False recognition in Lewy-body disease and frontotemporal dementia.

The primary goal of this study was to evaluate the false recognition phenomenon in persons with frontotemporal dementia (FTD) and those with Lewy-body disease (LBD). Patients with LBD (n=10) or FTD (n=15) and their corresponding controls (n=30) were subjected to the Deese-Roediger-McDermott (DRM) paradigm to induce false recognition. Patients were first presented with items semantically related to a nonpresented critical target. The critical target was later included in a word list shown to patients to assess level of recognition. Both groups of patients showed a reduced level of false recognition of the critical target when controlling for their overall level of false alarms. This reduction was greater in persons with LBD than in those with FTD. Correlational analyses of performance on neuropsychological tests and the DRM variables indicated that the reduced DRM effect was associated with inhibition deficits in patients with LBD and with inhibition deficits and verbal memory in those with FTD. Our results support current models suggesting that these cognitive components contribute to the false recognition effect.

Hypocalcemia, regardless of the vitamin D status, decreases epidermal growth factor receptor density and autophosphorylation in rat livers.

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] is known to influence cell proliferation/maturation, whereas epidermal growth factor (EGF) is a potent stimulant of proliferation. Recently, hypocalcemia of vitamin D (D) deficiency was shown to significantly perturbe hepatic regeneration, which could be only partly restored by normalizing extracellular calcium, whereas normalization of 1,25-(OH)2D3 fully restored the process. To define the calcium- and/or D3-sensitive mechanisms associated with liver growth, a study of the initial events transduced by EGF was initiated by probing EGF receptor (EGFR) density and affinity, its subsequent autophosphorylation, and the level of its steady state transcript. Studies were carried out in D-depleted rats kept either untreated or supplemented with D3, 1,25-(OH)2D3, or calcium alone. The hepatic EGFR number (picomoles per mg microsomal protein) was significantly affected by hypocalcemic D-depleted (0.82 +/- 0.2), but responded with similar increases to calcium (1.7 +/- 0.09; P < 0.05), D3 (1.6 +/- 0.3; P < 0.05), and 1,25-(OH)2D3 (2.1 +/- 0.3; P < 0.01). The EGFR mRNA level revealed, however, no significant effect of the calcium or D3 status, indicating that posttranscriptional events were playing an important role. Phosphorylation studies showed that EGFR autophosphorylation and tyrosine protein kinase activity paralleled receptor density, with the lowest autophosphorylation values obtained in hypocalcemic D-depleted rats (D-depleted hypocalcemic vs. D3 repleted, P < 0.007). When normalized for receptor number, however, EGFR autophosphorylation increased in D-depleted hypocalcemic rats to a level comparable to that observed in all other groups. To dissociate the effect of the D3 hormone from that of calcium alone on EGFR, D-depleted rats were treated with the nonhypercalcemic 1,25-(OH)2D3 analog 22-OXA-1,25-(OH)2D3 (OCT), with or without calcium supplementation. Hypocalcemic OCT-treated rats did not exhibit any increase in EGFR number (0.6 +/- 0.1) compared to D-depleted hypocalcemic rats, but the addition of dietary calcium to OCT restored extracellular calcium concentrations and EGFR density (1.8 +/- 0.2; P < 0.002) to values comparable to those observed after D3 or 1,25-(OH)2D3 treatment. EGFR autophosphorylation was also decreased in hypocalcemic OCT-treated animals (P < 0.03), but after normalization for receptor density, full restoration of EGFR autophosphorylation was achieved. Our data demonstrate that in normal hepatic tissue, EGFR is highly sensitive to the in vivo prevailing calcium concentration, i.e. hypocalcemia, regardless of the D3 status, leading to a significant decrease in receptor density and its subsequent autophosphorylation.

Influence of the calcium and vitamin D endocrine system on the "priming" of the liver for compensatory growth.

