A randomised controlled trial of energetic activity for depression in young people (READY): a multi-site feasibility trial protocol.

BACKGROUND: Prevalence of depression is increasing in young people, and there is a need to develop and evaluate behavioural interventions which may provide benefits equal to or greater than talking therapies or pharmacological alternatives. Exercise could be beneficial for young people living with depression, but robust, large-scale trials of effectiveness and the impact of exercise intensity are lacking. This study aims to test whether a randomised controlled trial (RCT) of an intervention targeting young people living with depression is feasible by determining whether it is possible to recruit and retain young people, develop and deliver the intervention as planned, and evaluate training and delivery. METHODS: The design is a three-arm cluster randomised controlled feasibility trial with embedded process evaluation. Participants will be help-seeking young people, aged 13-17 years experiencing mild to moderate low mood or depression, referred from three counties in England. The intervention will be delivered by registered exercise professionals, supported by mental health support workers, twice a week for 12 weeks. The three arms will be high-intensity exercise, low-intensity exercise, and a social activity control. All arms will receive a 'healthy living' behaviour change session prior to each exercise session and the two exercise groups are energy matched. The outcomes are referral, recruitment, and retention rates; attendance at exercise sessions; adherence to and ability to reach intensity during exercise sessions; proportions of missing data; adverse events, all measured at baseline, 3, and 6 months; resource use; and reach and representativeness. DISCUSSION: UK National Health Service (NHS) policy is to provide young people with advice about using exercise to help depression but there is no evidence-based exercise intervention to either complement or as an alternative to medication or talking therapies. UK National Institute for Health and Care Excellence (NICE) guidelines suggest that exercise can be an effective treatment, but the evidence base is relatively weak. This feasibility trial will provide evidence about whether it is feasible to recruit and retain young people to a full RCT to assess the effectiveness and cost-effectiveness of an exercise intervention for depression. TRIAL REGISTRATION: ISRCTN, ISRCTN66452702 . Registered 9 April 2020.

Review of health economic models exploring and evaluating treatment and management of hospital-acquired pneumonia and ventilator-associated pneumonia.

BACKGROUND: Hospital-acquired pneumonia (HAP) is pneumonia that occurs ≥48 h after hospital admission; it is the most common hospital-acquired infection contributing to death. Ventilator-associated pneumonia (VAP) arises ≥48-72 h after intubation. Opinions differ on whether VAP is a subset of HAP; the same pathogens predominate in both. Compared with VAP-free controls, patients developing VAP are twice as likely to die and have significantly longer stays in intensive care units. Guidelines recommend that microbiological cultures should guide antibiotic treatment, but these lack sensitivity and take 48-72 h to process, meaning that initial therapy must be empiric, generally with broad-spectrum agents. Given increasing pressure to improve both antibiotic stewardship and patient outcomes, the National Institute for Health and Care Excellence and the Infectious Diseases Society of America recommend research into rapid molecular diagnostic tests to identify causative organisms and their antibiotic resistances. Ideally, these would supersede culture, being quicker and more sensitive. In the UK, the INHALE research programme, funded by the National Institute for Health Research, is exploring rapid molecular diagnostics to inform treatment of HAP/VAP and, given resource implications, incorporates a health economic component. AIM: To identify previous economic modelling of HAP/VAP costs to inform this component. METHODS: Literature review of HAP/VAP studies with economic modelling identified from three databases. FINDINGS: Twenty studies were identified. Only one study specifically evaluated strategies to improve diagnosis; the remaining 19 studies omitted this important aspect. CONCLUSION: HAP/VAP modelling would be improved by better awareness of long-term outcomes and treatment complexity. To the authors' knowledge, no similar literature reviews of economic modelling for HAP/VAP have been published.

Microbial degradation of gasoline in soil: Effect of season of sampling.

