Publications on dementia in Medline 1974-2009: a quantitative bibliometric study.

OBJECT: The aim is to describe the development of the scientific literature on dementia. METHODS: We present a quantitative, bibliometric study of the literature on dementia, based on Medline, covering 36 years (1974-2009). Two samples of references to dementia papers were retrieved: The main sample based on the MeSH term Dementia holds more than 88,500 references. We have compared the annual additions of references on dementia with the addition to total Medline. Changes of 'the Dementia to Medline ratio' (%) give the best information on the development. RESULTS: Publications on dementia increased 5.6 times faster than Medline. Most of this relative acceleration took place during 1980-1997, when the references on dementia increased from 0.17 to 0.78%. During the recent 12 years, the publications on dementia have been keeping pace with Medline and have stabilized around 0.8%. CONCLUSIONS: We have shown a large increase of the literature on dementia, relative both to the development of all medical research and to all psychiatric research. The bibliometric approach may be questioned as quantitative methods treat articles as being of equal value, what is not true. If, for example, during a certain period, the research output is 'inflated' by a great number of repetitive papers, the quantitative method will give an unfair picture of the development. Our relative method, however, will give relevant results as, at each point of time, the proportion of 'valuable research' ought to be about the same in the dementia group as in total Medline.

Synaptotagmin VII splice variants alpha, beta, and delta are expressed in pancreatic beta-cells and regulate insulin exocytosis.

Synaptotagmins (SYT) are calcium-binding proteins that participate in regulated exocytosis. Although SYTI to IX isoforms are expressed in insulin-producing cell lines, hitherto only SYTIX has been associated with native beta-cell insulin granules and implicated in exocytosis. SYTVII was also proposed to regulate insulin exocytosis, but its subcellular location and number of alternative splice variants produced remain controversial. Only transcripts of SYTVII alpha, beta, and a novel splice variant delta are expressed in beta-cells and INS-1E cells. Western blotting revealed that INS-1E cells predominantly produced SYTVII alpha and low levels of SYTVII beta, whereas SYTVII delta was undetectable. The protein colocalized with insulin granules but not with synaptic-like microvesicles. Overexpression of SYTVII alpha resulted in decreased insulin granule content with a concomitant translocation of the variant to the plasma membrane, while SYTVII beta retained largely a granular pattern. Overexpressed SYTVII delta exhibited a distribution different to that of insulin granules and inhibited exocytosis when assessed by whole cell patch clamp capacitance recording. Silencing of SYTVII alpha by targeted RNA interference suppressed secretion, while repression of beta slightly increased release. Our results demonstrate that SYTVII is expressed on insulin granules and that only SYTVII alpha is implicated in exocytosis under physiological conditions.

Beta-cell secretory products activate alpha-cell ATP-dependent potassium channels to inhibit glucagon release.

Glucagon, secreted from islet alpha-cells, mobilizes liver glucose. During hyperglycemia, glucagon secretion is inhibited by paracrine factors from other islet cells, but in type 1 and type 2 diabetic patients, this suppression is lost. We investigated the effects of beta-cell secretory products zinc and insulin on isolated rat alpha-cells, intact islets, and perfused pancreata. Islet glucagon secretion was markedly zinc sensitive (IC(50) = 2.7 micromol/l) more than insulin release (IC(50) = 10.7 micromol/l). Glucose, the mitochondrial substrate pyruvate, and the ATP-sensitive K(+) channel (K(ATP) channel) inhibitor tolbutamide stimulated isolated alpha-cell electrical activity and glucagon secretion. Zinc opened K(ATP) channels and inhibited both electrical activity and pyruvate (but not arginine)-stimulated glucagon secretion in alpha-cells. Insulin transiently increased K(ATP) channel activity, inhibited electrical activity and glucagon secretion in alpha-cells, and inhibited pancreatic glucagon output. Insulin receptor and K(ATP) channel subunit transcripts were more abundant in alpha- than beta-cells. Transcript for the glucagon-like peptide 1 (GLP-1) receptor was not detected in alpha-cells nor did GLP-1 stimulate alpha-cell glucagon release. beta-Cell secretory products zinc and insulin therefore inhibit glucagon secretion most probably by direct activation of K(ATP) channels, thereby masking an alpha-cell metabolism secretion coupling pathway similar to beta-cells.

