Efficient retrovirus-mediated transfer of the multidrug resistance 1 gene into autologous human long-term repopulating hematopoietic stem cells.

Pre-clinical studies indicate that efficient retrovirus-mediated gene transfer into hematopoietic stem cells and progenitor cells can be achieved by co-localizing retroviral particles and target cells on specific adhesion domains of fibronectin. In this pilot study, we used this technique to transfer the human multidrug resistance 1 gene into stem and progenitor cells of patients with germ cell tumors undergoing autologous transplantation. There was efficient gene transfer into stem and progenitor cells in the presence of recombinant fibronectin fragment CH-296. The infusion of these cells was associated with no harmful effects and led to prompt hematopoietic recovery. There was in vivo vector expression, but it may have been limited by the high rate of aberrant splicing of the multidrug resistance 1 gene in the vector. Gene marking has persisted more than a year at levels higher than previously reported in humans.

Studies of the retention mechanism of the brain perfusion imaging agent 99mTc-bicisate (99mTc-ECD).

The structure-activity relationship in a series of analogues of 99mTc-bicisate (99mTc-N,N'-1,2-ethylenediylbis-L-cysteine diethyl ester dihydrochloride, RP-217) is described using in vivo studies in rodent and primate models and in vitro studies in rodent and primate brain tissue. All analogues investigated were 99mTc-diamine dithiol diesters, which were neutral and lipophilic and had modified brain uptake indexes (> or = 40) suggesting adequate first-pass extraction. All analogues were poorly retained by the rodent brain. In contrast, the stereochemistry and structure of the 99mTc-complexes affected their brain retention in primates. All compounds that demonstrated selective primate brain retention were L-diesters that were metabolized in primate brain tissue to nonlypophilic complexes resulting from ester hydrolysis. Unretained complexes were not metabolized in primate brain tissue. More extensive studies were performed with 99mTc-bicisate, which demonstrated poor brain retention in several nonprimate species (i.e., dogs, ferrets, pigs, and rodents). In rodent and nonhuman primate tissue, 99mTc-bicisate was rapidly metabolized to a monoacid ester (99mTc-N,N'-1,2-ethylenediylbis-L-cysteine monoethyl ester). Therefore, brain metabolism of 99mTc-bicisate results in the formation of an acid product(s) that is selectively trapped in primate brain.

The role of single photon emission computed tomography brain imaging with 99mTc-bicisate in the localization and definition of mechanism of ischemic stroke.

99mTc-bicisate (99mTc-ECD) is a new brain perfusion imaging agent formulated from a radiochemically stable kit (Neurolite). A multicenter trial was conducted to determine the sensitivity and specificity of single photon emission computed tomography (SPECT) imaging with 99mTc-bicisate in the localization of ischemic stroke; 170 subjects were enrolled, 128 patients with stroke and 42 controls. Imaging results from 148 subjects (107 stroke patients and 41 controls) were considered evaluable. In the evaluable subjects, SPECT brain imaging with 99mTc-bicisate (21.0 +/- 2.5 mCi) was interpreted without clinical information and was compared with a final assessment using all clinical, diagnostic, and laboratory procedures except the 99mTc-bicisate SPECT results. 99mTc-bicisate was safe and well-tolerated. SPECT imaging with 99mTc-bicisate demonstrated a specificity of 98% and a sensitivity of 86% for localization of strokes (kappa, 0.75; 95% confidence interval, 0.64-0.86). Results were unchanged over time and were similar for all stroke mechanisms except for lacunar disease (sensitivity, 58%). In a secondary analysis, a normal image or small, deep (e.g., subcortical) perfusion defect was highly predictive of a lacunar mechanism. Defects involving the cortical surface were strongly associated with nonlacunar mechanisms. SPECT imaging with 99mTc-bicisate is a sensitive marker in the localization of perfusion defects associated with ischemic stroke and may assist in the determination of the underlying mechanism of a stroke.

Metabolism of 99mTc-L,L-ethyl cysteinate dimer in healthy volunteers.

