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The analysis of the FA levels of staged worms revealed that the C17ISO level increases gradually from a relatively low level at L1 to its peak in gravid adults containing eggs . Based on the analysis of green fluorescent protein (GFP) reporter constructs (unpublished data) and in situ hybridization data (results from NextDB by Y. Kohara, Tokyo, Japan), neither elo-5 nor elo-6 is significantly expressed in eggs or L1. Therefore, C17ISO likely accumulates in embryos during oogenesis. It may be directly transported from gut to gonads, since both ELO-5 and ELO-6 were expressed mainly in the gut and since feeding C17ISO rescued the elo-5 mutant phenotypes. When RNAi-mediated disruption of elo-5 occurs at the L1 stage of a parent and consequently blocks C17ISO synthesis from that stage on, the eggs and L1 animals of the next generation are expected to contain a critically low concentration of C17ISO, halting further development. Because the arrested L1 can be rescued by a dietary supply of the mmBCFA, the deficiency is not likely to cause critical defects during the embryonic and early postembryonic periods.
|
15340492_p18
|
15340492
|
L1 Arrest of the elo-5(RNAi) Animals Is Reversible and Related to the Variations in Levels of C17ISO during Development
| 4.372597 |
biomedical
|
Study
|
[
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] |
en
| 0.999997 |
If elo-5 RNAi is applied to the parent worms at or after the L2 larval stage, when the amount of C17ISO has already been elevated and/or the RNAi effect is less penetrant, the progeny may receive sufficient C17ISO to pass the L1 arrest stage. The resulting animals, however, become visibly unhealthy at the L4 and adult stages as mentioned earlier, suggesting that C17ISO also plays a role in late developmental stages.
|
15340492_p19
|
15340492
|
L1 Arrest of the elo-5(RNAi) Animals Is Reversible and Related to the Variations in Levels of C17ISO during Development
| 4.067842 |
biomedical
|
Study
|
[
0.9992628693580627,
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] |
[
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en
| 0.999995 |
Based on these results, we propose a relationship between the amounts of C17ISO and developmental stages . In this model, the level of C17ISO is monitored at the first larval stage and the decision is made whether to proceed or pause in development. The analysis of GC data from staged animals has also indicated that the variation of the C17ISO level is correlated with only two other FA species, suggesting a potential compensatory and coregulatory mechanism.
|
15340492_p20
|
15340492
|
L1 Arrest of the elo-5(RNAi) Animals Is Reversible and Related to the Variations in Levels of C17ISO during Development
| 4.113562 |
biomedical
|
Study
|
[
0.9995201826095581,
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] |
[
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en
| 0.999997 |
FA homeostasis implies that relative amounts of various FA species are coordinated and balanced for optimal performance. To obtain information that may help us understand why and how numerous FAs and their specific metabolic enzymes are maintained in nature, we carried out analysis to determine a possible correlation between changes in the levels of C17ISO and other FAs detected in worms. We have analyzed a large amount of GC data ( n = 50) obtained from mixed populations of wild-type animals where the fractions of eggs, larvae, and adults randomly varied. We also included GC data separately obtained from staged worms: eggs, L1, L2, L3, L4, and gravid adults. We found that the amounts of C17ISO significantly correlated with only two other FA molecules: linoleic acid (C18:2 n6) and vaccenic acid (C18:1 n7) . A potential physiological significance of these correlations is intriguing.
|
15340492_p21
|
15340492
|
The C17ISO Level Correlates with the Levels of Two Other FAs during Development
| 4.106133 |
biomedical
|
Study
|
[
0.9995660185813904,
0.00019509706180542707,
0.0002388599532423541
] |
[
0.9994695782661438,
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] |
en
| 0.999997 |
The observed negative correlation between the levels of C17ISO and C18:1 n7 throughout development may indicate a compensatory adjustment important for physiological functions, such as retention of the cell membrane physical properties. mmBCFAs and monounsaturated straight-chain FAs have been previously implicated in regulating membrane fluidity, which depends on the ratio of saturated FA to monounsaturated and branched-chain FA content in bacterial cells . An elevation in monounsaturated FA amounts in response to the decrease of branched-chain FAs, but not vice versa, was observed in Streptomyces avermitilis , suggesting that monounsaturated FAs may sense a state of membrane fluidity.
|
15340492_p22
|
15340492
|
The C17ISO Level Correlates with the Levels of Two Other FAs during Development
| 4.303952 |
biomedical
|
Study
|
[
0.9994999170303345,
0.0002501228009350598,
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] |
[
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] |
en
| 0.999998 |
In the elo-5(RNAi) -treated worms, a substantial loss of C15ISO and C17ISO is also accompanied by a change in the FA composition, most noticeably by the elevation in C18:1 n7 , a result consistent with the above observation. To estimate the effect of the C15ISO and C17ISO deficiency on the membrane saturation, the saturation index (SI = [saturated FA]/[mmBCFA + monounsaturated FA]) was calculated. No significant differences were detected in elo-5(RNAi) worm compared to wild type (SI = 0.325 ± 0.011 [ n = 6] and SI = 0.320 ± 0.032 [ n = 5], respectively). Therefore, elo-5(RNAi) may not cause massive cell membrane dysfunction.
|
15340492_p23
|
15340492
|
The C17ISO Level Correlates with the Levels of Two Other FAs during Development
| 4.148248 |
biomedical
|
Study
|
[
0.9995450377464294,
0.00019695436640176922,
0.0002580215223133564
] |
[
0.9995561242103577,
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0.0002014494384638965,
0.00005076490924693644
] |
en
| 0.999996 |
A positive correlation between the amounts of C17ISO and C18:2 n6 may suggest a potential common function during development. In addition to the importance of linoleic acid as a substrate for polyunsaturated FA biosynthesis, its hydroxylated fatty acid derivative (HODEs) is known as a signaling molecule affecting chemotaxis , cell proliferation , and modulation of several enzymatic pathways . A correlation between C17ISO and linoleic acid may also suggest a similar regulation of biosynthesis of the two molecules.
|
15340492_p24
|
15340492
|
The C17ISO Level Correlates with the Levels of Two Other FAs during Development
| 4.22574 |
biomedical
|
Study
|
[
0.9996744394302368,
0.00010885929805226624,
0.00021682419173885137
] |
[
0.9948044419288635,
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0.00011243578774156049
] |
en
| 0.999998 |
The changes in the FA composition associated with a decrease in C15ISO and C17ISO indicate that the metabolism of straight-chain FA species is responsive to the mmBCFA levels and suggest a cross regulation. Interestingly, in the elo-5(RNAi) animals fed with C15ISO or C15anteISO containing bacterial supplement (S. maltophilia), the FA composition was significantly altered . It appears that mmBCFAs become principal components in a range of 16–18-carbon FAs. This suggests that large quantities of mmBCFAs are not toxic. In contrast, because these worms grow and proliferate well, mmBCFAs seem to be efficient substitutes for saturated and monounsaturated straight-chain FAs.
