Patterns of carbohydrate intake--a study of typology, associations and changes over time in an elderly Swedish population.

BACKGROUND: Patterns may explain part of the dietary variation between subjects. OBJECTIVE: To create a typology of carbohydrate intake among the elderly and to analyse whether it seems valuable or not. DESIGN: Factor and cluster-analyses of dietary interviews from two elderly cohorts of free-living elderly people in Göteborg, Sweden. SUBJECTS AND METHODS: Three hundred and thirty seven women and three hundred and twenty three men aged 70-79 was studied cross-sectionally and longitudinally. The altogether 917 dietary interviews were based on the dietary history method. Cluster analysis, based on factor scores, was used to create the typology. RESULTS: Seven clusters were identified: 1) Small eaters (high relative intake of starch and a low energy intake), 2) Lean and green eaters (high intake of dietary fibre), 3) Fruit eaters (high intake of monosaccharides), 4) Sweet tooth eaters (high intake of sucrose), 5) Gourmands (high absolute intake of starch, dietary fibre and energy), 6) Milk drinkers (high intake of lactose) and 7) Fat eaters (high intake of fat and low intake of carbohydrates). The different patterns were associated with different food consumption, different intake of micronutrients and different social and physiological factors. There were also changes over time of the proportion of subject within the clusters. CONCLUSIONS: The typology found by using cluster analysis, seems to be valid and was related to all analysed dimensions. Therefore, the methods may be valuable for describing and analysing the dietary intake among elderly.

In vitro models for the blood-brain barrier.

The aim of the present study was to identify a model for the blood-brain barrier based on the use of a continuous cell line, and to investigate the specificity of this model. A set of test compounds, reflecting different transport mechanisms and different degrees of permeability, as well as different physiochemical properties was selected. In vivo data for transport across the blood-brain barrier of this set of test compounds was generated as part of the study using two different in vivo models. A computational prediction model was also developed, based on 74 proprietary Pharmacia compounds, previously tested in one of the in vivo models. Molsurf descriptors were calculated and 21 descriptors were correlated with log(Brain(conc.)/Plasma(conc.)) using partial least squares projection to latent structures (PLS). However, the correlation between predicted and measured values was found to be rather low and differed between one and two log units for several of the compounds. The test compounds were analyzed in vitro using primary bovine and human brain endothelial cells co-cultured with astrocytes, and also using two different immortalized brain endothelial cell lines, one originating from rat and one from mouse. Cell models using cells not derived from the blood-brain barrier, ECV/C6, MDCK and Caco-2 cell lines, were also used. No linear correlation between in vivo and in vitro permeability was found for any of the in vitro models when all compounds were included in the analysis. The highest r2 values were seen in the bovine brain endothelial cells (r2=0.43) and MDCKwt (r2=0.46) cell models. Higher correlations were seen when only passively transported compounds were included in the analysis, bovine brain endothelial cells (r2=0.74), MDCKwt (r2=0.65) and Caco-2 (r2=0.86). By plotting in vivo Papp values against logDpH7.4 it was possible to classify compounds into four different classes: (1) compounds crossing the blood-brain barrier by passive diffusion, (2) compounds crossing the blood-brain barrier by blood-flow limited passive diffusion, (3) compounds crossing the blood-brain barrier by carrier mediated influx, and (4) compounds being actively excreted from the brain by active efflux. Papp and Pe values obtained using the different in vitro models were also plotted against logDpH7.4 and compared to the plot obtained when in vivo Papp values were used. Several of the in vitro models could distinguish between passively distributed compounds and efflux substrates. Of the cell lines included in the present study, the MDCKmdr-1 cell line gave the best separation of passively and effluxed compounds. Ratios between AUC in brain and AUC in blood were also calculated for six of the compounds and compared to ratios between Pe or Papp for transport in the apical to basolateral and basolateral to apical direction. Again the MDCKmdr-1 cell line gave the best correlation with only one compound (AZT) giving large discrepancy between in vitro and in vivo data. None of the in vitro models could identify compounds known to be substrates for carrier mediated influxed as such, and the results indicate that a tighter in vitro blood-brain barrier model probably is needed in order to facilitate studies on carrier mediated influx. The findings presented also indicate that identification of "batteries" of in vitro tests are likely to be necessary in order to improve in vitro-in vivo correlations and to make it possible to perform acceptable predictions of in vivo brain distributions from in vitro data.

