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The use of biomarkers is a promising approach to the study of human cancer risk. Bronchial metaplasia in sputum cytology may be a marker for potential premalignancy that can be used for population studies. We recently performed a randomized, controlled trial in smokers on the effect of 14 weeks beta-carotene (20mg/day) on markers for DNA damage. We now have evaluated the application of sputum cytology in this study and performed a preliminary evaluation of the effect of beta-carotene. Of the 150 potential participants in this trial 75 were not eligible because they failed to produce sputum samples (n = 29), or because samples were unsatisfactory (n = 46). The eligible group was older (41 vs 37 years) and had smoked longer (23 vs 19 years), but had similar cigarette consumption (mean 21/day) and plasma cotinine levels. Metaplasia was graded in seven categories. Only 11 subjects (15%) showed minor or mild atypia on study entry. Agreement within and between observers was 95% within the same or an adjacent category. We observed no significant correlation between before and after treatment final metaplasia scores in either the beta-carotene (Spearman R = 0.18, P = 0.3) or placebo group (Spearman R = 0.17, P = 0.3). Initial metaplasia scores were somewhat higher in the beta-carotene group (n = 33) than in the placebo group (n = 42) (P = 0.06). Final metaplasia scores were similar in both groups (P = 0.69), and there was no decrease in metaplasia scores in the beta-carotene group (P = 0.75). This study indicates that sputum cytology may not yet be a readily applicable marker in studies of a healthy asymptomatic population, because many smokers do not spontaneously produce sputum, more severe lesions are rare, and variation over time in the minor lesions in large. Therefore, the preliminary evidence that beta-carotene has no influence should be interpreted with care.

STUDY OBJECTIVE--The aim was to investigate whether dietary factors cluster in a favourable or unfavourable way and to characterise the groups identified by lifestyle and sociodemographic variables. DESIGN AND SETTING--This cross sectional study was based on data of the 1987-1988 Dutch national food consumption survey (DNFCS), obtained from a panel by a stratified probability sample of the non-institutionalised Dutch population. PARTICIPANTS--3781 adults (1802 males and 1979 females) of the DNFCS, aged 19 to 85 years, were studied. MEASUREMENTS AND MAIN RESULTS--To estimate dietary intake two day food records were used. Lifestyle factors were collected by structured questionnaire and sociodemographic variables were available from panel information. Cluster analysis was used to classify subjects into groups based on similarities in dietary variables. Subsequently, these groups were characterised by sociodemographic and lifestyle factors as well as by the consumption of food groups. Eight clusters were found. In comparison with the guidelines, the dietary quality in four clusters was poor. The cluster with the poorest dietary intake (high intake of fat, cholesterol, and alcohol; low intake of dietary fibre) showed on average a high consumption of animal products (except milk), fats and oils, snacks, and alcoholic beverages, and a low consumption of fruit, potatoes, vegetables, and sugar rich products. Smoking, body mass index, dietary regimen on own initiative, hours of sleep, gender, age, socioeconomic status, and day of the week were found to discriminate among the clusters. CONCLUSIONS--Cluster analysis resulted in substantial differences in mean nutrient intake and seems useful for dietary risk group identification. Undesirable lifestyle habits were interrelated in some clusters, but an exclusive lifestyle for health risk has not been found.

Administration of the colour additive Ammonia Caramel Colour (Caramel Colour III) to rats has been associated with decreased lymphocyte counts, specifically in rats fed a diet low in vitamin B6. This effect is rapidly reversible and is caused by an imidazole derivative (THI) in Caramel Colour III. In the present paper, the conduct of a human study with Caramel Colour III is outlined and the results of blood lymphocyte counts are presented. No decrease in the number of blood lymphocytes occurred in marginally vitamin B6-deficient humans who consumed Caramel Colour III at the acceptable daily intake level (200 mg/kg body weight/day) for 7 days. These data are discussed in relation to the effects of Caramel Colour III and THI on blood lymphocyte numbers in rats.