|
15340492_p25
|
15340492
|
The C17ISO Level Correlates with the Levels of Two Other FAs during Development
| 4.199767 |
biomedical
|
Study
|
[
0.9995434880256653,
0.0001973215985344723,
0.00025915997684933245
] |
[
0.9993755221366882,
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0.00005933946158620529
] |
en
| 0.999997 |
In mammals, straight-chain FA biosynthesis depends on the 1c isoform of sterol regulatory element binding protein (SREBP-1c), which promotes the expression of FA metabolic enzymes . There is only one protein in C. elegans that is homologous to mammalian SREBPs, Y47D3B.7 (the gene has been named lpd-1, for “lipid depleted 1”) . McKay and coauthors have shown that worms treated with lpd-1 RNAi display a lipid-depleted phenotype. They have also shown that lpd-1 regulates the expression of several lipogenic enzymes, acetyl-CoA carboxilase (ACC), FAS, and glycerol 3-phosphate acyltransferase (G3PA) . Thus, similar to its mammalian homolog, lpd-1 is involved in straight-chain FA biosynthesis.
|
15340492_p26
|
15340492
|
The Worm SREBP Homolog Controls Production of Branched-Chain FAs
| 4.286018 |
biomedical
|
Study
|
[
0.9996622800827026,
0.0001522482343716547,
0.00018543715123087168
] |
[
0.9986435770988464,
0.0006038521532900631,
0.0006766713340766728,
0.00007594619819428772
] |
en
| 0.999997 |
We wanted to see if lpd-1 also plays a role in mmBCFA metabolism. We first applied RNAi to lpd-1 and determined the FA composition of the mutant worms. As expected, the FA content of treated animals was significantly changed, but surprisingly the most reduced were the levels of C15ISO and C17ISO . Also significantly reduced was the amount of C18:2 n6. In contrast, the C16:0 level was elevated. These data indicate that, in addition to regulating the first steps of global FA biosynthesis through the activation of the ACC and FAS transcription, the worm SREBP homolog regulates mmBCFA elongation as well as desaturation of straight-chain FAs.
|
15340492_p27
|
15340492
|
The Worm SREBP Homolog Controls Production of Branched-Chain FAs
| 4.216076 |
biomedical
|
Study
|
[
0.9995288848876953,
0.0002544019080232829,
0.00021675704920198768
] |
[
0.999340832233429,
0.0003090740938205272,
0.0002798260247800499,
0.00007029456901364028
] |
en
| 0.999997 |
As reported previously, disruption of lpd-1 through a mutation or RNAi injection caused early larval arrest . The effect of lpd-1 RNAi feeding in our experiments was apparently less severe. The RNAi-treated animals displayed slow growth, morphological abnormalities, and egg-laying defects but no larval arrest. Supplementing C17ISO to the plates did not significantly rescue these defects.
|
15340492_p28
|
15340492
|
The Worm SREBP Homolog Controls Production of Branched-Chain FAs
| 3.911042 |
biomedical
|
Study
|
[
0.9994041919708252,
0.0001733139215502888,
0.00042250973638147116
] |
[
0.9990552067756653,
0.0006133249262347817,
0.0002629422233439982,
0.00006854314415249974
] |
en
| 0.999996 |
LPD-2 (C48E7.3) is another C. elegans homolog of a mammalian lipogenic transcription factor, CCAAT/enhancer-binding protein (C/EBP). McKay and coauthors have shown that the lpd-2(RNAi) and lpd-1(RNAi) phenotypes are quite similar; affected worms are defective in growth, pale and scrawny in appearance, and lacking in fat content . They have also shown that LPD-1 and LPD-2 control the expression of the same lipogenic enzymes: ACC, FAS, ATP-citrate lyase, and G3PA. We tested to see if LPD-1 and LPD-2 function similarly in the regulation of mmBCFA biosynthesis. In contrast to the result from lpd-1 (RNAi), the FA composition in lpd-2(RNAi) worms was not significantly different from that of wild-type animals even though these animals had a noticeably sick appearance (unpublished data). This result suggested that, in addition to having some common targets, LPD-1 and LPD-2 have distinct functions. LPD-1 is important for production of mmBCFAs as well as other very-long-chain FAs, whereas LPD-2 has no specificity for any particular type of FA.
|
15340492_p29
|
15340492
|
LPD-1 and LPD-2 Diverge in Functions
| 4.232779 |
biomedical
|
Study
|
[
0.9995682835578918,
0.00019916643213946372,
0.00023258349392563105
] |
[
0.9992714524269104,
0.00030912572401575744,
0.0003578285686671734,
0.00006163434591144323
] |
en
| 0.999997 |
The changes in FA composition observed in lpd-1(RNAi) would be consistent with downregulation of elo-5, elo-6 (decrease in mmBCFA), elo-2 (increase in C16:0) , and Δ 9- and/or Δ 12 -desaturase genes (decrease in C18:2 n6). The genes encoding mammalian orthologs of the C. elegans elo-2 and Δ 9 -desaturase genes are known targets of SREBP-1c . To examine if elo-5 and elo-6 are targets of lpd-1, we analyzed the expression of elo-5, elo-6, and lpd-1.
|
15340492_p30
|
15340492
|
elo-5 and elo-6 Are Likely Targets of LPD-1
| 4.175675 |
biomedical
|
Study
|
[
0.9994421601295471,
0.00020191556541249156,
0.00035585317527875304
] |
[
0.9993182420730591,
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0.00018424427253194153,
0.00005632481770589948
] |
en
| 0.999995 |
Evaluation of the expression from an lpd-1Prom :: GFP fusion construct (a gift of J. Graff) in transgenic animals revealed that, in addition to the previously reported expression in intestinal cells , the construct is strongly expressed in a subset of head neurons . Using a lipophilic dye, DiI, which highlights chemosensory ciliated neurons, we identified these neurons as amphids . In the strains carrying elo-5Prom :: GFP and elo-6Prom :: GFP reporter constructs, GFP fluorescence was also detected in the gut and several head neurons, including amphid neurons .