B-domain deleted recombinant factor VIII formulation and stability.

B-domain deleted recombinant factor VIII (BDDrFVIII) is a deletion form of human coagulation factor VIII. A lyophilized formulation of highly purified BDDrFVIII has been developed that does not require the use of blood-derived products such as human serum albumin (HSA). By avoiding the use of blood-derived products, the BDDrFVIII formulation minimizes the risk of transmitting blood-borne pathogens that may be present in plasma-derived factor VIII or in other recombinant factor VIII products that contain HSA in their formulation. Upon reconstitution with saline (4 mL), the composition of the reconstituted product (62.5 to 250 IU/mL BDDrFVIII) is 18 mg/mL sodium chloride, 3.0 mg/mL sucrose, 1.5 mg/mL L-histidine, 0.25 mg/mL calcium chloride dihydrate, and 0.1 mg/mL polysorbate 80. The optimal combination of these excipients in the lyophilized BDDrFVIII formulation provides long-term stability, as measured by a variety of analytical methods. The formulation preserves factor VIII activity of lyophilized BDDrFVIII during storage for at least 24 months at 8 degrees C, and for up to 6 months at room temperature (25 degrees C). The reconstituted product retains its factor VIII potency for at least 100 hours at 25 degrees C, which would allow it to be continuously administered via an infusion pump, assuming the product is handled under aseptic conditions.

Theoretical calculation and prediction of drug transport processes using simple parameters and partial least squares projections to latent structures (PLS) statistics. The use of electrotopological state indices.

A method of modeling and predicting drug transport processes using simple, theoretically computed molecular descriptors and multivariate statistics has been investigated in four data sets related to Caco-2 cell permeability, human intestinal absorption, brain-blood partitioning, and immobilized artificial membrane (IAM) chromatography. The program Molconn-Z was used to compute theoretical molecular descriptors related to electrotopological state indices. Additional parameters related to size and lipophilicity [i.e., calculated molar refraction (CMR) and octanol-water partition coefficient (CLOGP)] were also used in the statistical modeling. Good statistical models were derived (r(2) and Q(2) values ranged from 0.75 to 0.93 and 0.70 to 0.89, respectively) that permit fast computational (electronic) screening and prioritization of virtual libraries.

Theoretical calculation and prediction of brain-blood partitioning of organic solutes using MolSurf parametrization and PLS statistics.

Sixty-three structurally diverse compounds were investigated to statistically model the brain-blood partitioning of organic solutes using theoretically computed molecular descriptors and multivariate statistics. The program MolSurf was used to compute theoretical molecular descriptors related to physicochemical properties such as lipophilicity, polarity, polarizability, and hydrogen bonding. The multivariate Partial Least Squares Projections to Latent Structures (PLS) method was used to delineate the relationship between the brain-blood partitioning of organic solutes and the theoretically computed molecular descriptors. Good statistical models were derived. Properties associated with polarity and Lewis base strength had the largest impact on the blood-brain partitioning and should be kept to a minimum to promote high partitioning. The absence of atoms capable of hydrogen bonding interactions as well as high lipophilicity and the presence of polarizable surface electrons, i.e., valence electrons, were also found to promote high brain-blood partitioning. The results indicate that theoretically computed molecular MolSurf descriptors in conjunction with multivariate statistics of PLS type can be used to successfully model the brain-blood partitioning of organic solutes and hence differentiate drugs with poor partitioning from those with acceptable partitioning at an early stage of the preclinical drug-discovery process.