99mTc-L,L-Ethyl cysteinate dimer (ECD) is a brain-perfusion imaging agent, which exhibits selective retention in brain and rapid renal excretion. The pharmacokinetics and metabolism of ECD were studied in vivo in healthy humans and its metabolism in vitro was evaluated in tissue from human brain. In vitro studies showed 99mTc-L,L-ECD to be metabolized to a polar 99mTc-complex. It has been shown previously that most of the activity of 99mTc retained in the brain of the monkey in vivo is in the form of a polar 99mTc complex (Walovitch, Hill, Garrity, Cheesman, Burgess, O'Leary, Watson, Ganey, Morgan and Williams, 1989). Whole body images of the distribution of 99mTc-L,L-ECD (10 mCi i.v.) in four adult males showed good uptake in brain, with slow elimination (6.8 +/- 0.3% injected dose [mean +/- SE] at 5 min), with less than 25% decrease in activity during 4 hr of imaging. Background areas in the head and lungs washed out rapidly, providing ideal imaging conditions. Elimination of 99mTc from venous blood was biphasic, with a plateau of activity between 2-15 min (7-8% injected dose) before a terminal phase, with a t1/2 of a few hours. Organic extraction of whole venous blood showed greater than 50% of the 99mTc-L,L-ECD to be in the form of polar metabolite(s) at 5 min. They were identified in the urine as the 99mTc ethylenediylbis-L-cysteine, monoethyl ester complex (ECM) and the 99mTc-ethylenediylbis-L-cysteine complex (EC). These metabolites were excreted rapidly (75% injected dose in urine within 6 hr). The results of this study support the hypothesis that the selective retention in brain, rapid blood elimination and renal excretion of 99mTc-L,L-ECD is due to its metabolic transformation to polar end products.

Effect of load on preferred speed and cost of transport.

Horses have a tendency to utilize a relatively narrow set of speeds near the middle of a much broader range they are capable of using within a particular gait, i.e., a preferred speed. Possible explanations for this behavior include minimizing musculoskeletal stresses and maximizing metabolic economy. If metabolic economy (cost of transport, CT) and preferred speeds are linked, then shifts in CT should produce shifts in preferred speed. To test this hypothesis, preferred speed was measured in trotting horses (n = 7) unloaded on the level and loaded with 19% of their body weight on the level. The preferred speed on the level was 3.33 +/- 0.09 (SE) m/s, and this decreased to 3.13 +/- 0.11 m/s when loaded. In both conditions (no load and load), the rate of O2 consumption (n = 3) was a curvilinear function of speed that produced a minimum CT (i.e., speed at which trotting is most economical). When unloaded, the speed at which CT was minimum was very near the preferred speed. With a load, CT decreased and the minimum was also near the preferred speed of horses while carrying a load.

Is hypercholesterolemia a risk factor and should it be treated in the elderly?

PURPOSE: The 1993 National Cholesterol Education Program guidelines recommend cholesterol screening for elderly patients with and without known coronary heart disease. This review summarizes clinical trial evidence from the medical literature that addresses cholesterol treatment in the elderly. DATA SOURCES: References were obtained from a MEDLINE search, bibliographies, metaanalyses, and review articles. STUDY INCLUSION AND EXCLUSION CRITERIA: Randomized, controlled clinical trials, including all lipid intervention trials with elderly participants or subgroup analyses of the elderly designed to measure major cardiovascular disease endpoints, were selected. DATA EXTRACTION METHODS: A MEDLINE search of all clinical trials using key search terms yielded 1360 references. Journal titles and abstracts were reviewed for all references by one of us (K.M.H.). A full journal review was undertaken for 41 references to clinical trials. Five clinical trials fulfilled all criteria and represented unique data. DATA SYNTHESIS: A MEDLINE search (from 1966 to January 2000) and bibliography reviews yielded five important clinical trials with analyses of elderly participants. Data are presented in text form and a summary table. MAJOR CONCLUSIONS: Clinical trial evidence supports treating hyperlipidemia in elderly persons for secondary prevention of coronary heart disease. Evidence from four secondary prevention trials demonstrated that major coronary heart disease risk decreased by 25% to 30% in elderly subjects treated for 5 years. Unanswered questions include cholesterol treatment for primary prevention in the elderly, gender effect, and benefit of treatment in persons older than 70.

Spinal cord injury community follow-up. Role of the physical therapist.