In cases where fire debris contains soil, microorganisms can rapidly and irreversibly alter the chemical composition of any ignitable liquid residue that may be present. In this study, differences in microbial degradation due to the season in which the sample is collected was examined. Soil samples were collected from the same site during Fall, Winter, Spring and Summer and the degradation of gasoline was monitored over 30 days. Predominant viable bacterial populations enumerated using real-time PCR and reverse transcriptase polymerase chain reaction (RT-PCR) enumeration revealed the predominant viable bacterial genera to be Alcaligenes, Bacillus, and Flavobacterium. Overall, the compounds most vulnerable to microbial degradation are the n-alkanes, followed by the mono-substituted alkylbenzenes (e.g., toluene, ethylbenzene, propylbenzene and isopropylbenzene). Benzaldehyde (a degradation product of toluene) was also identified as a marker for the extent of biodegradation. Ultimately, it was determined that soil collected during an unusually hot and dry summer exhibited the least degradation with little to no change in gasoline for up to 4 days, readily detectable n-alkanes for up to 7 days and relatively high levels of resilient compounds such as o-xylene, p-xylene and 1,3,5-trimethylbenzene. These results demonstrate, however, that prompt preservation and/or analysis of soil evidence is required in order to properly classify an ignitable liquid residue.

Out-of-theatre tracheal intubation: prospective multicentre study of clinical practice and adverse events.

BACKGROUND: Tracheal intubation is commonly performed outside the operating theatre and is associated with higher risk than intubation in theatre. Recent guidelines and publications including the 4th National Audit Project of the Royal College of Anaesthetists have sought to improve the safety of out-of-theatre intubations. METHODS: We performed a prospective observational study examining all tracheal intubations occurring outside the operating theatre in nine hospitals over a 1 month period. Data were collected on speciality and grade of intubator, presence of essential safety equipment and monitoring, and adverse events. RESULTS: One hundred and sixty-four out-of-theatre intubations were identified (excluding those where intubation occurred as part of the management of cardiac arrest). The most common indication for intubation was respiratory failure [74 cases (45%)]. Doctors with at least 6 month's experience in anaesthesia performed 136 intubations (83%); consultants were present for 68 cases (41%), and overall a second intubator was present for 94 procedures (57%). Propofol was the most common induction agent [124 cases (76%)] and 157 patients (96%) received neuromuscular blocking agents. An airway rescue device was available in 139 cases (87%). Capnography was not used in 52 cases (32%). Sixty-four patients suffered at least one adverse event (39%) around the time of tracheal intubation. CONCLUSIONS: Out-of-theatre intubation frequently occurs in the absence of essential safety equipment, despite the existing guidelines. The associated adverse event rate is high.

Cost-effectiveness of a disease management programme for secondary prevention of coronary heart disease and heart failure in primary care.

OBJECTIVE: To determine if a disease management programme for patients with coronary heart disease and heart failure represents an efficient use of health services resources. METHODS: We carried out an economic evaluation alongside a cluster randomised control trial of 1163 patients with coronary heart disease and chronic heart failure in 20 primary care practices in the United Kingdom. Practices were randomised to either a control group, where patients received standard general practice care, or an intervention group where patients had access to a specialist nurse-led disease management programme. We estimated costs in both groups for coronary heart disease-related resource use. The main outcome measure used in the economic evaluation was quality adjusted life years (QALY) measured using the EuroQol. RESULTS: The disease management programme was associated with an increase in the QALY measured of 0.03 per year and an increase in the total NHS costs of 425 pounds (540 euros), of this only 83 pounds was directly associated with the provision of the nurse clinics. The clinics generated additional QALY at an incremental cost of 13 pounds 158 per QALY compared to the control group. CONCLUSIONS: The use of a nurse-led disease management programme is associated with increased costs in other coronary heart disease-related services as well as for the costs of the clinics. They are also associated with improvements in health. Even in the short term these disease management programmes may represent a cost-effective service, as additional QALY are generated at an acceptable extra cost.

Difficult decisions in the intensive care unit: an illustrative case.

