Gait variability in Parkinson's disease: levodopa and walking direction.

BACKGROUND: Levodopa treatment has been shown to improve gait spatio-temporal characteristics in both forward and backward walking. However, effect of levodopa on gait variability during backward walking compared with forward walking has not been reported. AIMS OF STUDY: To study the effects of levodopa on gait variability of forward and backward walking in individuals with Parkinson's disease (PD). METHODS: Forty individuals with PD were studied. Their mean age was 68.70 ± 7.46 year. The average time since diagnosis was 9.41 ± 5.72 year. Gait variability was studied while 'OFF' and 'ON' levodopa when the participants walked forward and backward at their usual speed. Variability in step time, swing time, stride length, double support time, and stride velocity were compared between medication condition and walking direction. RESULTS: Variability of step time, swing time, stride length, and stride velocity decreased significantly during forward and backward walks (P < 0.001; P < 0.001; P = 0.003, P = 0.001, respectively) after levodopa administration. Variability of double support time was not changed after levodopa administration (P = 0.054). CONCLUSIONS: Levodopa had positive effects on gait variability of forward and backward walking in individuals with PD. However, variability in double support time was not affected by the levodopa.

The relation of falls to fatigue, depression and daytime sleepiness in Parkinson's disease.

OBJECTIVE: To characterize non-motor symptoms in individuals with Parkinson's disease (PD) who experience falls compared to those who do not fall. METHODS: Fifty-four individuals with PD were studied. Thirty-six were fallers and 18 were non-fallers. Fatigue was assessed by the Iowa Fatigue Scale. Excessive daytime sleepiness was assessed by the Epworth Sleepiness Scale, and depressive symptomatology was assessed by the short-form Center for Epidemiologic Studies Depression Scale. RESULTS: Compared to non-fallers, fallers had more severe disability, greater general physical fatigue (p = 0.024), lower energy levels (p = 0.042) and less productivity (p = 0.007). Fallers had more depressive symptomatology than the non-fallers (p = 0.01). Excessive daytime sleepiness was not different between the two groups (p = 0.695). CONCLUSIONS: Individuals with PD who fell had more severe motor and non-motor symptoms than those who did not fall. These non-motor symptoms included physical fatigue, energy, productivity and depressive symptomatology.

An investigation of two interventions for micrographia in individuals with Parkinson's disease.

OBJECTIVE: This pilot study was designed to compare a change in micrographia between using grid lines and parallel horizontal lines as visual cues in individuals with Parkinson's disease. DESIGN: Single group pre- and post-test. SETTING: Research lab. PARTICIPANTS: Eleven males with Parkinson's disease. INTERVENTIONS: Practice writing words with parallel and grid lines. The sequence of practising was randomized. MAIN OUTCOME MEASURES: Length of words. RESULTS: The length of the words after practising with parallel lines was longer than in the initial free writing condition (17.83 ± 3.93 cm vs. 23.36 ± 5.82 cm, P =0.008). The length of the words after practising with grid lines was also longer than during free writing (17.83 ± 3.93 cm vs. 22.65 ± 4.04 cm, P =0.003). The length of the words after practising with parallel lines was not different from that after practising with grid lines. CONCLUSION: Improvements in letter size after practising with horizontal parallel lines and grid lines were not different. The addition of vertical lines to form a grid did not appear to improve the writing more than horizontal lines alone in persons with Parkinson's disease who experienced micrographia.

An evaluation of self-administration of auditory cueing to improve gait in people with Parkinson's disease.

