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- 2019
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Grabowski, Martin, et al.
(författare)
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Brain capillary density and cerebral blood flow after occlusion of the middle cerebral artery in normotensive Wistar-Kyoto rats and spontaneously hypertensive rats
- 1993
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Ingår i: Journal of Hypertension. - 1473-5598. ; 11:12, s. 1363-1368
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: In order to elucidate why spontaneously hypertensive rats (SHR) develop larger brain infarcts distal to an arterial occlusion than normotensive Wistar-Kyoto (WKY) rats, we determined the surface and volume densities of cerebral capillaries, and the regional cerebral blood flow distal to an arterial occlusion in SHR and WKY rats. DESIGN: Occlusion of the middle cerebral artery was chosen because the middle cerebral artery territory is most commonly affected by cerebral infarcts in man. METHODS: Surface and volume densities of capillaries in the neocortex of the middle cerebral artery territory were measured by stereological techniques on histological sections. Fifteen minutes after ligation of the right middle cerebral artery, regional cerebral blood flow was measured autoradiographically by the [14C]-iodoantipyrine method. RESULTS: The capillary density of the neocortex did not differ between the SHR and WKY rats. The blood flow was significantly lower within the middle cerebral artery territory in the SHR than in the WKY rats. CONCLUSIONS: The reduced blood flow distal to the occlusion in SHR is probably a consequence of structural adaptation of arterial resistance vessels, rather than being caused by reduced capillary density.
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| 4. |
- Grabowski, Martin, et al.
(författare)
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Fetal neocortical grafts implanted in adult hypertensive rats with cortical infarcts following a middle cerebral artery occlusion: ingrowth of afferent fibers from the host brain
- 1992
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Ingår i: Experimental Neurology. - 0014-4886. ; 116:2, s. 105-121
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Tidskriftsartikel (refereegranskat)abstract
- This study is focused on the survival of fetal neocortical grafts placed in the infarcted adult host cortex of the spontaneously hypertensive rat and describes the ability of host axonal regeneration into the graft after a focal ischaemic lesion. Five to seven days following ligation of the right middle cerebral artery, dissociated neocortical primordium from fetuses of gestational age 12-18 days was implanted into the infarcted cortical area. Surviving transplants were seen in all rats, although grafts derived from gestational age 12-14 days displayed an irregular morphology rich in sinusoid-like cavities and containing fewer cells of apparently mature neuronal morphology. Grafts from older donors contained perikarya of neuronal appearance; however, they lacked normal cortical lamination. Ten days postgrafting, fibers stained by acetylcholinesterase histochemistry, dopamine-beta-hydroxylase, and 5-hydroxytryptamine immunohistochemistry were found in the grafts, and by 10-23 weeks after transplantation the fiber density had increased substantially. When the retrograde tracer Fluoro-Gold was injected into the grafted tissue, labeled cells were found in several subcortical nuclei of the host, including the nucleus basalis of Meynert, ventral pallidum, thalamus, dorsal raphe, locus coeruleus, as well as the ipsilateral and contralateral neocortex. This study shows that grafts of dissociated neocortical tissue exhibit good survival and growth potential when implanted into infarcted neocortex and that several nerve fiber systems of the adult host have a regenerative capacity sufficient to innervate the grafted tissue.
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| 5. |
- Grabowski, Martin, et al.
(författare)
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Fetal neocortical grafts placed in brain infarcts do not improve paw-reaching deficits in adult spontaneously hypertensive rats
- 1996
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Ingår i: Acta Neurochirurgica. Supplementum. - 0065-1419. ; 66, s. 68-72
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to study if neural grafts placed brain infarcts could improve functional recovery. The middle cerebral artery was occluded (MCAO) in 19 spontaneously hypertensive rats. Nine rats were sham operated. Twelve to 16 days after the ischemic insult, 9 of the MCAO rats received transplants of dissociated fetal neocortical tissue (MCAO-T) and 1, 3 and 6 months after transplantation surgery, the rats were behaviorally evaluated by a test for forelimb function. Infarct and transplant sizes were measured morphometrically. The remaining volume of the infarcted hemisphere was 66 +/- 7% (mean +/- SD) in the MCAO group and 71 +/- 9% in the MCAO-T group of the non-operated hemisphere. All grafted rats had surviving transplants. Contralateral to the lesion, paw-reaching was highly impaired in both infarcted groups compared with sham-operated controls with no significant difference between MCAO and MCAO-T. The lesion size correlated significantly with contralateral paw-reach performance at all test periods. We conclude that neocortical grafts did not alleviate the impaired forepaw function.
