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Biomedical subjects

G M Knudsen

Publications and source records attributed to G M Knudsen.

At least 55 records · Page 3Linked to original sources
PubMed1996

Cerebral glucose metabolism is decreased in white matter changes in patients with phenylketonuria.

Cerebral magnetic resonance imaging (MRI) has revealed white matter changes in patients with phenylketonuria (PKU), an inborn error of metabolism with increased plasma phenylalanine level. Because the significance of these lesions is unknown, this study was undertaken to determine whether glucose metabolism was depressed in cerebral white matter MRI changes in patients with PKU. Four patients with PKU and nine healthy volunteers with an average age of 23 y (range 19-26 y) and 23 y (range 20-27 y), respectively, were studied. The IQ of patients with PKU was between 58 and 97. Cerebral MRI and positron emission tomography images with 18F-deoxyglucose were obtained, and arteriovenous differences for oxygen and glucose as well as cerebral blood flow was measured simultaneously to determine global cerebral oxygen and glucose metabolism. Cerebral MRI revealed that all patients with PKU had white matter changes with characteristic localization. In patients with PKU, regional glucose metabolism was 36% lower in the anterior periventricular areas, 0.14 +/- 0.06 compared with 0.22 +/- 0.04 mumol.g-1.min-1 in controls (mean +/- SD, p < 0.05, Mann-Whitney). Further, the ratio between glucose metabolism in the affected white matter and the cortex was 14% lower in the patients, decreasing from 0.57 +/- 0.05 to 0.48 +/- 0.06 (p < 0.05). Global cerebral blood flow, oxygen and glucose consumption were similar in the two groups. In conclusion, regional glucose metabolism is lower in MRI-demonstrated white matter changes. In mildly intellectually impaired patients with PKU, global cerebral glucose and oxygen metabolism remain intact.

Adult↗
PubMed1995

Blood-brain barrier transport of amino acids in healthy controls and in patients with phenylketonuria.

Blood-brain barrier permeability to phenylalanine and leucine in four patients with phenylketonuria and in four volunteers was measured five times by the double-indicator method at increasing plasma concentrations of phenylalanine. Based on the permeability-surface area product (PS) from blood to brain (PS1) and on plasma phenylalanine levels, Vmax and the apparent Km for phenylalanine were determined. Statistically significant relationships between plasma phenylalanine and PS1 were established in three out of four volunteers, the average Vmax value being 46.7 nmol/g per min and the apparent Km 0.328 mmol/L. Owing to saturation of the carrier, such a relationship could not be established in the patients. In phenylketonuria, PS1 for phenylalanine and leucine decreased significantly by 55% and 46%, respectively. Transport from brain back to blood, PS2, decreased significantly and cerebral large neutral amino acid net uptake was generally decreased in patients with phenylketonuria. In conclusion, the transport of L-phenylalanine across the human blood-brain barrier follows Michaelis-Menten kinetics. In phenylketonuria, brain permeability to large neutral amino acids is reduced by about 50% and net uptake appears decreased.

Adult↗
PubMed1995

Functional loss of cerebral blood flow autoregulation in patients with fulminant hepatic failure.

In management of patients with fulminant hepatic failure, it is recommended that mean arterial pressure should be raised if cerebral perfusion pressure is lower than 50 mmHg, but the influence of such therapy on cerebral blood flow is unknown. We examined cerebral blood flow autoregulation in seven consecutive patients with fulminant hepatic failure during treatment of imminent insufficient cerebral perfusion pressure. Cerebral perfusion was evaluated by transcranial Doppler assessed mean flow velocity in the middle cerebral artery and by the arterio-venous difference for oxygen. Intracranial pressure was recorded by a subdural transducer and cerebral perfusion pressure calculated as the difference between mean arterial pressure and intracranial pressure. After 20 (range 10 to 43) min, mean arterial pressure was raised from 74 (43-80) to 94 (76-114) mmHg by i.v. noradrenaline, cerebral perfusion pressure increased from 49 (26-75) to 82 (50-108) mmHg (p < 0.01) as the intracranial pressure remained unchanged at 26 (3-35) mmHg. The mean flow veolocity increased from 68 (30-134) to 108 (48-168) cm s-1 and the arterio-venous difference for oxygen by 46 (10-82)% (p < 0.05). Both mean flow velocity (r = 0.63) and arterio-venous difference for oxygen (r = 0.71) were correlated to mean arterial pressure (p < 0.001), and a lower blood pressure limit of autoregulation could not be identified in any of the patients. These data suggest that the cerebral blood flow is not autoregulated in patients with fulminant hepatic failure and therefore cerebral blood flow should be "clamped" within the normal physiologic range by manipulation of arterial blood pressure in order to avoid cerebral hypoxia and/or hypertensive induced cerebral oedema.

