Longitudinal changes in quality of life among elderly people with and without dementia.

ABSTRACTObjective:To study longitudinal changes in the quality of life (QoL) in persons with and without dementia, and explore the factors associated with baseline QoL and changes of QoL over the follow-up period. DESIGN: Prospective longitudinal study. SETTING: Data were collected from 17 municipalities in Norway in the period from January 2009 to August 2012. A total of 412 persons were included, 254 (61.7 %) persons without dementia and 158 (38.3 %) with dementia at baseline. SUBJECTS: Persons 70 years of age or older, receiving municipal care services. Main outcome measures include the following: self-rated and proxy-rated QoL over a period of 18 months, cognitive status, functional status, neuropsychiatric symptoms, and demographics. RESULTS: Longitudinal changes in QoL were small, despite changes in clinical variables. Proxy ratings of patients QoL were lower than the patients' own ratings. Belonging to a group with low QoL trajectory was associated with symptoms of depression, reduced physical and instrumental functioning, and more severe dementia. CONCLUSION: Patients and proxies evaluated the patients' QoL differently and QoL did not necessarily correspond with deterioration in clinical parameters. To prevent impaired QoL, we need to address identified factors and keep an approach open to the individual perceptions of QoL.

Change in psychotropic drug use in Norwegian nursing homes between 2004 and 2011.

ABSTRACTBackground:We aimed to assess whether there were any changes in the use of psychotropic drugs in Norwegian nursing homes between 2004 and 2011. Also, we investigated whether the predictors of use of specific psychotropic drug groups have changed. METHODS: We conducted a secondary analysis of two cohort studies of two Norwegian nursing home samples (2004/05 and 2010/11). Multivariate models were applied. RESULTS: We found a significant decrease in the prescription of antipsychotic drugs between 2004 and 2011 (0.63 OR, 95%CI = 0.49-0.82, p < 0.001) even after adjusting for relevant demographic and clinical variables. There are only minor changes for the other psychotropic drugs. We found that (1) the use of specific psychotropic drug groups as well as the number of psychotropic drugs used was associated with more affective symptoms and (2) the use of specific psychotropic drug groups as well as the number of psychotropic drugs used was associated with lower scores on the Physical Self-Maintenance scale. CONCLUSION: This is the first study to show a robust decrease in antipsychotic drug use in nursing home patients with dementia unrelated to possible changes in case mix. The change might be explained by treatment recommendations against its use except in the most severe conditions of aggression or psychosis. Our findings indicate that it takes several years to implement scientific knowledge in clinical practice in nursing homes.

The impact of dementia on the use of general practitioners among the elderly in Norway.

OBJECTIVE: To assess the use of general practitioners (GPs), in elderly home-dwelling persons in Norway and explore the impact of cognitive decline, age, and living situation. DESIGN: Prospective longitudinal study. SETTING: Data were collected from municipalities in four counties in Norway in the period from January 2009 to August 2012. SUBJECTS: Home-dwelling persons 70 years of age or older, receiving in-home care. MAIN OUTCOME MEASURES: Use of GPs over a period of 18 months related to cognitive state, functional status, neuropsychiatric symptoms, and demographics. RESULTS: A total of 599 persons were included. The mean annual number of consultations per participant was 5.6 (SD = 5.4). People with moderate to severe dementia had fewer consultations per year compared with those with mild or no dementia (3.7 versus 5.8 per year, p = 0.004). In the multivariate model higher age predicted fewer consultations while affective neuropsychiatric symptoms were associated with an increase in frequency of consultations. The most frequent reason to consult a GP was cardiovascular diseases (36.8% of all consultations), followed by musculoskeletal complaints (12.1%) and psychiatric diagnoses (8.7%). CONCLUSION: Our study shows that the home-dwelling elderly with moderate to severe dementia in Norway consult their GP less often than persons with mild or no dementia. This could indicate a need for better interaction between the municipal care and social services and the general practitioners.

The age and size of the universe.