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| 6. |
- Grabowski, Martin, et al.
(författare)
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Functional integration of cortical grafts placed in brain infarcts of rats
- 1993
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Ingår i: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 34:3, s. 362-368
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Tidskriftsartikel (refereegranskat)abstract
- Five to 6 days after a right middle cerebral artery occlusion, a cell suspension of fetal neocortex was grafted into the infarcted area of adult spontaneously hypertensive rats. Three to 17 months later, functional integration of the grafts into the afferent somatosensory pathway was tested using the 2-[14C]deoxyglucose method for estimation of glucose utilization. Grafted rats (n = 8) and control rats (n = 5) with no arterial occlusion were stimulated in the left vibrissal region resulting in an increased glucose utilization in the left trigeminal sensory nucleus and the right ventroposterior nucleus of the thalamus, whereas the same regions in a group (n = 5) of nonstimulated grafted rats were not activated. Glucose uptake in the right somatosensory cortex of control rats was 96 +/- 5 (mean +/- SEM) mumol/100 gm/min. Neocortical grafts consumed less glucose than cortex in control rats but the vibrissae-stimulated group displayed a 110% higher value than the nonstimulated grafted group (32 +/- 5 vs 15 +/- 2, p < 0.05). We conclude that graft glucose metabolism is increased following stimulation of the host somatosensory pathway, which demonstrates that transplanted neurons can be functionally integrated with neural circuitries of the host after an ischemic insult.
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| 7. |
- Grabowski, Martin, et al.
(författare)
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Influence of an enriched environment and cortical grafting on functional outcome in brain infarcts of adult rats
- 1995
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 133:1, s. 96-102
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this work was to study if enriched housing conditions and fetal neocortical transplantation could enhance the functional outcome after focal brain ischemia in adult rats. The right middle cerebral artery (MCA) was ligated in 34 inbred, spontaneously hypertensive male rats, which were then randomly divided into three groups. Groups A and B were transferred to an enriched environment, i.e., a large cage with opportunities for various activities but not forcing the rats to do any particular tasks; group C was kept in standard laboratory cages. Three weeks after the MCA occlusion blocks of fetal neocortical tissue (Embryonic Day 17) were transplanted to the infarct cavity in groups B and C. Rats in group A (n = 11) and group B (n = 11) performed equally well and significantly better than rats in group C (n = 10) when placed on an inclined plane and when traversing a rotating pole 6 and 9 weeks after the MCA occlusion and in a leg placement test at 9, but not 6 and 12 weeks. Skilled forelimb function did not differ between the groups. Infarct size and thalamic atrophy did not differ between the groups and graft size was similar in group B and C. There was no correlation between infarct size and motor function in any of the tests in rats housed in an enriched environment. Since the environment can significantly alter functional outcome without reducing infarct size we suggest that more attention should be given to the role of the laboratory environment and to long term behavioral outcome in experimental stroke.
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| 8. |
- Grabowski, Martin, et al.
(författare)
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Neocortical grafts placed in the infarcted brain of adult rats: few or no efferent fibers grow from transplant to host
- 1995
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 134:2, s. 273-276
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Tidskriftsartikel (refereegranskat)abstract
- The present study examines the capacity of fetal neocortical grafts placed in a brain infarct to exchange axonal projections with the host brain. Five to 7 days after a middle cerebral artery occlusion in adult spontaneously hypertensive rats, dissociated neocortical primordium from fetuses of gestational age 15-16 days was implanted into the infarcted area. Four to 11 months later, the neural tracers Phaseolus vulgaris-leucoagglutinin and Fluoro-Gold were injected in the grafts and host neocortex. An extensive axonal network was present in the transplants but only one of eight rats with appropriate placed injections displayed efferent connections from transplant to host. The sparse axonal outgrowth indicates major limitations for fetal rat cortical grafts to form connections with host neural circuitries after an ischemic insult.
