Differential analysis of serum and urine S100 proteins in juvenile-onset systemic lupus erythematosus (jSLE).

Up to 80% of juvenile-onset systemic lupus erythematosus (jSLE) patients develop lupus nephritis (LN) that affects treatment and prognosis. Easily accessible biomarkers do not exist to reliably diagnose LN, leaving kidney biopsies as the gold-standard. Calcium-binding S100 proteins are expressed by innate immune cells and epithelia and may act as biomarkers in systemic inflammatory conditions. We quantified S100 proteins in the serum and urine of jSLE patients, matched healthy and inflammatory (IgA vasculitis) controls. Serum S100A8/A9, and serum and urine S100A12 are increased in jSLE patients when compared to controls. Furthermore, serum S100A8/A9, and serum and urine S100A12 are increased in jSLE patients with active as compared to patients with inactive/no LN. No differences in S100A4 levels were seen between groups. This study demonstrates potential promise for S100A8/A9 and S100A12 as biomarkers for jSLE and active LN. Findings require to be confirmed and tested prospectively in independent and larger multi-ethnic cohorts.

Characterization of a newly discovered T-cell receptor beta-chain heterodimer expressed on a CD8+ bone marrow subpopulation that promotes allogeneic stem cell engraftment.

The facilitating cell is a rare CD8+ bone marrow subpopulation that can enhance allogeneic hematopoietic stem cell engraftment across complete major histocompatibility complex barriers without inducing acute graft-versus-host disease. Here we describe a CD3epsilon-associated complex on the facilitating cell surface that consists of the T-cell receptor beta-chain disulfide-linked to a previously unknown 33-kilodalton glycoprotein. Provisionally called FCp33, this glycoprotein does not represent any of the known protein chains or surrogates associated with CD3-T-cell receptor beta. Expression of this CD3-T-cell receptor beta-FCp33 complex directly correlates with the facilitating cell's functional ability to enhance allogeneic stem cell engraftment in vivo.

Potassium stimulation of aldosterone secretion in vivo is reversed by nisoldipine, a calcium transport antagonist.

The effects of a novel calcium transport antagonist, nisoldipine, on K-stimulated aldosterone secretion have been examined in vivo. Direct KCl infusion into the adrenal gland stimulated aldosterone secretion. Infusion of nisoldipine, concomitantly with KCl at two rates, abolished the stimulation of aldosterone independently of its effects on K transport. The results suggest that K stimulation of aldosterone secretion in vivo is at least in part mediated by alterations in transmembrane Ca flux.

Alterations in osmotic but not pressor responses to ACTH by optic recess lesions in sheep.

This study examines whether neural structures in the region of the optic recess of the third ventricle may be involved in the genesis of adrenocorticotrophic hormone (ACTH)-induced hypertension in sheep. Five sheep were prepared with lesions in an area of the forebrain that included the organum vasculosum of the lamina terminalis (OVLT) and surrounding periventricular tissue. In these animals the dipsogenic response to systemically infused hypertonic sodium chloride (NaCl) was abolished. ACTH treatment (20 micrograms/kg/day) for 5 days caused an increase in mean arterial pressure (MAP) of 19 mm Hg, a response identical to that seen in normal sheep. With ACTH treatment, increases in plasma osmolality were greater than normal, but polydipsia did not occur in the lesioned sheep. In six other sheep with lesions either lateral or anterior to the optic recess of the third ventricle, the dipsogenic response to hypertonic NaCl and pressor response to ACTH were normal. These studies establish that in ACTH-treated sheep the integrity of the anterior ventral part of the third ventricle is not essential for the development of the hypertension. This is in contrast to the finding in other models of experimental hypertension in the rat.

Further studies of elevated cerebrospinal fluid neuronal cell adhesion molecule in schizophrenia.