Modern distance determinations to galaxies were reviewed and placed on a uniform and self-consistent scale. Based on eight separate but not entirely independent techniques, the distance to the Virgo cluster was found to be 15.8 +/- 1.1 megaparsec. Twelve different determinations yield a Coma/Virgo distance ratio of 5.52 +/- 0.13 and hence a Coma distance of 87 +/- 6 megaparsec. With a cosmological redshift of 7210 kilometers per second, this gives a Hubble parameter H(0) (local) of 83 +/- 6 kilometers per second per megaparsec. From the velocity-distance relation of rich clusters of galaxies, the ratio of the value of H(0) (global) to the value of H(0) (local) was determined to be 0.92 +/- 0.08. In other words, the cluster data do not show a statistically significant difference between the local and global values of the Hubble parameter. If one nevertheless adopts this relation between H(0) (global) and H(0) (local), then the value of H(0) (global) is 76 +/- 9 kilometers per second per megaparsec. This observed value differs at the approximately 3sigma level (where sigma is the standard deviation of the distribution) from values in the range 36 less, similar H(0) less, similar50 kilometers per second per megaparsec, which are derived from stellar evolutionary theory in conjunction with standard cosmological models with a density parameter (Omega) that is equal to 1 and a cosmological constant (lambda) that is equal to 0.

Size and age of the universe.

The age of the universe based on abundances of isotopes is in the range 10 billion to 15 billion years. This is consistent with the age range 12 billion to 20 billion years calculated from the evolution of the oldest galactic stars. A third estimate of the age of the universe is based on the Hubble relation between the velocities of galaxies and their distances from us, where the inverse of the Hubble parameter H is a measure of the age of a uniformly expanding universe. Evidence that has been accumulating over the past few years indicates that the expansion of the universe may exhibit a rather large local perturbation due to the gravitational attraction of the Virgo supercluster. Different types of observations still produce conflicting evidence about the velocity with which the Local Group of galaxies (of which our Milky Way system is a member) is falling into the Virgo cluster. The results to date indicate that this velocity lies somewhere in the range 0 to 500 kilometers per second. The resulting ambiguity in the flow pattern for relatively nearby galaxies makes values of H derived from galaxies with radial velocities less than 2000 kilometers per second particularly uncertain, and this restricts determinations of H to distant galaxies, for which distances are particularly uncertain. The best that can be said at present is that H(-1) yields a maximum time scale in the range 10 billion to 20 billion years.

The morphological evolution of galaxies.

Many galaxies have taken on their familiar appearance relatively recently. In the distant Universe, galaxy morphology deviates significantly (and systematically) from that of nearby galaxies at redshifts (z) as low as 0.3. This corresponds to a time approximately 3.5 x 10(9) years in the past, which is only approximately 25% of the present age of the Universe. Beyond z = 0.5 (5 x 10(9) years in the past), spiral arms are less well developed and more chaotic, and barred spiral galaxies may become rarer. At z = 1, around 30% of the galaxy population is sufficiently peculiar that classification on Hubble's traditional "tuning fork" system is meaningless. On the other hand, some characteristics of galaxies have not changed much over time. The space density of luminous disk galaxies has not changed significantly since z = 1, indicating that although the general appearance of these galaxies has continuously changed over time, their overall numbers have been conserved.

Galaxies, human eyes, and artificial neural networks.

The quantitative morphological classification of galaxies is important for understanding the origin of type frequency and correlations with environment. However, galaxy morphological classification is still mainly done visually by dedicated individuals, in the spirit of Hubble's original scheme and its modifications. The rapid increase in data on galaxy images at low and high redshift calls for a re-examination of the classification schemes and for automatic methods. Here are shown results from a systematic comparison of the dispersion among human experts classifying a uniformly selected sample of more than 800 digitized galaxy images. These galaxy images were then classified by six of the authors independently. The human classifications are compared with each other and with an automatic classification by an artificial neural network, which replicates the classification by a human expert to the same degree of agreement as that between two human experts.

The oxidation of long-chain unsaturated fatty acids by isolated rat liver mitochondria as a function of substrate concentration.

1. The oxidation of linoleate by rat-liver mitochondria has been studied as a function of substrate concentration. The oxidation of other long-chain unsaturated fatty acids shows similar characteristics. 2. At low concentrations, linoleate is readily oxidized in the absence of carnitine. Its rate of activation by the intramitochondrial acyl-CoA synthetase (EC 6.2.1.2) and subsequent oxidation is limited by the availability of intra-mitochondrial ATP. 3. A gradual increase of the linoleate concentration leads to (i) a strong depression of the rate of linoleate oxidation, and (ii) uncoupling of respiratory-chain phosphorylation together with induction of a mitochondrial ATPase activity. At still higher linoleate concentrations this ATPase activity is lowered rather than further stimulated and, concomitantly, the rate of linoleate oxidation increases again. 4. Evidence is presented that the inhibition by linoleate of the ATPase activity occurs at the level of the ATPase complex itself. This oligomycin-like effect of linoleate allows intramitochondrial linoleate activation to take place at the expense of ATP derived from substrate-level phosphorylation. 5. At very high concentrations of linoleate, its detergent action predominates and causes a complete inhibition of respiration as well as an extensive stimulation of an oligomycin-insensitive, Mg2+-dependent ATPase activity. 6. Measurement of the binding of radioactively labelled linoleate by isolated mitochondria shows that, at a given ratio of linoleate to mitochondrial protein, the ratio of bound to added linoleate is dependent on the concentration of the mitochondria.