This study was conducted over a 14-month period to assess the physical therapy intervention needs of 201 patients who attended monthly spinal cord injury (SCI) outpatient clinics conducted in three outlying local communities of northern California. Methods to identify and provide appropriate physical therapy services for the patients were explored. An experienced physical therapist from a regional SCI center and other clinic staff members screened the patients and identified 66 patients (33%) who needed physical therapy services, including evaluation (82%), patient education (62%), and referrals to appropriate local health care professionals or equipment vendors (52%). Losses of joint range of motion, changes in sitting posture as a result of increased muscle tone or contracture, and malaligned or misfitting lower extremity orthoses were identified as problem areas not commonly recognized in routine follow-up examinations. Recommendations based on our study findings included the use of a screening form for physical therapy needs at each clinic, improved patient education about the role of the physical therapist as a resource person during follow-up care, coverage for each of the three clinics on a biannual basis, and continued study of the mechanisms used by other SCI centers to fulfill the outpatient needs of their patients. Physical therapy involvement in SCI follow-up services can maximize efficient use of our health care resources and provide early identification and management of specific postdischarge needs.

Commentary on model systems of care in neurotrauma: clinical perspectives and future directions.

The first section of this article discusses the principal clinical components of a model system of care for traumatic brain injury (TBI) or spinal cord injury (SCI). The next section, "The Future of Model Systems", addresses the advantages of such a system, as related to the changing health care climate and predicted future directions of health care in the United States. The need for innovative approaches to rehabilitation is upon us. In addressing this need, the last section, "Recommendations for Change", outlines cost-effective measures for providing rehabilitation services to our clientele.

Premorbid history and traumatic brain injury.

The literature is replete with studies investigating predictors of outcomes in traumatic brain injury. Few, however, have addressed the pre morbid life events and behaviors that may significantly impact the physical, behavioral, cognitive, and/or psychosocial and vocational status of individuals after a traumatic brain injury (TBI). Findings of studies on premorbid history are reviewed and data are presented on a sample of 82 cases on which premorbid psychosocial information, severity of initial injury and outcome status were obtained. Cases were dichotomized into groups at high risk and at low risk for TBI, based on premorbid history. High risk and low risk groups were comparable in the severity of initial injury. Outcomes were defined by the Functional Independence Measure and the Disability Rating Scale scores at 1 year after injury. No differences were found in FIMTM or DRS scores between those with and without premorbid learning disability, psychiatric history, incarcerations, arrests, academic difficulties, or substance abuse. Explanations for the lack of significant differences are discussed. Based on experience in completing this study, a screening tool incorporating documentation of a number of pre morbid factors that might impact status at outcome is presented.

Relationship between constructional praxis and dressing in the head-injured adult.

The purpose of this study was to explore the potential relationship between dressing ability and constructional praxis performance in a head-injured population. Thirty-seven patients with severe head injuries were rated on dressing ability and constructional praxis tasks in a rehabilitation setting. Three constructional praxis measures were taken: graphic, two-dimensional, and three-dimesional abilities. A significant relationship was found between mean dressing ability scores and all three constructional praxis scores. These findigs suggest that a portion of inability to dress is perceptual not motor, in origin in individuals with severe head-injuries, and that constructional praxis re-training has functional significance for the patient. No relationship was found between presencce or absence of Computerized Axial Tomography (CAT scan) abnormality and dressing or constructional praxis disability.

Establishing a national traumatic brain injury information system based upon a unified data set.

In alliance with payers and persons with disabilities, rehabilitation professionals can create an outcome data system for traumatic brain injury (TBI) that will provide the knowledge necessary to improve the effectiveness and cost-effectiveness of rehabilitation programs. A nationwide TBI data system is needed to identify reasonably homogeneous subgroups given different treatments whose outcomes can be meaningfully compared. The advantages of a national outcome data system for gathering and analyzing this information include large sample sizes, objective assessment, measurement across the whole continuum of care, and adequate severity adjusters. Proposed methods and content for such a database are described, for reflecting general functional levels of clients along the continuum of care: acute care, TBI rehabilitation programs, and the community. Tools proposed are brief, have proven reliability and validity, and measure characteristics common to traumatically brain injured individuals. Possible data analysis approaches for a National Information System (database) dedicated to TBI are described for discussion within the rehabilitation community.

Outcomes evaluation in TBI Rehabilitation. Part I: overview and system principles.

Questions of how to measure outcomes are commonly heard in rehabilitation today. In this supplement we review the current state of the art of outcomes measurement in traumatic brain injury rehabilitation, discuss key issues, and identify steps that need to be taken. The underlying question is not simply that of outcomes measurement but how to infer effective and cost-effective treatment. The validity of such inferences rests on multiple features of the entire clinical information system. Requirements for valid, feasible, outcome-oriented clinical data systems are described. Effectiveness is inferred from variations in outcomes experienced by similar persons who received differing interventions. Outcome data systems need large sample sizes and technically adequate severity adjusters. A nationwide TBI data system is needed to identify reasonably homogeneous subgroups in different programs whose outcomes can be meaningfully compared. In alliance with payors and persons with disabilities, rehabilitation professionals can create outcome data systems that will provide the knowledge necessary to improve the effectiveness and cost-effectiveness of rehabilitation programs.