The theme of the Heelsum Workshops is nutrition and dietary patterns as determinants of individual and public health. The meetings thus find themselves on the turning point between public health and individual health care¿a crucial turning point from a public health point of view. `Nutrition¿ has always contributed to the population's health status in both a positive (raised life expectancy) and negative way (welfare diseases). In individual health care, however, nutrition seems to play second fiddle at best in treatment while it plays a role in prevention and treatment of the most prevalent chronic diseases and disorders. This was an important conclusion drawn at the end of the first Heelsum workshop in 1995. Subsequent meetings focused on strengthening the turning point of public health and primary care from that perspective: nutrition does matter! This is a challenge that cannot be faced with one single innovation¿public health and individual health care have developed independently from each other for too long a time, and nutrition is a complex of chemistry, culture and behaviour. Heelsum successfully entered into the dialogue between collective and individual care and continued doing so in 2007. An evident indicator of its success is the realization of an own position for nutrition counselling in the Cochrane Collaboration, the international collaboration established to analyze and publish the scientific state-of-the-art of medical interventions. Prof. Jaap van Binsbergen, who might be viewed as the personification of the nutrition mission in general practice, has shaped by now a permanent position for this `field¿. There cannot be Cochrane reviews without scientific studies that can be analyzed systematically. A second attainment is stimulation of new research, and a third one the notion that collective and individual interventions should be offered coherently. For example, patients with (imminent) overweight will be more readily inclined to adjust their dietary pattern in a social environment with positive loadings for physical exercise and a healthy diet. This leads us automatically to the programme of `Heelsum V¿: an overview of current studies, stimulation of further collective/individual coherence in policy and innovations and progress on the Cochrane forefront with, as a new programme, the options for rendering tested dietary interventions in (general) practice `nutrition specific¿. This is a new shoot of the Heelsum tree; its results are available as this supplement to Family Practice.

Twenty-four healthy, male volunteers (age 20–30 years) participated in a 14-week double blind study to determine the influence of marginal vitamin B-1, B-2 and/or B-6 deficiency on humoral (IgG, IgA, IgM, IgE, IgD) and cellular (total lymphocyte count, OKT3/Cd3, OKT4/Cd4, OKT8/Cd8, OKT9/Cd71, OKT10/Cd38, OKT11/Cd2, Leu1/Cd5, Leu7/Cd57, Leu11/Cd16, IL-2 receptor/Cd25, BA1/Cd24, B4/Cd19 and OKIa/HLA-Dr positive lymphocytes) immunity as well as on acute- phase reactants (C3, C4, C3 pro- activator and α-1-acid glycoprotein, α-1-antitrypsin, haptoglobin, ceruloplasmin, transferrin, prealbumin and C- reactive protein). The diet consisted of conventional, mixed solid foods, deficient in vitamin B-1 (0.43 mg/d), B-2 (0.94 mg/d) and B-6 (0.39 mg/d). The volunteers were either or not supplemented with one or more of the vitamins B-1, B-2 and B-6, thus constituting 8 experimental groups. Although at the end of 11 weeks of depletion statistically significant differences (p

In evaluating dietary data with reference to guidelines for a healthy diet, some potential pitfalls (i.e., method of food consumption assessment and calculation to include or exclude energy derived from alcohol) were investigated. The percentage of energy intake (en%) derived from total fat, saturated fatty acids (SFA), mono- and disaccharides (MD) and intake of cholesterol and dietary fiber per megajoule were calculated using 2-day records obtained in the Dutch National Food Consumption Survey of 1987-1988. Subjects (aged 4-85, n = 5595) were classified into age-sex groups. Mean values and intake distributions were calculated with and without adjustment for within-person variation. Except for the intake of cholesterol and MD, mean intake levels were not in accord with guidelines. About 20% of the women and 23% of the men met the goal for fat intake, 20% of the men and 27% of the women for dietary fiber, and about 60 and 70% for MD and cholesterol. Only 3% of subjects had SFA intakeor = 10 en%, whereas1% had a diet in accord with all criteria studied. After adjustment for within-person variation, percentages meeting the guidelines were generally lower for fat, SFA and dietary fiber and slightly higher for cholesterol and MD. Among elderly, unadjusted results were more in agreement with the prevalence estimates based on habitual dietary intake data than with adjusted ones. Fat intake (en%) was inversely related with intake of added MD and alcohol. Our data indicate that guidelines should state explicitly whether energy-related recommendations include energy derived from alcohol, and that the prevalence of a high-fat intake is more affected by the calculation method than by food consumption assessment.