Difficult clinical decision-making is a common experience in intensive care units. There is often considerable pressure on time and decisions may have to be made in a stressful environment. Patients in the intensive care unit not infrequently present with extreme or rare manifestations of a disease process. Clinical evidence to guide management of such patients may be incomplete, non-existent, or its relevance to the problem at hand may be questionable. In this context, formal decision-making analytical tools are often impractical. Unconscious cognitive biases have been shown to play an important role in medical decision-making, particularly in these settings. While mostly these contribute to doctors making appropriate and timely decisions, occasionally they lead to errors. Despite 30 years of research into models of clinical reasoning, most doctors are unaware of how biases affect their thinking and are unfamiliar with techniques of detecting and neutralising bias in clinical practice. We present the case of a patient with Wegener's granulomatosis, which highlights many of the difficulties outlined above. We review the clinical evidence for our decisions at each stage and explain the rationale for our choices, highlighting the many situations for which high quality evidence was lacking. Examples of cognitive bias are identified and techniques of metacognition (thinking about thinking) that can be useful in limiting the effects of bias on complex decision-making are reviewed. The intensivist's evaluation of management alternatives has an important role in steering medical management towards optimal patient outcomes.

Systematic review and evaluation of methods of assessing urinary incontinence.

OBJECTIVES: To identify and synthesise studies of diagnostic processes of urinary incontinence and to construct an economic model to examine the cost-effectiveness of simple, commonly used primary care tests. DATA SOURCES: The electronic databases MEDLINE (1966--2002), CINAHL (1982--2002) and EMBASE (1980--2002). REVIEW METHODS: Studies were selected and assessed using the Quality Assessment of Diagnostic Studies (QUADAS) tool. Studies that reported the results of applying the same diagnostic procedure using the same threshold value (cut-off) were pooled using a random effects meta-analysis model to produce pooled estimates of sensitivity, specificity and diagnostic odds ratio together with 95% confidence intervals. RESULTS: In total, 6009 papers were identified from the literature search, of which 129 were deemed relevant for inclusion in the review, and these papers compared two or more diagnostic techniques. The gold-standard diagnostic test for urinary incontinence with which each reference test was compared was multichannel urodynamics. In general, reporting in the primary studies was poor; there was a lack of literature in the key clinical areas and minimal literature dealing with diagnosis in men. Only a limited number of studies could be combined or synthesised, providing the following results when compared with multichannel urodynamics. A clinical history for diagnosing urodynamic stress incontinence (USI) in women was found to have a sensitivity of 0.92 and specificity of 0.56 and for detrusor overactivity (DO) a sensitivity of 0.61 and specificity of 0.87. For validated scales, question 3 of the Urogenital Distress Inventory was found to have a sensitivity of 0.88 and specificity of 0.60. Seven studies compared a pad test with multichannel urodynamics; however, four different pad tests were studied and therefore it was difficult to draw any conclusions about diagnostic accuracy. Of the four studies comparing urinary diary with multichannel urodynamics, only one presented data in a format that allowed sensitivity and specificity to be calculated. Their reported values of 0.88 and 0.83 suggest that a urinary diary may be effective in the diagnosis of DO in women. Examination of the incremental cost-effectiveness of three primary care tests used in addition to history found that the diary had the lowest cost-effectiveness ratio of between pound 35 and pound 77 per extra unit of effectiveness (or case diagnosed). Imaging by ultrasound to determine leakage was found to be effective in the diagnosis of USI in women, with a sensitivity of 0.94 and specificity of 0.83. CONCLUSIONS: This is the first systematic review of methods for diagnosing urinary incontinence. As reporting of the primary studies was poor, clinical interpretation was often difficult because few studies could be synthesised and conclusions made. The report found that a large proportion of women with USI can be correctly diagnosed in primary care from clinical history alone. On the basis of diagnosis the diary appears to be the most cost-effective of the three primary care tests (diary, pad test and validated scales) used in addition to clinical history. Ultrasound imaging may offer a valuable alternative to urodynamic investigation. The clinical stress test is effective in the diagnosis of USI. Adaptation of such a test so that it could be performed in primary care with a naturally filled bladder may prove clinically useful. If a patient is to undergo an invasive urodynamic procedure, multichannel urodynamics is likely to give the most accurate result in a secondary care setting. There is a dearth of literature on the diagnosis of urinary incontinence in men, with no studies meeting the study criteria for data extraction in the diagnosis of bladder outlet obstruction. There is a need for large-scale, high-quality primary studies evaluating the use of a number of diagnostic methods in a primary care setting to be undertaken so that the results of this systematic review can be verified or not. Such studies should include not only an assessment of clinical effectiveness, in this case diagnostic accuracy, but also an assessment of costs and quality of life/satisfaction to inform future health policy decisions. Studies carried out should be reported to a better standard. The recommendations of the Standards for Reporting Diagnostic Accuracy (STARD) initiative should be followed to ensure the accuracy and completeness of reporting design and results.