The liver is known to be sensitive to dietary challenge and to reduction in its functional mass. To investigate the influence of the vitamin D endocrine system on the hepatic growth response, liver DNA synthesis (S phase of cell cycle) was primed by dietary manipulation (high carbohydrate/protein-free diet x 3 d followed by high protein diet x 15-18 hr) in animals presenting various calcium and vitamin D status. Data indicate the dietary manipulation increased [3H]thymidine incorporation into DNA following vitamin D3 (D3) or 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) administration (p less than 0.0001) while vitamin D depleted (D-) rats (both hypo and normocalcemic) showed no significant increases over unchallenged rats (p less than 0.0001). Studies on the hepatic EGF receptor indicate that while no significant between-group difference was observed in receptor density or affinity, evaluation of the receptor density in relation to the [3H]thymidine incorporation response revealed a higher receptor density in responders (D3 and 1,25(OH)2D3 supplemented groups) with 30.2 +/- 1.4% maximum binding than in non-responders (hypo and normocalcemic D- groups) with 25.4 +/- 1.8% maximum EGF binding (p less than 0.03); EGF EC50 was found to be 50.2 +/- 4.4 and 63.8 +/- 9.7 ng/ml in responders and non-responders respectively (p = 0.1). These data indicate that vitamin D depletion is accompanied by hyporesponsiveness when challenged by a dietary protocol known to prime the liver for growth inducing stimuli.

Hepatic expression of regeneration marker genes following partial hepatectomy in the rat. Influence of 1,25-dihydroxyvitamin D3 in hypocalcemia.

BACKGROUND/AIMS: Vitamin D (D) depletion is a common feature of chronic liver diseases. In past years, disturbances in calcium metabolism involving inadequate D and parathyroid hormone status have been reported to significantly impair the hepatic regeneration process following partial hepatectomy in the rat. The purpose of this study was to investigate how hypocalcemia and D deficiency affect specific cell markers of hepatic compensatory growth. METHODS: Steady-state mRNA levels of gene markers of the regeneration process were investigated following 2/3 partial hepatectomy. The response of hypocalcemic D-depleted rats was compared to that of animals whose calcium status had been normalized by repletion with the active D hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). RESULTS: The transcript for the major hepatic mitogen HGF increased in both groups after partial liver resection but the increase was significantly lower as well as delayed in livers obtained from calcium deficient rats in the prereplicative phase of the regeneration process. TGF alpha mRNA levels were also found to be significantly lower in calcium deficient rats at all time-points following partial hepatectomy, while the relative behavior of the tandem TGF alpha-EGFR indicated an early dominant effect in normocalcemic 1,25(OH)2D3-repleted animals. HGF-c-met mRNA levels also indicated that the 1,25(OH)2D3-repleted animals reacted more promptly to the regeneration stimuli. Indeed, while relative (1,25(OH)2D3/D-Ca- ratio) maximum mRNA levels were observed 12 h following liver resection in 1,25(OH)2D3-treated animals, relative peak levels were only apparent 24 h post-surgery in hypocalcemic rats. Maximum cyclin D1 (a marker of the G1 phase of the cell cycle) mRNA occurred between 8-18 h after partial hepatectomy in 1,25(OH)2D3-repleted animals to return to base-line value thereafter, but in hypocalcemic rats the transcript levels remained significantly below 1,25(OH)2D3-repleted animals during the prereplicative period with increases above initial values between 12-24 h post-surgery. Both cyclin A (an S phase marker) transcripts (1.8 and 2.9 kb) were influenced by the regeneration process. The transcripts significantly and sharply increased in hypocalcemia between 30-36 h following partial hepatectomy to decrease thereafter, while the increase was observed between 24-30 h, and at 48 h (1.8 kb) in 1,25(OH)2D3-repleted animals. Liver weight recovery was also found to be decreased in D-depleted rats over the 48 h period of observation. CONCLUSIONS: Our data further confirm the presence of an impaired regeneration process in hypocalcemia of D deficiency which seems to be associated with gene markers indicating an inefficient transit across the G1 phase of the cell cycle.

Human platelet spreading on substrata of known surface chemistry.

Using platelet-rich plasma freshly obtained by plasmapheresis, the spread areas of human platelets settled onto substrata of different surface energies were measured to evaluate the hypothesis that initial platelet spreading response is surface dependent. At 37 degrees C, minimal platelet spread areas were found on substrata with critical surface tension between 20 and 30 mN/m (dynes/cm), and increased spreading and morphologic changes occurred on substrata of both higher and lower critical surface tension. This differential response was absent at 25 degrees C. Therefore, measurement of spread platelet area at physiologic temperature rather than number of attached cells is proposed as a superior method of estimating apparent blood compatibility of new biomaterials.