BACKGROUND: The purposes of the present study were to attempt to replicate a previous finding of increased cerebrospinal fluid (CSF) neuronal cell adhesion molecule (N-CAM) in schizophrenia, and to assess whether the increases could be related to medication, clinical state effects, or brain structural measures. METHODS: CSF N-CAM was measured by the Western blot technique in 45 DSM-III-R diagnosed male schizophrenic patients both on and off haloperidol treatment and in 20 healthy male control subjects. RESULTS: CSF N-CAM was significantly increased in schizophrenic patients, with no overlap in the ranges, when compared to controls. There were no significant effects of medication or exacerbation on CSF N-CAM. No associations with measures of brain structure were found. CONCLUSIONS: Because N-CAM levels were not shown to be different on and off treatment or in exacerbated versus nonexacerbated patients, the higher levels seen in schizophrenic patients may be inherent to the disorder and possibly related to neurodevelopment.

Adrenocorticotrophin-induced hypertension in the rat: haemodynamic, metabolic and morphological characteristics.

Adrenocorticotrophin (ACTH) administration has been systematically studied in man and sheep. It raises systolic blood pressure (SBP) in the rat, but this has been little studied. ACTH was injected once daily at 0.5 mg/kg for 12 days in male Sprague-Dawley rats (n = 19). Sham-injected animals were studied in parallel (n = 15). ACTH increased SBP from 94 +/- 4 to 121 +/- 4 mmHg (P less than 0.001), significantly greater (P less than 0.02) than sham injection. The SBP of ACTH-treated rats was significantly higher than that of sham-injected rats when the same animals were measured by both the tail-cuff method (ACTH, 126 +/- 3 mmHg; sham, 99 +/- 3 mmHg) and direct arterial cannulation (ACTH, 137 +/- 2 mmHg; sham, 123 +/- 3 mmHg): P less than 0.005 and P less than 0.001, respectively. There was a loss of body weight, and increased water intake and urine output in ACTH-treated animals compared with both control (P less than 0.001) and sham treatments (P less than 0.02). ACTH increased plasma [Na] (sham, 140 +/- 1 mmol/l; ACTH, 145 +/- 1 mmol/l; P less than 0.001) and urinary Na excretion compared with control (P less than 0.01) and sham injection (P less than 0.05), and also decreased plasma [K] (sham, 4.6 +/- 0.2 mmol/l; ACTH, 3.3 +/- 0.8 mmol/l; P less than 0.01) and increased urinary K excretion (P less than 0.01) compared with control. SBP in adrenalectomized animals (n = 10) was unchanged by ACTH. ACTH increased adrenal, renal, cardiac and brain weights compared with sham injection (P less than 0.05). There were no significant changes in vascular morphology, although ACTH treatment increased glomerular epithelial cell droplets and abolished the adrenal zona glomerulosa.

Evaluation of the biological properties of parathyroid hormone and analogues in a vascularly isolated parotid gland-based assay.

Infusion of bovine parathyroid hormone (bPTH) preparations into the arterial blood supply of the vascularly isolated parotid gland in anaesthetized sheep increases salivary phosphate concentration and gland blood flow rate with rapid onset and offset of action. These responses have been used as a bioassay for PTH and PTH analogues and for assessing the properties of an in-vitro inhibitory analogue [Nle-8, Nle-18, Tyr-34]bPTH-(3-34)amide. [Nle-8, Nle-18, Tyr-34]bPTH-(1-34)amide at 10(-9) to 10(-8) mol/l was four to five times more potent than bPTH(1-34) on both salivary phosphate and blood flow assays. Human PTH(1-34) was not significantly more potent than bPTH(1-34). The [Nle-8, Nle-18, Tyr-34]bPTH-(3-34)amide analogue had very slight agonist activity at 3 X 10(-7) mol/l and at a 100:1 ratio of analogue to PTH it completely inhibited the action of bPTH(1-34) on phosphate secretion and gland blood flow. It caused partial inhibition at 10:1 and had no evident effect at 1:1. These results differ from previous in-vitro results and indicate that the preparation may be valuable for evaluation of agonist and antagonist analogues of PTH. The vascularly isolated parotid gland of the sheep permits repeated random testing of analogues in a control-test-control sequence and the results indicate high sensitivity to PTH in a rapidly reactive in-vivo system with two responding parameters.