The cost-effectiveness of influenza vaccination of healthy adults 50-64 years of age.

Influenza can cause significant morbidity and mortality. Influenza vaccination is an effective and safe strategy in the prevention of influenza. Currently the National Health Service (NHS) vaccinates 'at-risk' individuals only. This definition includes everyone over 65 years of age but excludes individuals 50-64 years of age unless they have an additional risk factor, such as underlying heart disease or lung disease. In order to examine the cost-effectiveness of an extension of the vaccination policy to include this age group we constructed an economic model to estimate the costs and benefits of vaccination from both a health service and a societal perspective. Data to populate the model was obtained from the literature and the outcome measure used was the quality adjusted life year (QALY). Influenza vaccination prevented an estimated 4508 cases (95% CI: 2431-7606) per 100,000 vaccinees per influenza season for a net cost to the NHS of pound653,221 (95% CI: 354,575-1,072,257). The net cost increased to pound1,139,069 (95% CI 27,052-2,030,473) when non-NHS costs were included and the estimated cost-per-QALY were pound6174 and pound10,766 for NHS and all costs respectively. Extension of the current immunisation policy has the potential to generate a significant health benefit at a comparatively low cost.

MRI predictors of risk of incident Alzheimer disease: a longitudinal study.

OBJECTIVE: To determine if baseline entorhinal and hippocampal volumes and their rate of atrophy could predict the risk of incident Alzheimer disease (AD). METHODS: The authors used proportional odds models to assess the relationship between entorhinal and hippocampal size and risk of incident AD among 58 nondemented elderly people. All participants were followed with annual clinical evaluations and structural MRI scans for up to 5 years (baseline and 5 years of follow-up). At baseline, 23 of 58 participants received a diagnosis of amnestic mild cognitive impairment (MCI) and 35 of 58 were healthy control subjects with no cognitive impairment. Structural MRI scans were acquired with a T1-weighted three-dimensional spoiled gradient-recalled echo pulse sequence in a 1.5 T scanner. Entorhinal and hippocampal volumes were derived from 1.6-mm gapless coronal images reformatted to be perpendicular to the long axis of the hippocampus and were normalized by dividing with intracranial volume. RESULTS: Fourteen of 58 nondemented participants developed AD during the follow-up period. Initial diagnosis of MCI was a significant predictor of incident AD. In addition, both baseline entorhinal volume and its slope of decline were independent predictors of incident AD, but initial hippocampal size and its rate of decline were not, after controlling for entorhinal volume. CONCLUSION: In nondemented individuals, entorhinal cortex atrophy is associated with risk of Alzheimer disease.

Interaction between tissue oxygen tension and NADH imaging during synaptic stimulation and hypoxia in rat hippocampal slices.