Outcomes evaluation in TBI Rehabilitation. Part II: measurement tools for a nationwide data system.

In Part II we address tools for describing general functional levels of clients in acute care, in traumatic brain injury (TBI) rehabilitation programs, and in the community. Tools must be brief, have proven reliability, and measure characteristics common to moderately and severely brain-injured individuals. Possible components of a uniform dataset dedicated to TBI are described.

Evaluation of acute surgical intervention in traumatic paraplegia.

A retrospective study was conducted over a two-year period of 95 consecutive admissions for traumatic paraplegia. The average age was 32 years. Seventy-two (76%) of these patients had acute surgical intervention. Fifty had Harrington rod placement with posterior fusion, 10 had additional laminectomy and one had rodding and anterior fusion. Seven laminectomies (alone) were performed at other hospitals. For those with rodding and/or fusion, rehabilitation stay was 70 days; for those with no surgery, 81 days. This difference was not statistically significant. However, when days of acute medical/surgical and rehabilitation hospitalization were combined, those having spinal surgery of any kind had a significantly shorter stay than those not having surgery (95 vs. 136 days). Complications were significantly greater in the patients who underwent internal fixation surgery. The neurological condition did not appear to be jeopardized by rodding and fusion.

Evaluation of the acute management of tetraplegia: conservative versus surgical treatment.

A retrospective study of 106 tetraplegic patients admitted consecutively to the Santa Clara Valley Medical Center (SCVMC) between August, 1981 and September, 1983 was conducted. The average age was 28; and 20 (19%) were female. The majority sustained their spinal cord injury in a motor vehicle accident (65%) or in a diving accident (19%). Forty-nine percent (52/106) of these patients had acute surgical intervention, and 63% (33/52) of these patients had this prior to admission to SCVMC. The majority (35/52) had posterior fusion alone. Twelve patients had an anterior fusion (11 at other hospitals) and four a laminectomy alone (three carried out at other hospitals). The length of rehabilitation stay was 133 days for those having surgery, and 119 days for non-surgical cases; statistically a non-significant difference. When acute medical/surgical hospitalisation and rehabilitation days were combined, those having surgery had a significantly longer stay (197 versus 153 days), but only when surgery was done other than at SCVMC. Complications occurred in 50/106 (47%) of the patients: 50% who had surgery and 44% who were treated conservatively. The most commonest complication was respiratory (43%), including 20% who had pneumonia. Complications were no greater in those patients who underwent posterior fusion than in those who had no spinal surgery. However, other types of surgery carried a higher risk of complications by approximately 20%. Anterior fusions and laminectomies, performed almost totally at other institutions (15/17), had a higher rate of complications.

Fatigue in postpolio syndrome.

A survey was conducted to better understand complaints of fatigue in patients previously diagnosed as having polio. Eighty-six individuals with postpolio syndrome and 20 healthy controls completed a questionnaire about their fatigue, the Beck Depression Inventory, and the CAGE questionnaire. The results showed that fatigue in postpolio syndrome usually occurred on a daily basis and increased in severity as the day progressed. Both the study group and controls described their fatigue as tiredness and a lack of energy. However, physical weakness was reported only in the postpolio group. Minimal physical exercise exacerbated fatigue in 48% of the postpolio group, whereas it diminished fatigue in 70% of the controls and in 15% of the postpolio group. Twenty-seven percent of the postpolio group and none of the controls reported mild to moderate depressive symptoms. However, depression, age, alcohol abuse, and employment status did not significantly affect the differences between groups in reported prevalence or description of chronic fatigue. Criteria to separate psychologic from organic causes of fatigue and treatment interventions are discussed.

Family stressors in traumatic brain injury: a two-year follow-up.

