Niels A. Lassen

Regional cerebral blood flow distribution in newly diagnosed schizophrenia and schizophreniform disorder

Regional cerebral blood flow distribution (rCBF) in 24 first admissions with schizophrenia or schizophreniform disorder and in 17 healthy volunteers was examined. Single photon emission computed tomography with a brain-retained tracer, technetium-99m-d,l-hexamethyl-propylene amine oxime, was used to study subjects under resting conditions and during performance of the Wisconsin Card Sorting Test. The study is a replication of a previous investigation in an independent series of patients and healthy volunteers. The patients had significantly lower relative blood flow in prefrontal regions during activation than did the healthy volunteers. An earlier series of 19 patients and 7 healthy volunteers was studied using exactly the same procedure. Analyses of the combined samples from the two studies (43 patients and 24 healthy volunteers) showed the patients to have significantly lower relative flow in prefrontal regions both at rest and during activation and higher flow in the left striatum during activation. The same finding emerged when analyses were confined to drug-naive patients and patients educationally matched to the healthy volunteers. The study suggests a defective frontostriatal interrelationship in schizophrenia and schizophreniform disorder.

Neuronal pH Regulation: Constant Normal Intracellular pH is Maintained in Brain during Low Extracellular pH Induced by Acetazolamide—31P NMR Study:

The intracellular pH in the brain was studied in six healthy volunteers before and immediately after the administration of 2 g of acetazolamide. Phosphorus-31 nuclear magnetic resonance spectroscopy by a 1.5 tesla whole-body scanner was used. The chemical shift between the inorganic phosphate and the phosphocreatine resonance frequencies was used for indirect assessment of the intracellular pH. The mean baseline intracellular pH was 7.05 ± 0.04 (SD). The mean pH changes obtained at 15-min intervals within the first hour of acetazolamide administration were −0.03 ± 0.04 (SD), −0.02 ± 0.03 (SD), and 0.00 ± 0.04 (SD), i.e., no statistically significant pH decrease was observed during the period where extracellular pH is known to drop markedly. Although several factors contribute to the lack of change of the intraneuronal pH, we will discuss that this observation in addition might suggest a direct intracerebral effect of acetazolamide.

Filtration as the main transport mechanism of protein exchange between plasma and the peritoneal cavity in hepatic cirrhosis

Fractional peritoneal reabsorption rates (FPRR) were determined from the plasma activity after simultaneous intraperitoneal injection of 131I-labelled serum albumin (a) and 125I-labelled immunoglobulin G-IgG (g) in eight patients with cirrhosis (+ ascites 6, -ascites 2) and in one patient with carcinomatous ascites. Trans-vascular escape rates of albumin (TERa) and IgG (TERg) were determined in the cirrhotic patients from the disappearance of simultaneously intravenously injected 131I-labelled serum albumin and 124I-labelled IgG. Peritoneal space to plasma appearance times ranged 0.1-3.3 h, and the appearance times of albumin and IgG were almost identical. In patients with cirrhosis FPRRa and FPRRg were on average 1.27 and 1.21% of intraperitoneal protein masses returning to plasma per hour, respectively. Mean FPRRg/FPRRa ratio was 0.95 and this value was not significantly different from unity, but significantly higher (P < 0.001) than the ratio between the free diffusion coefficients of IgG and albumin (0.06). The calculated ascitic fluid flow rate was on average 61 ml/h. TERa and TERg were on average 9.6 and 8.6% of intravascular protein masses per hour, mean TERg/TERa ratio was 0.95. Peritoneal space to plasma protein flux averaged 0.4% of the intravascular protein mass per hour. The results point to filtration (convective flux) as the main transport mechanism responsible for protein passage into the peritoneal cavity as well as for the protein passage (lymphatic drainage) back into the plasma. Pressure measurements during catheterization confirmed pressure differences essential for convective flux.