Glucose stimulates glucagon release in single rat alpha-cells by mechanisms that mirror the stimulus-secretion coupling in beta-cells.

In isolated rat pancreatic alpha-cells, glucose, arginine, and the sulfonylurea tolbutamide stimulated glucagon release. The effect of glucose was abolished by the KATP-channel opener diazoxide as well as by mannoheptulose and azide, inhibitors of glycolysis and mitochondrial metabolism. Glucose inhibited KATP-channel activity by 30% (P<0.05; n=5) and doubled the free cytoplasmic Ca2+ concentration. In cell-attached recordings, azide opened KATP channels. The N-type Ca2+-channel blocker omega-conotoxin and the Na+-channel blocker tetrodotoxin inhibited glucose-induced glucagon release whereas tetraethylammonium, a blocker of delayed rectifying K+ channels, increased secretion. Glucagon release increased monotonically with increasing K+ concentrations. omega-Conotoxin suppressed glucagon release to 15 mM K+, whereas a combination of omega-conotoxin and an L-type Ca2+-channel inhibitor was required to abrogate secretion in 50 mM K+. Recordings of cell capacitance revealed that glucose increased the exocytotic response evoked by membrane depolarization 3-fold. This correlated with a doubling of glucagon secretion by glucose in intact rat islets exposed to diazoxide and high K+. In whole-cell experiments, exocytosis was stimulated by reducing the cytoplasmic ADP concentration, whereas changes of the ATP concentration in the physiological range had little effect. We conclude that glucose stimulates glucagon release from isolated rat alpha-cells by KATP-channel closure and stimulation of Ca2+ influx through N-type Ca2+ channels. Glucose also stimulated exocytosis by an amplifying mechanism, probably involving changes in adenine nucleotides. The stimulatory action of glucose in isolated alpha-cells contrasts with the suppressive effect of the sugar in intact islets and highlights the primary importance of islet paracrine signaling in the regulation of glucagon release.

Glucose sensitivity and metabolism-secretion coupling studied during two-year continuous culture in INS-1E insulinoma cells.

Rat insulinoma-derived INS-1 cells constitute a widely used beta-cell surrogate. However, due to their nonclonal nature, INS-1 cells are heterogeneous and are not stable over extended culture periods. We have isolated clonal INS-1E cells from parental INS-1 based on both their insulin content and their secretory responses to glucose. Here we describe the stable differentiated INS-1E beta-cell phenotype over 116 passages (no. 27-142) representing a 2.2-yr continuous follow-up. INS-1E cells can be safely cultured and used within passages 40-100 with average insulin contents of 2.30 +/- 0.11 microg/million cells. Glucose-induced insulin secretion was dose-related and similar to rat islet responses. Secretion saturated with a 6.2-fold increase at 15 mm glucose, showing a 50% effective concentration of 10.4 mm. Secretory responses to amino acids and sulfonylurea were similar to those of islets. Moreover, INS-1E cells retained the amplifying pathway, as judged by glucose-evoked augmentation of insulin release in a depolarized state. Regarding metabolic parameters, INS-1E cells exhibited glucose dose-dependent elevations of NAD(P)H, cytosolic Ca(2+), and mitochondrial Ca(2+) levels. In contrast, mitochondrial membrane potential, ATP levels, and cell membrane potential were all fully activated by 7.5 mm glucose. Using the perforated patch clamp technique, 7.5 and 15 mm glucose elicited electrical activity to a similar degree. A K(ATP) current was identified in whole cell voltage clamp using diazoxide and tolbutamide. As in native beta-cells, tolbutamide induced electrical activity, indicating that the K(ATP)conductance is important in setting the resting potential. Therefore, INS-1E cells represent a stable and valuable beta-cell model.

A 4-h hyperglycaemic excursion induces rapid and slow changes in major electrolytes in blood in healthy human subjects.

