallic stents were endovascularly placed across the necks of experimentally created side aneurysms in the carotid arteries of three dogs; aneurysms were also created in the opposite carotid arteries in these animals to serve as controls. RESULTS Before stent placement, angiography of the carotid arteries demonstrated whirl-like, vortex flow of blood within the lumens of the aneurysms. Inflow was seen along the distal aneurysm wall; outflow was demonstrated along the proximal wall; slower vortex flow was present in the central lumen. Immediately after stent placement there was disruption of the usual vortex flow with stasis of contrast media and blood within the lumen. Inflow and outflow patterns were no longer seen. Complete ablation of these aneurysms was evident at follow-up angiographic studies--1 week, 1 month, and 2 months after stent placement. The stented carotid arteries remained widely patent; control aneurysms and carotid arteries were patent and unchanged. Histopathologic analysis revealed fibrotic reactive scar tissue completely filling the stented aneurysm pouches. CONCLUSION Treatment of selected intracranial aneurysms via an endovascular approach has merit and could supplant more invasive, risky, and costly surgical procedures in some cases.

The aged monkey basal forebrain: rescue and sprouting of axotomized basal forebrain neurons after grafts of encapsulated cells secreting human nerve growth factor.

Abstract: Six Rhesus monkeys between 24 and 29 years of age received unilateral transections of the fornix. Three monkeys then received intraventricular transplants of polymer-encapsulated baby hamster kidney (BHK) fibroblasts that had been genetically modified to secrete human nerve growth factor (hNGF). The remaining three monkeys received identical grafts except the cells were not modified to secrete hNGF. Monkeys receiving the fornix transection and control grafts displayed extensive reductions in the number of choline acetyltransferase- (57-75%) and p75 NGF receptor- (53%) immunoreactive medial septal neurons ipsilateral to the lesion/implant. In contrast, monkeys receiving transplants of encapsulated hNGF-secreting cells display only a modest loss of choline acetyltransferase- (0-36%) and p75 NGF receptor-(7-22.4%) immunoreactive septal neurons. Additionally, all monkeys receiving the hNGF-secreting implants, but none receiving control implants, displayed robust sprouting of cholinergic fibers within the septum ipsilateral to the transplant. Just prior to sacrifice, the capsules were retrieved and found to contain viable BHK cells releasing biologically relevant levels of hNGF. These data demonstrate that hNGF can provide trophic and tropic influences to aged primate basal forebrain neurons undergoing lesion-induced degeneration, supporting the contention that hNGF may prevent the degeneration of basal forebrain neurons in Alzheimer disease.

Implants of polymer-encapsulated human NGF-secreting cells in the nonhuman primate: Rescue and sprouting of degenerating cholinergic basal forebrain neurons

Abstract: Baby hamster kidney (BHK) cells were genetically modified to secrete high levels of human nerve growth factor (BHK-hNGF). Following polymer encapsulation, these cells were implanted into the lateral ventricle of four cynomolgus monkeys immediately following a unilateral transection/aspiration of the fornix. Three control monkeys received identical implants, with the exception that the BHK cells were not genetically modified to secrete hNGF and thus differed only by the hNGF construct. One monkey received a fornix transection only. All monkeys displayed complete transections of the fornix as revealed by a comprehensive loss of acetylcholinesterase-containing fibers within the hippocampus ipsilateral to the lesion. Control monkeys that were either unimplanted or received BHK-control (non-NGF secreting) cell implants did not differ from each other and displayed extensive losses of choline acetyltransferase and p75 NGF receptor (NGFr)-immunoreactive neurons within the medial septum (MS; 53 and 54%, respectively) and vertical limb of the diagonal band (VLDB; 21 and 30%, respectively) ipsilateral to the lesion. In contrast, monkeys receiving implants of BHK-hNGF cells exhibited a only a modest loss of cholinergic neurons within the septum (19 and 20%, respectively) and VLDB (7%). Furthermore, only implants of hNGF-secreting cells induced a dense sprouting of cholinergic fibers within the septum, which ramified against the ependymal lining of the ventricle adjacent to the transplant site. Examination of the capsules retreived from monkeys just prior to their death revealed an abundance of cells that produced detectable levels of hNGF in a sufficient concentration to differentiate PC12A cells in culture. These findings support the use of polymer-encapsulated cell therapy as a potential treatment for neurodegenerative diseases such as Alzheimer disease where basal forebrain degeneration is a consistent pathological feature. Moreover, this encapsulated xenogeneic system may provide therapeutically effective levels of a number of neurotrophic factors, alone or in combination, to select populations of neurons within the central nervous system.