Hyaluronan in human cerebrospinal fluid

We studied the concentration of hyaluronan in cerebrospinal fluid (CSF) in various diseases and attempted to define its reference interval. A radioassay utilizing cartilage proteins with affinity for hyaluronan was used in determining the concentration of 200 lumbar and 27 ventricular CSF specimens and 11 brain cyst fluids. Molecular weight distributions were determined by gel chromatography and localization in brain tissue by histochemistry. The hyaluronan level of lumbar CSF showed an increase with age; comparatively healthy children had (mean +/- SD) 50 +/- 41 micrograms/L (n = 40) and adults 166 +/- 77 micrograms/L (n = 9); i.e. significantly different values. The highest level was recorded in a patient with meningitis (> 8000 micrograms/L). More than 4000 micrograms/ L was noted in a patient with tumour metastasis in the cerebellum. Significantly elevated levels were especially found with spinal stenosis, head injury and cerebral infarction, but also in inflammatory medical disorders, hydrocephalus and encephalitis. We found no significant increase in multiple sclerosis and some other neurological diseases. Ventricular CSF of adults contained significantly less hyaluronan (53 +/- 73 micrograms/L; n = 16) than lumbar CSF. Hyaluronan in cyst fluids varied from 31 to 25,000 micrograms/L. Weight average molecular weight of hyaluronan in CSF was 2.9-3.0 x 10(5) and in brain tumour cyst fluid 2.4 x 10(6). In search for the origin of hyaluronan in CSF it was found that its concentration in the choroid plexus and leptomeninges was low, but that hyaluronan was accumulated in the superficial layer of the cerebral cortex. Continued screening for hyaluronan in CSF may be valuable in cases of inflammatory diseases, tumours and obstruction to CSF flow.     

Ligand-like effects induced by anti-c-erbB-2 antibodies do not correlate with and are not required for growth inhibition of human carcinoma cells

The c-erbB-2 gene encodes a M(r) 185,000 tyrosine kinase receptor (p185) with extensive homology to the epidermal growth factor receptor. We have conducted mechanistic studies with several anti-p185 monoclonal antibodies (TAb 250, -255, -257, -260, and -263) directed against the extracellular domain of p185 utilizing the SKBR-3, BT-474, and SKOV-3 cancer cell lines. Several of these antibodies exhibited ligand-mimicking properties: they induced tyrosine phosphorylation of p185; increased the catalytic activity of the receptor substrate phospholipase C-gamma 1; exhibited time- and pH-dependent internalization; induced receptor down-regulation; and increased the turnover of the p185 protein delta 3-fold. However, there was not a universal correlation between the antibody-mediated ligand-like effects and growth inhibition. TAb 250 inhibited BT-474 cells but did not alter p185 phosphotyrosine content or increase receptor turnover in these cells. TAb 260 increased p185 protein turnover but did not affect proliferation of the SKOV-3 cell line. Furthermore, blockade of TAb 250-induced receptor phosphorylation with the tyrosine kinase inhibitor tyrphostin 50864-2 did not abrogate TAb 250-mediated growth inhibition of SKBR-3 cells. These data suggest that ligand-like effects mediated by p185 antibodies are not critical for the growth inhibition of c-erbB-2-overexpressing carcinoma cells.     

hSK4, a member of a novel subfamily of calcium-activated potassium channels

The gene for hSK4, a novel human small conductance calcium-activated potassium channel, or SK channel, has been identified and expressed in Chinese hamster ovary cells. In physiological saline hSK4 generates a conductance of approximately 12 pS, a value in close agreement with that of other cloned SK channels. Like other members of this family, the polypeptide encoded by hSK4 contains a previously unnoted leucine zipper-like domain in its C terminus of unknown function. hSK4 appears unique, however, in its very high affinity for Ca2+ (EC50 of 95 nM) and its predominant expression in nonexcitable tissues of adult animals. Together with the relatively low homology of hSK4 to other SK channel polypeptides (approximately 40% identical), these data suggest that hSK4 belongs to a novel subfamily of SK channels.     

A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice

Cancer complicating pregnancy is uncommon, with an incidence of approximately 1 in 1000 pregnancies. The obstetrician attending 250 deliveries per year would need to accumulate 40 years of clinical experience to encounter two to three cases of PABC. The increases in the size, weight, vascularity, and density of the breasts associated with pregnancy make the detection of mass lesions difficult both clinically and mammographically. Most of the benign lesions seen in pregnancy are the same ones seen in the nongravid state. Most cases of PABC present as painless masses, and as many as 90% of these masses are detected by breast self-examination. Women with PABC generally have more advanced disease with larger tumors, a higher percentage of inoperable lesions, and a higher percentage of nodal involvement. Because most PABC presents with a palpable mass, the role of imaging modalities in the evaluation of these patients remains limited. Fine-needle aspiration cytology is the initial procedure of choice for evaluating breast masses during pregnancy and lactation. Therapeutic abortion does not improve survival. The general principle is to treat the cancer and to allow the pregnancy to proceed. No studies have shown an adverse effect of a subsequent pregnancy even in patients with positive axillary nodes and patients in whom pregnancy occurs earlier than 2 years after treatment.     

Dynamic cortical networks of verbal and spatial working memory: effects of memory load and task practice

Working memory (WM), the ability to briefly retain and manipulate information in mind, is central to intelligent behavior. Here we take advantage of the high temporal resolution of electrophysiological measures to obtain a millisecond timescale view of the activity induced in distributed cortical networks by tasks that impose significant WM demands. We examined how these networks are affected by the type and amount of information to be remembered, and by the amount of task practice. Evoked potentials (EPs) were obtained from eight subjects performing spatial and verbal versions of a visual n-back WM task (n = 1, 2, 3) on each of three testing days. In well-trained subjects, WM tasks elicited transient responses reflecting different subcomponents of task processing, including transient (lasting 0.02-0.3 s) task-sensitive and load-sensitive EPs, as well as sustained responses (lasting 1-1.5 s), including the prestimulus Contingent Negative Variation (CNV), and post-stimulus frontal and parietal Slow Waves. The transient responses, with the exception of the P300, differed between the verbal and spatial task versions, and between trials with different response requirements. The P300 and the Slow Waves were not affected by task version but were affected by increased WM load. These results suggest that WM emerges from the formation of a dynamic cortical network linking task-specific processes with non-specific, capacity-limited, higher-order attentional processes. Practice effects on the EPs suggested that practice led to the development of a more effective cognitive strategy for dealing with lower-order aspects of task processing, but did not diminish demands made on higher order processes. Thus a simple WM task is shown to be composed of numerous elementary subsecond neural processes whose characteristics vary with type and amount of information being remembered, and amount of practice.     

Tolyporphins J and K, two further porphinoid metabolites from the cyanobacterium Tolypothrix nodosa

Two new porphinoids, tolyporphins J (1) and K (2), have been isolated from the terrestrial cyanobacterium, Tolypothrix nodosa (HT-58-2) and identified by NMR and mass spectral analysis. The activities of tolyporphins J and K in cell sensitization and drug accumulation assays for multidrug resistance (MDR) reversal were compared with those of tolyporphin A. Unusual NMR spectroscopic shifts were observed for tolyporphin J (1) in CDCl3.