Serum anti-gliadin antibodies (AGAs) of the IgG and IgA isotypes were determined in 17 children (mean age of 5.6 years) by means of an enzyme-linked immunosorbent assay (ELISA). All children were suspected of celiac disease. They had been on dietary treatment for at least 10 months before they were challenged with gluten. Based on jejunal biopsy findings, 10 of the 17 children had to be considered positive. The sensitivity of the measurement of AGA at 6 weeks after gluten challenge was found to be 90% for IgG, 100% for IgA, and 100% for IgG/IgA combined. The specificity for IgG, IgA, and the IgG/IgA combination was 100, 71, and 100%, respectively. Twelve weeks after gluten challenge, the sensitivity as well as the specificity of AGA determination for IgG, IgA, and IgG/IgA were 100%. It is concluded that testing both IgG AGA and IgA AGA in children suspected of celiac disease is valuable in monitoring the course of the diagnostic provocation protocol and that jejunal biopsies can be abolished. This inexpensive tool can be useful in reducing the number of intestinal biopsies.

The nutritional quality of our diet is reflected in the balanced nutrient composition as well as in the absence, or at least the presence in acceptable low levels, of xenobiotics. Extreme nutrient intakes, either too much or too little, and excessive concentrations of contaminants and/or additives can cause major health risks.

A recently developed three-compartment model for the absorption and elimination of ingested alcohol was applied to re-analyse a study on the effects of various factors known to influence the blood-alcohol curve. The absorption and elimination of alcohol after drinking diluted alcohol were studied in healthy volunteers under strictly standardized conditions. The factors studied were sex, dose, concentration, physical exercise, meal consumption before drinking, energy content and composition of the meal, and time of drinking in relation to meal consumption. Gastric emptying and absorption from the small intestine were assumed to be first-order, and a possible delay (or acceleration) of gastric emptying was accounted for by a feedback-control parameter. The elimination process was assumed to follow Michaelis-Menten kinetics. Clear effects were observed of sex and dose, and aspects of meal consumption on absorption and elimination of alcohol. The ingestion of a meal prior to the intake of alcohol reduced both the gastric emptying rate and absorption efficiency of alcohol, increased the gastric emptying delay and reduced the rate of elimination. The absorption efficiency was even lower when the alcohol was consumed during the meal instead of after the meal. Using alcohol during the meal accelerated gastric emptying and reduced absorption efficiency as well as rate of elimination. High-fat meals resulted in the highest gastric emptying rate and rate of absorption from the small intestine, whereas high-protein and high-sucrose meals resulted in the lowest gastric emptying rate. Simultaneous consumption of a high-sucrose meal and alcohol increased gastric emptying delay.(ABSTRACT TRUNCATED AT 250 WORDS)

To obtain more insight into the effect of dietary fiber on vitamin B6 status among elderly people, we studied dietary interrelationships as well as associations between dietary intake and plasma pyridoxal-5'-phosphate (PLP) and cofactor stimulation of aspartate aminotransferase in erythrocytes (EAST-AC) among 441 nonvegetarian (aged 65-79) and 32 vegetarian elderly (aged 65-94). EAST-AC was found to be inversely related with intake of vitamin B6 and dietary fiber in bivariate regression analyses. After adjustment for age, intake of energy, protein, and fiber, the intake of vitamin B6 was still inversely related with EAST-AC. The association between EAST-AC and dietary fiber disappeared in the multivariate analysis, whereas total protein intake proved to be positively related with EAST-AC in the multivariate analysis only. The differences between bi- and multivariate analyses are most likely due to the observed interrelationships between intake of vitamin B6, fiber, and protein. It is concluded that dietary fiber does not have a significant impact on the vitamin B6 status among Dutch elderly people, since only protein (positively) and vitamin B6 (inversely) intake appeared to be related with EAST-AC in the multivariate analysis.

