Using sensory properties of food to trigger swallowing: a review.

The effect of food consistency on swallowing function has been widely studied, and it is well recognized that by delaying the flow of the food bolus, thickened liquids can help in the management of swallowing dysfunction. However, fewer studies have been carried out on the impact of food sensory properties and related liking on swallowing function. This paper reviews the role of taste, olfaction, and trigeminal perceptions on swallowing function and highlights the need for a deeper investigation of this aspect of patient diet modification.

A unique family of endothelial cell polypeptide mitogens: the antigenic and receptor cross-reactivity of bovine endothelial cell growth factor, brain-derived acidic fibroblast growth factor, and eye-derived growth factor-II.

Bovine brain, hypothalamus, pituitary, and retina contain potent anionic polypeptide mitogens for endothelial cells. Immunological assays using murine monoclonal antibodies against bovine endothelial cell growth factor (ECGF) and radioreceptor assays using [125I]ECGF were performed to determine the cross-reactivity of ECGF with bovine acidic pI brain-derived fibroblast growth factor (acidic FGF) and bovine eye-derived growth factor-II [EDGF-II). We observed that acidic FGF and EDGF-II are recognized by anti-ECGF monoclonal antibodies and compete with [125I] ECGF for receptor occupancy. Furthermore, the biological activity of ECGF, acidic FGF, and EDGF-II is potentiated by the glycosaminoglycan, heparin. These results argue that ECGF, acidic FGF, and EDGF-II belong to a common family of polypeptide growth factors.

Phase II study of docetaxel and cisplatin in advanced non-small-cell lung cancer.

PURPOSE: Docetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, France) and cisplatin are two of the most active single agents used in the treatment of non-small-cell lung cancer (NSCLC). A recently reported phase I study of the combination of docetaxel and cisplatin recommended a dose of 75 mg/m2 of both drugs every 3 weeks for subsequent phase II study. PATIENTS AND METHODS: Eligible patients were aged 18 to 75 years with a World Health Organization (WHO) performance status < or = 2 and life expectancy > or = 12 weeks, with metastatic and/or locally advanced NSCLC proven histologically or cytologically. Patients were not permitted to have received prior chemotherapy, extensive radiotherapy, or any radiotherapy to the target lesion and must have had measurable disease. Concurrent treatment with colony-stimulating factors (CSFs) or prophylactic antibiotics was not permitted. Docetaxel (75 mg/m2) in 250 mL 5% dextrose was given intravenously (i.v.) over 1 hour immediately before cisplatin (75 mg/m2) in 500 mL normal saline given i.v. over 1 hour in 3-week cycles. Premedication included ondansetron, dexamethasone, promethazine, and standard hyperhydration with magnesium supplementation. RESULTS: A total of 47 patients, two thirds of whom had metastatic disease, were entered onto this phase II study. The majority of patients were male (72%) and of good (WHO 0 to 1) performance status (85%). All 47 patients were assessable for toxicity and 36 were for response. Three patients were ineligible and eight (17%) discontinued treatment because of significant toxicity. In assessable patients, the overall objective response rate was 38.9% (95% confidence limits [CL], 23.1% to 56.5%), 36.1% had stable disease, and 25% progressive disease. On an intention-to-treat analysis, the objective response rate was 29.8%. Median survival was 9.6 months and estimated 1-year survival was 33%. Significant (grade 3/4) toxicities included nausea (26%), hypotension (15%), diarrhea (13%), and dyspnea mainly related to chest infection (13%). One patient experienced National Cancer Institute (NCI) grade 3 neurosensory toxicity after eight cycles. Grade 3/4 neutropenia was common and occurred in 87% of patients, but thrombocytopenia > or = grade 3 was rare (one patient). Significant (grade 3/4) abnormalities of magnesium levels were common (24%). Febrile neutropenia occurred in 13% of patients and neutropenic infection in 11%, contributing to two treatment-related deaths. No neutropenic enterocolitis or severe fluid retention was reported. CONCLUSION: Compared with other active regimens used in this setting, the combination of docetaxel and cisplatin in advanced NSCLC is an active regimen with a similar toxicity profile to other combination regimens.

Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacokinetics of the combination of docetaxel and cisplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) who have not received prior chemotherapy and to recommend a dose for phase II studies. PATIENTS AND METHODS: Patients with advanced NSCLC and performance status 0 to 2 who had not received prior chemotherapy received docetaxel over 1 hour followed by cisplatin over 1 hour with hydration. Dose levels studied were (docetaxel/cisplatin) 50/75, 75/75, 75/100, and 100/75 mg/m2 repeated every 3 weeks. Colony-stimulating factor (CSF) support was not used. Pharmacokinetics of docetaxel and cisplatin were studied in the first cycle of therapy. Most patients (79%) had metastatic disease or intrathoracic recurrence after prior radiation and/or surgery. RESULTS: Of 24 patients entered, all were assessable for toxicity and 18 for response. The MTD schedules were docetaxel 75 mg/m2 with cisplatin 100 mg/m2 (dose-limiting toxicities [DLTs] in five of six patients), and docetaxel 100 mg/m2 with cisplatin 75 mg/m2 (DLTs in two of two patients, including one fatal toxicity). Limiting toxicities were febrile neutropenia and nonhematologic, principally diarrhea and renal. Two patients had neutropenic enterocolitis. Pharmacokinetics of both drugs were consistent with results from single-agent studies, which suggests no major pharmacokinetic interaction. Neutropenia was related to docetaxel area under the plasma concentration-versus-time curve (AUC). An alternative schedule was investigated, with cisplatin being administered over 3 hours commencing 3 hours after docetaxel, but toxicity did not appear to be less. Independently reviewed responses occurred in eight of 18 patients (44%; 95% confidence interval, 22% to 69%), most following 75 mg/m2 of both drugs. CONCLUSION: Docetaxel 75 mg/m2 over 1 hour followed by cisplatin 75 mg/m2 over 1 hour is recommended for phase II studies. The responses seen in this phase I study suggest a high degree of activity of this combination in previously untreated advanced NSCLC.

Acidic and basic fibroblast growth factors similarly regulate the rate of biosynthesis of rat astroblast proteins.

Quiescent rat astroblasts in culture have been treated for various periods of time with acidic and basic fibroblast growth factors. Both factors elicited similar effects on the cell proliferation and glutamine synthetase activity. The rate of biosynthesis of the proteins analyzed on autoradiograms of polyacrylamide gels after two-dimensional electrophoresis was also similarly modulated by the two growth factors. These results suggest that the two fibroblast growth factors act through the same membrane receptors on rat astroblasts in culture.

Biochemical comparative studies between eye- and brain-derived growth factors.

Two bovine brain-derived growth factors, BDGF I and BDGF II, were isolated using the same extraction procedure as previously described for eye-derived growth factors (EDGF). The hypothesis that these growth factors were identical to EDGF I and EDGF II, respectively, was supported by their similar molecular weights (16,000 and 15,000, respectively) and isoelectric points (9.0 and 5.0, respectively), their identical retention behavior on reverse-phase chromatography and their similar amino acid compositions. From studies on their binding properties to cell surfaces, competition between EDGF I and BDGF I as well as competition between EDGF II and BDGF II to the same receptor was observed. The amino terminal sequence of EDGF II (1-16) was shown to be identical to the amino acid residues (7-22) of the acidic FGF, strongly confirming our observations on the identity of the factors isolated from bovine brain and retina.

Bovine retina contains three growth factor activities with different affinity to heparin: eye derived growth factor I, II, III.