Filtration as the main mechanism of increased protein extravasation in liver cirrhosis

Transvascular escape rates of albumin and immunoglobulin-G, IgG (TERalb and TERIgG, i.e, the fractions of intravascular mass of albumin and IgG passing to the extravascular space per unit time) were determined simultaneously from the disappearance of intravenously injected 131I-labelled human serum albumin and 125I-labelled human IgG in eight patients with cirrhosis of the liver. The mean wedged hepatic venous pressure was 22 mmHg (range 13-34). TERalb and and TERIgG/TERalb ratio was on average 8.4 +/- 0.8%/h (SD), and 7.4 +/- 1.9%/h (SD), respectively and these values are significantly increased compared to normal subjects [TERalb = 5.2 +/- 1.0 %/h (SD) and TERIgG = 3.0 +/- 0.7 %/h (SD), P less than 0.001]. The TERIgG/TERalb ratio was on average 0.88 +/- 0.20 (SD), which is significantly higher than that of normals [0.58 +/- 0.08 (SD), P less than 0.005]. The results indicated that increased filtration (bulk flow) is the dominant process of the increase microvascular protein escape in cirrhosis, due most likely to increased hepatic, but also to increased extrahepatic splanchnic transcapillary protein flux.

SHAM, a method for biexpone ial carve resolution using initial slope, height, area and moment of the experimental decay type curve

Abstract A method for biexponesitial fitting of decay type curves is described. Basically the four unknowns are calculated from four curve parameters, viz. the initial slope (S), the initial height (H), the area (A) and the first time moment (M) with extrapolation to infinity being accomplished algebraically. The SHAM algorithm was considerably faster than a conventional iterative regression analysis (Gauss) and the results of the two methods were quite comparable both in synthetic and real data. The latter stemmed from 133xenon wash-out studies of regional blood flow in the human brain. Fast analysis of such data was the primary aim of developing the new method.

Increased transvascular escape rate of albumin during experimental portal and hepatic venous hypertension in the pig. Relation to findings in patients with cirrhosis of the liver

Transvascular escape rate of albumin [TERalb, i.e. the fraction of the intravascular mass of albumin (IVMalb) passing to the extravascular space per unit time] was determined from the disappearance of i.v. injected radioiodinated serum albumin in anaesthetized pigs during control conditions and during regional venous congestion in the infradiaphragmatic area. Balloon catheters were placed in the portal vein (infrahepatic portal congestion) and in the inferior vena cava above (suprahepatic caval congestion) and below (infrahepatic caval congestion) the outlets of the hepatic veins. TERalb was on the average 13% IVMalb.h-1 under basal pressure conditions. TERalb rose significantly (p less than 0.01) during suprahepatic caval and infrahepatic portal congestion to an average of 29 and 19% IVMalb.h-1, respectively. TERalb was positively correlated to the portal pressure (r = 0.75, P less than 0.001). Only a minor increment in TERalb was found during infrahepatic caval congestion. The hepatic share of the increased TERalb during stasis above the hepatic veins was estimated to be threefold that of the extrahepatic splanchnic area. Our results point to filtration of protein, predominantely through the lining of the sinusoids and perisinusoidal space of the liver into the interstitial space around the portal vessels and further into the lymphatics, as the main mechanism of the previously demonstrated marked increase in TERalb in patients with portal venous hypertension due to cirrhosis of the liver.

Diffusion bypass of xenon in brain circulation.

The diffusion bypass of 133Xe between arteries and veins was studied in the brains of anesthetized dogs. A mixture of 51Cr-labeled red cells and 133Xe was injected as a bolus into the internal carotid artery. Gas-tight venous samples were taken every 0.4–0.8 seconds from the superior sagittal sinus. An excess of 133Xe in the early venous blood samples over that expected from blood-tissue equilibration considerations was demonstrated in all the experiments. The excess was most marked in the first samples, and it was enhanced by lowering cerebral blood flow by decreasing the cerebral perfusion pressure to 20–30 mm Hg. We concluded that diffusion bypass of the tissue by 133Xe is the most likely explanation for these experimental findings. The fraction of the bolus which appeared to bypass the tissue amounted to about 2–3% at the normal perfusion pressure (i.e., normal blood flow) and about 10% at a reduced cerebral perfusion pressure of 20–30 mm Hg (i.e., about half of normal blood flow). We concluded that measurement of cerebral blood flow by a bolus injection of 133Xe in the internal carotid artery and external detection of the washout is not influenced significantly by the diffusion bypass of 133Xe in the normal flow range.

