Measurement of cerebral blood flow in the pig by the 133Xe clearance technique

The ¹³³Xe clearance technique is used to measure cerebral blood flow in the pig. Previous publications have shown that the two-compartmental model is inadequate for interpreting the experimental data. The present study deals with certain phenomena seen during the initial part of the clearance curves, which can lead to incorrect estimation of the blood flow rate.Two types of initial peaks can be distinguished: one is a very fast type, which is interpreted as being due to transit of the tracer via large vessels and is referred to in the literature as the arterial peak; the second is a slower tissue peak, seen in animal experiments at high CO₂ levels and in clinical patients with cerebrovascular instability.In animal preparations discrepancies were found between flow measurements according to the ¹³³Xe clearance technique and those made with the aid of an electromagnetic flow probe situated around the carotid artery. A hysteresis effect was also found in the relation between respired CO₂ level and cerebral blood flow.All these findings can be interpreted in terms of arteriovenous shunting, i.e., non-nutrient flow of blood, which is not necessarily due to anatomical anastomosis but can also be explained by the assumption that the clearance is partly limited by diffusion.The possibility of diffusion-limited clearance can have important clinical implications. Further research may provide a better basis for analysis of clearance curves to detect cerebral perfusion deficiencies that give rise to false flow calculations in present techniques.     

Creatine kinase in tibial shaft fractures

Summary The creatine kinase (CK) activity of the serum of 33 male and 24 female patients with tibial shaft fractures has been assayed. In 40 of the 57 patients the CK level surpassed the maximal normal limit of 1.7 tkat/l. Patients with fractures due to direct violence had significantly higher levels than those with fractures due to indirect violence. When the fracture was displaced the CK level was more often abnormal than when there was no displacement. Patients with extensive swelling of the injured leg had significantly higher levels than patients with minor or no swelling. CK determinations could be used to quantify muscle injury.

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Zusammenfassung Die Serum-Kreatinkinase (CK)-Werte von 33 männlichen and 24 weiblichen Patienten mit einer Tibiadiaphysenfraktur wurden gemessen. Bei 40 von 57 Patienten lag der Serum-CK-Spiegel über dem oberen Normalwert von 1,7 kat/l. Bei Patienten mit Frakturen, verursacht durch ein direktes Trauma, wurden signifikant höhere Serum-CK-Werte gemessen als bei Patienten mit Frakturen, entstanden durch ein indirektes Trauma. Der Serum-CK-Spiegel war öfter erhöht bei Patienten mit einer Fraktur mit Fehlstellung, verglichen mit Patienten mit einer Fraktur ohne Fehlstellung. Patienten mit einer außergewöhnlichen Schwellung des geschädigten Beines hatten signifikant höhere Serum-CK-Werte als Patienten mit geringer oder keiner Schwellung. Die Serum-CK kann dazu benutzt werden, den Muskelschaden quantitativ zu beurteilen.

     

Hydrolysis and determination of meprobamate

Most pharmacopoeial methods for meprobamate are based on acid hydrolysis, followed by determination of the ammonia formed. In order to find optimum conditions the hydrolysis was studied with the aid ofTlc. Various types and concentrations of acid were tested. Refluxing with 25% (wt/vol) HCl for two hours proved to be sufficient to achieve complete hydrolysis (99.4±1%). This method is less time-consuming than that of theEuropean Pharmacopoeia and the hydrolysate does not turn brown as is the case with high concentrations of H₂SO⁴.     

Cerebrospinal fluid probenecid studies: a reinterpretation

Probenecid is used to block the transport of acid monoamine metabolites from cerebrospinal fluid (CSF), on the assumption that the resultant rise in CSF concentrations of the metabolites will reflect presynaptic "turnover" of the parent monoamine. However, CSF levels of probenecid correlate with CSF levels of the metabolite, suggesting that the blockade is incomplete at the probenecid levels obtained in human studies. This article reviews the literature on CSF probenecid-metabolite correlations and presents data demonstrating variations in the correlations across diagnostic groups. These cross-diagnostic variations may be due to group differences in membrane transport characteristics and and confound attempts to "correct for" CSF probenecid concentrations in studies of monoamine turnover.     

The clinical and histopathological effects of pancreatic duct occlusion in experimental acute pancreatitis in dogs

A continuous production of significant pancreatic enzymes, which are thought to be responsible for the maintenance of the digesting process, is frequently found in fulminant necrotizing pancreatitis. Since the medical therapies known to be effective are based upon the rationale of slowing pancreatic secretion, a simple measure which permits the "burning out" of residual pancreatic tissue might therefore have a therapeutic value. In this study, 2 hr after the induction of acute hemorrhagic pancreatitis, 5 dogs (Group I) were treated with 1.5 ml Ethibloc injected into the pancreatic duct; 5 other animals (Group II) were given 1.5 ml saline; Group III (5 dogs) had no treatment. All animals in Group II and 4 of the 5 animals in Group III expired within 8 days postoperatively. In contrast, 4 of 5 animals from Group I survived. Although some of the biochemical parameters showed significant changes after the induction of acute pancreatitis, no differences were seen between the three groups. In the expired animals, the picture of histological examination was that of a fulminant acute hemorrhagic pancreatitis of the left lobe. In the survival dogs although normal pancreatic tissue was present in the right lobe at necropsy at intervals, there was always a pancreatic atrophy of the left lobe and striking adhesions with the surrounding tissues suggesting the severity of the disease in the acute phase. These findings suggest that pancreatic duct occlusion causing the exocrine secretion to stop may have beneficial effects in the treatment of acute fulminant pancreatitis in the acute phase and may improve the survival rate.     