|
15340492_p31
|
15340492
|
elo-5 and elo-6 Are Likely Targets of LPD-1
| 4.166143 |
biomedical
|
Study
|
[
0.9994737505912781,
0.0002255854633403942,
0.0003006999031640589
] |
[
0.999309778213501,
0.00038735507405363023,
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0.00006649146962445229
] |
en
| 0.999998 |
If LPD-1 promotes elo-5 and elo-6 expression, then RNAi of lpd-1 should alter GFP intensity in elo-5Prom :: GFP and elo-6Prom :: GFP reporter strains. The level of GFP expression driven by elo-5 and elo-6 promoters is high in conventionally cultured animals. In the worms maintained on the lpd-1(RNAi) plates, the expression was noticeably weakened, suggesting a downregulation of the promoter activities . No significant changes in GFP expression were detected in a control strain containing a kqt-1Prom :: GFP construct that also expresses GFP in head neurons and the gut (unpublished data).
|
15340492_p32
|
15340492
|
elo-5 and elo-6 Are Likely Targets of LPD-1
| 4.113282 |
biomedical
|
Study
|
[
0.9992246627807617,
0.0002091784554067999,
0.0005661235773004591
] |
[
0.9993088245391846,
0.0004883455112576485,
0.0001538784708827734,
0.00004889732372248545
] |
en
| 0.999995 |
To test if the disruption of FAS, a target of LPD-1 , could contribute to the observed decrease of C15ISO and C17ISO in lpd-1(RNAi), we analyzed FA composition in FAS(RNAi) strains. There is one predicted FAS gene, F32H2.5, and its shorter homolog, F32H2.6, in the C. elegans genome. The latter can only encode the N-terminal portion of the protein. These genes share extended nucleotide identity, and RNAi of one could thus possibly affect the other. Consistent with a critical role for FAS in the first steps of FA biosynthesis, the RNAi-mediated disruption of F32H2.5 and F32H2.6 resulted in multiple defects and a lethal growth arrest (unpublished data). The FA composition (the content and relative amounts of various FA species) of the affected animals remained, however, unchanged. This suggests that disruption of FAS does not selectively alter FA biosynthesis and that neither FAS protein is specific for mmBCFA. Therefore, downregulation of FAS by loss of lpd-1 cannot account for the severe deficiency of mmBCFA in lpd-1(RNAi).
|
15340492_p33
|
15340492
|
elo-5 and elo-6 Are Likely Targets of LPD-1
| 4.356578 |
biomedical
|
Study
|
[
0.999403715133667,
0.0003629089624155313,
0.00023336877347901464
] |
[
0.999148964881897,
0.0004365772183518857,
0.0003013605310115963,
0.00011309333058306947
] |
en
| 0.999998 |
Thus, we have shown that disruption of lpd-1 affects C15ISO and C17ISO biosynthesis. The fact that lpd-1, elo-5, and elo-6 are expressed in the same cells concurrently and that the GFP reporter analysis indicated that elo-5 and elo-6 transcription is downregulated in the absence of lpd-1 suggests that elo-5 and elo-6 are likely to be the targets of lpd-1.
|
15340492_p34
|
15340492
|
elo-5 and elo-6 Are Likely Targets of LPD-1
| 4.091791 |
biomedical
|
Study
|
[
0.9992929697036743,
0.0002588112838566303,
0.00044810835970565677
] |
[
0.9992783665657043,
0.0005146147450432181,
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0.00005651982792187482
] |
en
| 0.999998 |
Since ACC and FAS catalyze the first steps in the biosynthesis of straight-chain FAs while ELO-5 and ELO-6 extend mmBCFA molecules, LPD-1 appears to integrate conventional and “unusual” FA biosyntheses. It seems reasonable to predict that in order to differentiate between these metabolic pathways and mediate compensatory or adaptive changes in FA composition, LPD-1 must interact with other factors such as nuclear receptors activated by specific FA ligands. It is thus important to screen for such interactions to better understand FA homeostasis in C. elegans.
|
15340492_p35
|
15340492
|
elo-5 and elo-6 Are Likely Targets of LPD-1
| 4.201555 |
biomedical
|
Study
|
[
0.9995754361152649,
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] |
[
0.9958264231681824,
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0.00011944902507821098
] |
en
| 0.999997 |
Because mammalian SREBP-1c regulates polyunsaturated FA biosynthesis and is feedback inhibited by polyunsaturated FAs , we asked if lpd-1 could be regulated by mmBCFAs at the transcriptional level. Our microarray data (discussed below) indicated a 1.68-fold upregulation of lpd-1 in the elo-5(RNAi) animals, while no changes were detected in its levels between samples from wild-type animals at different developmental stages (see Materials and Methods ).
|
15340492_p36
|
15340492
|
A Reciprocal Correlation between lpd-1 Expression and mmBCFA Levels
| 4.087458 |
biomedical
|
Study
|
[
0.9995480179786682,
0.00019047192472498864,
0.00026146171148866415
] |
[
0.9994317889213562,
0.0003231045266147703,
0.00018820044351741672,
0.00005680926187778823
] |
en
| 0.999997 |
To examine the influence of the mmBCFA deficiency on lpd-1 expression, we grew the lpd-1Prom :: GFP -containing strain on the elo-5(RNAi) and control plates to compare GFP fluorescence. No obvious difference in the GFP expression driven by the lpd-1 promoter in intestinal cells was detected on the elo-5(RNAi) plates versus the control plates. A modest change in the transcription level (1.68-fold) could be masked by a variability of the expression between individual animals and even between individual cells (unpublished data). In contrast to the observation for the intestinal cells, a strong induction of GFP was detected in amphid neurons of lpd-1Prom :: GFP ; elo-5(RNAi) animals . This suggests that a chronic deficiency of mmBCFA in elo-5(RNAi) animals may transcriptionally stimulate LPD-1 production, at least in neuronal cells.
|
15340492_p37
|
15340492
|
A Reciprocal Correlation between lpd-1 Expression and mmBCFA Levels
| 4.136425 |
biomedical
|
Study
|
[
0.9994714856147766,
0.0002617652644403279,
0.0002668245288077742
] |
[
0.9994977712631226,
0.0002588393690530211,
0.00018392449419479817,
0.000059379333833931014
] |
en
| 0.999997 |
Collectively, our results suggest that the relationship between lpd-1 and C15ISO/C17ISO is reciprocal; while downregulation of lpd-1 transcription results in the C17ISO deficiency, the C15ISO and C17ISO deficiency upregulates lpd-1 transcription at least in a subset of cells. Therefore, the worm SREBP homolog, LPD-1, may play an important role in mmBCFA homeostasis.