Kinetic Analysis of the Uptake of Glucose and Some of its Analogs in the Brain Using the Single Capillary Model: Comments on Some Points of Controversy

In 1961 Crone (1) demonstrated that the glucose transport across the blood-brain barrier occurs by facilitated diffusion. Since then, many studies with a variety of techniques have confirmed this observation and extended our knowledge of the process in details (2, 3, 4, 5, 6, 7, 8). In particular, the finding that glucose analogs share the facilitated transport mechanism has proven fertile. It forms the basis for Sokoloff’S ingenious autoradiographic method of determining the local rate of glucose metabolism (ICGU) in animals by measuring the rate of phosphorylation of the analog 2-deoxyglucose (2DG) which is trapped in brain (9). Using positron-emitting derivatives, this method has even been applied to man, yielding spectacular maps of the local rates of metabolism, the intensity of which change during changes of brain activity of motor, sensory, or mental type (10). It is perhaps worth noting, however, that the facilitated diffusion of glucose, one of the major prerequisites of the model on which the method is based, never has been documented in man. The use of positron emission technology would be one approach to the solution of this problem.

The effect of ascitic fluid hydrostatic pressure on albumin extravasation rate in patients with cirrhosis of the liver

Overall transvascular escape rate of albumin [TERalb, i.e. the fraction of intravascular mass of albumin (IVMalb) passing to the extravascular space per unit time] was determined from the disappearance of i.v. injected radioiodinated serum albumin. Patients with tense ascites due to liver cirrhosis and pigs with posthepatic portal hypertension and intraperitoneally instilled fluid were studied before and after abdominal paracentesis in order to evaluate the effect of ascitic fluid hydrostatic pressure on the transvascular escape rate of albumin. TERalb of the ascitic patients (n = 6) were on average 7.8% IVMalb.h-1, which is somewhat higher but not significantly above normal (mean 5.6% IVMalb.h-1). After paracentesis and removal of the ascitic fluid, TERalb rose significantly to an average of 11.9% IVMalb.h-1 (P less than 0.05). The fraction of IVMalb passing into the peritoneal cavity was on average 0.21 and 0.38% IVMalb.h-1 before and after paracentesis, respectively (n = 4). In ascitic, posthepatic portal-hypertensive pigs (n = 6), TERalb averaged 15.1% IVMalb.h-1, a value not being significantly different from non-ascitic, normotensive controls (mean 16.1% IVMalb.h-1). After paracentesis, TERalb rose significantly to an average of 24.3% IVMalb.h-1. The increased albumin extravasation rate after removal of ascites is best explained by an increased sinusoidal-tissue pressure difference caused by a decreased hydrostatic fluid pressure in the liver interstitium (portal and subcapsular spaces) due to the hydrostatic effect of the removed ascitic fluid.

Noninvasive xenon-133 measurements of cerebral blood flow using stationary detectors compared with dynamic emission tomography

Repeated bedside measurements of CBF have been made possible by the recent development of a mobile unit with 10 stationary detectors using the intravenous xenon-133 method. To evaluate this technique, comparative CBF studies at rest and following the application of a cerebral vasodilatory stimulus (acetazolamide, 1 g i.v.) were performed with the mobile equipment and with xenon-133 single-photon emission inhalation tomography in patients with cerebrovascular disease. The CBF level and the flow response to acetazolamide as determined with the two methods were well correlated, although at low flow levels the stationary detectors yielded somewhat lower CBF values than did emission tomography. Considering the side-to-side asymmetry, an excellent correlation was obtained. Using the initial slope index, the stationary detectors revealed quantitatively 83% of the interhemispheric asymmetry and 63% of the asymmetry in the middle cerebral artery territory shown with the tomograph. As illustrated by a case history, the nontomographic CBF unit used in this study may provide reliable and useful information in patients with occlusive cerebrovascular disease by performing repeated CBF studies and challenging the cerebral circulation with acetazolamide.