Serum SP-1 levels were measured serially in 94 patients with non-seminomatous germ cell tumors to evaluate its clinical significance as a tumor marker. In 12 out of 80 patients (15%) with active tumors serum SP-1 was found to be elevated, whereas serum HCG and AFP in the same sample were raised in 53 and 45% respectively. Elevation of serum SP-1 levels was always associated with raised HCG levels, and with AFP in 7 patients. During chemotherapy, serum SP-1 and HCG disappeared when a complete remission was obtained. In contrast to HCG, serum SP-1 failed to detect tumor progression in two patients. Serum HCG and AFP are superior as tumor markers to serum SP-1.

Protein analyses were performed in 15 cyst fluids (CF) from mature teratoma (TD) and in 15 corresponding sera from 9 nonseminomatous germ cell tumor patients. Qualitatively, many similarities between the protein compositions of CF and corresponding sera were seen. Quantitative comparisons suggested free diffusion of plasma proteins into the cyst lumen in nine cases, whereas in five CF a decreased size selectivity of the blood-TD barrier was observed. From the quantitative data it was concluded that the significantly increased CCF/Cserum concentration ratios for the tumor markers alpha-fetoprotein (8/14), human chorionic gonadotropin (3/14), and carcinoembryonic antigen (13/13) as well as for lysozyme (12/13), ferritin (12/13), and fibronectin (3/6) were either due to local synthesis or to concentrating properties of the TD cells. The results of the current study encourage further research for new tumor-associated proteins in cyst fluids.

Vindesine, a new vinca alkaloid, was administered in thirteen patients with advanced multiple myeloma (stages IIIA and IIIB ), resistant to alkylating agents. Eleven patients received two complete courses and could be evaluated. Six patients ( 55% ) showed objective improvement. This was indicated by a decrease of greater than 50% of pretreatment myeloma protein serum levels, normalization of elevated serum calcium levels, and improvement of haemoglobin concentration and renal function. Neutropenia of short duration, mild paraesthesias and alopecia were noted as side effects.

Immune responsiveness was investigated in a family comprising 12 first- and second-degree relatives, one of whom had k-myelomatosis, one igA-λ paraproteinaemia, two Graves' disease and a further two thyroid antibodies without disease. Relatives by marriage served as controls. Parameters of immune capacity studied were the humoral and cellular immune response to haemo-cyanin of Helix pomatia (HPH), dinitrochloroben-zene (DNCB) skin reactivity and in vitro lymphocyte proliferation capacity to phytohaemagglutinin (PHA). Mean antibody titres to HPH were higher in the family than in the control group in all main Ig classes and IgG subclasses after primary and secondary immunization, and the difference was statistically significant for IgG, IgG2 and IgG4 titres. This could not have been predicted from the (normal) serum Ig levels in this family. In vitro lymphocyte proliferation capacity to HPH after primary and secondary immunization was also significantly increased. DNCB skin reactivity also tended to be high in the family, whereas PHA-induced lymphocyte proliferation was normal. These findings support the idea that myelomatosis clusters in families with immune dysregulation.