Physical state of L-histidine after freeze-drying and long-term storage.

Liquid samples of L-histidine of varying pH values and mixed with salt, metal ions, polysorbate 80 and sucrose have been analysed by differential scanning calorimetry to evaluate the influence of these additives on the glass transition temperature and crystallisation of L-histidine during freezing and thawing. L-Histidine solutions of varying pH were freeze-dried with and without a thermal cycle and the physical state of the freeze-dried cakes, following long-term storage, were studied by powder X-ray diffraction. Amorphous L-histidine crystallised when it was exposed to moisture, and the identity of the crystalline materials is reported. The crystallisation of L-histidine during freezing and thawing is dependent on the pH of the solution and is shown to be at a minimum at pH 6, which coincides with the pK(a) of the imidazoline function. Sucrose inhibited the crystallisation of L-histidine during thawing, while sodium chloride or polysorbate 80 did not. The addition of metal ions (Ca2+ and Mg2+) up to 10% (w/w) did not depress the glass transition temperature significantly, while the addition of Zn2+ increased it. The physical state of L-histidine after freeze-drying is shown to be dependent on both the pH of the solution and the freezing cycle. The risk of crystallisation of amorphous L-histidine is low if the freeze-dried material is protected from moisture.

Theoretical calculation and prediction of P-glycoprotein-interacting drugs using MolSurf parametrization and PLS statistics.

A method for the modelling and prediction of P-glycoprotein-associated ATPase activity using theoretically computed molecular descriptors and multivariate statistics has been investigated using 22 diverse drug-like compounds. The program MolSurf was used to compute theoretical molecular descriptors related to physicochemical properties such as lipophilicity, polarity, polarizability and hydrogen bonding. The multivariate partial least squares projections to latent structures (PLS) method was used to delineate the relationship between the P-glycoprotein-associated ATPase activity and the theoretically computed molecular descriptors. The PLS analysis of the entire data set, with the exclusion of tamoxifen, resulted in one significant PLS component according to cross-validation with R(2)=0.718, Q(2)=0. 695, S.D.=0.475, F=48.37, RMSE(tr)=0.452, p<0.001. Properties associated with the size of the molecular surface, polarizability and hydrogen bonding had the largest impact on the P-glycoprotein-associated ATPase activity. All these properties should be high to promote high ATPase activity.

Prediction of drug transport processes using simple parameters and PLS statistics. The use of ACD/logP and ACD/ChemSketch descriptors.

A method of modelling and predicting biopharmaceutical properties using simple theoretically computed molecular descriptors and multivariate statistics has been investigated for several data sets related to solubility, IAM chromatography, permeability across Caco-2 cell monolayers, human intestinal perfusion, brain-blood partitioning, and P-glycoprotein ATPase activity. The molecular descriptors (e.g. molar refractivity, molar volume, index of refraction, surface tension and density) and logP were computed with ACD/ChemSketch and ACD/logP, respectively. Good statistical models were derived that permit simple computational prediction of biopharmaceutical properties. All final models derived had R(2) values ranging from 0.73 to 0.95 and Q(2) values ranging from 0.69 to 0.86. The RMSEP values for the external test sets ranged from 0.24 to 0.85 (log scale).

Theoretical calculation and prediction of intestinal absorption of drugs in humans using MolSurf parametrization and PLS statistics.

A method for modeling and prediction of the intestinal absorption of drugs in humans using theoretically computed molecular descriptors and multivariate statistics has been investigated using 20 diverse drug-like compounds. The program MolSurf was used to compute theoretical molecular descriptors related to physicochemical properties such as lipophilicity, polarity, polarizability and hydrogen bonding. The multivariate Partial Least Squares Projections to Latent Structures (PLS) method was used to delineate the relationship between the intestinal absorption of drugs in humans and the theoretically computed molecular descriptors.Good statistical models were derived. Properties associated with hydrogen bonding had the largest impact on absorption and should be kept to a minimum to promote high absorption. High charge-transfer properties and the presence of surface electrons, i.e. valence electrons, which are not tightly bonded to the molecule, were also found to promote high absorption.