OBJECTIVE: To evaluate a self-administration of auditory cueing on gait difficulties in people with Parkinson's disease over a one-week period. DESIGN: Single group pre and post test. SETTING: Research lab, community. PARTICIPANTS: Twenty-one individuals with Parkinson's disease. INTERVENTIONS: Self-application of an auditory pacer set at a rate 25% faster than preferred cadence. MAIN OUTCOME MEASURES: Self-selected gait speed, cadence, stride length, and double support time with and without the pacer at the initial visit and after one week of pacer use. RESULTS: During the initial visit, the auditory pacer improved gait speed (79.57 (18.13) cm/s vs. 94.02 (22.61) cm/s, P<0.0005), cadence (102.88 (11.34) step/min vs. 109.22 (10.23) steps/min, P=0.036) and stride length (94.33 (21.31) cm vs. 103.5 (22.65) cm, P =0.012). After one week, preferred gait speed was faster than the initial preferred speed (79.57 (18.13) vs. 95.20 (22.23) cm/s, P<0.0005). Stride length was significantly increased (94.33 (21.31) vs. 107.67 (20.01) cm, P =0.001). Double support time was decreased from 21.73 (5.23) to 18.94 (3.59)% gait cycle, P =0.016. CONCLUSION: Gait performance in people with Parkinson's disease improved significantly after walking with the auditory pacer for one week.

A two-year toxicology study of bisphenol A (BPA) in Sprague-Dawley rats: CLARITY-BPA core study results.

We report the data from the guideline-compliant two-year toxicology study conducted as part of the Consortium Linking Academic and Regulatory Insights on Bisphenol A Toxicity (CLARITY-BPA). BPA (0, 2.5, 25, 250, 2,500, and 25,000 µg/kg body weight (bw)/day) was administered daily by gavage in 0.3% carboxymethylcellulose vehicle to NCTR Sprague-Dawley rats from gestation day 6 through the start of parturition and then directly to pups from the day after birth until postnatal day 21 (stop-dose arm) or continuously until termination at one or two years. The stop-dose arm was included to assess the potential for any BPA effects that were due to developmental exposure. No BPA-related effects were evident in the in-life and non-histopathology data. Neoplastic and nonneoplastic lesions diagnosed in both females and males were common age-associated lesions that were variable across control and BPA-treated groups. The lack of consistent responses within the continuous- and stop-dose arms within and across tissues brought into question the plausible relationship of most of these lesions to BPA treatment. There was a possible relationship between the increased incidences of lesions in the female reproductive tract and the male pituitary and exposure to the 25,000 µg BPA/kg bw/day dose level.

Decline of the hemoglobin adduct of 4-aminobiphenyl during withdrawal from smoking.

The hemoglobin adduct of the human bladder carcinogen 4-aminobiphenyl (4ABP-Hb) declined in the blood of 34 smokers enrolled in a withdrawal program, from a mean of 120 +/- 7 (SE) pg/g of hemoglobin at the start to a mean of 82 +/- 6 pg/g after 3 weeks and a mean of 34 +/- 5 pg/g among the 15 exsmokers who had not resumed smoking after 2 months. Although 4ABP-Hb declined faster than expected under the assumption that the human erythrocyte has a life span of 120 days, it persisted much longer than cotinine. Therefore, 4ABP-Hb may complement the use of cotinine as a marker of exposure to tobacco smoke. The strength of the within-person association of 4ABP-Hb with smoking, coupled with the weakness of the between-person association (correlation coefficient, 0.33), is evidence that between-person variation in modifying factors is substantial. Study of the modifiers of 4ABP-Hb levels may help elucidate the etiology of human susceptibility to aromatic amine-induced bladder cancer.

Hemoglobin adducts of 4-aminobiphenyl in smokers and nonsmokers.

