Mia von Euler

Clip Compression Injury in the Spinal Cord: A Correlative Study of Neurological and Morphological Alterations ☆

Rats subjected to experimental spinal cord compression of different degrees induced by aneurysm clips were neurologically tested 3 and 5 weeks postinjury. The development of spinal cord tissue destruction over time was similar to what has been described for other experimental spinal cord injuries with characteristics such as early edema, axonal swelling, and later necrosis. Three weeks after injury a reactive gliosis was found at the injury epicenter and regenerating axons could be identified in the otherwise necrotic cavity. The extent of degeneration was highly correlated with the closing force of the aneurysm clip. The results of a number of neurological tests were correlated to the degree of clip-induced compression, to lesion volume, and to the remaining area of white matter at the epicenter. The neurological tests with the highest correlation to morphological descriptors were beam walk (r(s) = 0.89-0.95) and motor performance score (r(s) = 0.88-0.92). We conclude that the motor performance score, previously validated for photochemically induced ischemic spinal cord injuries, is equally suitable for clip compression injuries as a fast and reliable neurological test paradigm.

Motor Performance Score: A New Algorithm for Accurate Behavioral Testing of Spinal Cord Injury in Rats

To evaluate the usefulness of standard neurological tests in predictin g the neurological outcome after photochemically induced spinal cord lesions in rats, we inflicted injuries of different severity to adult female rats. The behavior of the rats was followed for 6 weeks and the results of the behavioral tests were correlated with morphological indicators of tissue destruction at the end of this period. We found many behavioral tests to be highly correlated with the loss of tissue, whereas some tests were inaccurate in correlating with degree of tissue destruction. Motor score, beam walk, and righting reflect were all highly correlated with the volume of the lesion as well as the depth of the lesion cavity at its epicenter. We propose a protocol for neurological evaluation of this type of spinal cord injury consisting of six individual tests, hierarchally organized such that injured rats can be divided into 11 groups ofn eurological deficit, scored from 10 to 0. This so-called motor performance score is fast and easy to perform and shows high correlation with the lesion volume, and is thus suitable for neurological evaluation of photochemically induced spnial cord injury.

Inhalation of Low Concentrations of Toluene Induces Persistent Effects on a Learning Retention Task, Beam-Walk Performance, and Cerebrocortical Size in the Rat

The organic solvent toluene is widely used in industry. The threshold limit value for extended occupational exposure to toluene is presently set to 200 ppm in the United States. We have investigated the effect of an inhalation exposure of 80 ppm for 4 weeks (6 h/day, 5 days/week), followed by a postexposure period of at least 4 weeks, on behavior and brain features in the rat. Toluene exposure appeared to affect spatial memory, since toluene-exposed rats showed a longer time in the correct quadrant in a Morris swim maze. This effect may indicate that the exposed rats used their praxis strategy longer before they started to look for the platform elsewhere. Toluene-exposed rats showed trends for increases in both locomotion and rearing behaviors and a significantly reduced beam-walk performance. The area of the cerebral cortex, especially the parietal cortex, was decreased by 6-10% in toluene-exposed rats, as shown by magnetic resonance imaging of living rats and autoradiograms of frozen brain sections. The K(D) and B(max) values of the dopamine D(3) agonist [(3)H]PD 128907 were not affected by toluene, as measured in caudate-putamen and subcortical limbic area using biochemical receptor binding assays and in caudate-putamen and islands of Calleja using quantitative receptor autoradiography. Hence, previously demonstrated persistent effects by toluene on the binding characteristics of radioligands binding to both D(2) and D(3) receptors seem to indicate a persistent effect of toluene selectively on dopamine D(2) receptors. Taken together, the present results indicate that exposure to low concentrations of toluene leads to persistent effects on cognitive, neurological, and brain-structural properties in the rat.

Higher Prehospital Priority Level of Stroke Improves Thrombolysis Frequency and Time to Stroke Unit The Hyper Acute STroke Alarm (HASTA) Study

Background and Purpose— Early initiated treatment of stroke increases the chances of a good recovery. This randomized controlled study evaluates how an increased priority level for patients with stroke, from level 2 to 1, from the Emergency Medical Communication Center influences thrombolysis frequency, time to stroke unit, and whether other medical emergencies reported negative consequences. Methods— Patients aged 18 to 85 years in Stockholm, Sweden, with symptoms of stroke within 6 hours were randomized from the Emergency Medical Communication Center or emergency medical services to an intervention group, priority level 1, immediate call of an ambulance, or to a control group with standard priority level, that is, priority level 2 (within 30 minutes). Before study start, an educational program on identification of stroke and importance of early initiated treatment was directed to all medical dispatchers and ambulance and emergency department personnel. Results— During 2008, 942 patients were randomized of which 53% (n=496) had a final stroke/transient ischemic attack diagnosis. Patients in the Emergency Medical Communication Center randomized intervention group reached the stroke unit 26 minutes earlier than the control group (P<0.001) after the emergency call. Thrombolysis was given to 24% of the patients in the intervention group compared with 10% of the control subjects (P<0.001). The higher priority level showed no negative effect on other critical ill patients requiring priority level 1 prehospital attention. Conclusion— This randomized study shows negligible harm to other medical emergencies, a significant increase in thrombolysis frequency, and a shorter time to the stroke unit for patients with stroke upgraded to priority level 1 from the Emergency Medical Communication Center and through the acute chain of stroke care.