Oxygen and NADH are essential components in the production of ATP in the CNS. This study examined the dynamic interaction between tissue oxygen tension (pO(2)) and NADH imaging changes within hippocampal tissue slices, during metabolic stresses including hypoxia and synaptic activation. The initiation of abrupt hypoxia (from 95% O(2) to 95% N(2)) caused a rapid decrease in pO(2), onset of hypoxic spreading depression (hsd; at 6.7+/-1.3 mm Hg; n=15), and a monophasic increase in NADH. Provided that reoxygenation was prompt, synaptic responses, pO(2) and NADH levels returned to baseline following hsd. Longer hypoxia caused irreversible neuronal dysfunction, an increase in pO(2) beyond baseline (due to decreased tissue demand), and hyperoxidation of NADH (10+/-2% decrease below baseline; n=7). Synaptic activation in ambient 95% O(2) caused a decrease or 'initial dip' in pO(2) and a biphasic NADH response (oxidation followed by reduction). The oxidizing phase of the NADH response was mitochondrial as it was synchronous with the 'initial' dip in pO(2). Following slow graded reductions in ambient oxygen levels to 8%, four of seven slices developed hsd following synaptic stimulation. The hypoxic threshold for graded oxygen reductions occurred at 7.9+/-5.8 mm Hg O(2) (n=7). Our hypoxic threshold range (6.7-7.9 mm Hg O(2) from abrupt and graded oxygen reduction, respectively) correlates well with reported in vivo values of <12 mm Hg O(2). The major findings of this study include: 1) determination of the critical physiological threshold of pO(2) (based upon hsd), which is a marker of imminent neuronal death if oxygen is not rapidly restored; 2) NADH hyperoxidation and an increase in pO(2) beyond baseline levels following longer periods of hypoxia; and 3) the occurrence of a pO(2) 'dip' during synaptic stimulation, which correlates with the early oxidizing phase of the biphasic NADH response.

Altered cortical visual processing in PD with hallucinations: an fMRI study.

OBJECTIVE: To compare fMRI activation during two visual stimulation paradigms in Parkinson disease (PD) subjects with chronic visual hallucinations vs PD patients who had never hallucinated. METHODS: Twelve pairs of PD subjects, matched for age, PD duration, and dopaminergic drug exposure duration, participated in this study. The authors examined group differences in activation during stroboscopic (flashing) vs no visual stimulation and kinematic (apparent motion) vs stationary visual stimulation. RESULTS: During stroboscopic stimulation, non-hallucinating PD subjects showed significantly greater activation in the parietal lobe and cingulate gyrus compared to hallucinating PD subjects. In contrast, the hallucinating subjects showed significantly greater activation in the inferior frontal gyrus and the caudate nucleus. During kinematic stimulation, non-hallucinating PD subjects showed significantly greater activation in area V5/MT, parietal lobe, and cingulate gyrus compared to hallucinating PD subjects. Hallucinating PD subjects showed significantly greater activation in the superior frontal gyrus. CONCLUSIONS: PD patients with chronic visual hallucinations respond to visual stimuli with greater frontal and subcortical activation and less visual cortical activation than non-hallucinating PD subjects. Shifting visual circuitry from posterior to anterior regions associated primarily with attention processes suggests altered network organization may play a role in the pathophysiology of visual hallucinations in PD.

MRI-derived entorhinal volume is a good predictor of conversion from MCI to AD.

With high-resolution quantitative magnetic resonance imaging (MRI) techniques, it is possible to examine alterations in brain anatomy in vivo and to identify regions affected in the earliest stages of Alzheimer's disease (AD). In the present study, 27 patients diagnosed with mild cognitive impairment (MCI) received a high-resolution MRI scan at baseline and were followed with yearly clinical evaluations. Ten of the 27 patients converted to AD during a 36-month period following the baseline clinical evaluation. Hippocampal and entorhinal cortex volumes derived from the baseline scan were compared to determine which of these two regions, known to be pathologically involved very early in the course of AD, could best differentiate MCI converters from non-converters. Although both entorhinal and hippocampal volumes were found to be independent predictors of the likelihood of conversion to AD, it was the right hemisphere entorhinal volume that best predicted conversion with a concordance rate of 93.5%.

The cost of clinically significant urinary storage symptoms for community dwelling adults in the UK.