A quantitative method has been developed for the analysis of 4-aminobiphenyl (4-ABP) covalently bound as the sulfinic acid amide to the 93 beta cysteine of human hemoglobin. The method uses mild basic hydrolysis of hemoglobin to release the parent amine, derivatization to form the pentafluoropropionamide, and capillary gas chromatography with detection by negative-ion chemical ionization mass spectrometry. The method is precise and gives reproducible results on multiple blood samples taken from individuals over 48 h. Application of this method to blood samples from cigarette smokers and nonsmokers revealed consistently higher adduct levels in smokers. The mean value for smokers was 154 pg 4-ABP per g Hb compared to 28 pg/g Hb for nonsmokers, with no overlap of adduct levels between the two groups. Studies on quitting smokers revealed that adduct levels declined over a period of 6-8 weeks to nonsmoker levels. The finding of 4-ABP adducts in all nonsmokers was not anticipated but is consistent with low-level ubiquitous contamination of air, food, or water. In other animals sampled, rats and dogs had measurable adduct levels, but monkeys and fish did not. The hemoglobin adduct of 4-ABP is the product of a series of reactions between the hemoprotein and N-hydroxy-4-ABP. The formation of hydroxylamines from carcinogenic aromatic amines and their subsequent reactions with DNA are generally thought to be critical events in the initiation of bladder tumors. We suggest that the observed hemoglobin adduct levels formed by this proximate carcinogen will reflect the extent to which these steps have occurred. This is the first report of 4-ABP adducts in human blood.

In vivo dosimetry of 4-aminobiphenyl in rats via a cysteine adduct in hemoglobin.

The feasibility of monitoring doses of 4-aminobiphenyl (ABP) via adduction to hemoglobin was investigated. Rats dosed with ABP (from 0.5 micrograms/kg to 5 mg/kg) formed a stable covalent hemoglobin:ABP adduct. Approximately 5% of a single dose was bound as hemoglobin:ABP; chronic dosing led to an accumulation of the adduct to a level 30 times greater than that found after a single dose. Facile in vitro hydrolysis of the adduct regenerated ABP, allowing detection at the sub-ng level. Human hemoglobin was also readily adducted, using N-hydroxy-ABP in vitro. The predominant site of adduction appeared to be the cysteine residue in hemoglobin. The use of such adducts as dosimeters for arylamine exposures in humans is discussed.

Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice.

We have been developing a series of nonpeptidic, small molecule farnesyl protein transferase inhibitors that share a common tricyclic nucleus and compete with peptide/protein substrates for binding to farnesyl protein transferase. Here, we report on pharmacological and in vivo studies with SCH 66336, a lead compound in this structural class. SCH 66336 potently inhibits Ha-Ras processing in whole cells and blocks the transformed growth properties of fibroblasts and human tumor cell lines expressing activated Ki-Ras proteins. The anchorage-independent growth of many human tumor lines that lack an activated ras oncogene is also blocked by treatment with SCH 66336. In mouse, rat, and monkey systems, SCH 66336 has excellent oral bioavailability and pharmacokinetic properties. In the nude mouse, SCH 66336 demonstrated potent oral activity in a wide array of human tumor xenograft models including tumors of colon, lung, pancreas, prostate, and urinary bladder origin. Enhanced in vivo efficacy was observed when SCH 66336 was combined with various cytotoxic agents (cyclophosphamide, 5-fluorouracil, and vincristine). In a Ha-Ras transgenic mouse model, prophylactic treatment with SCH 66336 delayed tumor onset, reduced the average number of tumors/mouse, and reduced the average tumor weight/animal. In a therapeutic mode in which gavage treatment was initiated after the transgenic mice had developed palpable tumors, significant tumor regression was induced by SCH 66336 in a dose-dependent fashion. This was associated with increased apoptosis and decreased DNA synthesis in tumors of animals treated with SCH 66336. Enhanced efficacy was also observed in this model when SCH 66336 was combined with cyclophosphamide. SCH 66336 is presently being evaluated in Phase I clinical trials.

Orally bioavailable farnesyltransferase inhibitors as anticancer agents in transgenic and xenograft models.

The in vivo evaluation process described here was instrumental in the identification of SCH 66336 as a clinical candidate. Our lead FTI, SCH 66336, and several other FTIs are being evaluated in early-phase clinical trials to establish proof-of-principle for farnesyl transferase inhibition in human patients. The preclinical studies described here suggest that FTIs may have utility against a wide array of human cancers as a single agent and may, at least in some cases, lead to tumor regression. In addition, the results to date in combination with cytotoxic chemotherapeutic agents in animal models indicate that these combinations may enhance the clinical efficacy of FPT inhibitors. Further preclinical studies should help to guide the clinical development of this class of novel antitumor agents.