Adverse Drug Reactions and Impaired Renal Function in Elderly Patients Admitted to the Emergency Department: A Retrospective Study

BackgroundAdverse drug reactions (ADRs) are common in elderly patients. There are various reasons for this, including age- and disease-related alterations in pharmacokinetics and pharmacodynamics as well as the common practice of polypharmacy. The decline in renal function in elderly patients may also predispose them to pharmacological ADRs (type A, augmented). Patients receiving home healthcare may be at even higher risk.ObjectivesTo study ADRs as a cause of acute hospital admissions in a defined cohort of elderly patients (aged ≥65 years) registered to receive home healthcare services, with special reference to impaired renal function as a possible risk factor.MethodsThis was a retrospective study of 154 elderly patients aged ≥65 years admitted to the emergency department of a university hospital in Stockholm, Sweden, in October–November 2002. Estimated creatinine clearance (eCLCR) was calculated from the Cockcroft-Gault formula, and estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease (MDRD) equation. ADRs were defined according to WHO criteria. All medications administered to patients at admission and at discharge were collated. These and other data were collected from computerized hospital records.ResultsADRs were judged to contribute to or be the primary cause of hospitalization in 22 patients, i.e. 14% of 154 patients registered to receive home healthcare. Eleven of the 22 patients were women. All but one ADR were type A. Excessive doses or drugs unsuitable in renal insufficiency were present in seven patients in the ADR group compared with only four patients in the group without ADRs (p=0.0001). Patients with ADRs did not differ significantly from those without ADRs in relation to age, plasma creatinine, eCLCR, weight or number of drugs prescribed at admission. However, women with ADRs were significantly older than women without ADRs (mean±SD age 88.8±5.7 years vs 82.5±8.0 years, respectively; p=0.014) and had significantly lower mean±SD eCLCR values (25.5±10.8 and 37.1±17.1 mL/min, respectively; p=0.035). Median MDRD eGFR was significantly higher than median eCLCR (59 [range 6–172] mL/min/1.73 m2 vs 38 [range 5–117] mL/min, respectively; p=0.0001).ConclusionsIn elderly patients registered to receive home healthcare, 14% of hospital admissions were primarily caused by ADRs. One-third of these ADRs were related to impaired renal function, generally in very old women. These ADRs may be avoided by close monitoring of renal function and adjustments to pharmacotherapy (drug selection and dose), particularly in very elderly women.

Reproducible loss of CA1 neurons following carotid artery occlusion combined with halothane-induced hypotension

The 2-vessel occlusion approach to produce global ischemia in rats requires concomitant reduction of systemic blood pressure. We have utilized the hypotensive effect of halothane administrated by artificial respiration to prevent respiratory arrest and to ensure stable physiological conditions. Systemic blood pressure was reduced to 40-45 mmHg by instant adjustments of the halothane concentration. Bilateral occlusion of the carotid arteries caused a profound and reproducible ischemia, as analyzed by laser-Doppler flowmetry. In the rats exposed to 11, 12, or 13 min of ischemia, 5% died and 5% developed seizures. The extent of neuronal death in CA1 was highly correlated to the duration of ischemia. Following 11 min of ischemia, CA1 neuronal cell death, as analyzed by Fluoro-Jade, was absent 1 day after injury, variable at day 4, and consistent at day 7. The numbers of cresyl violet- and NeuN-positive neurons at day 7 were 8% and 20% of control, respectively. OX42 immunoreactivity was low and variable at day 4, but pronounced at day 7. In conclusion, this rat global ischemia model is relatively simple to perform, has a low mortality, and produces a profound and highly reproducible delayed cell death of hippocampal CA1 neurons.