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| 9. |
- Grabowski, Martin, et al.
(författare)
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Paw-reaching, sensorimotor, and rotational behavior after brain infarction in rats
- 1993
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 24:6, s. 889-895
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Functional tests that are stable and consistent over time are an advantage for long-term evaluation of treatment in experimental stroke research. Because little information on this subject is available in rodents with focal cerebral ischemia, we investigated the outcome of three behavioral tests for a period of 3 months after the insult. METHODS: Spontaneously hypertensive rats were sham-operated (n = 27) or underwent an occlusion (n = 36) of the right middle cerebral artery. Before surgery all rats were tested for amphetamine-induced rotational behavior, and half of the rats were trained in a paw-reaching task. One, 2, and 3 months after surgery the tests were repeated, together with a test for sensorimotor function. Infarct size was measured morphometrically. RESULTS: In the lesion group, total hemisphere area was reduced by 22%, caudate putamen by 47%, and the thalamus by 24%. Contralateral to the lesion, paw-reaching was highly impaired, regardless of whether or not the rats had been pretrained, and lesion size correlated significantly to paw-reach performance. Ipsilateral rotation increased and sensorimotor function recovered with time in infarcted rats. CONCLUSIONS: In contrast to amphetamine-induced rotation and sensorimotor behavior, the paw-reaching test provides a stable behavioral parameter after a middle cerebral artery occlusion. Moreover, the lesion-induced deficit in paw-reaching is highly correlated to the extent of the infarct, suggesting that this test is useful in evaluating treatment effects for a longer period of time.
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| 10. |
- Grabowski, Martin, et al.
(författare)
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Sensorimotor performance and rotation correlate to lesion size in right but not left hemisphere brain infarcts in the spontaneously hypertensive rat
- 1991
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Ingår i: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 547:2, s. 249-257
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Tidskriftsartikel (refereegranskat)abstract
- In order to correlate behavioural deficits to lesion size and to reveal possible functional asymmetries in the rat brain, locomotor activity, rotation and sensorimotor integration to touch were studied in spontaneously hypertensive rats (SHR) subjected to right or left middle cerebral artery occlusion. Control and infarcted rats showed no difference in locomotor activity. Infarcted rats tended to rotate towards the side of the lesion. A large sensorimotor deficit was found contralateral to the infarcted hemisphere. The absolute values of the side-biases for the rotation and sensorimotor tests were of the same degree irrespective of lesion side. Whereas the left hemisphere lesion size did not correlate to the behavioural outcome, the size of the right hemisphere lesion was highly correlated to the total sensorimotor deficit. Furthermore, the sensorimotor deficit of specific body parts was found to correlate to the damage of certain brain regions in a rostrocaudal fashion, reminiscent of a somatotopical organization. The extent of ipsilateral rotation correlated to brain tissue loss at the level of the posterior caudate-putamen. The present results indicate an asymmetrical organization for brain functions involved in the performance of the rotation and sensorimotor tests.
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| 11. |
- Grabowski, Martin, et al.
