Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial.

Down syndrome (DS) is the most common genetic cause of intellectual disability. The N-methyl-D-aspartate (NMDA) receptor uncompetitive antagonist, memantine hydrochloride (memantine), has been shown to improve learning/memory and rescue one form of hippocampus synaptic plasticity dysfunction in the best-studied mouse model of DS available, the Ts65Dn mouse. Given the status of memantine as a treatment for Alzheimer's disease (AD) approved by the Food and Drug Administration, the preclinical evidence of potential efficacy in Ts65Dn mice, and the favorable safety profile of memantine, we designed a study to investigate whether the findings in the mouse model could be translated to individuals with DS. In this pilot, proof-of-principle study we hypothesized that memantine therapy would improve test scores of young adults with DS on measures of episodic and spatial memory, which are generally considered to be hippocampus dependent. Accordingly, in this randomized, double-blind, placebo-controlled trial, we compared the effect of 16-week treatment with either memantine or placebo on cognitive and adaptive functions of 40 young adults with DS using a carefully selected set of neuropsychological outcome measures. Safety and tolerability were also monitored. Although no significant differences were observed between the memantine and placebo groups on the two primary outcome measures, we found a significant improvement in the memantine group in one of the secondary measures associated with the primary hypothesis. Only infrequent and mild adverse events were noted.

Youth smoking prevention and tobacco industry revenue.

OBJECTIVES: Epidemiological surveys make it clear that youth smoking contributes to both current and future tobacco industry revenue: over 80% of adult smokers reportedly began smoking before age 18. This paper estimates annual and lifetime revenue from youth smoking, and highlights the association between declines in youth smoking and declines in tobacco industry revenue. MAIN OUTCOME MEASURES: This paper reports the amount of tobacco industry revenue generated by youth smoking at two points in time (1997 and 2002), and describes the distribution of youth generated tobacco income among the major tobacco companies. The authors project the amount of tobacco industry revenue that will be generated by members of two cohorts (the high school senior classes of 1997 and 2002) over the course of their lifetimes. RESULTS: In 1997, youth consumed 890 million cigarette packs, generating $737 million in annual industry revenue. By 2002, consumption dropped to 541 million packs and revenue increased to nearly $1.2 billion. Fifty eight per cent of youth generated revenue goes to Philip Morris USA, 18% to Lorillard, and 12% to RJ Reynolds. The authors project that, over the course of their lives, the 1997 high school senior class will smoke 12.4 billion packs of cigarettes, generating $27.3 billion in revenue. The 2002 high school senior class is projected to smoke 10.4 billion packs, generating $22.9 billion in revenue over the course of their lives. CONCLUSIONS: Cigarette price increases from 1997 to 2002 have resulted in greater revenue for the tobacco industry, despite declines in youth smoking prevalence. However, in the absence of further cigarette price increases, declines in youth smoking are projected to lead ultimately to a loss of approximately $4 billion in future tobacco industry revenue from a single high school cohort.

A tale of two countries: environmental impacts on social participation after spinal cord injury.

STUDY DESIGN: Comparative analysis of survey data produced in two countries. OBJECTIVES: To assess the degree to which environmental barriers impact social participation, and to identify the aspects of participation most affected. SETTING: Community-dwelling individuals with spinal cord injury in the USA and Turkey. METHODS: Subjects completed the Functional Independence Measure (FIM) motor score, the Craig Hospital Inventory of Environmental Factors (CHIEF), and the Craig Handicap Assessment and Reporting Technique (CHART). Analysis of co-variance was used to analyze CHIEF and CHART differences within and between country. RESULTS: US subjects reported higher participation scores (CHART) and lower barriers (CHIEF), however, when controls for age, gender, time since injury and motor ability (FIM) were applied, country differences in reports of barriers were limited. Motor ability was the major predictor of participation, which was minimally affected by barriers. CONCLUSION: Conceptualization and measurement issues may have been the reason for the minimal support for the hypothesis that environment affects participation. Suggestions for future research are made. SPONSORSHIP: National Institute on Disability and Rehabilitation Research, Centers for Disease Control and Prevention.

Ageing with spinal cord injury: cross-sectional and longitudinal effects.

STUDY DESIGN: Longitudinal and cross-sectional. OBJECTIVE: To determine whether, for studies of ageing with a spinal cord injury, the cross-sectional differences in outcomes across both age and years post injury (YPI) differ from the longitudinal change. SETTING: Two SCI centres in England: the National Spinal Injuries Centre in Aylesbury, and the Regional Spinal Injuries Centre in Southport. METHODS: A total of 315 people who sustained spinal cord injuries prior to 1971 underwent comprehensive health and psychosocial status interviews at one or more of the study assessments (1990, 1993, 1996, and 1999). A range of continuous and dichotomous outcomes was analyzed to detect both cross-sectional differences by age and average individual changes over multiple measurements. RESULTS: Frequently, outcomes changed longitudinally without showing any cross-sectional differences. Cross-sectional age was more commonly associated with the worsening of a condition while cross-sectional YPI was commonly associated with improvement. After controlling for cross-sectional effects, psychological measures generally showed minor deterioration, measures of community integration both improved and deteriorated, upper extremity pain increased, lower enxtremity pain decreased, and participants tended to quit smoking. CONCLUSION: Using longitudinal findings that control for cross-sectional differences produces a more complete description of ageing with a spinal cord injury.