Risk scoring and thromboprophylactic treatment of patients with atrial fibrillation with and without access to primary healthcare data: Experience from the Stockholm health care system

BACKGROUND Earlier validation studies of risk scoring by CHA2DS2VASc for assessments of appropriateness of warfarin treatment in patients with atrial fibrillation have been performed solely with diagnoses recorded in hospital based care, even though many patients to a large extent are managed in primary care. METHODS Cross-sectional registry study of all 43 353 patients with a diagnosis of non-valvular atrial fibrillation recorded in inpatient care, specialist ambulatory care or primary care in the Stockholm County during 2006-2010. RESULTS The mean CHA2DS2VASc score was 3.82 (4.67 for women and 3.14 for men). 64% of the entire cohort of patients with atrial fibrillation had the diagnosis in primary care (12% only there). The mean CHA2DS2VASc score of patients with a diagnosis only in inpatient care or specialist ambulatory care increased from 3.63 to 3.83 when comorbidities registered in primary care were added. In 2010 warfarin prescriptions were claimed by 47.2%, and ASA by 41.6% of the entire cohort. 34% of patients with CHA2DS2VASc=1 and 20% with CHA2DS2VASc=0 had warfarin treatment. ASA was more frequently used instead of warfarin among women and elderly patients. CONCLUSIONS Registry CHA2DS2VASc scores were underestimated without co-morbidity data from primary care. Many individuals with scores 0 and 1 were treated with warfarin, despite poor documentation of clinical benefit. In contrast, warfarin appears to be underused and ASA overused among high risk atrial fibrillation patients. Lack of diagnoses from primary care underestimated CHA2DS2VASc scores and may thereby have overestimated treatment benefits in low-risk patients in earlier studies.

Degeneration of newly formed CA1 neurons following global ischemia in the rat.

The pyramidal neurons of the hippocampal CA1 region are essential for spatial learning and memory and are almost entirely destroyed 7-14 days after transient cerebral ischemia (DAI). Recently, we found that CA1 neurons reappeared at 21-90 DAI, in association with a recovery of ischemia-induced deficits in spatial learning and memory. However, at 125 DAI the number of neurons was fewer than at 90 DAI, suggesting that the new nerve cells undergo neurodegeneration during this time period. We therefore investigated whether neuronal degeneration occurred between 90 and 250 DAI and how this related to learning and memory performance. We found that many of the new CA1 neurons previously seen at 90 DAI had disappeared at 250 DAI. In parallel, large mineralized calcium deposits appeared in the hippocampus and thalamus, in association with neuroinflammatory and astroglial reactions. In spite of the extensive CA1 damage, the ischemic rats showed no deficiencies in spatial learning and memory, as analyzed in the Morris water maze and a complimentary water maze test based on sequential left-right choices. However, ischemia rats showed a general increase in swim length in the Morris water maze suggesting altered search behaviour. Taken together, these results indicate that the CA1 neurons that reappear after transient global ischemia to a large extent degenerate at 125-250 DAI, in parallel with the appearance of a less efficient search strategy.

Erratum to: Adverse Drug Reactions and Impaired Renal Function in Elderly Patients Admitted to the Emergency Department

Background Adverse drug reactions (ADRs) are common in elderly patients. There are various reasons for this, including age- and disease-related alterations in pharmacokinetics and pharmacodynamics as well as the common practice of polypharmacy. The decline in renal function in elderly patients may also predispose them to pharmacological ADRs (type A, augmented). Patients receiving home healthcare may be at even higher risk.

Renal function estimations and dose recommendations for dabigatran, gabapentin and valaciclovir: a data simulation study focused on the elderly

Objectives The thrombin inhibitor dabigatran is mainly excreted by the kidneys. We investigated whether the recommended method for estimation of renal function used in the clinical trials, the Cockcroft-Gault (CGold) equation and the estimated glomerular filtration rate (eGFR) modification of diet in renal disease equation 4 (MDRD4), differ in elderly participants, resulting in erroneously higher dose recommendations of dabigatran, which might explain the serious, even fatal, bleeding reported. The renally excreted drugs gabapentin and valaciclovir were also included for comparison. Design A retrospective data simulation study. Participants Participants 65 years and older included in six different studies. Main outcome measure Estimated renal function by CG based on uncompensated (‘old Jaffe’ method) creatinine (CGold) or by MDRD4 based on standardised compensated P-creatinine traceable to isotope-dilution mass spectrometry, and the resulting doses. Results 790 participants (432 females), mean age (±SD) 77.6±5.7 years. Mean estimated creatinine clearance (eCrCl) by the CGold equation was 44.2±14.8 ml/min, versus eGFR 59.6±20.7 ml/min/1.73 m2 with MDRD4 (p<0.001), absolute median difference 13.5, 95% CI 12.9 to 14.2. MDRD4 gave a significantly higher mean dose (valaciclovir +21%, dabigatran +25% and gabapentin +37%) of all drugs (p<0.001). With MDRD4 58% of the women would be recommended a full dose of dabigatran compared with 18% if CGold is used. Conclusions MDRD4 would result in higher recommended doses of the three studied drugs to elderly participants compared with CG, particularly in women, and thus increased the risk of dose and concentration-dependent adverse reactions. It is important to know which method of estimation of renal function the Summary of Products Characteristics was based on, and use only that one when prescribing renally excreted drugs with narrow safety window. Doses based on recently developed methods for estimation of renal function may be associated with considerable risk of overtreatment in the elderly.