Local action of parathyroid hormone (1-34) and (1-84) at the parotid gland of sheep.

Administration of bovine parathyroid hormone (PTH) preparations increased the phosphate concentration in the parotid saliva of sheep. Data on the site of action of PTH (1-84) were obtained by (a) equimolar infusions of PTH (1-84) and (1-34) directly into the arterial blood supply of the vascularly isolated parotid gland in anaesthetized sheep, (b) intravenous infusion of PTH (1-84) at a similar rate and (c) intra-arterial infusion of PTH (1-84) with complete drainage of the venous effluent from the gland during the infusion. Results showed substantial time- and dose-response identity of the two peptides, at 10(-9) to 4 X 10(-9) mol/l in arterial blood, in raising salivary phosphate concentration. The effect of PTH (1-84) was not due to recirculated fragments because the response was obtained when recirculation was prevented by complete venous drainage and little or no response occurred when the same infusion was given i.v.

A dose-response comparison of the actions of angiotensin II and angiotensin III in sheep.

Comparisons of aldosterone responses to [des-Asp1]-angiotensin II and angiotensin II, often at single dose levels, have shown a wide range of potency ratios. Therefore four-point dose-response comparisons were performed in sodium-replete sheep, using i.v. infusion rates of angiotension II and angiotensin II amide that reproduced the physiological range of blood concentration of angiotensin II for sheep. Angiotensin III was infused i.v. at the same rates. Effects on arterial blood pressure, cortisol secretion rate, adrenal blood flow and plasma levels of NA+ and K+ were also compared. The potency ratio, angiotensin III : angiotensin II amide, was 0.87 for actual aldosterone secretion rate and 0.90 for the calculated increase in aldosterone secretion. For angiotensin III : angiotensin II the ratios were 0.80 and 0.91 respectively. These ratios were not significantly different from 1.00 but the tendency for angiotensin II to be slightly more potent was probably due to a contribution from derived angiotensin III during infusion of angiotensin II. Angiotensin II or angiotensin II amide was approximately four times as potent as angiotensin III in raising arterial blood pressure. Cortisol secretion rate was slightly but significantly increased by all peptides at the higher infusion rates. Infusions had no effect on adrenal blood flow or plasma levels of Na+ but raised plasma levels of K+ slightly. These results confirm the conclusion from adrenal arterial infusion experiments that angiotensin II and III are almost equipotent in stimulating aldosterone secretion in sheep.

Dopaminergic modulation of aldosterone secretion?

Metoclopramide (10 mg i.v. injection followed by 10 mg/h i.v. for 2 h) caused a transient rise in blood concentrations of aldosterone in sodium-replete and sodium-depleted sheep. Infusion of metoclopramide into the adrenal artery of sheep with an autotransplanted adrenal gland, at a rate to give a similar concentration of metoclopramide at the adrenal cell level (calculated from rate of infusion and adrenal blood flow), resulted in no alteration in aldosterone secretion rate in either sodium-replete or sodium-deplete animals, even though intravenous metoclopramide caused transient stimulation of aldosterone secretion in the same sheep when sodium replete. Dopamine administered either into the adrenal arterial blood supply or intravenously had no significant effect on aldosterone secretion and did not reverse the stimulatory effects of angiotensin II on aldosterone secretion in the adrenal transplant. The data do not support the suggestion that direct dopaminergic elements play a tonic inhibitory role in aldosterone secretion. It is possible that the agonist effect of metoclopramide on aldosterone secretion may occur by some non-dopaminergic mechanism and it is tempting to speculate that the effect is centrally mediated.

The absorption of ultraviolet light by cell nuclei. A technique for identifying neoplastic change.

A technique for measuring the absorption of 260-nm ultraviolet light by cell nuclei is described. The results of such measurements of normal thyroid epithelial cells and benign and malignant thyroid neoplastic cells demonstrate a progressive increase in absorbance that correlates with the histologic appearance of neoplasia. The possible theoretic basis for this phenomenon is explored. The increased nuclear absorbance observed in neoplastic cells is hypothesized to result from the disruption of hydrogen bonds between the DNA base pairs, which allows unwinding of the double helix and loss of the normal control of mitosis.