The relationship between neurological level of injury and symptomatic cardiovascular disease risk in the aging spinal injured.

STUDY OBJECTIVES: To describe the distribution of clinically apparent cardiovascular disease (CVD) in people with long-term spinal cord injury (SCI) according to neurologic level and severity of injury. DESIGN: Historical prospective study. SETTING: Two British Spinal Injuries Centers. PARTICIPANTS: Five hundred and forty-five individuals surviving at least 20 years with SCI were divided into three neurologic categories by level of injury and Frankel/ASIA grade as follows: Tetra ABC, Para ABC, and All D. MAIN OUTCOME MEASURES: Cardiovascular disease outcomes defined by ICD/9 codes 390-448 and obtained through medical record review. Cardiovascular disease outcomes measured included All CVD, coronary heart disease (CHD), hypertension, cerebrovascular disease, valvular disease, and dysrhythmia. RESULTS: After age-adjustment, the rates of All CVD were 35.2, 29.9, and 21.2 per 1000 SCI person-years in the Tetra ABC, Para ABC, and All D groups, respectively. Rates of All CVD increased with increasing age in all neurologic groups. Tetraplegic level of SCI conferred an excess 16% risk of All CVD (95% Confidence interval [CI], 0.93-1.46), a fivefold risk of cerebrovascular disease (relative risk [RR] 5.06; 95% CI, 1.21-21.15), and 70% less CHD (RR 0.30; 95% CI, 0.13-0.70) when compared with paraplegics. More complete SCI was associated with an excess 44% All CVD risk (95% CI, 1.16-1.77). CONCLUSIONS: Risk of All CVD increased with increasing age, rostral level of SCI, and severity of SCI. More rostral level of SCI was associated with cerebrovascular disease, dysrhythmia, and valvular disease. Conversely, there was an inverse relationship between level of SCI and CHD

Hospital readmissions in people with chronic spinal cord injury.

STUDY DESIGN: Longitudinal observational. OBJECTIVES: To examine frequency and duration of hospital readmissions in a population based sample of people with chronic spinal cord injury (SCI) and to look at medical reasons necessitating readmissions and factors influencing them. SETTING: National Spinal Injuries Centre, Stoke Mandeville Hospital, Aylesbury, UK and Regional Spinal Injuries Centre, District General Hospital, Southport, UK. METHODS: One-hundred-and-ninety-eight SCI patients, all injured more than 20 years ago, were interviewed on three occasions and their medical records reviewed for the period 1990 - 1996. RESULTS: Between 1990 and 1996, 127 patients (64% of the sample) required hospital treatment for late medical complications, with 481 readmissions between them and the mean length of stay of 12.03 days per readmission. Only 58% of all readmissions were into specialised spinal injuries centres. Averaged over the entire sample, the readmission rate was 0.4 readmissions per person at risk per year, and the occupancy rate was 4.9 bed-days per person at risk per year. The most frequent reason for readmissions were urinary tract complications (40.5% of all readmissions) and the highest bed occupancy was for skin problems (32.2% of all bed-days). When compared with the non-hospitalised group (36% of the sample), the readmitted patients had longer duration of paralysis and lower disability and handicap scores as measured by Functional Independence Measure (FIM) and Craig Handicap Assessment & Reporting Technique (CHART). The subgroups did not differ significantly by neurological grouping or age. CONCLUSIONS: Urinary and skin complications are the two main reasons for hospital readmissions in people with chronic SCI. Risk of readmissions increases with time since injury and with disability and handicap severity. Hospital bed requirements for people with chronic SCI are greater than the amount of clinical provision currently available in specialised spinal centres. In order to meet the needs of the growing SCI population, more specialised spinal injuries care beds will be needed. Spinal Cord (2000) 38, 371 - 377.

Longitudinal outcomes in spinal cord injury: aging, secondary conditions, and well-being.