Potent, selective, and orally bioavailable tricyclic pyridyl acetamide N-oxide inhibitors of farnesyl protein transferase with enhanced in vivo antitumor activity.

We previously reported compound 1 as a potent farnesyl protein transferase (FPT) inhibitor that exhibited reasonable pharmacokinetic stability and showed moderate in vivo activity against a variety of tumor cell lines. The analogous C-11 single compound, pyridylacetamide 2, was found to be more potent than 1 in FPT inhibition. Further studies showed that modification of the ethano bridge of the tricyclic ring system by conversion into a double bond with concomitant introduction of a single bond at C-11 piperidine resulted in compound 3 that had superior FPT activity and pharmacokinetic stability. Compound 4, a 5-bromo-substituted analogue of 3, showed improved FPT activity, had good cellular activity, and demonstrated a remarkably improved pharmacokinetic profile with AUC of 84.9 and t1/2 of 82 min. Compound4 inhibited the growth of solid tumor in DLD-1 model by 70% at 50 mpk and 52% at 10 mpk.

Inhibitors of farnesyl protein transferase. 4-Amido, 4-carbamoyl, and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]- cyclohepta[1,2-b]pyridin-11-yl)piperazine and 1-(3-bromo-8-chloro-6,11- dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperazine.

The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl) piperazine to explore the SAR of this series of FPT inhibitors is described. This resulted in the synthesis of the 4- and 3-pyridylacetyl analogues 45a and 50a, respectively, both of which were orally active but were found to be rapidly metabolized in vivo. Identification of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interesting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. Novel replacements for the pyridylacetyl moiety were also sought, and this resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopiperidinylacetyl derivatives 135a and 160a, respectively. All of these derivatives exhibited greatly improved pharmacokinetics. The synthesis of the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b (+/-) and 85b [11S(-)] and the 4-carboxamidopiperidinylacetamido derivative 160b (+/-), all of which exhibited potent FPT inhibition in vitro. All three showed excellent oral bioavailability in vivo in nude mice and cynomolgus monkeys and exhibited excellent antitumor efficacy against a series of tumor cell lines when dosed orally in nude mice.

Structure-activity relationship of 3-substituted N-(pyridinylacetyl)-4- (8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene )- piperidine inhibitors of farnesyl-protein transferase: design and synthesis of in vivo active antitumor compounds.

Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure-activity relationship (SAR) study of compounds arising from substitution at the 3-position of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.

Development of fast atom bombardment mass spectral methods for the identification of carcinogen-nucleoside adducts.

An analytical strategy using fast atom bombardment (FAB) ionization and tandem mass spectrometry has been developed to determine the molecular weight and major fragment ions, and to provide limited structural characterization of low picomole levels of carcinogen-nucleoside adducts. This strategy consists of three main components: (1) the sensitivity for analysis by FAB combined with mass spectrometry is increased via chemical derivatization; (2) the nucleoside adducts are selectively detected by using constant neutral loss scans; and (3) structurally characteristic fragments are obtained by using daughter ion scans. Trimethylsilyl derivatized arylamine-nucleoside adducts have been detected at levels as low as a few picomoles by using this approach. After experimental determination of the mass of the BH 2 (+) fragment ion, daughter ion spectra have been used to probe the structure specificity associated with collision-activated decomposition of this fragment. With model C-8 substituted arylamine adducts [N-(deoxyguanosin-8-yl)-4-aminobiphenyl, N-(deoxyadenosin--yl)-4-aminobiphenyl, and N-(deoxyguanosin-8-yl)-2-aminofluorene], nucleoside-specific and carcinogen-specific fragmentation have been observed in daughter ion spectra.

Detection and characterization of DNA adducts at the femtomole level by desorption ionization mass spectrometry.