Genetic factors have been proposed to play a role in the aetiology of a monoclonal proliferation of B lymphocytes. As an additional genetic factor we postulate that a restriction in the idiotypic variability of an individual contributes to a genetic predisposition to monoclonal gammopathy. To support our hypothesis, we have examined three families with multiple occurrence of M-components for sharing of idiotypic antigenicity between the related M-components and between the M-components and the sera of unaffected relatives. Idiotypic antisera against five isolated M-components were raised in guinea-pigs and used in a radiobinding inhibition assay. In none of the three families was idiotypic cross-reactivity observed between the familial M-components. However, in a family with three members with an M-component, sera of first-degree relatives showed a higher inhibitory capacity than sera of non-related individuals when an idiotypic antiserum, raised against the M-component of proposita, was employed. Within this particular family the observed restriction in the idiotypic variability could have contributed to the multiple occurrence of M-components.

In the present investigation we compared CEA immunoperoxidase staining in testicular tumors (before PVB chemotherapy) and retroperitoneal tumors (after PVB chemotherapy) with CEA levels in the cyst fluid of retroperitoneal mature teratoma and in the patients' serum. CEA had no value as a serum tumor marker since serum CEA elevations were not associated with tumor activity. Only one elevated CEA level after chemotherapy was associated with bleomycin pneumonitis. Despite normal serum levels, CEA was localized immunohistochemically in yolk sac tumor and mature teratoma in the primary tumors and in retroperitoneal mature teratoma following PVB chemotherapy. The presence of CEA in cells lining cystic mature teratoma was associated with high CEA levels in the cyst fluid.

We investigated the reproducibility of the inter- and intra-individual variations in the conversion of nitrate to nitrite in saliva. Saliva samples were collected from 20 volunteers just before and at regular intervals after a nitrate load on four non-consecutive days within a period of 2 months. On three occasions beetroot juice was the nitrate source and on one occasion a nitrate solution was given. Despite large day-to-day variations it was possible to discriminate between subjects with a consistently high or low nitrate conversion after a nitrate load. Neither saliva sampling before a nitrate load nor single saliva samples are sufficient to obtain clear information about individual capacities for nitrate-nitrite conversion.

SummaryThe combination of vindesine and prednisone was administered to twenty-four patients with advanced multiple myeloma, resistant to alkylating agents. Vindesine was given at a dosage of 2 mg/m2 intravenously in two courses of weekly injections combined with oral prednisone. Twenty patients received two complete courses and could be evaluated. Eleven patients (55%) showed objective improvement. Five patients were classified as non-responders, whereas four patients showed progressive disease. Major side effects consisted of neutropenia of short duration, alopecia and mild paresthesias.

Beta 2-microglobulin (B2-m) determinations in serum have recently been introduced as a method of stratifying patients suffering from multiple myeloma. Conflicting results from several studies prompted us to study retrospectively the correlation of B2-m with presenting features and disease stage, as well as the prognostic value of B2-m, in 87 myeloma patients. Significant correlations were found between B2-m and presenting features such as haemoglobin level, serum calcium level and total body myeloma cell mass. The strongest correlation existed between B2-m and serum creatinine (r = 0.68). B2-m did not discriminate between the different disease stages as defined by Durie and Salmon, nor between myeloma Stage IA and monoclonal gammopathy of undetermined significance (MGUS). Considered alone, B2-m was found to have prognostic value in terms of survival. This correlation disappeared after correction for serum creatinine level and tumour load (multivariate analysis). Furthermore, changes in tumour load during therapy were not reflected in changes in B2-m levels, thereby rendering B2-m levels invalid as tumour marker. Our findings indicate no value for B2-m determinations in the staging and follow-up of myeloma patients.

A population of 291 healthy North American Black subjects of different ages was studied for immunoglobulin (Ig) allotypes and the prevalence of autoantibodies, to determine possible associations between Ig allotypes and age, autoantibodies and age, and Ig allotypes and autoantibodies. Indirect immunofluorescence was used to detect anti-gastric parietal cell, anti-smooth muscle, anti-thyroid microsomal, anti-nuclear, and anti-mitochondrial antibodies. The sera were typed for the Ig allotypes Gm(1, 2, 3, 5, 6, 13, 14, 17, and 21) and Km(1) with a hemagglutination-inhibition assay. A significant association between advanced age and an increased prevalence of anti-nuclear antibodies was observed in females. There was no significant association between Ig allotypes and the autoantibodies tested. The results suggest that Ig allotypes are not involved in the development of autoantibodies in healthy Blacks.

