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.     

Responses of cat horizontal cells to sinusoidal gratings.

The spatiotemporal properties of cat horizontal (H-) cells were studied by recording the intracellular responses in the optically intact, in vivo, eye to sinusoidal gratings at a photopic mean illumination level. In order to investigate the linearity of spatial summation a "null test" was performed in which the responses to contrast reversal gratings were measured at different positions of the grating relative to the receptive field. Spatial and temporal transfer functions were measured using drifting sinusoidal gratings of variable spatial and temporal frequencies. The amplitudes of cat H-cell responses to contrast reversal gratings modulated with a square wave time-course showed a sinusoidal dependence on spatial phase. When zero crossings of the grating were lined up with the receptive field center, as defined by the maximum of the measured line weighting function, contrast reversal produced no response modulation. This result did not depend on the spatial frequency of the grating or the temporal frequency of contrast modulation over substantial ranges. The response waveform was found not to depend on the spatial phase of the grating. The spatial transfer function of cat H-cells has low-pass characteristics with a cut-off frequency in the range of about 0.4-1.5 c/deg. The shape of the spatial transfer function was roughly the same for temporal frequencies ranging from 3 to 10 Hz. The temporal transfer function exhibited band-pass characteristics with a maximum response amplitude at 3-6 Hz. The amplitude fall-off for low and high temporal frequencies was independent of the spatial frequency of the grating. The results obtained with sine gratings were found not to agree with the receptive field profiles measured with narrow slits flashed at different positions in the receptive field.     

Effects of bromazepam on single-trial event-related potentials in a visual vigilance task

Thirty females performed a visual vigilance task under the influence of bromazepam (6 and 12 mg) in a placebo-controlled, double blind, experiment. Measures employed were percentage of hits, percentage of false alarms, response latency (RT), A (sensitivity), B (cautiousness), and RI (responsivity), as well as signal-and non-signal event-related potentials (ERPs). Bromazepam did not aggravate the normally occurring decrement in performance in vigilance tasks, but had an effect on overall level of performance: accuracy was reduced under the influence of the drug, but speed improved. A Drug×Period interaction for cautiousness (B) indicated increasingly less cautiousness with bromazepam, which probably contributed to faster motor responses (and more errors) than in the placebo group. The ERP data suggest that the effects of bromazepam are already manifest in the early stages of information processing (attention-detection) as mirrored by a drug effect on N1 amplitude. Deterioration at this early stage may affect later processing stages (P2–N2 amplitudes). As a result, subjects under the influence of the drug probably accumulate less signal evidence for their final evaluation.     

Low doses of oxytocin facilitate social recognition in rats

Social recognition of juveniles by adult male residents has been shown to be modulated by neurohypophyseal hormones. The decrease of social investigation behavior during a second encounter with the same juvenile serves as index for social recognition. In the present study it was found that low doses (0.09–6.0 ng · kg^–1) of oxytocin (OXT) given subcutaneously dose dependently facilitated social recognition. The effect of OXT appeared specific, since no change in social investigation was found when a novel juvenile was tested during the second encounter. No disturbances of social recognition by the low doses of OXT could be detected, in contrast to higher doses of this hormone. Other neurohypophyseal hormones, vasopressin and vasotocin, did not facilitate social recognition when tested in the same range of low doses.