Accumulation of pyruvate by isolated rat liver mitochondria.

1. Various methods to measure the rate of accumulation of [3-14C]pyruvate in the sucrose-impermeable space of isolated rat liver mitochondria are tested and compared with respect to their ability to distinguish between carrier-linked pyruvate transport and non-carrier-linked processes (adsorption and diffusion). 2. Evidence is presented that the cinnamic acid derivatives commonly used as specific inhibitors of the pyruvate carrier (i) do not completely abolish all carrier-mediated pyruvate transport; (ii) inhibit pyruvate adsorption, and (iii) at higher concentrations lead to a removal of previously accumulated pyruvate from the mitochondria. It is concluded that procedures which avoid the use of transport inhibitors allow more reliable estimates of carrier-linked pyruvate transport. 3. It is proposed to measure pyruvate adsorption as the accumulation of pyruvate in the presence of an uncoupler. Using this procedure, it could be shown that, with 1 mM pyruvate, adsorption represents only a small part of the total pyruvate accumulation, the main part being carrier-linked transport driven by the pH gradient across the mitochondrial inner membrane.

Persistent changes in the initial rate of pyruvate transport by isolated rat liver mitochondria after preincubation with adenine nucleotides and calcium ions.

1. Preincubation of isolated rat-liver mitochondria in the presence of adenine nucleotides or Ca2+ results in definite and persistent changes in the initial rate of pyruvate transport. 2. These changes in the rate of pyruvate transport are accompanied by equally persistent changes in the opposite direction of the activity of pyruvate dehydrogenase (EC 1.2.4.1). 3. Changes of the transmembrane pH gradient and of the membrane potential, brought about by the pretreatments of the mitochondria, cannot account for the observed changes in the rate of pyruvate transport. 4. It is proposed that the pretreatment of the mitochondria directly modulates the activity of the mitochondrial pyruvate carrier. The possible regulatory role of such a modulation system is discussed.

Semi-automated solid-phase DNA sequencing.

Increasing the efficiency of DNA sequencing necessitates the development of systems which reduce the need for manual operations by integrating template preparation, sequencing reactions, product separation and detection. A semi-automated system, whereby PCR-amplified biotinylated genomic or plasmid DNA is immobilized on streptavidin-coated magnetic beads, has been developed.

Analysis of a polyketide synthesis-encoding gene cluster of Streptomyces curacoi.

A gene cluster homologous to the beta-ketoacyl synthase-encoding gene, actl, was cloned by Southern blot hybridization from Streptomyces curacoi, and a 5469-bp fragment was sequenced. Analysis of the sequence revealed seven open reading frames (ORFs). A striking similarity to the whiE locus (encoding spore pigment synthesis) of Streptomyces coelicolor was found throughout the whole cluster, with conservation of the size and position of the seven ORFs. The structure of these two gene clusters suggests that they have a common origin, although the lower similarity in the noncoding regions suggests that the regulatory regions have diverged through evolution.

Glycogen metabolism in Schistosoma mansoni worms after their isolation from the host.

Adult Schistosoma mansoni worms rapidly degrade their endogenous glycogen stores immediately after isolation from the host. In NCTC 109 or in a diphasic culture medium the glycogen levels slowly recovered again after the initial decrease. The rapid degradation of glycogen could be prevented, even in a simple salt medium, if 100 mM glucose and 1% bovine serum albumin were present. Incubations with 14C-labelled glucose under different conditions revealed that the degradation of glycogen was induced by the limited catabolism of external glucose. Conditions are described which induce glycogen degradation or resynthesis by S. mansoni. The physiological function of the glycogen stores is probably to provide substrate during periods of insufficient supply of external glucose. It is speculated that such periods occur when the worm pair moves into the small mesenteric veins of the host. This hypothesis explains the remarkable wandering behaviour of the parasite in the mesenteric veins, since the schistosomes would have to return to larger vessels when their endogenous glycogen stores are exhausted.

The reversible effect of glucose on the energy metabolism of Schistosoma mansoni cercariae and schistosomula.