|
15340492_p38
|
15340492
|
A Reciprocal Correlation between lpd-1 Expression and mmBCFA Levels
| 4.195054 |
biomedical
|
Study
|
[
0.9996182918548584,
0.00019069651898462325,
0.00019106606487184763
] |
[
0.9990963935852051,
0.00045652687549591064,
0.00037210778100416064,
0.00007500432548113167
] |
en
| 0.999997 |
Because C15ISO and C17ISO play critical roles in animal development and growth, we suspected mechanisms might exist to respond to and regulate their levels. Regulation of mmBCFA homeostasis may involve transcription factors, metabolic enzymes, and transport and binding proteins. It is reasonable to suggest that a deficiency of mmBCFA triggers a compensatory alteration in the expression of these genes. It is also possible that a comparative analysis of global gene expressions between wild-type and mmBCFA-deficient animals may reveal these potential changes and the changes underlying developmental and growth functions of mmBCFA.
|
15340492_p39
|
15340492
|
Screening for Additional Genes Involved in mmBCFA Homeostasis
| 4.064134 |
biomedical
|
Study
|
[
0.9995622038841248,
0.0001275425893254578,
0.00031033027335070074
] |
[
0.9983856678009033,
0.0009684056276455522,
0.0005789688439108431,
0.0000669157670927234
] |
en
| 0.999995 |
We used DNA microarray analysis to compare the total gene expression in elo-5(RNAi) and wild-type animals. To select candidate genes, we applied restrictive criteria and excluded genes of which the expression was also changed in the spt-1(RNAi) strain ( Protocol S1 and Table S1 ). The spt-1 (C23H3.4) gene encodes a predicted C. elegans homolog of serine-palmitoyl transferase subunit 1. RNAi of spt-1 strongly affects the FA composition without reducing the C15ISO or C17ISO levels (unpublished data). The F1 generation of spt-1(RNAi) animals developed gonadal and egg-laying defects that were similar to the phenotype of F1 animals from parents treated with elo-5(RNAi) at a late larval stage . We thought that by deselecting genes that have altered expressions in spt-1(RNAi), we would be able to eliminate variations in gene expressions unrelated to the mmBCFA deficiency. Such variations might emerge from altered straight-chain FA metabolism and from general sickness. Here, we discuss the analysis of the first set of candidate genes that are differentially expressed in elo-5(RNAi) and may relate to the C15ISO and C17ISO homeostasis.
|
15340492_p40
|
15340492
|
Screening for Additional Genes Involved in mmBCFA Homeostasis
| 4.154697 |
biomedical
|
Study
|
[
0.9994832277297974,
0.0002946367021650076,
0.00022204170818440616
] |
[
0.9994614720344543,
0.00018335407366976142,
0.00028528564143925905,
0.00006993506394792348
] |
en
| 0.999997 |
Twenty-five genes were selected in the screen ( Table 1 ) and each was functionally tested by RNAi and GC analysis for its role in C15ISO and C17ISO metabolism. RNAi of four of these genes ( pnk-1 [C10G11.5], nhr-49 [K10C3.6], acs-1 [F46E10.1], and C27H6.2) significantly affected the FA composition . All four genes encoded products structurally homologous to the known proteins (PNK-1, human pantothenate kinase; NHR-49 , nuclear hormone receptor; ACS-1, very-long-chain FA CoA ligase; and C27H6.2, RuvB-like DNA binding protein).
|
15340492_p41
|
15340492
|
Screening for Additional Genes Involved in mmBCFA Homeostasis
| 4.128772 |
biomedical
|
Study
|
[
0.9995561242103577,
0.00024686194956302643,
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] |
[
0.9994101524353027,
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0.000307406357023865,
0.00006852206570329145
] |
en
| 0.999997 |
Circumstantial evidence suggests that these four candidate genes may be involved in feedback regulation of mmBCFA biosynthesis. First, the expression of these genes is not variable in nature, as judged by a comparison of the microarray data obtained from developmentally different populations of N2 ( Protocol S1 ) as well as for vulval development pathway mutants (data obtained for an unrelated project, J. Chen, personal communication). Second, the direction of the changes for three of the genes is in concordance with the proposed feedback regulation: pnk-1, nhr-49, and acs-1 were upregulated in C17ISO-deficient elo-5(RNAi) . Lastly, a functional analysis shows that these three candidate genes are required for the normal level of mmBCFA production (RNAi of the genes affects mmBCFA production). The fourth candidate gene, C27H6.2, affects the level of vaccenic acid (C18:1 n7), which is related to the levels of mmBCFA , suggesting cross-talk.
|
15340492_p42
|
15340492
|
Analysis of the Candidate Genes
| 4.262154 |
biomedical
|
Study
|
[
0.9993690848350525,
0.00029826516401953995,
0.000332606490701437
] |
[
0.9993557333946228,
0.0002702434721868485,
0.00030290347058326006,
0.00007104668475221843
] |
en
| 0.999998 |
To detect potential feedback regulation involving acs-1 and pnk-1, we made reporter strains with GFP expression driven by acs-1 and pnk-1 promoters, acs-1Prom :: GFP and pnk-1Prom :: GFP, respectively. These two genes showed a higher degree of upregulation than the other candidates according to the microarray data. In addition, RNAi of these two genes resulted in a significant loss in the mmBCFA fraction. The GFP fluorescence from acs-1Prom :: GFP and pnk-1Prom :: GFP was readily detectable in the gut. Expression of acs-1Prom :: GFP was also detected in the canal-associated neurons in the head neurons and vulval cells. A comparison of synchronized animals grown on the control and elo-5(RNAi) plates indicated a significantly brighter fluorescence in the RNAi worms , suggesting upregulation of acs-1 and pnk-1 under C15ISO or C17ISO deficiency. These results were in concordance with the microarray data. Moreover, pnk-1, but not acs-1, seemed to be regulated by LPD-1 because pnk-1Prom :: GFP expression was significantly reduced on lpd-1(RNAi) .
|
15340492_p43
|
15340492
|
Analysis of the Candidate Genes
| 4.229646 |
biomedical
|
Study
|
[
0.9994078874588013,
0.0003285637649241835,
0.00026359179173596203
] |
[
0.9994176626205444,
0.00022873361012898386,
0.0002740435302257538,
0.00007962096424307674
] |
en
| 0.999997 |
It was interesting to note that the pnk-1 and acs-1 genes were previously selected in two different screens as potential targets of the daf-2/daf-16 (Y55D5A.5 and R13H8.1, respectively) pathway. pnk-1 had been identified in a screen for genes affecting the life span and metabolism of C. elegans through analysis of promoter regions, and it was confirmed as a direct target of DAF-16, a forkhead transcriptional factor . acs-1 had been identified in a microarray screen for DAF-16 targets that influence life span . A third gene, nhr-49, had been previously selected in a screen for fat regulatory genes . It was shown that RNAi of this gene leads to an increase in fat accumulation in affected animals. Our analysis of nhr-49(RNAi) animals showed that reduction of nhr-49 activity results in upregulation of saturated FA biosynthesis that may contribute to fat accumulation. Although the regulatory path for this process remains unknown, the involvement of daf-2 has not been ruled out.