Current methodologies for the detection and isolation of carcinogen-DNA adducts have advanced beyond the capabilities of the methods used to elucidate their structures. This difficulty seriously limits the potential use of DNA-carcinogen adducts in human dosimetry. We have investigated two general strategies for the analysis of model arylamine-nucleoside adducts using desorption ionization mass spectrometry (MS). Using fast atom bombardment MS-MS with constant neutral loss scans, we can identify the protonated molecule of derivatized adducts in samples as small as 1 pmole, and then apply daughter ion MS-MS scans to obtain structure-specific fragmentation. Using this strategy we have differentiated adducts having the same carcinogen and different bases [e.g., N-(deoxyadenosin-8-yl)-4-aminobiphenyl and N-(deoxyguanosin-8-yl)-4- aminobiphenyl] or the same base and different carcinogens [e.g., N-(deoxyguanosin-8-yl)-4- aminobiphenyl and N-(deoxyguanosin-8-yl)-2-aminofluorene]. In the second approach we used laser desorption time-of-flight MS to obtain spectra from adduct samples as small as 20 fmole. These data indicate that MS can be used for the analysis of very low (picomole-femtomole) levels of nucleoside adducts, including isomers, and that desorption ionization MS and MS-MS have significant potential for applications in human dosimetry.

Analysis of 4-aminobiphenyl-DNA adducts in human urinary bladder and lung by alkaline hydrolysis and negative ion gas chromatography-mass spectrometry.

Analysis of carcinogen-DNA adducts has been regarded as a useful means of assessing human exposure to chemical carcinogens. We have established a method for quantitation of 4-aminobiphenyl (4-ABP)-DNA adducts by alkaline hydrolysis and gas chromatography with negative ion chemical ionization mass spectrometry (GC-NICI-MS). Aliquots of DNA (typically 100 micrograms/ml) were spiked with an internal standard, d9-4-ABP, and were hydrolyzed in 0.05 N NaOH at 130 degrees C overnight. The liberated 4-ABP was extracted with hexane and derivatized using pentafluoropropionic anhydride in trimethylamine for 30 min at room temperature prior to GC-NICI-MS. With in vitro [3H]N-hydroxy-4-ABP modified DNA standards, we observed 59 +/- 7% (n = 9) recovery of the 4-ABP and a linear correlation between hydrolyzed 4-ABP and the adduct levels ranging from about 1 in 10(8) to 1 in 10(4) nucleotides (r = 0.999, n = 9). The method was further validated by comparison of the results with that obtained by the 32P-postlabeling method. There was excellent agreement (r = 0.994, p < 0.001) between the two methods for quantitation of the adduct in eight samples of Salmonella typhimurium DNA treated with 4-ABP and rat liver S9, although the 32P-postlabeling method gave slightly higher values. The DNA adducts in 11 human lung and 8 urinary bladder mucosa specimens were then determined by our GC-NICI-MS method. The adduct levels were found to be < 0.32 to 49.5 adducts per 10(8) nucleotides in the lungs and < 0.32 to 3.94 adducts per 10(8) nucleotides in the bladder samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Lability of steroid hormone receptors following devascularization of breast tumors.

Ischemia may invalidate hormone-receptor analyses. This study determined the effects of progressive ischemia on steroid hormone-receptor analyses. Breast cancer was induced in 50- to 60-day-old female Holtzman rats by intragastric administration of 25 mg of 7,12-dimethylbenz[a]anthracene. After 90 days, rats were anesthetized and breast tumors were devascularized in vivo. At 0, 30, 60, 90 and 150 minutes, a biopsy specimen from each tumor was taken and rapidly frozen. Steroid binding capacity for estrogen (ER), progesterone (PR), and androgen (AR) receptors was determined by incubation with tracer receptor ligand. Ischemia decreased ER and AR levels by 30 minutes, whereas PR levels were unchanged through 150 minutes of ischemia. Following mastectomy, tylectomy, or breast biopsy, PR may be the most reliable of the hormone receptors for determining endocrine-responsive breast cancer. However, for accurate determination of all hormone receptors, specimens should be frozen in liquid nitrogen immediately, then preserved at -70 degrees C, or processed immediately.