OBJECTIVES: To estimate the cost of clinically significant urinary storage symptoms (CSUSS), including costs borne by the National Health Service (NHS) and individuals, in terms of the use of goods and services in community-dwelling adults. SUBJECTS AND METHODS: The subjects were community-dwelling adults aged >/= 40 years and living in Leicestershire. The prevalence of CSUSS was estimated using a postal questionnaire with a randomly selected sample of 23 182 respondents. The costs associated with CSUSS were estimated using home interviews with 613 cases with and 523 subjects without CSUSS. Cases were defined on the basis of urinary symptoms of leakage, urgency, frequency and nocturia. Willingness-to-pay was used to measure intangible costs as an indicator of the value of alleviating symptoms. RESULTS: The estimated total annual cost to the NHS for treating CSUSS cases in community-dwelling adults was pound 536 million at 1999/2000 prices ( pound 303 million and pound 233 million for men and women, respectively). The total value of costs borne by individuals was estimated to be pound 207 million ( pound 29 million and pound 178 million for men and women, respectively). This gives total annual costs related to the use of services of pound 743 million. There were large intangible costs borne by individuals estimated to be pound 669 million ( pound 301 and pound 368 million for men and women) for the UK in terms of willingness-to-pay. CONCLUSIONS: The costs of CSUSS in the community amounted to approximately 1.1% of overall NHS spending for 1999/2000. Personally borne and intangible costs are also large and important components of the costs of CSUSS. There are large gender differences in the proportion of costs borne by the NHS, i.e. 91% of male and 57% of female costs.

The physiological effects of elevated intra-abdominal pressure following aneurysm repair.

OBJECTIVES: Elevated intra-abdominal pressure (IAP) may cause widespread organ dysfunction (abdominal compartment syndrome) through effects on the respiratory, cardiac, renal and gastro-intestinal systems. The aim of this study was to document IAP following aneurysm surgery, and to determine the effect of IAH on outcome. DESIGN: Prospective observational study. SETTING: University Hospital. SUBJECTS: The patient cohort comprised 75 patients undergoing infra-renal aneurysm repair (53 non-ruptured [40 conventional--1 death, 13 endovascular] and 22 conventionally repaired ruptured AAA--8 deaths). IAP was quantified by bladder manometry at the termination of the procedure and at 24 h intervals in patients who remained intubated. Physiological indices of organ function were recorded. Statistical analysis utilized the unpaired t-test, Fischer's exact test and Pearson's correlation. RESULTS: IAP was significantly higher at abdominal closure following ruptured aneurysm repair (15.4 mmHg [SE 1.6]) than conventional (10.5 [0.89]) or endovascular elective repair (6.4 [1.0]) of non-ruptured AAA. The sensitivity and specificity of IAP to predict subsequent mortality was analysed using a receiver characteristic operating curve. This analysis demonstrated that a cut off of 15 mmHg was the most useful for indicating patients at risk (sensitivity 0.66, specificity 0.79). Physiological indices of organ dysfunction (pH[P = 0.027], base excess [p = 0.005], peak inspiratory pressure [p = 0.0015], CVP and urine output [p = 0.0029]) were significantly impaired in patients with IAP > or = 15 mmHg, in comparison to patients with lower pressures. IAP correlated significantly with indices of cardiac (CVP p = 0.038), respiratory (PaO2/FiO2, p = 0.026), and renal function (urine output p = 0.046). CONCLUSIONS: These data suggest that the management of IAH may have a role following repair of ruptured AAA. High intra-abdominal pressures rarely complicate elective or endovascular aneurysm repair.

Glutamic acid decarboxylase-67-positive hippocampal interneurons undergo a permanent reduction in number following kainic acid-induced degeneration of ca3 pyramidal neurons.