|
15340492_p44
|
15340492
|
Analysis of the Candidate Genes
| 4.221807 |
biomedical
|
Study
|
[
0.9995001554489136,
0.0002551522047724575,
0.0002447060542181134
] |
[
0.9993314743041992,
0.00022763955348636955,
0.0003703857655636966,
0.00007057932816678658
] |
en
| 0.999997 |
A potential link between the candidate genes and DAF-2/insulin signaling is very intriguing. The C. elegans insulin-signaling pathway is involved in sensing nutritional state and metabolic conditions as well as controlling growth and diapause . As we report in this paper, a mmBCFA deficiency causes transient L1 arrest. This phenotype strikingly resembles L1 arrest of worms hatched in the absence of food (a method commonly used to obtain synchronized animals). An investigation of possible roles for mmBCFA in food sensation and insulin signaling pathways is underway.
|
15340492_p45
|
15340492
|
Analysis of the Candidate Genes
| 3.974844 |
biomedical
|
Study
|
[
0.9995352029800415,
0.00012107415386708453,
0.00034373559174127877
] |
[
0.9981266856193542,
0.0012453378876671195,
0.0005402390961535275,
0.00008773928129812703
] |
en
| 0.999998 |
Downregulation of the fourth candidate gene, C27H6.2, may result in a significant increase in monounsaturated FA levels . This is consistent with the enlarged fraction of monounsaturated FAs observed in the elo-5(RNAi) animals . Downregulation of C27H6.2 may have an adaptive effect to compensate for the loss of mmBCFAs in cell membranes. If so, C27H6.2 may be part of a mechanism that senses and tunes physical properties of membranes. C27H6.2 is homologous to RuvB/TIP49a/Pontin52, an evolutionarily conserved protein essential for growth and proliferation . Its mammalian ortholog acts as a transcriptional cofactor that binds to β-catenin, TATA-box binding protein, and likely to a number of other diverse transcription factors .
|
15340492_p46
|
15340492
|
Analysis of the Candidate Genes
| 4.370564 |
biomedical
|
Study
|
[
0.9994915723800659,
0.00021334200573619455,
0.0002950004709418863
] |
[
0.9980060458183289,
0.0013836410362273455,
0.0004636986705008894,
0.00014651590026915073
] |
en
| 0.999997 |
Two mmBCFAs are normally detected in C. elegans: C15ISO and C17ISO. A deficiency of these FAs is lethal and cannot be compensated by any other FA present, indicating their crucial importance for growth and development. There are two sources of C15ISO and C17ISO available for worms. First, they possess a system for mmBCFA biosynthesis that includes two FA elongation enzymes, ELO-5 and ELO-6, which are regulated at least in part by the nematode homolog of SREBP-1c (lpd-1). Second, worms may obtain mmBCFAs from their diet (bacteria). Therefore, C. elegans is able to produce, activate, transport, and utilize mmBCFAs and is vitally dependent on this system.
|
15340492_p47
|
15340492
|
Concluding Remarks
| 4.276237 |
biomedical
|
Study
|
[
0.999536395072937,
0.00015549169620499015,
0.00030811000033281744
] |
[
0.995964765548706,
0.003098126268014312,
0.000830884906463325,
0.00010617266525514424
] |
en
| 0.999997 |
The level of C15ISO and C17ISO in eggs appears to be critical for growth and development, as animals depleted of C15ISO or C17ISO completely arrest at the L1 stage. The uniformity and reversibility of the arrest would be consistent with a regulatory role in growth and development for these mmBCFAs or for more complex lipid molecules containing them. However, it cannot be ruled out that the arrest is due to the failure of a metabolic or structural function that is essential for growth and development at the first larval stage. In addition, C15ISO and C17ISO may directly or indirectly regulate genes involved in FA homeostasis. Consistent with this, their deficiency triggers a large alteration in gene expression that may reflect a complex feedback mechanism. Among the potentially responsive genes are transcription factors and metabolic genes.
|
15340492_p48
|
15340492
|
Concluding Remarks
| 4.287327 |
biomedical
|
Study
|
[
0.9995144605636597,
0.0002615494013298303,
0.0002239539462607354
] |
[
0.9989786148071289,
0.0003733096527867019,
0.0005700800102204084,
0.00007799054583301768
] |
en
| 0.999997 |
Ubiquitous and unattended mmBCFAs come forth as physiologically important molecules that regulate essential functions in eukaryotes. Many interesting questions regarding mmBCFAs remain to be addressed. What are the other components of the mmBCFA biosynthetic machinery? What are the components of their transport system? Does an organism have a mechanism by which the mmBCFA level is measured? What are the signaling pathways involved in the mmBCFA responses? How do mmBCFAs exert their physiological function? Do mmBCFAs act alone or as parts of more complex lipids? How are mmBCFAs synthesized in mammals? Lastly, what are the specific physiological functions of mmBCFAs in mammals? Both genetic and biochemical approaches will be taken to address these questions.
|
15340492_p49
|
15340492
|
Concluding Remarks
| 4.041247 |
biomedical
|
Review
|
[
0.9977015852928162,
0.0006389300688169897,
0.0016595358029007912
] |
[
0.11992546170949936,
0.14263008534908295,
0.7363499402999878,
0.0010945291724056005
] |
en
| 0.999997 |
The RNAi feeding vectors were either made in our laboratory using Taq PCR and cloning genomic fragments into a double T7 vector, pPD129.36 (gift of A. Fire), or obtained from the C. elegans whole genome RNAi feeding library (J. Ahringer, MRC Geneservice, Cambridge, United Kingdom).
|
15340492_p50
|
15340492
|
RNA interference by feeding
| 3.730495 |
biomedical
|
Study
|
[
0.999201238155365,
0.00016448530368506908,
0.0006342664710246027
] |
[
0.9493627548217773,
0.049327172338962555,
0.0010227651800960302,
0.0002874089404940605
] |
en
| 0.999996 |
The RNAi feeding strain was E. coli HT115 transformed with either empty pPD129.36 vector (controls) or with dsRNA-producing constructs. Plates were prepared as described in Kamath et al. . Unless stated differently, wild-type N2 Bristol animals were plated as synchronized adults. To obtain synchronized worms of various stages, a large quantity of N2 gravid adults were collected, bleached, and grown to the required stage on HT115 that had been transformed with pPD129.36 (control).