Acute Disease↗
PubMed1995

Blood-brain barrier permeability of glucose and ketone bodies during short-term starvation in humans.

The blood-brain barrier (BBB) permeability for glucose and beta-hydroxybutyrate (beta-OHB) was studied by the intravenous double-indicator method in nine healthy subjects before and after 3.5 days of starvation. In fasting, mean arterial plasma glucose decreased and arterial concentration of beta-OHB increased, whereas cerebral blood flow remained unchanged. The permeability-surface area product for BBB glucose transport from blood to brain (PS1) increased by 55 +/- 31%, whereas no significant change in the permeability from brain back to blood (PS2) was found. PS1 for beta-OHB remained constant during starvation. The expected increase in PS1 due to the lower plasma glucose concentration was calculated to be 22% using previous estimates of maximal transport velocity and Michaelis-Menten affinity constant for glucose transport. The determined increase was thus 33% higher than the expected increase and can only be partially explained by the decrease in plasma glucose. It is concluded that a modest upregulation of glucose transport across the BBB takes place after starvation. Brain transport of beta-OHB did not decrease as expected from the largely increased beta-OHB arterial level. This might be interpreted as an increase in brain transport of beta-OHB, which could be caused by induction mechanisms, but the large nonsaturable component of beta-OHB transport makes such a conclusion difficult. However, beta-OHB blood concentration and beta-OHB influx into the brain increased by > 10 times. This implies that the influx of ketone bodies into the brain is largely determined by the amount of ketones present in the blood, and any condition in which ketonemia occurs will lead to an increased ketone influx.

Adult↗
PubMed1995

Delayed onset of fatal basilar thrombotic embolus after whiplash injury.

BACKGROUND: Whiplash injuries are generally seen after rear-end rather than frontal car collisions. Previous reports have documented death up to 8 days after serious whiplash injury. We report a case of lethal basilar thrombotic embolus that occurred 2 months after the patient's injury in a collision. CASE DESCRIPTION: After whiplash trauma in a car accident, a 50-year-old taxi driver suffered from headache and episodic visual disturbances. Two months after the accident he suddenly lost consciousness and was admitted to the hospital. A CT scan performed at that time was indicative of basilar thrombosis. The patient died 3 days later. The autopsy revealed a thrombosis in the right vertebral artery and a thrombotic embolus in the basilar artery. Microscopically, a lesion of the right vertebral artery was found at the level of the atlantoaxial joint. CONCLUSIONS: We conclude that the whiplash injury caused a lesion of the right vertebral artery, leading to repeated transient ischemic attacks and finally to a fatal basilar thrombotic embolus. We suggest that in patients with disturbances of the vertebrobasilar circulation, attention should be paid to occurrence of neck trauma in the preceding 3 months. Further, anticoagulant therapy should particularly be considered in patients who after suffering neck injuries develop signs of transient ischemic attacks with origin from the posterior cerebral circulation.

Basilar Artery↗
PubMed1995

Cerebral blood flow autoregulation and transcranial Doppler sonography in patients with cirrhosis.

Impairment of cerebral blood flow (CBF) autoregulation may have serious implications for patients with cirrhosis if arterial hypotension occurs during coma, anesthesia, bleeding, or sepsis. In this study, CBF autoregulation was investigated in patients with cirrhosis with no or mild encephalopathy. Ten patients (median age, 45 years; range, 30 to 61 years) and six healthy volunteers (median age, 30 years; range 21 to 61 years) were included. Catheters were placed in a radial artery and in the internal jugular veins. Baseline CBF was measured using single-photon emission computed tomography (SPECT) with concomitant measurements of cerebral arteriovenous oxygen content differences (AVDO2). CBF autoregulation was evaluated using the AVDO2 method and changes in mean flow velocity in the middle cerebral artery (Vmean) as determined by transcranial Doppler (TCD). Mean arterial pressure (MAP) was increased by 30 mm Hg by intravenous norepinephrine, and subsequently decreased by a combination of lower body negative pressure and ganglion blockade, whereas AVDO2 and Vmean were measured at each 5 mm Hg change in MAP. CBF was 61 (range, 45 to 78) mL 100 g-1 min-1 in patients with cirrhosis and 65 (range < 53 to 88) mL 100 g-1 min-1 in volunteers (not significant [NS]). There were no regional differences in CBF between the two groups. Arterial carbon dioxide tension was 31 (23 to 35) mm Hg in patients with cirrhosis and lower, compared with 36 (range, 34 to 47) mm Hg in the volunteers (P < .01). For evaluation of autoregulation, MAP was raised to 116 (range, 100 to 145) and then decreased to 39 (range, 34 to 50) mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Cerebral blood flow autoregulation is absent in rats with thioacetamide-induced hepatic failure.