Chromatographic retention of drug molecules on immobilised liposomes prepared from egg phospholipids and from chemically pure phospholipids.

The partitioning of a chemically diverse set of drugs into liposomes was studied by immobilised liposome chromatography (ILC). For this purpose liposomes composed of (i) purified egg phospholipids (EPL), (ii) synthetic phosphatidylcholine (PC), (iii) PC--synthetic phosphatidylethanolamine (PE) 80:20 (mol/mol) and (iv) PC--synthetic phosphatidylserine (PS) 80:20 (mol/mol) were immobilised in gel beads by freeze-thawing. The drug partitioning was assessed from the retention volume, which was expressed as a capacity factor, K(s), normalised with respect to the amount of immobilised phospholipid. The drug retention on EPL, PC and PC--PE liposomes was very similar, whereas the negatively charged PC--PS liposomes increased the retention of positively charged and decreased retention of negatively charged drugs. The partitioning of drugs on liposome columns (log K(s)) versus their octanol--water partitioning (log P(oct)) showed three separate rectilinear relationships, depending on the charge of the compound (neutral, positive, or negative). Statistical analysis (ANCOVA) proved that the lines had similar slopes. Repeated analysis of four reference compounds showed a low variation (<0.12 log units) over time (about 250 days). A close relationship was observed between the drug retention in short EPL columns with a low content of phospholipids and the retention in longer standard EPL columns. The short 'quick screen bilayer columns' permit analysis of highly lipophilic compounds within 30 min and are thus applicable for medium-throughput screening in drug discovery settings. A very strong rectilinear relationship (r(2)=0.95, n=13) between log K(s) (EPL) and published liposome partitioning data (log D(mem)) confirmed that the ILC drug retention reflects the drug partitioning into the lipid bilayers. A moderate to fair rectilinear relationship was observed between the normalised retention on PC, PC-PE and EPL liposomes (r(2)=0.79, 0.86 and 0.85, respectively, n=24) and corresponding published log k'(IAM) data obtained on immobilised artificial membrane (IAM) columns. Transport across Caco-2 cell monolayers (log P(c)) showed curvilinear relationships with log K(s), log k'(IAM), log P(oct) and log D(oct). The drug fraction absorbed in humans showed a similar relationship to log K(s) values as to surface plasmon resonance signals representing drug-liposome interaction (Danelian et al., 2000 J Med Chem, 43, 2083--2086).

Tobacco smoking: a major risk factor for loss of teeth in three 70-year-old cohorts.

Oral health was examined in a random sample of 1377 people in three 70-year-old cohorts studied within 5-yr intervals. During the studied period 1971-1983 the prevalence of toothlessness decreased from 52 to 34%. Toothlessness in men was more common in smokers, 48%, and ex-smokers, 32%, than in non-smokers, 20%. Eichner's index was used as a measurement of dental invalidity. This index showed a worse dental state among smokers and ex-smokers compared to non-smokers. Multivariate analyses indicated that tobacco smoking was a major independent risk factor for tooth loss in elderly men.

Dental health and parity in three 70-year-old cohorts.

In three cohorts of 70-yr-olds in Gothenburg, Sweden, born in 1901/02, 1906/07 and 1911/12, the relationship between oral health and parity was studied in 713 women and between oral health and the reported number of children in 660 men of the same cohorts. For women in all three cohorts, the number of teeth decreased in relation to increasing number of children that they had given birth to. Significantly more women with high parity were edentulous in one or both jaws compared to the other groups. Among parous compared to nulliparous women the age for becoming edentulous occurred earlier. The number of intact teeth was lower in parous compared to nulliparous women. Among the men no relation was found between oral health and the number of their children. When socioeconomic factors were taken into consideration the above described relations between declining dental health and increasing parity remained on about the same level of significance. Although pronounced cohort differences were found, a relationship between parity and dental health was found in all cohorts, indicating a general biological influence of repeated pregnancies.