|
15340492_p51
|
15340492
|
RNA interference by feeding
| 4.047822 |
biomedical
|
Study
|
[
0.9995667338371277,
0.0001593204215168953,
0.0002739130286499858
] |
[
0.9987258315086365,
0.000962592544965446,
0.0002566318435128778,
0.00005484436042024754
] |
en
| 0.999996 |
A mixed population of well-fed worms were washed off the plates with water, rinsed 3–4 times, and, after aspirating away water, frozen at −80 °C. FA methyl esters and lipid extraction were performed as described in Miquel and Browse . GC was performed on the HP6890N (Agilent, Palo Alto, California, United States) equipped with a DB-23 column (30 m × 250 μm × 0.25 μm) . Each experiment was repeated at least five times. Average values and standard deviations were then calculated for each of the compounds in the experiments.
|
15340492_p52
|
15340492
|
GC analysis
| 4.064158 |
biomedical
|
Study
|
[
0.9996108412742615,
0.00016558241622988135,
0.00022359714785125107
] |
[
0.9990766048431396,
0.0005773772136308253,
0.00029003460076637566,
0.000055972552218008786
] |
en
| 0.999997 |
After bleaching gravid adults, an aliquot of the eggs was set apart, and the rest was incubated overnight in M9 at room temperature. On the next day, an aliquot of L1 was frozen for GC analysis. The rest of L1 was plated on agar plates. Subsequently, L2, L3, L4, young adults, and adults along with hatched L1 were collected as the separate samples. Mixed populations of worms starved for 24–100 h were included in the experiment to monitor a possible effect of the starvation.
|
15340492_p53
|
15340492
|
Staging worms to test for FA composition
| 4.013259 |
biomedical
|
Study
|
[
0.9995076656341553,
0.00019258627435192466,
0.00029975376673974097
] |
[
0.9988415837287903,
0.0008552384679205716,
0.00024012727953959256,
0.00006307470903266221
] |
en
| 0.999998 |
Ninety microliters of the 4 mM solution of FA (Sigma, St. Louis, Missouri, United States) in 1% NP40 was dropped on the side of the bacterial lawn that contained either elo-5 dsRNA-producing plasmid or the control HT115 vector. Two synchronized young adults were plated and their progeny was scored 4 and 5 d later. Each experiment was performed in at least 30 replicates. For recovering elo-5(RNAi) worms from L1 arrest, wild-type adults were placed on the elo-5(RNAi) plates. Four days later, their progeny was removed and eggs of the next generation were left on the plates. Hatched L1 were kept for 2 or 4 d before transferring as agar chunks to new elo-5(RNAi) plates. FA supplements were added to spots next to the chunks. Ten plates were prepared for each FA supplement. Control plates contained no supplements. To verify that an addition of supplements did not affect RNA interference per se, we used let-418(RNAi) animals, which have a sterile phenotype, as a control. Neither C15 nor C17 mmBCFA added to let-418(RNAi) plates modified the expected phenotype.
|
15340492_p54
|
15340492
|
Phenotype rescue using FA supplements.
| 4.123899 |
biomedical
|
Study
|
[
0.9994484782218933,
0.0002838950604200363,
0.0002676017174962908
] |
[
0.9993500113487244,
0.00034721745760180056,
0.00024427202879451215,
0.00005853126276633702
] |
en
| 0.999995 |
To prepare the GFP fusion constructs, genomic fragments were PCR amplified and cloned in frame into one of the GFP fusion vectors (gift of A. Fire). The locations of the genomic fragments and PCR primers used are listed below:
|
15340492_p55
|
15340492
|
Designing of GFP reporter constructs.
| 3.226633 |
biomedical
|
Study
|
[
0.9980394244194031,
0.0002710704575292766,
0.0016895525623112917
] |
[
0.9027727842330933,
0.09534025937318802,
0.0014047628501430154,
0.0004821677866857499
] |
en
| 0.999996 |
(1) elo-5Prom :: GFP, starting at 3.894 kb genomic upstream of the first codon and ending 4 bp into the first exon; primers, F-BamHI-TTTAGGTCATTTTTTGAGTCGCCA and R-BamHI-TAGTCTGGAATTTTGAAATTGAACGG; vector, pPD95.69;
|
15340492_p56
|
15340492
|
Designing of GFP reporter constructs.
| 3.599212 |
biomedical
|
Other
|
[
0.9971789121627808,
0.0006581845227628946,
0.0021628448739647865
] |
[
0.2969176173210144,
0.700887143611908,
0.0008744958322495222,
0.001320748939178884
] |
en
| 0.999998 |
(2) elo-6Prom :: GFP, a 4.764-kb fragment covering 3,104 bp upstream and 1,660 bp downstream of the predicted start codon and ending 14 bp into the third exon; primers, F-Sph1-GCCCTTGGAAACCATCTACGACGAATC and R-Sma1-TCCGAACAGAACGACATAAGAGATTTCC; vector, pPD95.77;
|
15340492_p57
|
15340492
|
Designing of GFP reporter constructs.
| 3.847518 |
biomedical
|
Other
|
[
0.9975218176841736,
0.0006792503991164267,
0.0017989010084420443
] |
[
0.4265669286251068,
0.5713930726051331,
0.0007243810687214136,
0.0013155544875189662
] |
en
| 0.999996 |
(3) acs-1Prom :: GFP, a 3.142-kb genomic fragment containing 3,048 kb upstream of the first predicted ATG and ending 24 bp into the second predicted exon; primers, F-SphI-CATAATTACTATTGCGTCACATG and R-SphI-CTCTTCCAAACTGGCGATGTCGA; vector, pPD95.69;
|
15340492_p58
|
15340492
|
Designing of GFP reporter constructs.
| 3.891913 |
biomedical
|
Other
|
[
0.9982074499130249,
0.0005850419984199107,
0.0012074722908437252
] |
[
0.49831587076187134,
0.49944451451301575,
0.0008260595495812595,
0.0014136249665170908
] |
en
| 0.999995 |
(4) pnk-1Prom :: GFP, a 1.14-kb fragment that includes 937 bp upstream of the first predicted codon of the C10G11.5 and 203 bp downstream, ending 24 bp into the second exon; primers, F-SphI-TCGTACGATCGGACCATAGGCTAA and R-SphI-CTGATCCTCTGTAGCAGCGGCCCT; vector, pPD95.69.
|
15340492_p59
|
15340492
|
Designing of GFP reporter constructs.