Cerebral blood flow normally remains constant within a wide range of mean arterial blood pressure values. In fulminant hepatic failure, however, it is not known whether autoregulation of cerebral blood flow is maintained. In the present study, cerebral blood flow autoregulation was investigated in rats 3 days after induction of fulminant hepatic failure. Wistar rats were given intraperitoneal thioacetamide or saline injections. The mean arterial blood pressure was varied by means of norepinephrine infusion or venesection, respectively. As mean arterial blood pressure declined, repeated cerebral blood flow measurements were performed by the intracarotid 113Xenon injection method. The relation between mean arterial blood pressure and cerebral blood flow was examined by statistical regression analysis, and the lower limit of autoregulation was determined in each rat. Cerebral blood flow baseline values were unaltered in liver failure compared to the control group (73 (36-92) vs. 79 (57-87) ml.100 g-1.min-1, median and range). Baseline mean arterial blood pressure was also similar in the two groups (90 (75-113) vs. 95 (70-112)). Mean arterial blood pressure varied between 40 (35-50) and 110 (90-135) mmHg in the control rats and between 50 (45-68) and 110 (95-126) mmHg in the rats with liver failure. A lower limit of autoregulation was identified in all control rats at a mean arterial blood pressure of 67 (55-78) mmHg. Below this limit, cerebral blood flow declined in parallel with mean arterial blood pressure. None of the rats with liver failure exhibited autoregulation, and cerebral blood flow changed in parallel with mean arterial blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Brain metabolism during short-term starvation in humans.

During prolonged starvation, brain energy requirements are covered in part by the metabolism of ketone bodies. It is unknown whether short-term starvation of a few days' duration may lead to reduced brain glucose metabolism due to the change toward ketone body consumption. In the present study we measured the cerebral metabolism of glucose and ketone bodies in nine healthy volunteers before and after 3.5 days of starvation. Regional glucose metabolism was measured by dynamic positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose. The mean value of K1* in gray and white matter increased by 12% (p < 0.05), whereas k2* and k3* were unchanged compared with control values. Regional glucose metabolism in cortical gray matter was reduced by 26% from 0.294 +/- 0.054 to 0.217 +/- 0.040 mumol g-1 min-1 (p < 0.001). White matter glucose metabolism decreased by 27% (p < 0.02). The decrease was uniform in gray and white matter with regional decreases ranging from 24 to 30%. A determination using Fick's principle confirmed the reduction in glucose metabolism yielding a decrease of 24% from 0.307 +/- 0.050 to 0.233 +/- 0.073 mumol g-1 min-1 (p < 0.05), whereas CBF did not change (0.57 +/- 0.07 vs. 0.57 +/- 0.06 ml g-1 min-1). The global net uptake of beta-hydroxybutyrate increased 13-fold from 0.012 +/- 0.024 to 0.155 +/- 0.140 mumol g-1 min-1 (p < 0.05). Net uptake of acetoacetate and net efflux of lactate and pyruvate did not change significantly during starvation. The present study shows that the human brain adapts to the changes in energy supply as early as 3 days following initiation of starvation, at which time ketone bodies account for approximately one-fourth of the cerebral energy requirements.

Adult↗
PubMed1994

Atypical visual loss in giant cell arteritis.

Three patients with atypical ocular involvement due to histologically verified giant cell arteritis are reported. Prior to diagnosis, the first patient had periods of amaurosis fugax. He presented with normal vision. In spite of high-dose systemic corticosteroid therapy, he became blind in the terminal stage of his disease due to bilateral occipital cortex infarctions, verified by CT-scan. Autopsy revealed involvement of several intracranial arteries. In case No. 2 there was severe unilateral visual loss and cotton-wool exudates in both eyes. Central vision recovered after corticosteroid therapy; in our experience this is unusual. In case No. 3 irreversible unilateral visual loss was typical for GCA, but the association with polyneuropathy unique. Neurological remission coincided with systemic corticosteroid therapy.

