Perceived barriers and solutions by generalist physicians to work towards timely young-onset dementia diagnosis.

Objectives: Timely diagnosis of young-onset dementia (YOD) is an important prerequisite to initiate appropriate support. However, YOD diagnosis is often late. We aimed to explore the perspectives of referring general practitioners and occupational physicians, to better understand their barriers to YOD diagnosis and reveal potential solutions to facilitate timely diagnosis.Methods: We conducted 16 semi-structured qualitative interviews with general practitioners and occupational physicians in the Netherlands. Inductive thematic analysis was applied to the transcripts with a team including researchers from various (clinical) backgrounds.Results: Thematic analysis revealed three themes related to: (1) disease characteristics that hinder YOD recognition, being the low incidence and the fact that they mimic other prevalent conditions like burn-out and depression; (2) physicians' attitudes that delay YOD diagnosis, as fear of mis-diagnosis and therapeutic nihilism; and (3) proposed solutions to navigate the challenging YOD diagnostic trajectory including monitoring people with depression and burn-out to consider YOD when recovery stagnates, and more effective interprofessional collaboration.Conclusion: In this study, referring physicians confirmed barriers known to YOD diagnosis and suggested potential solutions to improve YOD diagnosis. Future prospective studies in people with a primary diagnosis of depression or burn-out may show whether these interventions are potentially effective.

A calibrated UV-LED based light source for water purification and characterisation of photocatalysis.

Photocatalysis has a potential to become a cost effective industrial process for water cleaning. One of the most studied photocatalysts is titanium dioxide which, as a wide band gap semiconductor, requires ultraviolet (UV) light for its photoactivation. This is at the wavelengths where the efficiency of present-day light emitting diodes (LEDs) decreases rapidly, which presents a challenge in the use of UV-LEDs for commercially viable photocatalysis. There is also a need for accurate photocatalysis measurement of remediation rates of water-borne contaminants for determining optimum exposure doses in industrial applications. In response to these challenges, this paper describes a UV-LED based photocatalytic test reactor that provides a calibrated adjustable light source and pre-defined test conditions to remove as many sources of uncertainty in photocatalytic analysis as possible and thereby improve data reliability. The test reactor provides a selectable intensity of up to 1.9 kW m-2 at the photocatalyst surface. The comparability of the results is achieved through the use of pre-calibration and control electronics that minimize the largest sources of uncertainty; most notably variations in the intensity and directionality of the UV light emission of LEDs and in LED device heating.

The interaction of adriamycin with cardiolipin in model and rat liver mitochondrial membranes.

The interaction of adriamycin with cardiolipin in model membranes and in various membrane preparations derived from rat liver mitochondria was studied and the results are analyzed in the light of a possible specific interaction between adriamycin and cardiolipin. It was found that adriamycin binds to cardiolipin-containing model membranes with a fixed stoichiometry of two drug molecules per cardiolipin. Furthermore, the extent of drug complexation by mitochondria and mitoplasts (inner membrane plus matrix) is in reasonable agreement with their cardiolipin content. In contrast, adriamycin-binding curves of inner membrane ghosts and submitochondrial particles reveal considerable association to an additional site, presumably RNA. The evidence for the potential importance of RNA as a target comes from experiments on outer membranes and microsomes which both appear to bind substantial amounts of adriamycin. Removal of the major part of the RNA associated with these fractions by EDTA treatment is accompanied by a dramatic reduction of binding capacity. We propose that endogenous RNA present in mitochondria and mitoplasts is not accessible for adriamycin at low concentrations of the drug due to the presence of an intact lipid barrier. This potential site comes to expression in ghosts and submitochondrial particles, due to the absence of an intact lipid bilayer and due to the inside-out orientation of the limiting membrane, respectively. Electron microscopical studies show that adriamycin induces dramatic changes in mitochondrial morphology, similar to the uncoupler-induced effects described by Knoll and Brdiczka (Biochim. Biophys. Acta 733, 102-110 (1983). Adriamycin has an uncoupling effect on mitochondrial respiration and oxidative phosphorylation. The concentration dependence of this effect correlates with the adriamycin-binding curve for mitochondria which implies that only bound adriamycin actively inhibits respiration.

Localization of aromatase in the brain of the male African catfish, Clarias gariepinus (Burchell), by microdissection and biochemical identification.