Several ocular tissues have been shown to contain growth factor activity designated under a generic name as Eye Derived Growth Factor. Purification from bovine retina was undertaken and a fraction which could induce target cells to proliferate at doses of 5 ng per ml of culture medium was obtained. Using heparin sepharose chromatography we now show that this mitogenic activity can be fractionated into three different activities. Crude extract of bovine retina used as starting material was separated into two major fractions, one with no affinity for heparin and which was named Eye Derived Growth Factor III, and one with a strong affinity for heparin and eluted from the column with 1.4 M NaCl named Eye Derived Growth Factor I. This fraction EDGF I induces cell proliferation at doses of 100 pg/ml of culture medium. A 10(5) fold purification was achieved by this single chromatography step. Cibacron Blue purified EDGF was also further fractionated by heparin sepharose. All biological activity was found to bind to heparin. One fraction eluted at 1 M NaCl named Eye Derived Growth Factor II had a biological activity at doses of 1 ng while the other growth factor was the EDGF I with biological activity at 25 pg. At this step of purification EDGF I runs as a single band on SDS polyacrylamide gel at a molecular weight of 17 000 d. These data strongly suggest that Eye Derived Growth Factors I and II are respectively similar to Brain Fibroblast Growth Factor and to Endothelial Cell Growth Factor from hypothalamus.

Overview of docetaxel (Taxotere)/cisplatin combination in non-small cell lung cancer.

Cisplatin-based chemotherapy is effective in non-small cell lung cancer (NSCLC), although it prolongs survival only modestly. Single-agent docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) is highly active against NSCLC. The activity and tolerability of two docetaxel/ cisplatin regimens were therefore investigated in two multicenter phase II studies, one in Australia and one in France. Chemotherapy-naive patients with inoperable NSCLC received either docetaxel 75 mg/m2 on day 1 plus cisplatin 75 mg/m2 3 weekly (n = 47; Australian study) or docetaxel 75 mg/m2 on day 1 plus cisplatin 100 mg/m2 every 3 weeks for three cycles then every 6 weeks (n = 51; French study). The majority of the population (74%) had metastatic disease. Seventy-eight patients were evaluable for efficacy. Overall response rates were 36% (95% confidence interval, 25 to 47) in all evaluable patients and 34% in patients with metastases. Median duration of response was 6 months, with a 4-month median time to progression. Median survival time was 9 months, with a 1-year survival rate of 34%. A median of four (range, one to nine) treatment cycles were administered. Febrile neutropenia occurred in 14% of patients. Severe infection, which occurred in less than 7% of patients, led to two toxic deaths. Other severe toxicities were rare, with severe stomatitis and severe neurosensory side effects reported in 2% and 1%, respectively, of treated patients. No severe fluid retention occurred. Docetaxel/cisplatin, administered as two different schedules, is well tolerated and exhibits efficacy in the range of the most established combinations in the treatment of advanced NSCLC.

IGF-binding protein-6 is involved in growth inhibition in SH-SY5Y human neuroblastoma cells: its production is both IGF- and cell density-dependent.

The IGF system is involved in the growth and differentiation of neuroblastoma cells, but the precise roles played by the IGF-binding proteins (IGFBPs) remain unknown. We have examined the expression and functions of IGFBPs produced by the neuroblastoma cell line, SH-SY5Y, in the presence of: insulin, IGF-I, IGF-II, des(1-3)IGF-I (an IGF-I analogue with weak affinity for IGFBPs), acidic fibroblast growth factor, basic fibroblast growth factor, or nerve growth factor. Under basal conditions, SH-SY5Y cells in serum-free medium secreted IGF-II, and traces of IGF-I, IGFBP-2 and IGFBP-4. After 24 h of culture, comparative mitogenic potencies were: des(1-3)IGF-I > IGF-I > IGF-II > insulin. After 48 h, when IGFBP-2 and IGFBP-4 concentrations in the culture media had increased, des(1-3)IGF-I remained the most active, but the activity of insulin now equalled or exceeded that of IGF-I and IGF-II. This suggests a negative feedback mechanism involving partial sequestration of IGF-I and IGF-II by IGFBP-2 and IGFBP-4. At high cell density and with high concentrations of IGF-I, des(1-3)IGF-I (40 ng/ml) or IGF-II (80 ng/ml), the mitogenic activities of the IGFs diminished concomitantly with the appearance in the culture medium of an additional IGFBP identified as IGFBP-6, whose production depended on activation of the type 1 IGF receptor. These findings suggest that IGFBP-6 contributes as an autocrine inhibitor in the regulation of growth by the IGF system in these neuroblastoma cells.

Physical and related sensory properties of a swallowable bolus.