| 3.944099 |
biomedical
|
Study
|
[
0.9978424310684204,
0.0006344023859128356,
0.001523172133602202
] |
[
0.548909604549408,
0.4491739273071289,
0.0007188013987615705,
0.0011976161040365696
] |
en
| 0.999996 |
These constructs were injected into C. elegans at 10–50 ng/μl to form extrachromosomal arrays. In the case of acs-1, the extrachromosomal array had been integrated into the C. elegans genome.
|
15340492_p60
|
15340492
|
Designing of GFP reporter constructs.
| 3.720126 |
biomedical
|
Study
|
[
0.998933732509613,
0.0002516907698009163,
0.0008145166793838143
] |
[
0.9588528871536255,
0.040097661316394806,
0.0007662527495995164,
0.00028315657982602715
] |
en
| 0.999995 |
Worms were soaked in a 5-μg/ml solution of DiI (Molecular Probes, Eugene, Oregon, United States) in M9 buffer for 1 h. They were then rinsed three times with M9 and visualized by fluorescence using the Texas Red filter.
|
15340492_p61
|
15340492
|
Staining chemosensory ciliated neuron with DiI
| 3.791327 |
biomedical
|
Study
|
[
0.9992836117744446,
0.0003080079914070666,
0.00040838998393155634
] |
[
0.8825044631958008,
0.11505692452192307,
0.0017894392367452383,
0.0006492268294095993
] |
en
| 0.999997 |
The FA quantities obtained by GC were expressed as a percentage of the total. t test (two-tailed distribution) and correlation analysis were performed using the Microsoft Excel program.
|
15340492_p62
|
15340492
|
Correlation analysis
| 2.897682 |
biomedical
|
Study
|
[
0.9985833168029785,
0.00031288282480090857,
0.0011038323864340782
] |
[
0.9790331721305847,
0.019620968028903008,
0.0010101967491209507,
0.00033556370181031525
] |
en
| 0.999998 |
Synchronized adults were placed on control (HT115 bacterial strain transformed with empty vector, pPD129.36) and RNAi (HT115 bacterial strain transformed with dsRNA construct) plates. Several worms of the next generation were picked from the control and RNAi plates and mounted on the same microscopic slide. GFP images were obtained with the fixed settings and exposure.
|
15340492_p63
|
15340492
|
Visualization and scoring of the GFP expression in promoter::GFP lines
| 3.867094 |
biomedical
|
Study
|
[
0.9993991851806641,
0.00017831410514190793,
0.0004224913427606225
] |
[
0.9887653589248657,
0.010418741963803768,
0.0006632310687564313,
0.0001526768901385367
] |
en
| 0.999997 |
One young adult of the N2 Bristol strain was plated on each control and RNAi feeding plate. Control plates contained the E. coli HT115 strain transformed with empty pPD129.36 vector. Experimental RNAi plates contained E. coli HT115 transformed with corresponding dsRNA constructs. The growth conditions, RNA preparations, and data analyses are described in detail in Protocol S1 . Expression data are presented in Dataset S1 .
|
15340492_p64
|
15340492
|
Microarray analysis
| 3.924757 |
biomedical
|
Study
|
[
0.9995013475418091,
0.00016021305054891855,
0.0003383581934031099
] |
[
0.9980084300041199,
0.001626528799533844,
0.00028701784322038293,
0.00007811546674929559
] |
en
| 0.999997 |
The emergency department (ED) is intended to treat medical urgencies or emergencies, but a large proportion of visits are due to problems that could be treated in the primary care setting . ED services are available 24 hours a day while primary care facilities have limited service hours. In the Israeli health system patients can be referred to the ED by their family practitioner, or by other community health providers, or be self referred. Recently many out of hours community based services have been established but without a significant reduction in visiting rates to in-hospital ED.
|
15298721_p0
|
15298721
|
Background
| 1.839153 |
biomedical
|
Other
|
[
0.5189564228057861,
0.38712194561958313,
0.09392163902521133
] |
[
0.0038759990129619837,
0.9926149845123291,
0.0005243744235485792,
0.0029845985118299723
] |
en
| 0.999995 |
The visit to the ED constitutes a brief, yet an important point in the continuum of medical care. In today's era of cost effectiveness and increasingly competent primary care physicians, ambulatory investigation, treatment and follow-up have largely replaced prolonged and costly hospitalizations . The ED visit however, remains a cross-road which may mark a sudden change in the patient's medical condition. In many cases it may result in introducing new medications, withdrawing others and recommendation of further investigations. The family practitioner is the one expected to coordinate and carry out the treatment and follow-up. The new information given from the ED should be effectively delivered to the family practitioner, the modality usually used is the discharge letter.
|
15298721_p1
|
15298721
|
Background
| 2.751437 |
clinical
|
Other
|
[
0.22549039125442505,
0.7580734491348267,
0.016436176374554634
] |
[
0.0016686575254425406,
0.9840297698974609,
0.002411611145362258,
0.01189002301543951
] |
en
| 0.999995 |
The continuation of treatment between hospital departments and the primary care physician had been issued in several studies using discharge letters audit . Raval et. al. assessed the adequacy of the discharge summary in reporting important investigative results and future management plans in patients hospitalized and discharged with a diagnosis of heart failure . They found substantial inadequacies in communicating to the community physician that may have implications for continuity of care and subsequent clinical outcome. Wilson et. al. examined the reliability, effectiveness, accuracy and timeliness of hospital to general practitioner information transfer by discharge summaries. In a retrospective audit of 569 patient discharge summaries and related medical records they found that summaries written for patients discharged from hospital were estimated to be received by the patient-nominated general practitioner in 27.1% of cases . Bolton et al assessed the quality of communications between hospitals and general practitioners. The general practitioner's(GP) name was recorded in 88% of audited records. Few inaccuracies were detected in the medications recorded in the discharge summaries, and on contrary to Wilson et al 77% of discharge summaries were received by the GP . The continuity of care between the ED and the primary care physician had been assessed for children with asthma but we did not find data about the continuity of care for adults.
|
15298721_p2
|
15298721
|
Background
| 4.004257 |
biomedical
|
Study
|
[
0.9962813258171082,
0.0024770493619143963,
0.001241598860360682
] |
[
0.8812101483345032,
0.0012484523467719555,
0.11697301268577576,
0.0005683446070179343
] |
en
| 0.999996 |
To evaluate the continuity of care after ED visits, we evaluated the ED referral and discharge letters, their content, and the documentation of the ED visit in the patients' primary care files. We have focused on discharges from the internal medicine ED. We expected that in these cases the patients would be followed up by their family practitioner.