This study on isolated cercarial bodies demonstrates that the biological transformation from cercaria to schistosomulum and the biochemical transition from an aerobic to an anaerobic energy metabolism are separate processes, which are not necessarily linked. The metabolic transition depends on the external glucose concentration and is fully reversible. In the presence of only a tracer amount of [6-14C]glucose, carbon dioxide was the major end product, but at higher glucose concentrations mainly lactate was formed. This effect could be demonstrated in cercarial bodies in water as well as in fully transformed schistosomula. In non-transformed cercariae a change towards a more anaerobic energy metabolism could be induced by an increase in the external glucose concentration, which demonstrated that the biochemical transition can occur in the absence of the biological transformation. Furthermore, the biological transformation can occur without a concomitant biochemical transition: in the presence of 5 mM glucose, lactate production by cercarial bodies during transformation was increased 50-fold, whereas in the presence of only a tracer amount of glucose the metabolic profile remained that of cercariae. Also, in fully transformed schistosomula, this transition to a more anaerobic energy metabolism was induced by increased glucose concentrations, but at low glucose concentrations carbon dioxide was the major end product, as in cercariae. The effect of external glucose on the metabolism was fully reversible. After a high glucose concentration had induced a more anaerobic metabolism in cercariae in water, the metabolism returned to an aerobic one upon removal of the glucose. Likewise, the metabolism in schistosomula switched back and forth between anaerobic and aerobic patterns, following successive changes in the glucose concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Differences in intermediary energy metabolism between juvenile and adult Fasciola hepatica.

A comparison of glucose catabolism by juvenile and adult liver flukes, Fasciola hepatica, showed that in the adult the cytosolic degradation of glucose via phosphoenolpyruvate carboxykinase (PEPCK) was the most important route, whereas in the freshly excysted juvenile a large part was degraded via pyruvate kinase (PK). However, it was also shown that the adult did not exclusively use the PEPCK pathway, nor did the juvenile exclusively use the PK pathway. When the juvenile was forced to anaerobic functioning it produced propionate and acetate just like the adult, but this did not imply that it switched to the pathways of the adult: the pathway via PK remained important. Malic enzyme (NADP(H)-dependent) was demonstrated to be present in the cytosol and in the mitochondria of both juveniles and adults. These enzyme activities enable the parasite to use a mixture of malate and pyruvate in any ratio as substrate for the mitochondrial production of propionate and acetate. Pyruvate dismutation was important in the anaerobically functioning juvenile, whereas in the adult malate was the major, but not the only mitochondrial substrate. The pH profiles of PK and PEPCK showed that the pathway of PEP metabolism at the PK/PEPCK branchpoint can be regulated by the pH. However, the end products of glucose breakdown were not dependent on the pH. During its development, the liver fluke will gradually be forced to anaerobic functioning. At first, the acidic end product will favour a partitioning of PEP at the PK/PEPCK branchpoint towards malate formation. Later, a lasting predominance of the PEPCK pathway occurs as PK activity almost completely disappears.(ABSTRACT TRUNCATED AT 250 WORDS)

The energy metabolism of Fasciola hepatica during its development in the final host.

Mature liver flukes, Fasciola hepatica, of different ages were isolated from the bile ducts of experimentally infected rats. Their energy metabolism was studied during aerobic incubation with [6-14C]glucose. The results showed that the aerobic potentials of the parenchymal liver flukes are not lost immediately after arrival in the bile ducts, but in a later phase. During the development of the newly excysted juvenile into the mature adult the major part of ATP production in aerobic incubations is successively contributed by three different pathways of glucose breakdown. The Krebs cycle, which is by far the main energy-yielding pathway of the juvenile fluke, is gradually replaced by aerobic acetate formation and, finally, by the anaerobic dismutation reactions of the adult liver fluke. This observed decrease in Krebs-cycle activity per mg protein is not the result of a decrease in activity per individual fluke. The Krebs-cycle activity per fluke actually increases enormously during its whole development. This indicates that the aerobic potential of adult F. hepatica is not just a remnant of earlier aerobic stages but that classical, mammalian type mitochondria are produced during the entire development of the fluke. Calculations are presented which demonstrate that the Krebs-cycle activity of the developing F. hepatica is directly proportional to the surface area of the fluke. This supports our view that Krebs-cycle activity is limited by the diffusion of oxygen and can only occur in the outer layer of the liver fluke during its entire development in the final host.

Changes in energy metabolism of the juvenile Fasciola hepatica during its development in the liver parenchyma.