(författare)
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Survival of fetal neocortical grafts implanted in brain infarcts of adult rats: the influence of postlesion time and age of donor tissue
- 1994
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 127:1, s. 126-136
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Tidskriftsartikel (refereegranskat)abstract
- We have previously found that fetal cortex taken from 16- to 18-day-old donors survives grafting to the infarcted cortex 5-7 days after middle cerebral artery occlusion. The present study was undertaken to examine the effect on graft survival of varying the age of the fetal donor tissue and the time between vessel occlusion and graft implantation. First, a cell suspension of neocortical tissue was grafted from fetuses aged 15, 17, or 20 gestational days to the infarcted cortex of hypertensive rats which had undergone arterial occlusion 5-7 days earlier. There were no significant differences in the mean size or general morphology assessed in Nissl- and acetylcholinesterase-stained sections between the groups. Second, neocortical tissue was grafted from fetuses aged 15 gestational days to the infarcted cortex at different times following arterial occlusion. When surgery was delayed until 5-7 days, 3 weeks, or 8 weeks postocclusion, graft survival was significantly better than when implanted 1 day postocclusion. Implantation after 3 weeks yielded grafts that also were significantly larger than those in rats grafted 5-7 days after cortical infarction. The results indicate that there is no crucial upper donor age limit for dissociated fetal neocortical grafts in terms of graft survival and volume. Furthermore, a delay between lesion and transplantation is desirable in this stroke model. The host brain environment seems to be most hospitable around 3 weeks after arterial occlusion.
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| 12. |
- Grabowski, Martin, et al.
(författare)
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Vascularization of fetal neocortical grafts implanted in brain infarcts in spontaneously hypertensive rats
- 1992
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Ingår i: Neuroscience. - 1873-7544. ; 51:3, s. 673-682
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Tidskriftsartikel (refereegranskat)abstract
- The vascularization of neural grafts in ischemic brain was studied in spontaneously hypertensive rats grafted with a suspension of fetal neocortical tissue into the infarcted area five to six days after ligation of the middle cerebral artery. The brain vasculature was examined by scanning electron microscopy of corrosion vascular casts and the cortical microvasculature was stereologically quantified in light microscopy three months after the occlusion. Patent anastomoses were present between the middle cerebral artery distal to occlusion and the proximal part, as well as to the anterior and posterior cerebral arteries, in both grafted and non-grafted rats. A vascular plexus covering the infarct cavities and the grafts contained leptomeningeal vessels intermingled with a thin capillary network which is not normally found on the brain surface. The graft vessels were derived from this vascular plexus. The regular pattern of arterioles and venules penetrating from the cortical surface in normal neocortex was absent in the grafts but the capillary morphology was similar in both types of tissue. The grafts had a lower capillary density than normal tissue and lacked the laminar distribution of capillaries characteristic of normal neocortex. The results demonstrate the plasticity of the vascular system where remodeling of the vascular tree after an ischemic insult provides suitable conditions for the vascularization of neocortical grafts.
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| 15. |
- Hjelmgren, Jonas, et al.
(författare)
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Estimating the value of novel interventions for Parkinson's disease: An early decision-making model with application to dopamine cell replacement.
- 2006
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Ingår i: Parkinsonism & Related Disorders. - : Elsevier BV. - 1873-5126 .- 1353-8020. ; 12:7, s. 443-452
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Tidskriftsartikel (refereegranskat)abstract
- A long-term cost-effectiveness model for early decision-making and estimation of outcomes of novel therapeutic procedures for Parkinson's disease (PD) was developed based on the Hoehn and Yahr (HY) stages of PD. Results provided support for model validity. Model application to a future dopamine cell replacement therapy indicated long-term cost offsets and gains in quality-adjusted life years (QALYs) in early onset PD (HY III-IV), as compared to standard drug therapy. The maximum price premium (i.e., profit or compensation for developmental costs) for the intervention to remain cost-effective was estimated to EURO12000-64000 according to cost-per-QALY thresholds of EURO38000-70000 and depending on whether all or only medical direct costs are considered. The study illustrates the value of early health economic modeling and the described model shows promise as a means to estimate outcomes and aid decision-making regarding novel interventions for PD. (c) 2006 Elsevier Ltd. All rights reserved.
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| 16. |
- Johansson, Barbro, et al.