Aromatase activity was determined in small discrete areas of the brain of the African catfish, Clarias gariepinus, by a radiometric assay. The fore- and midbrain were divided into eighteen 500-microns transverse sections. From these sections several punches (0.3 mg of tissue) were taken and incubated with [19-3H]-androstenedione. The aromatase activity, calculated from the release of tritium label during aromatization, is expressed in pmol mg-1 tissue hour-1. The highest activity (3.7 pmol) was detected in the preoptic region. The more caudally located area tuberalis, including the nucleus lateralis tuberis and the nucleus recessus lateralis, also showed a relatively high activity (2.5 pmol). A similar activity was found in the most rostral part of the telencephalon and the dorsal parts of the mesencephalon, i.e., the tectum opticum and torus semicircularis (2.3 pmol). A moderate aromatase activity was observed in remaining parts of the brain, except the cerebellum and hindbrain, in which aromatase activity was hardly detectable (0.1-0.3 pmol). It is concluded that a high aromatase activity is present in regions known to be involved in the regulation of reproduction. Since both the torus semicircularis and the tectum opticum display a high aromatase activity, it is suggested that also these structures are involved in reproductive processes.

Selective precipitation of Cu from Zn in a pS controlled continuously stirred tank reactor.

Copper was continuously and selectively precipitated with Na(2)S to concentrations below 0.3 ppb from water containing around 600 ppm of both Cu and Zn in a Continuously Stirred Tank Reactor. The pH was controlled at 3 and the pS at 25 (pS=-log(S(2-))) by means of an Ag(2)S sulfide selective electrode. Copper's recovery and purity were about 100%, whereas the total soluble sulfide concentration was below 0.02 ppm. X-ray diffraction (XRD) analysis showed that copper precipitated as hexagonal CuS (covellite). The mode of the particle size distribution (PSD) of the CuS precipitates was around 36 microm. The PSD increased by high pS values and by the presence of Zn. Depending on the turbulence, the CuS precipitates can grow up to 200 microm or fragment in particles smaller than 3 microm in a few seconds. Zn precipitation with Na(2)S at pH 3 and 4, in batch, always lead to Zn concentrations above 1 ppm. Zn precipitated as cubic ZnS (spharelite).

Measurement of aromatase activity in the brain of the African catfish, Clarias gariepinus--a comparison of two assay methods.

In the brain of the African catfish aromatase activity was demonstrated with two different methods using [7-3H]androstenedione and [19-3H]androstenedione as substrates. Kinetic analysis of estrogen formation following incubations of a cell-free fraction of brain homogenates showed that the apparent Km is the same for both substrates (0.03 micro M), but the Vmax is smaller with [19-3H]androstenedione as substrate. This indicates a so-called isotope effect. A time course study showed that after an incubation of 4 hr the aromatase activity is still linearly time dependent. Comparing the amount of estrogens formed from both precursors showed that the value of the isotope effect is 3.4 Incubation of symmetric punches of telencephalon and diencephalon with the two substrates likewise showed an isotope effect of 3.4

Catechol-O-methyltransferase in the brain of the male African catfish,Clarias gariepinus; distribution and significance for the metabolism of catecholestrogens and dopamine.

Catechol-O-methyltransferase, involved in the methylation of catechol substrates, was localized in the brain of the male African catfish,Clarias gariepinus, by means of a radiometric assay using [Methyl-(3)H]S-adenosylmethionine as methyldonor and catecholestrone as substrate. Fore- and midbrain were divided into eighteen, 500 µm thick, transverse sections. With a hollow needle (diameter 1 mm), specific areas of the brain were punched out and assayed. The catechol-O-methyltransferase activity was calculated from the amount of radioactive methoxyestrone formed from catecholestrone and expressed in pmol.mg(-1) tissue.h(-1).The enzyme could be demonstrated throughout the brain. Although the enzyme activity did not differ very much between the various brain regions (max. 15.4; min. 7.5 pmol), there were some areas in the brain with a more than average activity,i.e., the lateral telencephalon (10.3 pmol), the nucleus preopticus (13.1 pmol), nucleus lateralis tuberis (11.0 pmol) and nucleus recessus posterioris (12.0 pmol) of the diencephalon, the tectum opticum (15.4 pmol) and torus semicircularis (13.6 pmol) of the mesencephalon, and the caudal cerebellum of the metencephalon (10.8 pmol). The lowest activity was detected in the caudal metencephalon (7.5 pmol).The presence of the enzyme catechol-O-methyltransferase in the brain of the African catfish and the observation that both catecholestrogens and dopamine can be methylated by this enzyme suggest that catecholestrogens can influence the methylation (inactivation) of dopamine. Incubations of forebrain homogenates with dopamine and catecholestrone or catecholestradiol confirmed that both catecholestrogens can inhibit the methylation of dopamine. Lineweaver-burk plots with various concentrations of the catecholestrogens indicated that the inhibition is competitive. Dixon plots from the inhibition studies gave inhibition constants of 1.4 and 0.6 µM for catecholestrone and catecholestradiol, respectively, indicating that catecholestradiol is a two times stronger inhibitor than catecholestrone.The significance of the inhibition of the methylation of dopamine by the catecholestrogens in the brain is discussed in the light of the negative feedback of gonadal steroids on the central regulation of reproductive processes.