Aged↗
PubMed1994

Blood-brain barrier permeability measurements by double-indicator method using intravenous injection.

The double-indicator technique with intracarotid bolus injection is useful for the estimation of transfer rates across the human blood-brain barrier. A method using intravenous tracer injection is developed whereby the input is measured at a peripheral artery and the output is measured at the jugular vein. To correct for differences in the brain input of test and reference substances, a five-parameter Dirac impulse response for passage through the cerebrovascular bed is computed from the input and output of the reference substance. This response is then combined with a capillary model of the brain. This is then convoluted with the arterial input curve of the test substance to yield a theoretical test output curve, which is compared with the actual test output curve. On the basis of these two curves and an appropriate mathematical model for the brain, estimates of blood-brain barrier permeability are obtained. In the present study, the techniques are compared in 13 patients in whom alternating intracarotid and intravenous bolus injections were given. For D-glucose, the two techniques yielded similar results. This was also the case for L-phenylalanine, provided that the erythrocyte compartment was taken into account. Data obtained after intravenous injection of leucine and water yielded similar results compared with previous intracarotid data.

Adult↗
PubMed1994

Transcranial Doppler is valid for determination of the lower limit of cerebral blood flow autoregulation.

BACKGROUND AND PURPOSE: This study validates transcranial Doppler sonography (TCD) for determination of the lower limit of cerebral blood flow (CBF) autoregulation and establishes a relation between global CBF and mean flow velocity (Vmean) in the middle cerebral artery. METHODS: Relative changes in CBF and in Vmean were compared in 12 normal volunteers (2 women and 10 men; median age, 30 years [range, 21 to 61 years]). Catheters was placed in the left radial artery and in the bulb of the right internal jugular vein, respectively. Baseline CBF was measured by single-photon emission computed tomography scanning; concomitantly, blood samples were drawn for calculation of the cerebral arteriovenous oxygen difference. Then changes in mean arterial pressure (MAP) were induced, and relative changes in global CBF were calculated according to Fick's principle assuming a constant cerebral oxygen metabolism. MAP was increased 30 mm Hg by norepinephrine infusion and was decreased by lower body negative pressure. Vmean was measured in the right middle cerebral artery by a 2-MHz probe, and blood samples were drawn at intervals of 5 mm Hg. RESULTS: MAP values between 122 (range, 110 to 140) and 48 (range, 34 to 75) mm Hg were measured. The lower limit of autoregulation (the blood pressure under which autoregulation is off) as determined by Vmean did not differ significantly from that determined by relative changes in global CBF: 91 (range, 41 to 108) and 79 (range, 53 to 113) mm Hg, respectively. A significant correlation between Vmean and relative changes in global CBF was demonstrated below the lower limit of autoregulation (R2 = .73, P < .001; CBF = -6.3 + 1.0.Vmean). Above the lower limit both values were stable. CONCLUSIONS: TCD is valid for determination of the lower limit of CBF autoregulation, and changes in CBF may be reliably evaluated by TCD during changes in cerebral perfusion pressure in normal subjects.

Adult↗
PubMed1994

Application of the double-indicator technique for measurement of blood-brain barrier permeability in humans.

This review examines and evaluates the double-indicator technique for utilization in quantitative measurements of the transport of substances across the human blood-brain barrier (BBB). The classic double-indicator method and its limitations are described along with a new approach for correction of capillary heterogeneity and tracer backflux. This approach considers the total course of the venous outflow curves and involves a short-time experiment model that incorporates calculations of parameters for transport from the blood into the brain and from the brain back to the blood, for the uptake of neurons and glia cells, and for the tracer distribution volume. A modification of the double-indicator technique with intravenous instead of intracarotid bolus injection is discussed along with advantages and limitations of this technique. The application of the method is described and examples are given for D-glucose as well as for some large neutral amino acids and flow tracers. On the basis of the model, it is demonstrated that after crossing the BBB, D-glucose distributes in the brain interstitial fluid volume, and already at the peak of the glucose outflow curves, the apparent extraction is significantly influenced by backflux from the brain. For large neutral amino acids, the permeability from the interstitial fluid space back to the blood is approximately 10 times higher than the permeability from the blood into the brain. Such a difference in permeabilities across the BBB can almost entirely be ascribed to the effect of a nonlinear transport system combined with a relatively small brain amino acid metabolism. This high and rapid backflux causes methodological problems when estimating blood-to-brain transfer of amino acids with traditional in vivo methods. The method is also evaluated for high-permeable substances. Water and the two flow tracers ethyl cysteinate dimer and hexamethylpropyleneamine oxime and the obtained values for brain extraction and distribution volume compare well with those obtained by other methods. Finally, ethical aspects and the future role and possibilities of the double-indicator technique are discussed and related to other methods for determination of BBB permeabilities in the living human brain.