In a prospective study serum levels of Alpha Feto Protein (AFP), Human Chorionic Gonadotropin (HCG), Ferritin (SF), Lactoferrin (LF) and Lysozyme (LY) were determined before and during four cycles of combination chemotherapy in 10 patients with disseminated non-seminomatous germ cell tumors (NSGCT) of the testis. The tumor markers AFP and HCG showed markedly different profiles as compared to those for SF, LF and LY. During chemotherapy AFP and HCG levels steadily declined in the nine positive patients. SF, LF, and LY levels were peaking in eight patients. In two patients only SF levels were peaking. SF levels increased during the five days of drug-administration whereas the simultaneous increases of LF and LY followed one week later. The results reject SF as a reliable tumor marker in NSGCT patients and suggest an extra-tumoral origin of SF during combination chemotherapy.

The hemolytic activities (HA) of the classical and alternative pathway of complement activation in the synovial fluids of 26 patients with reumatoid arthritis were compared with the levels of lactoferrin (LF), lysozyme (LY), IgM reumatoid factor (IgM-RF), C3, C4 and protein factor B. Low HA for the classical and the alternative complement pathways was significantly associated with high levels of LF and LY. Preliminary results of dose-response experiments for the influence of LF and LY on the hemolytic systems showed an inhibitory effect of LF but not of LY. These results suggest a regulatory function of LF in the inflammatory process in the knee joint at the level of the complement system.

It is suggested that selenium intake is marginal for a large part of the Dutch popu­lation as compared with the safe and adequate daily dietary intake of 50–200 ig day−1. In order to evaluate the selenium intake, knowledge is required regarding the bioavailability of selenium in the main sources of the average daily selenium supply. The bioavailability of selenium in wheat has been studied (Levander et al. 1983; Thomson et al. 1985), but as far as we know no information is available on the bioavailability of selenium in meat. The aim of this study was to evaluate the influence of a variable selenium intake on various blood parameters and to establish the bioavailability of selenium in wheat products in comparison with that in meat products.

In a retrospective study serumferritin levels were evaluated for their use as tumor associated marker in patients with nonseminomatous testicular tumors(NSTT), and negative for the known markers AFP and HCG. In ten of eleven NSTT patients ferritin levels were within the normal range at the time of tumorload but before chemotherapy. Randomly chosen samples during chemotherapy all but one showed an increase in ferritin levels. After chemotherapy in all samples ferritin levels decreased to the normal range. Multiple ferritin determinations in serumspecimen before, during, and after chemotherapy showed peaking values in direct relationship to the five days induction chemotherapy. Our data reject the suggestion that ferritin is useful as tumor marker in NSTT patients.

In 14 of 35 stage III patients with nonseminomatous testicular tumors (NSTT) elevated activities of Alkaline Phosphatase (AP)(n=13) and/or Gamma-Glutamyl Transpeptidase (GGT)(n=11) were found. The course of both elevated enzyme activities during chemotherapy was very similar to the course of the known tumor markers, AFP, HCG and LDH. This suggests that AP and GGT are synthesized by the tumor cells. The isoenzyme pattern of AP in agar gels showed the presence of the liver-type AP. Surprisingly, in all patients with elevated GGT activities an extra AP band (eAP) was found as well. In the patients with complete remission eAP disappeared. In the three patients with tumor progression and elevated GGT and AP activities, eAP could be visualised. It is concluded that eAP is synthesized by the testicular tumor cells. The concomitant presence of elevated GGT activities and eAP suggests a production in the same tumor cells. The value of eAP as tumor marker is limited. Determination of eAP gives more information than the known tumor markers in only one patient. Characterization of eAP suggests that this enzyme band is the liver-type AP loaded with membrane fragments.