A review of the literature suggests that psychosocial disability in traumatic brain-injured (TBI) individuals and distress in families continues long after the initial injury. In this study the relationship of family stress to a number of factors was studied longitudinally. Caregivers of 51 TBI inpatients were interviewed at rehabilitation admission and by phone at 6, 12, and 24 months postinjury. Caregivers' most common complaints about their relatives were a lack of involvement in leisure activities, fatigue, slowness, and forgetfulness. Increasingly severe temper outbursts, anxiety, and self-centeredness were reported over time. Aggressiveness was reported by caregivers as moderate or severe in 31% of cases by 2 years postinjury. Of all complaints, only reports of inappropriate social behavior decreased over time. Despite caregivers' increasing complaints about their relatives, there were no trends toward greater self-reported stress over time. At the 2-year assessment, stress was significantly higher for caregivers of those with an at risk psychosocial history, and for those without sufficient funds for services. Caregivers reporting financial strain increased 22% from rehabilitation admission. Forty-seven percent of caregivers had altered or given up their jobs at 1 year postinjury, and 33% at 2 years postinjury. Although self-perceived measurements of stress did not increase over time, caregivers reported notable increases in medication use and substance use, and decreases in employment and financial status over the 2-year time period. When spouse and parent caregiver responses were compared, spouses reported a consistently greater number of behavioral problems, which increased in severity over time. Those behaviors associated with mood disturbances predominated.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain injury: analysis of outcome in a post-acute rehabilitation system. Part 1: General analysis.

During the past decade the rehabilitation field has developed new, non-hospital based programmes of cognitive, behavioural, social, educational and vocational treatments to address the higher order cognitive, behavioural and social deficits following brain injury. These new arrays of programmes are referred to under the term 'post-acute' rehabilitation. No comprehensive, methodologically sound study of the effects of these new treatments has been made to date. This paper reports data from brain-injured patients who underwent treatment within a co-ordinated system of post-acute brain-injury rehabilitation programmes. This system consists of a continuum of neurobehavioural, residential, day treatment and community and home programmes, and provides overt components of medical and rehabilitation care: behavioural management; activities of daily living, self-management, substance-abuse, social, academic and vocational skills training; counselling; and family education. The changes in function during the course of treatment by this post-acute sequence of rehabilitation have been obtained and are reported here. A defined total population of N = 192 is examined, with exclusions for appropriate causes (e.g. patients seen only for evaluation) producing a study population of N = 173; of these, follow-up was achieved in 145 cases, a follow-up rate of 83.8%. Time from date of injury to data of admission, severity of deficit at time of admission to programme, and other appropriate independent variables are used to characterize the population. A single-blind interview methodology was employed in obtaining dependent measures of outcome at 6, 12, or 24 month periods post-discharge. Measures of outcome included residential status, level of productivity activity and hours per day of attendant care or supervision required. Dependent variables were analysed for the total study population and a subgroup greater than 1 year from date of injury at entry to treatment and not from a treatment facility. Results are presented in terms of the percentage change in dependent measures from the point of admission to follow-up. Appropriate parametric and non-parametric statistical analyses of significance have been carried out. The results document substantial improvements in function during the post-acute rehabilitation of this population and such improvements are unlikely to be the result of spontaneous improvement alone.

Brain injury: analysis of outcome in a post-acute rehabilitation system. Part 2: Subanalyses.

The basic findings of brain-injured patients who underwent treatment within a co-ordinated system of post-acute brain-injury rehabilitation programmes have already been reported. The changes in function during the course of treatment by this post-acute sequence of rehabilitation were obtained and reported. A defined total population of N = 192 was examined, with exclusions for appropriate causes (e.g. patients seen only for evaluation) producing a study population of N = 173; of these, follow-up was achieved in 145 cases, a follow-up rate of 83.8%. Time from date of injury to date of admission, severity of deficit at time of admission to programme, and other appropriate independent variables were used to characterize the population. A single-blind interview methodology was employed in obtaining dependent measures of outcome at 6, 12 or 24 month periods post-discharge. Measures of outcome included residential status, level of productivity activity, and hours per day of attendant care or supervision required. In the work reported in this paper dependent variables are analysed for various subgroups of the total population. The subgroups analysed are: patients with traumatic brain injury only; mild moderate and severe grades of disability; and comparisons of outcomes at 6 months, 1 year, and 2 years post-discharge from treatment. The results are presented in terms of percentage change in dependent measures from point of admission to follow-up. Appropriate parametric and non-parametric statistical analyses of significance are carried out. Additionally, an analysis of cost associated with treatment, and some analysis of cost-benefit is provided. The results document substantial improvements in function during post-acute rehabilitation for both traumatic brain injury and brain dysfunction of other etiologies. Significant improvements are seen to occur in all grades of severity of dysfunction examined, and such improvements are robust and persist without evidence of decrement over the 2-year follow-up period. In addition, economic considerations suggest the potential for the recouping of costs of treatment within a reasonable period of time.