(författare)
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Functional recovery after brain infarction: plasticity and neural transplantation
- 1994
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Ingår i: Brain Pathology. - : Wiley. - 1750-3639 .- 1015-6305. ; 4:1, s. 85-95
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Tidskriftsartikel (refereegranskat)abstract
- In the past, little attention has been given to the role of brain plasticity for the long term functional outcome in experimental stroke although there is substantial evidence for plasticity in other experimental models of neurological disorders. Under clinical conditions, functional improvement occurs in most stroke survivors during the initial months after the ischemic incidence. Recent PET studies in stroke patients, investigated two months or later after stroke, indicate a considerable potential for functional plasticity in the adult human cerebral cortex. Research aimed at the identification of the mechanisms underlying functional recovery should be given high priority, particularly with regard to environmental factors and pharmacological interventions. Pilot experiments of environmental enrichment significantly improved the functional outcome of laboratory animals after brain infarction. Fetal neocortical tissue grafted into the infarcted area in adult rats received afferent fibres from the intact brain and responded to contralateral sensory stimulation with increased metabolic activity, indicating functional integration between neocortical grafts and host afferent systems. However, reciprocal connections from the graft to the host tissue were rare, and it remains to be shown whether grafting will be able to restore the complex cortical organization of the infarcted tissue.
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| 17. |
- Nacul, Luis, et al.
(författare)
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European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) : Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe
- 2021
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Ingår i: Medicina (Kaunas). - : MDPI AG. - 1010-660X .- 1648-9144. ; 57:5
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Tidskriftsartikel (refereegranskat)abstract
- Designed by a group of ME/CFS researchers and health professionals, the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) has received funding from the European Cooperation in Science and Technology (COST)-COST action 15111-from 2016 to 2020. The main goal of the Cost Action was to assess the existing knowledge and experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in European countries, and to enhance coordinated research and health care provision in this field. We report our findings and make recommendations for clinical diagnosis, health services and care for people with ME/CFS in Europe, as prepared by the group of clinicians and researchers from 22 countries and 55 European health professionals and researchers, who have been informed by people with ME/CFS.
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| 18. |
- Reimer, Jan, et al.
(författare)
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Use and interpretation of on/off diaries in Parkinson's disease.
- 2004
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 75:3, s. 396-400
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To explore the use and interpretation of self reported on/off diary data for assessment of daily motor fluctuations in Parkinson’s disease. Methods: 26 consecutive non-demented patients with fluctuating Parkinson’s disease received standardised training on how to fill out the four category CAPSIT-PD on/off diary, followed by four hours of clinical observation and four weeks of daytime on/off diaries every 30 minutes at home. Results: Overall patient–clinician agreement in diary entries was good ({kappa} = 0.62; weighted {kappa} = 0.84). Agreement for individual diary categories was good for "off" and "on with dyskinesias" ({kappa} = >=0.72), but moderate for "partial off" and "on" ({kappa} = 0.49). The overall validity of patient kept diaries was supported by expected symptom severity variability across diary categories, as assessed in the clinic. One day’s home diary data failed to predict outcomes from the full four weeks for all diary categories, and data from three days failed to yield good prediction (predefined as R2 = >=~0.7) for the time spent in "off" and "partial off". Data from one week yielded good prediction (R2 = >=0.74) in all instances except "partial off", which could not be well predicted even when two weeks’ home diary data were considered (R2 = 0.52). Conclusions: The data provide support for the overall accuracy and validity of the four category CAPSIT-PD on/off diary, but suggest that a three category diary format may improve accuracy and validity. Interpretation of diary data beyond the assessed time frame should be made with caution unless diaries have been kept for sufficiently long periods.
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| 19. |
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| 20. |
- Sorensen, Jens Christian, et al.