OBJECTIVE: To specify the degree to which current age, duration of injury, and neurologic status affect the frequency of secondary health and psychosocial conditions in persons with long-term spinal cord injury (SCI), using both longitudinal and cross-sectional analysis techniques. DESIGN: Prospective longitudinal examination and data collection involving individuals with SCI studied initially at their 5th, 10th, and 15th anniversaries postinjury, and subsequently 5 years later at their 10th, 15th, and 20th anniversaries postinjury. SETTING: Five Regional Model Spinal Cord Injury Systems. PARTICIPANTS: The 439 individuals who meet the inclusion criteria for the National SCI Database and who are enrolled in a longitudinal study of secondary conditions and SCI. MAIN OUTCOME MEASURES: Physical and psychosocial status at various times postinjury. RESULTS: There are different reports of various conditions when analyzing by neurologic groups, duration of injury, and age. Cross-sectional and longitudinal analyses also demonstrate different patterns of complications. CONCLUSIONS: The longitudinal method, like cross-sectional research, allows for identification of physical and psychosocial changes soon after they occur. Longitudinal research, however, also makes possible the development of predictive models for various long-term outcomes.

Correlates of stress in long-term spinal cord injury.

STUDY DESIGN: Longitudinal. OBJECTIVES: To characterize long-injured SCI persons with high reported stress; to assess the relationship between severity of disability and perceived stress; to identify correlates of future stress and outcomes of previous stress. SETTING: Two SCI centres in England: Stoke Mandeville Hospital in Aylesbury, and the District General Hospital in Southport. METHODS: In 1990, 1993 and 1996 187 persons who sustained spinal cord injuries prior to 1971 underwent comprehensive physical evaluations and health status interviews and completed a battery of tests to measure psychosocial functioning. Using mean scores on the Perceived Stress Scale (PSS) as the reference, a range of outcomes were analyzed to identify concurrent, previous, and future variables that were significantly correlated with perceived stress. RESULTS: No associations were found between stress and any of the proxy variables that represented injury severity. Such common SCI-related medical conditions as pressure sores and upper extremity pain were not related to stress; not even fatigue was significantly associated with stress in both time periods studied. However, depressive symptoms, poorer life satisfaction, and poorer perceived well being were associated with future stress and were outcomes that appeared to be related to earlier stress. CONCLUSION: Perceived stress in long-term SCI is not closely related to the severity of the disability or physical independence. It is, however, related to scores on several measures of adjustment and coping. Though mean stress scores in this sample did not appear to differ substantially from scores in the general nondisabled population, further controlled study is needed to definitively answer the question: Do SCI survivors report more stress than their nondisabled counterparts?

Bowel management outcomes in individuals with long-term spinal cord injuries.

Outcomes of bowel management were evaluated in 1993 among 221 British long-term spinal cord injury survivors who were followed-up as part of a longitudinal study of aging with spinal cord injury. Representing a population-based sample followed up by two regional spinal cord injury treatment centres - Stoke Mandeville Hospital in Aylesbury and the District General Hospital in Southport, England - all had been injured at least 20 years when the study was begun in 1990; all underwent comprehensive assessments and extensive interviewing at their centres in 1990 and 1993. When assessed in 1993, 42% of the entire sample reported constipation, 35% reported gastrointestinal pain, and 27% complained of bowel accidents. Physician examiners diagnosed significantly more hemorrhoids among those using primarily suppositories and enemas to manage their bowels (P < 0.05) and more constipation among persons with paraplegia (P < 0.05) and those using digital stimulation, manual evacuation, or increased abdominal pressure in their bowel programs. Fecal incontinence and diarrhea was diagnosed three times more often in participants with tetraplegia as in other neurological groupings. These and other findings suggest future research needs and directions relative to long-term bowel management for spinal cord injury survivors.

Spouses of spinal cord injury survivors: the added impact of caregiving.

OBJECTIVE: To better understand the needs of spouses who provide care to spinal cord injury (SCI) survivors, by comparing their self-perceptions and complaints with those of their partners with disabilities and with those of spouses who do not provide care. DESIGN: Survey, including demographics, health concerns questionnaire, and administration of the Center for Epidemiologic Studies Depression Scale (CES-D), the Perceived Stress Scale (PSS), the Life Satisfaction Index (LSI-Z), and the Quality of Life and Individual Needs Questionnaire. SETTING: Two British SCI treatment centers, serving a defined population-based catchment area. PARTICIPANTS: One hundred twenty-four spouses of a longitudinally followed sample of SCI survivors, all of whom had been injured 23 or more years when the study was conducted in 1993. OUTCOME MEASURES: Scores on the above standardized tests, and responses to survey questions. RESULTS: Spouses had more depressive affect (p < .001) than their partners with disabilities, as measured by the CES-D. On the PSS, they exhibited no significant differences. Compared with spouses who were not caregivers, the caregiving spouses reported more physical stress (p = .005), emotional stress (p = .011), burnout (p = .007), fatigue (p = .002), and anger and resentment (p = .029). On the CES-D, they had more symptoms of depressive affect (p = .004) and somatic depression (p = .005). CONCLUSIONS: Spouses of long-term SCI survivors who fulfill a caregiving role report more symptoms of stress and depression than their partners with disabilities and other spouses who are not caregivers.