The significance of the aminoterminal propeptide of type III procollagen in paroxysmal nocturnal haemoglobinuria and myelofibrosis

The level of the aminoterminal propeptide Col 1–3 of type III procollagen (PC-III) was determined in patients with paroxysmal nocturnal haemoglobinuria (PNH) and primary myelofibrosis (PMF), to study whether PC-III can be used as a parameter for the rate and/or degree of bone marrow replacement with collagen. Normal PC-III levels were found in PNH (6.6±1.1 g/l; N: 8.6±1.8 g/l), while significantly increased levels were found in PMF (24.8±2.2 g/l).During a follow-up of 1 year, a slight increase of 2 g/l occurred in three patients with a stable fibrosis, while one patient with more active disease demonstrated an increase of 25 g/l. Treatment with acetylsalicylic acid led to a decline of PC-III as well as -thromboglobulin level, although normalization did not occur. It was demonstrated by means of gel filtration that the antigens related to the PC-III peptide were heterogenous, and that in PMF at least two main peaks were present, with molecular masses equal to and smaller than PC-III peptide.These data demonstrate that the radioimmunoassay cannot be used for the quantitative determination of PC-III; nevertheless it gives some insight in the process of bone marrow fibrosis.     

Interactions of halogenated industrial chemicals with transthyretin and effects on thyroid hormone levels in vivo

Previous results in experimental systems have suggested that hydroxylated PCBs may decrease thyroid hormone levels through associative interaction with transthyretin. In the present paper it was investigated whether this property was also shared by various industrial chemicals, mainly pesticides. In total, 65 compounds from 12 chemical groups were analyzed for direct interference with the T4 binding site of transthyretin using a competitive binding assay. Sixty per cent of the compounds were competitive at a concentration level of 100 M. Relatively strong interactions were observed by several chlorophenols, chlorophenoxy acids and nitrophenols, as well as by individual compounds such as hexachlorobenzene, dicofol, bromoxynil and tetrachlorohydroquinone. Examples from these chemical groups, e.g. pentachlorophenol, 2,4-dichlorophenoxybutyric acid, dinoseb and bromoxynil, also reduced plasma TT4 levels in rats. In addition, bromoxynil decreased plasma TT3 levels. The results suggest the existence of a number of halogenated industrial chemicals with a potential for lowering plasma thyroid hormone levels through interference with hormone transport carriers.     

An analysis of monoclonal antibody distribution in microscopic tumor nodules: consequences of a "binding site barrier"

Rational in vivo application of monoclonal antibodies for diagnosis and therapy of cancer requires an understanding of both the global and microscopic pharmacology of macromolecular ligands. Here, we introduce a new mathematical model for antibody distribution into small, prevascular, densely packed nodules (representing either primary or metastatic tumor). For the analysis, we link together several aspects of antibody pharmacology: the global (whole body) pharmacokinetics; transcapillary transport into normal tissue interstitium surrounding the nodule; diffusion into the nodule; nonspecific binding and/or partitioning; specific binding to tumor antigen; metabolism; and lymphatic outflow from the tissue space. Input parameter values are estimated from experimental studies in vitro, in animals, and in clinical trials. Our aim is to explore the sensitivity of antibody localization to variation in three of the important parameters of this model: the rate of transcapillary transport; the rate of lymphatic outflow; and the antigen density. Predictions based on this analysis include the following: (a) High rates of transcapillary transport influx or low rates of lymphatic efflux will enhance antibody percolation into the tumor nodule at early times after injection and increase the average antibody concentration in the tumor at all times; (b) Changes in antibody influx rate will affect the antibody distribution in the tumor at earlier times than do changes in the efflux rate; (c) Reducing the antigen concentration will increase the uniformity of antibody penetration but lower the average concentration in the tumor at all times after injection; and (d) Counter to intuition, lowering the antigen concentration can increase the peak concentrations achieved toward the center of the nodule. If, in addition, there is any metabolism of bound antibody, the concentration-time integral (i.e., the "area under the curve") for the center of the nodule will also be increased by decreasing the antigen concentration. These predictions directly reflect the "binding site barrier" hypothesis of Weinstein et al. (Ann. NY Acad. Sci., 507: 199-210, 1987) and Fujimori et al. (Cancer Res., 49:5656-5663, 1989; J. Nucl. Med., 31:1191-1198, 1990). In general, and perhaps surprisingly until one considers the problem carefully, the parameters governing antibody percolation can have opposite effects on the uniformity of antibody distribution at early and late times. These calculations, using the PERC program set, were done for antibodies, but we believe that the "binding site barrier" will also prove important for other injected macromolecules, for at least some highly bindable injected small molecules, for lymphokines and cytokines released from transfected cells injected in vivo, and, indeed, for endogenous species such as the autocrine-paracrine factors.     

Fatty acid composition of the human macula and peripheral retina.

The fatty acids in the human retina and the macular region were measured quantitatively (mole percent) by gas chromatography. The major fatty acids of the human retina and macula were palmitic, stearic, oleic, arachidonic, and docosahexaenoic. Surprisingly, there was much less docosahexaenoic acid in the macular region (15.9% of total) than in the peripheral retina (22.3% of total). There was a group of "other fatty acids," not any of the five major fatty acids, that were relatively more abundant in the macula (21.0% of total) than in the peripheral retina (10.7% of total). These results indicate that the human macula has a unique biochemical composition, which differs substantially from the peripheral retina. Establishment of the biochemical composition of the macula may be important for helping recognize possible changes associated with diseases such as age-related macular degeneration.