Effects of SCH 59228, an orally bioavailable farnesyl protein transferase inhibitor, on the growth of oncogene-transformed fibroblasts and a human colon carcinoma xenograft in nude mice.

The products of the Ha-, Ki-, and N-ras proto-oncogenes comprise a family of 21 kDa guanine nucleotide-binding proteins which play a crucial role in growth factor signal transduction and in the control of cellular proliferation and differentiation. Activating mutations in the ras oncogenes occur in a wide variety of human tumors. Ras proteins undergo a series of posttranslational processing events. The first modification is addition of the 15-carbon isoprene, farnesyl, to a Cys residue near the carboxy-terminus of Ras. Prenylation allows the Ras oncoprotein to localize to the plasma membrane where it can initiate downstream signalling events leading to cellular transformation. Inhibitors of the enzyme which catalyzes this step, farnesyl protein transferase (FPT), are a potential class of novel anticancer drugs which interfere with Ras function. SCH 59228 is a tricyclic FPT inhibitor which inhibits the farnesylation of purified Ha-Ras with an IC50 of 95 nM and blocks the processing of Ha-Ras in Cos cells with an IC50 of 0.6 microM. SCH 59228 has favorable pharmacokinetic properties upon oral dosing in nude mice. The in vivo efficacy of SCH 59228 was evaluated using a panel of tumor models grown in nude mice. These included several rodent fibroblast lines expressing mutationally-activated (val12) forms of the Ha-Ras oncogene. In some cases, these proteins contain their native C-terminal sequence (CVLS) which directs farnesylation. In one model, the C-terminal sequence was altered to CVLL, making the expressed protein a substrate for a distinct prenyl transferase, geranylgeranyl protein transferase-1. When dosed orally at 10 and 50 mg/kg (four times a day, 7 days a week) SCH 59228 significantly inhibited tumor growth of cells expressing farnesylated Ha-Ras in a dose-dependent manner; over 90% growth inhibition was observed at the 50 mg/kg dose. Tumor growth of cells expressing the geranylgeranylated form of Ha-Ras was less potently inhibited. Growth of tumors derived from a rodent fibroblast line expressing activated Ki-Ras containing its native C-terminal sequence (CVIM), which preferentially directs farnesylation, was also inhibited by SCH 59228. Inhibition in the Ki-Ras model was less than that observed in the Ha-Ras model. In contrast, tumors derived from cells transformed with the mos oncogene were not significantly inhibited even at the highest dose level. SCH 59228 also significantly and dose-dependently inhibited the growth of human colon adenocarcinoma DLD-1 xenografts (which express activated Ki-ras). These results indicate that SCH 59228 possesses in vivo antitumor activity upon oral dosing in tumor models expressing activated ras oncogenes. This is the first report of oral antitumor activity with an FPT inhibitor. These results are discussed in light of recent observations on alternative prenylation of some Ras isoforms.

Autogeneic fat transplants in the epidural space in routine lumbar spine surgery.

This report presents our experience with the use of autogeneic fat patch grafts to protect the exposed dura mater during lumbar spine operations. A total of 44 consecutive surgical procedures was performed primarily for discogenic or spondylotic disease from 1979 to 1982. Prophylactic antibiotics were used in 21 (48%) cases. The autogeneic fat transplants were well accepted by all recipients during 10.4 (1 to 32) months of follow-up. Fat grafts, greater than 1 cm in thickness, were easily identified on subsequent computed tomographic (CT) scans. There were no postoperative wound infections. However, 1 patient developed a large subcutaneous sterile fluid accumulation at the fat donor site, which required surgical intervention. Our results, both short and long term, indicate that autogeneic fat transplants may be well tolerated in the lumbar spine area. The fat graft viability as demonstrated by CT scanning and histological examination supports the contention that autogeneic fat interposed between dura mater and overlying musculature may serve as a barrier limiting the growth of cicatrix into the spinal canal.