Osmoregulatory thirst in sheep is disrupted by ablation of the anterior wall of the optic recess.

Ablation of the organum vasculosum of the lamina terminalis (OVLT) and adjacent midline tissue in the anterior wall of the optic recess of the third ventricle resulted in greatly reduced water drinking to intracarotid infusion of hypertonic NaCl in sheep. Daily food and water intake and angiotensin II drinking were not consistently reduced by these lesions. Tissue in or close to the OVLT is probably involved in osmotically induced water-drinking.

Morphology of the organum vasculosum of the lamina terminalis (OVLT) of the sheep.

Examination of the ventricular surface of the organum vasculosum of the lamina terminalis (OVLT) of sheep with the scanning electron microscope revealed an elongated protuberance occupying most of the frontal wall of the third ventricle below the level of the anterior commissure. This protuberance lacked ciliated ependymal cells. Examination of horizontal sections with the transmission electron microscope revealed an apparent lack of regularly apposed ependymal cells, suggesting that ependyma is either greatly modified or absent. The surface was composed of numerous intertwining cell processes with some scattered cells situated on this surface. The body of this structure was composed of many cell processes separated by a network of extracellular channels sometimes extending to the ventricular surface. Towards the base of this protuberance, a plexus of blood vessels was observed. Some of these vessels exhibited fenestrated endothelium. Neuronal processes were also apparent in this region. These unusual anatomical features suggest a specific function for this brain region in sheep.

Simultaneity in the Ternus configuration: psychophysical data and a computer model.

The Ternus configuration is an apparent motion display which is typically described as being bistable; subjects usually describe seeing either element motion or group motion, depending upon temporal properties of the display. The results of an experiment are reported in which subjects are also permitted to report seeing four stationary display elements (simultaneity). It was found that simultaneity was produced when both frame durations and interstimulus intervals (ISIs) were brief. A weaker than expected effect of stimulus onset asynchrony (SOA) was revealed because this third type of judgment was obtained. Furthermore, statistical analyses indicated that SOA was not by itself the best predictor of judgment type. The interaction between duration and ISI was also an important predictor. This suggested that a complete account of the Ternus configuration requires two mechanisms: a visible persistence mechanism, governed by an SOA law, and a motion correspondence mechanism, governed by an ISI law. These two mechanisms were added to Dawson's (1991) [Psychological Review, 98, 569-603] autoassociative network for motion correspondence processing. The resulting model could generate each of the three interpretations of the Ternus configuration at appropriate combinations of frame duration and ISI.

Location cue validity affects inhibition of return of visual processing.

Inhibition-of-return is the process by which visual search for an object positioned among others is biased toward novel rather than previously inspected items. It is thought to occur automatically and to increase search efficiency. We examined this phenomenon by studying the facilitative and inhibitory effects of location cueing on target-detection response times in a search task. The results indicated that facilitation was a reflexive consequence of cueing whereas inhibition appeared to depend on cue informativeness. More specifically, the inhibition-of-return effect occurred only when the cue provided no information about the impending target's location. We suggest that the results are consistent with the notion of two levels of visual processing. The first involves rapid and reflexive operations that underlie the facilitative effects of location cueing on target detection. The second involves a rapid but goal-driven inhibition procedure that the perceiver can invoke if doing so will enhance visual search performance.

Polarity matching in the Ternus configuration.

Two experiments were conducted to examine the effect of changes in the sign of element contrast on perceptions of the Ternus apparent motion display. In the first experiment, the contrast polarity of all three elements in the display were alternated from the first frame of view to the second. At short durations, this increased perceptions (relative to a control condition) of simultaneity in the display, decreased perceptions of element motion, and did not significantly affect perceptions of group motion. At long durations, this manipulation did not affect performance. In a second experiment, patterns of element polarity were manipulated to favour perceptions of either element motion or of group motion relative to a control condition in which all elements had identical contrast polarity. At a long duration, this manipulation affected perceptions of the configuration; this manipulation did not affect the appearance of the display at a short duration. Together, these results are inconsistent with the predictions of Grossberg and Rudd's [Psychological Review, 99, 78-121 (1992)] motion oriented contrast filter. However, they are consistent with a model of motion correspondence processing that includes a polarity matching constraint.