Aromatase activity in the brain of the three-spined stickleback, Gasterosteus aculeatus. I. Distribution and effects of season and photoperiod.

Tritiated androstenedione was in vitro aromatized to estrone and estradiol by the stickleback brain. Highest aromatase activity was found in the diencephalon, particularly in the periventricular hypothalamic region containing the nucleus preopticus (NPO), in the area containing the nucleus lateralis tuberis, and in the pituitary. This localization suggests a role of aromatase in controlling the secretion of gonadotropic hormone. The activity in the area containing the NPO was higher in May than in December. The possible role of seasonal changes in aromatase activity in the control of the yearly reproductive cycle is discussed.

Aromatase activity in the brain of the three-spined stickleback, Gasterosteus aculeatus. II. Effects of castration in winter.

Non-breeding stickleback males were gonadectomized or sham-operated in winter. Treatment with long photoperiod at high temperature stimulated sexual maturation in control fish. Brains were freeze-sectioned and punches were taken with hollow needles from different diencephalic regions and the punches incubated with [19-3H]-androstenedione. After extraction of steroids with CH2Cl2 tritium activity remaining in the water phase was measured. This gives a measure of aromatization as tritiated water and formic acid is formed when [19-3H]-androstenedione is aromatized to estrogens. Aromatase activity in the area containing the nucleus preopticus and the nucleus anterioris periventricularis was dramatically higher in sham-operated males than in gonadectomized ones or in the initial controls. There was no effect of gonadectomy in the other studied regions, including the nucleus lateralis tuberis, lobi inferioris, nucleus posterioris periventricularis and thalamic regions.

Estrogen-2-hydroxylase in the brain of the male African catfish, Clarias gariepinus.

Estrogen-2-hydroxylase activity, involved in the biosynthesis of catecholestrogens, was localized in the brain of the male African catfish, Clarias gariepinus, by means of a radiometric assay using [2-3H]estradiol as substrate. Fore- and midbrain were divided in 18, 500-microns thick, transverse sections from which small defined areas were punched out and assayed. The estrogen-2-hydroxylase activity was calculated from the release of tritium during hydroxylation, and expressed in femtomole catecholestradiol.milligram-1 tissue.hour-1. The enzyme could be demonstrated throughout the brain. A high activity (greater than 350 fmol) was observed in the telencephalon, in particularly the rostral part and the area ventralis pars dorsalis; in the diencephalon in the preoptic region, including the magnocellular part of the preoptic nucleus and the rostral part of the anterior periventricular nucleus; and in the area tuberalis, including the nucleus lateralis tuberis, the rostral part of the nucleus anterior tuberis, the caudal part of the nucleus posterior periventricularis, and in the nucleus recessus posterioris. Also a high activity was detected in the mesencephalic tectum opticum and the dorsolateral part of the torus semicircularis. The ventral mesencephalon showed a moderate (200-350 fmol) to low (less than 200 fmol) activity, whereas the lowest activity was found in the hindbrain (118 fmol). The significance of the biosynthesis of catecholestrogens in the brain is discussed in light of the negative feedback mechanism of gonadal steroids on gonadotropin release.

Catecholestrogens inhibit dopamine methylation in the gonadotrops of the African catfish,Clarias gariepinus.

Isolated gonadotrops of the African catfish,Clarias gariepinus, were incubated with dopamine (DA) and/or catecholestrone and the activity of the enzyme catechol-O-methyltransferase (COMT) was determined by measuring the methylated products. From the apparent Km values for DA and catecholestrone of 0.4-1.3 µM and 17.9-25.2 µM respectively, it was concluded that catecholestrone is a better substrate for the enzyme COMT, compared to DA. Moreover, the methylation of DA is inhibited by comparatively low concentrations of catecholestrone.