(författare)
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Fetal neocortical tissue blocks implanted in brain infarcts of adult rats interconnect with the host brain
- 1996
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 138:2, s. 227-235
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was to study if the connectivity of fetal neocortical tissue blocks placed in ischemic brain infarcts of adult rats would be enhanced in rats housed in an enriched environment. We also investigated whether the enriched housing conditions could enhance the postischemic and postgrafting functional outcome, in terms of motor behavior. This part of the study has been published recently. The middle cerebral artery was ligated on the right side in 37 inbred, adult male spontaneously hypertensive rats. The rats were placed at random either in an enriched environment (groups A and B) or in standard laboratory cages (group C). Three weeks after the artery occlusion, blocks of fetal sensorimotor cortex (embryonic day 17) were transplanted into the infarct cavity of rats from groups B and C. After 9 weeks all transplanted rats received an injection, into the graft, of a mixture containing the two tracers Fluoro-Gold and biotinylated Dextran amine. The transplants revealed a structured morphology with whorls and bands of cells reminiscent of normal neocortex. Tracing of efferent transplant to host fibers with biotinylated Dextran amine showed pronounced intrinsic transplant projections, as well as fibers, although significantly fewer, to the host ipsilateral sensorimotor cortex, striatum, and thalamus. Host to transplant projections were revealed by Fluoro-Gold-labeled cells found in the ipsilateral host sensorimotor cortex, the basal nucleus of Meynert, the thalamic ventrobasal, ventrolateral and posterior nuclei, and in the dorsal raphe nuclei. We conclude that fetal frontal neocortical block grafts placed in brain infarcts of adult rats develop a morphology reminiscent of normal neocortex and that both afferent and efferent neural connections, although sparse, are established with the host brain, whether the rats are reared under enriched housing conditions or not.
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| 21. |
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The Seventeenth Data Release of the Sloan Digital Sky Surveys : Complete Release of MaNGA, MaStar, and APOGEE-2 Data
- 2022
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Ingår i: Astrophysical Journal Supplement Series. - : Institute of Physics (IOP). - 0067-0049 .- 1538-4365. ; 259:2
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Tidskriftsartikel (refereegranskat)abstract
- This paper documents the seventeenth data release (DR17) from the Sloan Digital Sky Surveys; the fifth and final release from the fourth phase (SDSS-IV). DR17 contains the complete release of the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey, which reached its goal of surveying over 10,000 nearby galaxies. The complete release of the MaNGA Stellar Library accompanies this data, providing observations of almost 30,000 stars through the MaNGA instrument during bright time. DR17 also contains the complete release of the Apache Point Observatory Galactic Evolution Experiment 2 survey that publicly releases infrared spectra of over 650,000 stars. The main sample from the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), as well as the subsurvey Time Domain Spectroscopic Survey data were fully released in DR16. New single-fiber optical spectroscopy released in DR17 is from the SPectroscipic IDentification of ERosita Survey subsurvey and the eBOSS-RM program. Along with the primary data sets, DR17 includes 25 new or updated value-added catalogs. This paper concludes the release of SDSS-IV survey data. SDSS continues into its fifth phase with observations already underway for the Milky Way Mapper, Local Volume Mapper, and Black Hole Mapper surveys.
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| 22. |
- Von Clarmann, T., et al.
(författare)
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A blind test retrieval experiment for infrared limb emission spectrometry
- 2003
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Ingår i: Journal of Geophysical Research - Atmospheres. - 2169-897X .- 2169-8996. ; 108:D23
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Tidskriftsartikel (refereegranskat)abstract
- The functionality and characteristics of six different data processors (i.e., retrieval codes in their actual software and hardware environment) for analysis of high-resolution limb emission infrared spectra recorded by the space-borne Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) have been validated by means of a blind test retrieval experiment based on synthetic spectra. For this purpose a self-consistent set of atmospheric state parameters, including pressure, temperature, vibrational temperatures, and abundances of trace gases and aerosols, has been generated and used as input for radiative transfer calculations for MIPAS measurement geometry and configuration. These spectra were convolved with the MIPAS field of view, spectrally degraded by the MIPAS instrument line shape, and, finally, superimposed with synthetic measurement noise. These synthetic MIPAS measurements were distributed among the participants of the project “Advanced MIPAS level-2 data analysis” (AMIL2DA), who performed temperature and species abundance profile retrievals by inverse radiative transfer calculations. While the retrieved profiles of atmospheric state parameters reflect some characteristics of the individual data processors, it was shown that all the data processors under investigation are capable of producing reliable results in the sense that deviations of retrieved results from the reference profiles are within the margin that is consistent with analytical error estimation.
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