Hyperglycaemia is well known to cause reductions in plasma Na(+) levels or even hyponatraemia due to an osmotically induced dilution of the interstitium and blood. It is, however, unclear whether this dilution is significantly counteracted by ion regulatory homeostatic mechanism(s) or not. Furthermore, the effects of moderate hyperglycaemia on other major ions are less well known. To further clarify these questions, we measured the changes in blood osmolarity and concentrations of Na(+), K(+), Cl(-), Mg(2+) and Ca(2+) during a 4-h-long experimental hyperglycaemia in healthy subjects rendered temporarily insulin deficient using the hyperglycaemic clamp. Hyperglycaemia, 16.8 mM, was rapidly imposed from a baseline of 4.4 mM by intravenous somatostatin and glucose infusions in 19 healthy subjects (10 m, 9 f; age 36 ± 5 years (mean ± SD); BMI 22.7 ± 2.9 kg/m(2)). Subsequently, glycaemia was returned to basal and measurements continued until all dynamic changes had stopped (at ~8 h). Osmolarity increased from 281.8 ± 0.7 to 287.9 ± 0.7, while Na(+) decreased from 143.9 ± 0.3 to 138.7 ± 0.2, Cl(-) from 101.7 ± 0.2 to 99.5 ± 0.1, Ca(2+) from 1.98 ± 0.04 to 1.89 ± 0.02 and Mg(2+) from 0.84 ± 0.01 to 0.80 ± 0.00 mM. All these changes were rapidly reaching stable levels. K(+) increased from 4.02 ± 0.02 to 4.59 ± 0.02 mM (P < 0.0001) also reaching stable levels but with some delay. Na(+), Cl(-), Mg(2+) and Ca(2+) are essentially determined by blood dilution, and their values will remain diminished as long as the hyperglycaemia lasts. Partial suppression of insulin-stimulated Na(+)/K(+) pumping lead to increased K(+) levels. The combination of elevated K(+) and decreased Mg(2+) and Ca(2+) levels may lead to an altered excitability, which is particularly relevant for diabetic patients with heart disease.

Schizophrenia in Medline 1950-2006: a bibliometric investigation.

The aim was to perform a bibliometric study, and compare the quantity of publications on schizophrenia with the total medical literature in Medline during 57 years, 1950-2006. The annual additions of literature to Medline are continually increasing and form the Medline growth curve. Comparisons of the number of publications on schizophrenia, or any other disease, to this curve, may be used to estimate the research activity. Methods for the identification of relevant references to papers on schizophrenia were evaluated and three different samples were operationally defined, retrieved and counted. During 1950-2006, 16.28 million references were added to Medline. Nearly 68000, 0.42%, references were related to schizophrenia. The percentage of papers on schizophrenia among the psychiatric literature decreased from 5.2 to 2.6%. The present study indicates that the number of references on schizophrenia in Medline has followed the general increase of medical publications. This pattern differs compared to some other research fields such as dementia, HIV, and peptic ulcer. Samples of references on schizophrenia may be retrieved in Medline by operational definitions of search methods. The quantity of schizophrenia research during 57 years has kept pace with the total medical literature. One interpretation of the results is that more resources are needed to enhance research activities on schizophrenia.

The use of PubMed/Medline in psychiatry. 1: Presentation of NLM and PubMed.

A comprehensive view of the available literature on a psychiatric problem can be found in the large electronic databases. Medline at the National Library of Medicine (NLM) in USA is the largest medical database. PubMed is the searchable database at the NLM, having Medline as its major content. PubMed is free of charge, barrier-free and always accessible via the Internet. This paper describes the NLM, Medline and PubMed. The indexing of scientific papers in Medline is based on Medical Subject Headings, the MeSH terms. The hierarchic tree structure of MeSH is the basis of the search and retrieval system. The present paper is the first in a series of three, intended as a tutorial on the use of PubMed for inexperienced users. Information and examples on the MeSH system, together with exercises in its use, are presented in an appendix.

The use of PubMed/Medline in psychiatry. 2: The PubMed search window: a description and a tutorial.

A previous paper, in a series of three, presented the National Library of Medicine, Medline, PubMed and the MeSH system. Connection to PubMed via the Internet opens the PubMed search window that is the tool for retrieving references to scientific medical literature. This paper is intended as a tutorial for an inexperienced visitor to PubMed, and describes the search window in some detail. Several proposals for exercises in its use are given in the text, while explanations and comments to the exercises are presented in an appendix. The following procedures are described: retrieving references, ways to see the abstract, ways of displaying, sorting and showing the references, together with how to produce lists, import references to your own computer, and ways to get the full text of a paper.