Oral cancer after surgery for peptic ulcer.

Oral cancer was studied in a population of 3435 which constituted all persons who were operated upon because of peptic ulcer in Gothenburg 1952-61. This population formed a data base which was coordinated with the National Cancer Register and the Register of Causes of Deaths in Sweden. The expected number of oral cancers was 7.7 and the observed number was 17 (P less than 0.01). In gerontologic population studies of the elderly in Gothenburg it was shown that 70-yr-old men with a history of peptic ulcer surgery more often were tobacco smokers, edentulous and more often had sideropenic and megaloblastic anemia and also had a lower bone mineral content.

Symptoms and signs of mandibular dysfunction in 70-year-old men and women in Gothenburg, Sweden.

A representative systematic selection of 30% of all 70-year-olds in Gothenburg were invited to a population study. Forty percent of the sample (384 persons) were subjected to a comprehensive dental examination. The participation rate was 84%. The aim of the present study was to describe the function and dysfunction of the masticatory system of the 70-year-olds. 41% reported no symptoms of dysfunction while 46% had severe dysfunction according to HELKIMO'S Anamnestic Dysfunction Index. The clinical examination revealed that only 14% had no signs of dysfunction. 32% had moderate or severe dysfunction according to Helkimo's Index. In more than half of the subjects the masticatory muscles were tender to palpation and in 37% TMJ sounds were diagnosed. Several of the clinical findings were more common in the women than in the men but only concerning tenderness of the TMJ and the masseter muscle were the differences significant. The degree of dental invalidity was measured by Eichner's Index. The Index showed no or only weak relation to the Anamnestic and Clinical Dysfunction Indices. Neither did the degree of dysfunction in complete denture wearers vary with the condition of their prostheses.

Dental health and functional ageing. A study of 70-year-old people.

Functional ageing, including dental health, was studied in the gerontological population study in Gothenburg. This study was based on three 70-yr-old cohorts, born in 1901-2, 1906-7, and 1911-12 (n = 1380). The Eichner index was used as a measurement of deterioration in dental state and dental functional impairment. This impairment was significantly associated with a lower capacity in cognition, visual ability, hearing ability, lung volume, heart volume, muscle strength, and bone mineral content as well as a lower self-assessment of health. A multiple regression model showed that an index of seven functional capacities was the most predictive factor for dental status independent of confounding factors such as socioeconomic factors, tobacco smoking, and the most incapacitating diseases. These associations were more marked in men and the survival rate between 70 and 79 years of age was higher among men with a well preserved dental state of the age of 70. The co-variation between impairment in dental function and other functional variables and survival indicate a common functional ageing.

Cohort comparisons of dental status in the adult Swedish population between 1975 and 1981.

The aim was to describe and analyze changes in dental status in Sweden over a 6-yr period, and to establish a baseline for a subsequent investigation. Representative samples of the Swedish population in 1975, 1977, and 1981 were investigated by means of interviews. The participation rate varied between 81 and 86% and the number of participants between 11,582 and 14,964. Dental status, based on a question about natural teeth and/or removable denture(s), was analyzed in relation to demographic, socio-economic, social support and life style factors. The prevalence of edentulism in the age group 16-74 years decreased during the observation period from 12.7% to 9.9% in men and from 15.5% to 11.2 in women. Besides age, urbanization, occupation and tobacco smoking had the highest explanatory value for edentulism. The findings are discussed with respect to the increasing life expectancy and possible changes in the need and demand for dental care.

Prognosis of and factors associated with dental status in the adult Swedish population, 1975-1989.