Rheology and water content properties of cereal boluses collected just before swallowing were investigated. No specific physical markers for swallowing were found between subjects. Each subject had his own mastication strategy leading to food boluses with different rheological and water content properties. However, for most of the subjects, similar physical properties were found for food boluses obtained from consumption of different cereals. Results showed that the food boluses from different cereals exhibited gel-like properties being in a range from 14.1 kPa to 21.2 kPa (G'(1 Hz, 0.4%)), when swallowed. The food boluses had a static yield stress varying from 1.3 kPa to 4.3 kPa. Another interesting finding was that the water content of food boluses might be an important marker for swallowing since it was similar for different cereal food boluses (around 50%). This physical property might drive the fluid sensory perception, which could also be a sensory swallowing threshold.

Maturation-related gene expression of rat astroblasts in vitro studied by two-dimensional polyacrylamide gel electrophoresis.

Maturation of rat astroblasts was induced in vitro by acidic fibroblast growth factor (aFGF), hydrocortisone and dibutyryl cyclic AMP. Cells grown for 20 days were treated for 48 h and labelled with [35S]methionine only during the last 18 h of treatment. Cell proteins solubilized in lithium dodecyl sulfate were submitted to two-dimensional polyacrylamide gel electrophoresis. About 300 radioactive proteins could be analysed visually and compared. All treatments induced visible quantitative and sometimes qualitative changes. A total of 81 proteins had their rate of biosynthesis modified. For some proteins, this rate was changed by only one treatment, while for others it was changed by two or even by the three treatments, mostly in the same way. These results are consistent with the hypothesis that the proteins involved in the maturation process are organized in sets, proteins belonging to one set always being regulated together under a common control. Some sets would be regulated by only one effector while others would be regulated by several effectors.

Differential phenotypic expression induced in cultured rat astroblasts by acidic fibroblast growth factor, epidermal growth factor, and thrombin.

We compared the effects of three growth factors, acidic fibroblast growth factor (aFGF), epidermal growth factor (EGF), and thrombin, on rat astroblast proliferation, morphology, glutamine synthetase-specific activity, and phenotypic expression of proteins. In vitro experiments were made on 20-day-old primary cultures. Astroblast proliferation was stimulated transiently (after 48 h treatment) by the three growth factors, while the cell glutamine synthetase activity began to increase significantly only after 3 days of treatment. Acidic FGF and EGF, but not thrombin, modified the cell morphology. The effects on phenotypic expression were first determined after 5 days of treatment to minimize the mitogenic effect of the factors. Proteins synthesized during the last 18 h of the treatments were separated by two-dimensional polyacrylamide gel electrophoresis. About 600 spots were compared, 54 were modulated by the various treatments, 13 were altered similarly by all three factors, 28 by aFGF and EGF, 7 by only aFGF, 3 by only EGF, and 3 by only thrombin. These results indicate a large similarity of effects between aFGF and EGF (41 proteins) and show that these factors elicit a more extended modulation of the phenotypic expression than thrombin (13 proteins). Each of the three factors has a few specific effects, which suggests that even for aFGF and EGF, which are supposed to elicit their effects through membrane receptor-associated tyrosine kinase activity, some specificity appears in their mechanism of action. A model is proposed to suggest that cell maturation is characterized by the modulation of the synthesis of many proteins which can be grouped into classes. Each class appears to be under the control of one regulatory element. The specificity of the effect of a growth factor should result from the activation of a specific combination of such regulatory elements. Analysis of the proteins after only 18 h of treatment, when neither proliferation nor maturation were significantly affected, showed that 11 proteins were regulated only at that time. These proteins could be related to intermediate steps of the growth factor signal transduction.

[Effect of interleukins and somatomedins on the production of neurotensin by cell line SH-SY5Y derived from human neuroblastoma]. / Effet des interleukines et des somatomédines sur la production de neurotensine par la lignée cellulaire SH-SY5Y dérivée d'un neuroblastome humain.