The use of PubMed/Medline in psychiatry. 3: Searching PubMed.

This paper is the third in a series of three, intended as a tutorial in the use of PubMed/Medline for an inexperienced user. The papers have the following contents: I--a description of NLM, Medline, PubMed and the system of Medical Subject Headings (MeSH), which form the basis for the indexing of scientific articles, books and other items at NLM. II--A description and a tutorial of the PubMed search window. III--The present article deals mainly with the searching for references in PubMed. Ways of restricting and concentrating the search are presented, and exercises are proposed. A reader may also find guidance for a search for medical books in the NLM Catalog, and in the use of tools like Related Articles, Bookshelf, and Index. With eating disorders as an example, more information is presented on the use of MeSH terms.

SV2A and SV2C are not vesicular Ca2+ transporters but control glucose-evoked granule recruitment.

Synaptic vesicle protein 2 (SV2) is expressed in neuroendocrine cells as three homologous isoforms, SV2A, SV2B and SV2C. Ca2+-dependent function in exocytosis has been attributed to SV2A and SV2B, without elucidation of the mechanism. The role of SV2C has not yet been addressed. Here we characterize the three SV2 isoforms and define their involvement in regulated insulin secretion. SV2A and SV2C are associated with insulin-containing granules and synaptic-like-microvesicles (SLM) in INS-1E insulinoma and primary beta-cells, whereas SV2B is only present on SLM. Neither overexpression nor isoform-specific silencing of SV2A or SV2C by RNA interference modifies depolarization-triggered cytosolic [Ca2+] rises or secretory granule [Ca2+], measured with a VAMP-2 aequorin chimera. This strongly argues against any Ca2+ transport function of SV2. Moreover, up- or downregulation of these isoforms has no influence on K+-induced insulin release suggesting that SV2 does not affect the Ca2+-dependent step(s) of exocytosis. By contrast, glucose-elicited secretion is inhibited during the sustained rather than the early phase, placing the action of SV2 on the recruitment of granules from the reserve pool to the plasma membrane. This conclusion is reinforced by capacitance measurements in glucose-stimulated SV2C-deficient cells. Like capacitance, evoked and basal hormone release are attenuated more by silencing of SV2C compared with SV2A. This indicates only partial redundancy and highlights a key role for SV2C in the secretory process.

Granule-specific ATP requirements for Ca2+-induced exocytosis in human neutrophils. Evidence for substantial ATP-independent release.

Ca2+-induced exocytosis in neuronal and neuroendocrine cells involves ATP-dependent steps believed to 'prime' vesicles for exocytosis. Primed, docked vesicles are released in response to Ca2+ influx through voltage-gated Ca2+ channels. Neutrophils, however, do not possess voltage-gated Ca2+ channels and appear to have no docked vesicles. Furthermore, neutrophils have several types of granules with markedly different Ca2+ requirements for exocytosis. These differential Ca2+ dependencies were used as a tool to investigate the ATP dependence of different granule populations. Here we demonstrate distinct ATP requirements for release of neutrophil granule populations, with respect to rate as well as amplitude. Intracellular ATP was depleted to various levels, and exocytosis was stimulated with different Ca2+ concentrations and measured with the patch-clamp capacitance technique or by detecting enzyme release. Primary granule exocytosis displayed a distinct ATP dependence with an apparent K(m) of approximately 80 microM ATP and no ATP-independent exocytosis. Release of secondary and tertiary granules displayed a more shallow ATP dependence (K(m) approximately 330 microM), and more than 50% of secondary and tertiary granules appeared not to need ATP at all for their release. Individual granules in human neutrophils have distinct ATP requirements for exocytosis, suggesting that the ATP-sensitive elements are localised to the granules. Primary granule exocytosis has a very low affinity for ATP. Furthermore, substantial ATP-independent exocytosis of secondary and tertiary granule occurs despite the absence of docked granules. These characteristics should help neutrophils to fulfil their bactericidal functions at poorly irrigated sites of infection with low glucose supply.