Kainic acid (KA)-induced degeneration of CA3 pyramidal neurons leads to synaptic reorganization and hyperexcitability in both dentate gyrus and CA1 region of the hippocampus. We hypothesize that the substrate for hippocampal inhibitory circuitry incurs significant and permanent alterations following degeneration of CA3 pyramidal neurons. We quantified changes in interneuron density (N(v)) in all strata of the dentate gyrus and the CA1 and CA3 subfields of adult rats at 1, 4, and 6 months following intracerebroventricular (icv) KA administration, using glutamic acid decarboxylase-67 (GAD-67) immunocytochemistry. At 1 month postlesion, GAD-67-positive interneuron density was significantly reduced in all strata of every hippocampal region except stratum pyramidale of CA1. The reduction in GAD-67-positive interneuron density either persisted or exacerbated at 4 and 6 months postlesion in every stratum of all hippocampal regions. Further, the soma of remaining GAD-67-positive interneurons in dentate gyrus and CA3 subfield showed significant hypertrophy. Thus, both permanent reductions in the density of GAD-67-positive interneurons in all hippocampal regions and somatic hypertrophy of remaining GAD-67-positive interneurons in dentate gyrus and CA3 subfield occur following icv KA. In contrast, the density of interneurons visualized with Nissl in CA1 and CA3 regions was nearly equivalent to that in the intact hippocampus at all postlesion time points. Collectively, these results suggest that persistent reductions in GAD-67-positive interneuron density observed throughout the hippocampus following CA3 lesion are largely due to a permanent loss of GAD-67 expression in a significant fraction of interneurons, rather than widespread degeneration of interneurons. Nevertheless, a persistent decrease in interneuron activity, as evidenced by permanent down-regulation of GAD-67 in a major fraction of interneurons, would likely enhance the degree of hyperexcitability in the CA3-lesioned hippocampus.

Prolonged postlesion transplantation delay adversely influences survival of both homotopic and heterotopic fetal hippocampal cell grafts in Kainate-lesioned CA3 region of adult hippocampus.

Fetal hippocampal CA3 cell grafts exhibit dramatically enhanced survival when transplanted at an early postlesion delay of 4 days into the lesioned CA3 region of adult hippocampus. However, survival of these homotopic grafts following placement at late postlesion time points when the host milieu is considerably less receptive to grafts is unknown. We hypothesize that an extended postlesion delay at the time of grafting will lead to significant diminution in cell survival of both homotopic and heterotopic fetal transplants grafted to lesioned adult CNS. We quantitatively investigated absolute cell survival of 5'-bromodeoxyuridine-labeled fetal hippocampal CA3 and CA1 cell grafts, following transplantation into the lesioned CA3 region of adult rat hippocampus, at a delay of 45 days after a unilateral intracerebroventricular administration of kainic acid (KA). Survival of these grafts was also analyzed in intact CA3 of the hippocampus contralateral to KA administration for comparison. In lesioned CA3 region, CA3 (homotopic) and CA1 (heterotopic) grafts exhibited comparable but only moderate survival, with a recovery of only 21-31% of injected cells. Cell survival in these grafts into lesioned hippocampus was similar to survival of grafts placed into the contralateral intact CA3 region. These results are in sharp contrast to increased graft survival measured following transplants performed at 4 days postlesion. In such grafts placed early, there was both a significantly higher cell survival than grafts placed into the intact CA3 region and also a characteristic differential survival based on graft cell specificity to the lesioned CA3 region (Zaman et al., Exp. Neurol., 161:535-561, 2000). Thus, the enhanced conduciveness of lesioned CA3 region for survival of homotopic CA3 cell grafts observed at 4 days postlesion wanes by 45 days postlesion to that of intact CA3 region, in spite of residual loss of CA3 neurons with the lesion. Strategies that considerably augment graft cell survival may therefore be critical for optimal integration of fetal grafts into the adult CNS at late postlesion time points.

Management of acute cervical spinal cord injury.

BACKGROUND: Spinal cord injury affects approximately 10,000 new persons each year in the United States. Motor vehicle crashes, violence, and falls are the most common causes. The purpose of this review is to provide a rational management strategy for treating acute cervical spinal cord injuries. REVIEW SUMMARY: History-taking in these patients should focus on a few key points. Physical examination consists of determining the level of the lesion by a tailored motor, sensory, and reflex examination. An algorithm for the judicious use of plain radiographs, computed tomography scans, and emergent magnetic resonance imaging is presented. Management goals include protection of uninjured tissue, restoration of reversibly injured tissue, and achieving alignment and permanent spinal stability. The role of early surgery and high-dose steroids are discussed. CONCLUSION: Maximizing neurological function after cervical spinal cord injuries relies on rapid diagnosis and appropriate management. Although prognosis generally remains poor, recent advances in the basic sciences offer hope for the future.