The goal of this study was to investigate the regulation by insulin-like growth factors 1 and 2, and interleukins on the production of neurotensin in the SH-SY5Y cell line derived from a human neuroblastoma. Cultures were performed in RPMI1640 culture medium with heated foetal calf serum 12%. After 24 hrs. of fasting without serum, interleukins-1 alpha, IL-2, IL-4 and insulin-like growth factors 1 and 2 were added. Results showed: 1) A mitogenic effect of ILs (p < 0.001) and of IGFs (p < 0.001). 2) The presence of neurotensin in HCl0.1N cellular extracts (0.06 fmol/micrograms protein). 3) The increase of cellular neurotensin content in the presence of IL-4 (560%), IL-2 (480%), IGF-1 (610%) and IGF-2 (200%). Our results indicate that the human neuroblastoma cell line SH-SY5Y produces neurotensin and that ILs and IGFs act in vitro to modulate this production.

FGFs stimulate IGF binding protein synthesis without affecting IGF synthesis in rat astroblasts in primary culture.

The production of insulin-like growth factor (IGF)-I and -II and their binding proteins (BPs) has been studied in new-born rat astroblasts at confluency in primary culture. Under the influence of fibroblast growth factors (FGFs) (acidic and basic), the morphology of the astroblasts was altered, 125I-deoxyuridine incorporation was increased, and glutamine synthetase activity was stimulated. IGF production and IGF mRNA expression remained unchanged. Production of the 32 kDa BP (IGFBP-2), the sole or predominant form under base-line conditions, was enhanced and the 43-39 kDa forms (IGFBP-3) appeared or were increased. Epidermal growth factor (EGF) also stimulated production of these BPs, whereas thrombin and db-cAMP had no effect. Our data suggest that a relationship exists between FGF-induced maturation of astroblasts and the forms of BP they produce. The data also indicate that some factors may act specifically on BP synthesis, without affecting IGF synthesis, and in this way play a role in regulating the bioavailability of the IGFs.

Comparison of the morphological effects of acidic and basic fibroblast growth factors on rat astroblasts in culture.

The effects of acidic and basic fibroblast growth factors (aFGF and bFGF) on the morphology of cultured rat astroblasts and on the expression of glial fibrillary acidic protein (GFAP) were compared. The addition of either aFGF or bFGF affected the morphology of the flat, irregular, polygonal-shaped astroblasts, which formed processes and acquire a fibrous appearance. Appreciable different morphological aspects were observed between aFGF- and bFGF-induced cells, essentially between 11 and 14 days in culture. In the presence of bFGF the astroglial cells were more fibrous with a more compact perikaryon as compared to aFGF treated cells. At the ultrastructural level abundant intermediate filaments were observed in astroglial cells as an effect of aFGF and rare filaments but numerous microtubules were seen in bFGF-treated cells. The immunoreactivity for GFAP increased with time in culture and was much stronger in aFGF-treated cells compared to bFGF-treated cells at day 14. An intense positive staining was observed in the somata of the astroglial cells and their processes in the presence of aFGF, while essentially the processes were stained in the presence of bFGF. After 21 days in culture GFAP immunoreaction was also found in the perikarya of cells treated with bFGF. These results show that rat astroglial cells respond somewhat differently to aFGF and bFGF.

Evidence for FGF-like growth factor in adult bovine retina: analogies with EDGF I.

Eye Derived Growth Factor (EDGF) is the genus name for growth factor activities found in several ocular tissues. Purification from bovine retina by Cibacron blue affinity chromatography has previously given a fraction which can induce target cell proliferation at doses of 30 ng per ml of culture medium. Radioimmunoassay using a labelled synthetic decapeptide [Tyr 10]--FGF (1-10) including the 9 N terminal amino acids of brain Fibroblast Growth Factor (FGF) indicated that EDGF contained a FGF-like material. Further purification of Cibacron blue purified EDGF with heparin sepharose chromatography yielded two active fractions after elution with a sodium chloride gradient. One fraction named EDGF I eluted between 1.3 and 1.5 M NaCl and accounted for over 50% of the input biological activity and comigrated with purified FGF on SDS PAGE at a molecular weight of 16,000 d as a single band. FGF competed with EDGF I for binding to specific receptors on bovine epithelial lens cells. We conclude that retina contains a growth factor activity (EDGF I) similar if not identical to FGF.