Renal handling and acute urinary electrolyte effects of aminoglycoside antibiotics: use of a solitary renal autotransplant in the conscious sheep.

Renal handling of the aminoglycoside antibiotics gentamicin and tobramycin were studied before and after one hour of constant intravenous infusions adjusted to maintain a concentration of 15 micrograms/mL. A solitary renal autotransplant model in four conscious volume replete 40 Kg sheep was used. This unique surgical preparation allows sampling of renal arterial and renal venous blood as well as urine drained through an exteriorized parotid-ureteral fistula. This surgical preparation has considerable potential in renal pharmacology since it uses a conscious, large animal. Baseline studies in this preparation demonstrated normal, 51CrEDTA and 125 I PAH, clearances which were unaffected by the drugs. Aminoglycoside binding to pooled sheep sera was 11% at physiologic PH, calcium and magnesium concentrations. A-V difference was 1.3 +/- .3 micrograms/mL and extraction by the kidney was 9 +/- 3.2% with no differences between gentamicin and tobramycin. Clearance of gentamicin was 84% and tobramycin 86% of GFR. There was no evidence of tubular injury as evidenced by unchanged urinary beta-2 microglobulin excretion. Serum Na, K, Ca and Mg did not change over the course of the study. Both drugs caused a prompt decrease in absolute and fractional sodium excretion while only gentamicin produced a kaliuresis. Early aminoglycoside effects on electrolyte balance may be an eventual determinant of nephrotoxic potential rather than differences in renal drug handling.

A comparison of two macroscopic platelet agglutination assays for von Willebrand factor.

Plasma drawn from 22 patients with a broad range of von Willebrand factor (vWF) levels, including one patient with rare, severe type III von Willebrand's disease, was used to investigate the adaptability of the Bio/Data Corp. vW Factor Assay, a ristocetin cofactor-based kit developed for use with a platelet aggregometer, to a macroscopic platelet agglutination technique. The results were compared to those obtained using the General Diagnostics von Willebrand Factor Assay, another ristocetin cofactor-based kit developed for use as a macroscopic platelet agglutination procedure. No significant difference (p greater than 0.5) existed between results obtained by these two kits. The mean and standard deviation of the vWF levels (as percent of normal) were 132 +/- 66.7 by the General Diagnostics kit and 133 +/- 59.0 by the Bio/Data Corp. kit. The correlation coefficient (r) was 0.81. The Bio/Data Corp. kit is more costly per test than the General Diagnostics kit. However, it was shown to be compatible with the macroscopic agglutination technique and required no modification to be used in that manner.

Inattention and the perception of visual feature conjunctions.

Visual processing of objects in the absence of focused attention appears to be limited. We varied the degree of attention, or visual processing, that observers paid to objects using an instruction set manipulation. In 2 experiments, subjects performed tasks that required superficial or detailed visual analysis of the objects involved. In subsequent recognition tests, information about conjunctions of shape and internal color/texture pattern was limited when only superficial visual analysis was required to encode the object. This implies that the degree of visual processing, during object encoding affects the likelihood that feature conjunctions are incorporated into the visual representation of these objects.

Inattention and the perception of visual features.

Subjects selectively attended to one of two interleaved, novel figures while ignoring the other figure. In subsequent tests administered to determine the extent to which the ignored figure was perceived, recognition of shape and the location of contour gaps was at the chance level. Moreover, recognition of the presence of contour gaps was significantly below the chance level. These results indicate that preattentive visual processing of unattended objects is too crude to encode global shape and local features such as contour gaps. It is suggested that preattentive processing creates visual representations of unattended objects that contain very limited information about features.