The aim was to describe changes in dental status in the Swedish population during the period 1975-89 and to make a prognosis based on these data for the year 2000. This study is based on investigations of the living conditions in 1975, 1977, 1980/81 and 1988/89 performed by The National Central Bureau of Statistics. The samples varied for each year from 11,500 to 15,000 participants and a response rate from 80 to 86%. The odontological questions of the interview were focused on dental status, utilization of dental services and chewing ability. The prevalence of edentulism in age group 16-74 yr decreased from 15% in 1975 to 6% in 1988/89. In 1988/89 19% of the 65-74-yr-old inhabitants of the big cities were edentulous and 45% in rural populations, indicating a 15-20-yr delay of the development in rural areas. The prognosis for the year 2000 indicates a further decrease of edentulism to 3-4% in age groups 45-64 yr and in age 75-84 yr more than 60% will be dentate. As a consequence of the reduction in edentulism and changes in populations the number of dentate inhabitants in age group 25-74 yr increased by about 800,000 from 1975 to 1989 and a further increase of 400,000 will occur up to the year 2000. The consequences of these changes for the dental care services are discussed.

Smoking habits and tooth loss in Swedish women.

A longitudinal population study of 1462 women, aged 38-60, was started in Gothenburg, Sweden, in 1968-69. In univariate analysis of the results from 1968-69, smokers were found to have a significantly lower number of remaining teeth than non-smokers had. The differences between smokers and non-smokers with respect to edentulousness and number of remaining teeth was further accentuated 12 yr later. The mean number of teeth lost during the 12-yr follow-up period was 3.5 among smokers and 2.1 among non-smokers, i.e. 67% higher among smokers than among non-smokers. The associations were independent of age, education, socio-economic group, marital status, frequency of toothbrushing, and frequency of visits to a dentist. It is concluded that smoking seems to play an important role as far as tooth loss is concerned.

Variation in dental health in 70-year old men and women in Göteborg, Sweden. A cross-sectional epidemiological study including longitudinal and cohort effects.

Within the framework of an epidemiological, initially cross-sectional and subsequently longitudinal, population study of 70-year-old people, a representative sample of 386 subjects were subjected to odontological investigation. Forty six per cent of the men and 55% of the women were edentulous in both jaws and 20% of the men and 19% of the women were edentulous in one jaw. In dentulous subjects the mean number of teeth was 13.6 (men) and 13.5 (women). The tooth mortality rate was higher in the upper than in the lower jaw and higher in the lateral segments of the jaws than in the frontal region. The mean number of carious teeth was 3.2 for men and 2.4 for women and the mean number of intact teeth was 4.8 in men and 3.4 in women (p less than or equal to 0.05). Fifty four per cent of remaining teeth had been restored in men and 73% in women (p less than or equal to 0.01). Significantly more upper teeth were restored than lower teeth. Half of the dentulous subjects had worn their dentures for more than 10 years and only 14% had satisfactorily functioning dentures and acceptable occlusion. Poor retention and poor stability were very common in unsatisfactory dentures, more so in the upper than in the lower jaw. The proportion of dentures with these faults increased with increasing age of the dentures. The degree of dental invalidity was classified according to Eichner's index. This index was strongly correlated to the number of teeth and tooth contacts (p less than or equal to 0.001). The Eichner index covaried with frequency of visits to the dentist and special background factors such as income, education, marital status and past and present smoking habits. Married men tended to have a better level of dental health than other men (p less than or equal to 0.01), while the reverse was true for women. About half of the dentulous subjects were in need of prosthetic treatment and slightly less than half of them needed conservative dental treatment. Sixty per cent of edentulous subjects needed new dentures. The longitudinal comparisons between the ages of 70 and 75 showed small changes in dental invalidity. In a new cohort of 70-year-olds examined 5 years later the proportion of edentulous was significantly lower than in the first 70-year-old cohort.