Juvenile Fasciola hepatica at different stages of development were isolated from the liver parenchyma of experimentally infected rats. Their energy metabolism was studied by incubation with D-[16-14 C]glucose and compared with that of juveniles isolated immediately after in vitro emergence from the metacercarial cysts. These studies confirmed that freshly excysted juveniles have an aerobic energy metabolism, but are already fully equipped for life in the absence of oxygen. A functioning Krebs cycle was a true characteristic of all parenchymal stages of F. hepatica, but its capacity slowly decreased during development. Concomitantly, acetate became the major end product. This formation of acetate was an aerobic process and it was the most important source of energy for the exponentially growing fluke after twelve days of development. It might, therefore, be an important new target for anthelmintics. The decrease in Krebs cycle activity was not caused by a lack of oxygen nor by a decreased capacity of the respiratory chain. The freshly excysted juvenile had endogenous glycogen stores which were degraded during fasting and replenished in the presence of glucose.

The aerobic energy metabolism of the juvenile Fasciola hepatica.

Juvenile Fasciola hepatica were isolated immediately after in vitro emergence from the metacercarial cysts and incubated with uniformly labelled glucose. Under aerobic conditions, carbon dioxide was the main end product of glucose breakdown. In the absence of oxygen, glucose was fermented mainly to propionate and acetate in a molar ratio of 2 : 1, with lactate as a minor product. This anaerobic end-product pattern closely resembles that of the adult liver fluke. In the presence of oxygen and 1 mM cyanide, lactate accumulated. The difference between anaerobic glucose breakdown and that in the presence of cyanide is explained by an inhibitory effect of cyanide on the malic enzyme (EC 1.1.1.40) of the juvenile mitochondria. A substantial Pasteur effect is calculated from these incubations. The oxygen consumption of the juveniles was completely cyanide-sensitive. From these results it is concluded that in aerobic conditions the juvenile liver flukes have an aerobic energy metabolism. Since they can survive prolonged periods of anaerobiosis, they should be called facultative anaerobes.

Substrate cycling between glucose 6-phosphate and glycogen occurs in Schistosoma mansoni.

The regulation of glycogen metabolism in Schistosoma mansoni was studied in vitro with special emphasis on the possible occurrence of substrate ('futile') cycling. The partition of label between carbon atoms 1 and 6 of the glucose units in glycogen was analysed after the incubation of intact worm pairs in the presence of [6-14C]glucose. Under all conditions tested, more than 99% of the label in glycogen was still in the 6 position, demonstrating that glycogen was synthesised not via an indirect pathway involving 3-carbon units, but directly, from glucose. Increasing the glucose concentration stimulated glycogen synthase and decreased the activity of glycogen phosphorylase. An inverse relationship was shown between the actual glycogen content and the rate of glycogenesis. Substrate cycling occurred between glucose 6-phosphate and glycogen. Glucose was incorporated into glycogen during periods of net glycogen breakdown, and vice versa: glycogen degradation occurred during periods of net glycogen synthesis. Under our experimental conditions of net glycogen degradation, the rate of glycogen synthesis as a percentage of that of glycogen breakdown was dependent on the external glucose concentration and ranged from 5 to 68% for 2 to 100 mM glucose, respectively. The synthesis of glycogen during periods of net glycogen breakdown was shown to occur in each individual worm pair.

Continuous synthesis of glycogen by individual worm pairs of Schistosoma mansoni inside the veins of the final host.

Hamsters infected with Schistosoma mansoni were operated upon to install a permanent canula into their blood stream. After recovery of the hamster, this canula was used for the injection of radioactively labelled glucose. In this way the glycogen metabolism of S. mansoni could be studied while the parasites remained undisturbed in their natural habitat. The consecutive injection of [U-14C]glucose and [1-3H]glucose permitted an analysis of possible changes in the glycogen synthesis of individual worm pairs with time. The results showed that the synthesis of glycogen by each worm pair was fairly constant with time. Furthermore, all individual worm pairs synthesised glycogen continuously; not even 2 min passed without its formation. Only small differences in glycogen synthesis were observed between parasites isolated from different locations in the veins of the hamster. These results exclude the possibility that the worm pairs had alternating periods of glycogen synthesis and degradation, and they also disprove the idea that synthesis and degradation occur at two different sites in the bloodstream of the hamster. The experiments further showed that glycogen synthesis was proportional to the amount of glycogen already present, which in turn was shown to be proportional to the size of the parasite. From this study it can be concluded that the replenishment of the endogenous glycogen reserves of S. mansoni is not induced by a marked decrease in the glycogen levels, but occurs slowly and continuously.