Blood-Brain Barrier↗
PubMed1994

Brain extraction and distribution of 99mTc-bicisate in humans and in rats.

Blood-brain barrier (BBB) passage of the flow tracer ethylenediylbis-L-cystein diethylester (bicisate, ECD) was measured repeatedly in five patients by means of the intravenous (i.v.) double-indicator technique using 24Na+ as an intravascular cotracer. After i.v. injection, the arterial concentration curve of 99mTc-bicisate was delayed and dispersed compared with that of the intravascular cotracer, presumably due to lung retention of the flow tracer. The corrected cerebral venous output curves were fitted using a three-compartment model with four parameters. At resting cerebral blood flow (CBF) values, the unidirectional brain extraction was 0.57 +/- 0.05, the permeability-surface area product for passage from blood to brain (PS1) was 0.48 +/- 0.07 ml/g/min, and the distribution volume for bicisate was 0.74 +/- 0.20 (mean +/- SD). In a single patient, BBB transport after i.v. injection of bicisate was compared with that of a similar flow tracer, d,l-hexamethylpropyleneamine oxime (HM-PAO), and similar values were found for the two tracers. In 19 rats, the brain extraction of bicisate was measured by means of the intracarotid double-indicator technique. The brain extraction was measured at resting, decreased, and increased CBF values. Low CBF values were obtained by hyperventilation and high values by hypercapnia. The degree of backflux of tracer from brain to blood was evaluated by means of the three-compartment model and was found to be negligible in these experiments. The brain extraction was 0.70 +/- 0.1 and PS1 was 0.94 +/- 0.27 ml/g/min. During hypercapnia, CBF increased from 0.77 to 1.09 ml/g/min, leading to a significant decrease in brain extraction, from 0.70 to 0.56.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Passage of amino acids and glucose across the blood-brain barrier in patients with hepatic encephalopathy.

We repeatedly measured blood-brain barrier passage of phenylalanine, leucine, glucose and GABA in nine patients with hepatic encephalopathy using the intravenous double-indicator technique. Controls were four patients without liver disease and two of the patients who had recovered completely from their hepatic encephalopathy. The corrected cerebral venous output curves were fitted by use of a three-compartment model with four parameters. In the patients with hepatic encephalopathy, the permeability-surface area products for phenylalanine and leucine from the blood to the brain and from the brain interstitial fluid to the intracellular compartment, the unidirectional extraction and the brain amino acid influx were similar in the two groups. The permeability from the brain back to blood for phenylalanine was decreased by 72% in patients with hepatic encephalopathy compared with that in the control group (p < 0.05), whereas no difference was seen for leucine. The permeability from the brain back to the blood for phenylalanine decreased with coma grade and normalized in the two patients who recovered. Correspondingly, the calculated brain interstitial fluid concentration of phenylalanine was increased in the patients with hepatic encephalopathy. The transfer variables for blood-brain barrier passage of glucose were similar in the two groups. The permeability from the blood to the brain for GABA was very low in both the patients with hepatic encephalopathy and the control group. We conclude that in hepatic encephalopathy the permeability from brain to blood for phenylalanine decreases with coma grade. The decrease is caused by an increased interstitial fluid concentration of the amino acid. No evidence was found of general or selective blood-brain barrier disturbance in hepatic encephalopathy.

Adult↗
PubMed1992

The influence of haematocrit and blood glucose on cerebral blood flow in normal and in diabetic rats.

Cerebral blood flow (CBF) was measured at varying haematocrit values in 8 streptozotocin-diabetic and in 7 control rats using the intracarotid 133Xe technique. A hyperbolic relationship between CBF and haematocrit was established for the individual rats in both groups. Diabetic animals showed a preserved CBF response to changes to haematocrit. In 10 normal rats, CBF was measured during acute hyperglycaemia induced by intraperitoneal glucose injection. A significant, inverse correlation was found between CBF and blood glucose. We conclude that the CBF response to changes in haematocrit and thereby in pO2 is preserved in experimental diabetes. Secondly, in acute hyperglycaemia CBF varies inversely with blood glucose, by mechanisms not fully understood.

Animals↗