|
15298721_p3
|
15298721
|
Background
| 1.851978 |
clinical
|
Study
|
[
0.4905732274055481,
0.49523022770881653,
0.014196562580764294
] |
[
0.8327939510345459,
0.13839150965213776,
0.0033161891624331474,
0.02549836039543152
] |
en
| 0.999995 |
The study was conducted in the district medical center (Kaplan), serving more than 500,000 inhabitants, and in 12 primary care clinics (32 family practitioners), of The Clalit Health Services in the Rehovot region, Israel.
|
15298721_p4
|
15298721
|
Methods
| 1.785328 |
biomedical
|
Study
|
[
0.9720057845115662,
0.0070274299941957,
0.020966842770576477
] |
[
0.9256539344787598,
0.07204394787549973,
0.0009029422071762383,
0.001399168511852622
] |
en
| 0.999996 |
In Israel the entire population have a national health insurance by law and each citizen can choose to be a member of one of four HMOs. Every member of the Clalit Health Services, the largest HMO in Israel, is registered to a single family physician, and have a medical record in his physician's clinic. Visits to the emergency department are regulated in the national health insurance law. A referral by a physician or by ambulance is free of charge, but this referral should be with a referral letter and not by a phone call to the ED or to the patient. A self referral may cost the patient a co-payment of up to 100 USD.
|
15298721_p5
|
15298721
|
Methods
| 1.507705 |
other
|
Other
|
[
0.08746299147605896,
0.05934877693653107,
0.8531882762908936
] |
[
0.0020667111966758966,
0.9969774484634399,
0.0002452927874401212,
0.0007106281700544059
] |
en
| 0.999996 |
We reviewed retrospectively all the charts of the ED visits for a period of one month, excluding the visits to the pediatric and the gynecologic-obstetrics EDs (see flow-chart 1). 5,898 visits documented that month, resulted in 4,256 discharges and 1,642 hospitalizations. There were 1,564 discharges from the general ED. Trauma, surgery and orthopedics accounted 2,209 discharges and the rest 483 were from other specialties (ophthalmology, ENT, dermatology etc.).
|
15298721_p6
|
15298721
|
Methods
| 2.735857 |
biomedical
|
Study
|
[
0.910435676574707,
0.08590548485517502,
0.0036588581278920174
] |
[
0.9808844327926636,
0.01205108966678381,
0.002339006867259741,
0.004725480452179909
] |
en
| 0.999997 |
Inclusion criteria were: visit to the general ED, age above 18 years, discharge to the community (not hospitalized) at that visit, living and getting medical care in a family medicine group practice in the Rehovot region. Visits due to accidents, trauma, surgery, orthopedics, ENT, ophthalmology and other specialities were excluded from the study. The 1,564 discharges from the general ED were reviewed and 359 were found to be eligible to this study.
|
15298721_p7
|
15298721
|
Methods
| 2.36095 |
biomedical
|
Study
|
[
0.944336473941803,
0.051663488149642944,
0.00400006677955389
] |
[
0.988497793674469,
0.009383799508213997,
0.0003974534338340163,
0.0017209089128300548
] |
en
| 0.999997 |
Two physicians reviewed independently each ED medical chart. Data extracted included: age and gender of the patient, attendance date and hour, self referral, or a referral by a physician and the final diagnosis in the discharge letter. In cases of referrals the content and format of the referral letter were assessed, including: hand writing quality and whether the referring physician referred the patient with a specific question (for example: rule out new onset angina pectoris, suspected pneumonia, please make a chest X ray etc.).
|
15298721_p8
|
15298721
|
Methods
| 2.986612 |
clinical
|
Study
|
[
0.4048204720020294,
0.5919511914253235,
0.003228371497243643
] |
[
0.9173019528388977,
0.05063304677605629,
0.00474844966083765,
0.027316538617014885
] |
en
| 0.999995 |
Continuity of communication and care: The primary care files of ED visitors were retrieved and checked for the existence of the ED discharge letter and comments about the visit in the follow-up chart. If the discharge letter and / or any comment on the ED visit in the follow-up chart had been found the case was defined as "a case with good continuity of care".
|
15298721_p9
|
15298721
|
Methods
| 2.074106 |
clinical
|
Other
|
[
0.18770432472229004,
0.8031361103057861,
0.009159575216472149
] |
[
0.40665215253829956,
0.5277688503265381,
0.004838448017835617,
0.06074056401848793
] |
en
| 0.999995 |
The cases in which the family physician was the referring physician we looked for documentation of the encounter prior to ED attendance.
|
15298721_p10
|
15298721
|
Methods
| 1.56389 |
biomedical
|
Other
|
[
0.5569493770599365,
0.4146484434604645,
0.02840217389166355
] |
[
0.39491429924964905,
0.5530043244361877,
0.004650168586522341,
0.047431185841560364
] |
en
| 0.999998 |
Visits to the ED were divided into "working hours" visits – when the visit took place during working hours of primary care clinics in the community (Sunday to Thursday from 08:00 to 20:00, and Friday 08:00 to 14:00), and "out of hours" visits when primary care clinics in the community are closed (from 20:00 to 08:00 weekdays, and weekends from 14:00 on Friday to 08:00 on the following Sunday).
|
15298721_p11
|
15298721
|
Methods
| 1.82269 |
clinical
|
Other
|
[
0.40001147985458374,
0.5608919858932495,
0.039096541702747345
] |
[
0.14006143808364868,
0.8417108058929443,
0.0016154421027749777,
0.01661224663257599
] |
en
| 0.999998 |
A referral letter was defined as "any document written by a medical authority in the community prior to the index ED visit", including referrals from family practitioners, other practitioners in the community and arrival by an ambulance.
|
15298721_p12
|
15298721
|
Methods
| 2.048019 |
clinical
|
Other
|
[
0.43707242608070374,
0.543617844581604,
0.019309720024466515
] |
[
0.14841541647911072,
0.8305250406265259,
0.0016554604517295957,
0.019404012709856033
] |
en
| 0.999996 |
A recurrent visit to the ED was defined as a patient's visit to ED within less than two weeks from a previous visit with the same complaint, when in both cases the patient was not hospitalized.
|
15298721_p13
|
15298721
|
Methods
| 2.442632 |
biomedical
|
Other
|
[
0.6010496020317078,
0.3929395377635956,
0.006010851357132196
] |
[
0.2813289761543274,
0.6844260692596436,
0.0023368068505078554,
0.03190821036696434
] |
en
| 0.999996 |
Diagnoses at discharge were coded for a specific diagnosis and for the system involved according to the ICPC coding system.
|
15298721_p14
|
15298721
|
Methods
| 2.014574 |
biomedical
|
Study
|
[
0.9139605760574341,
0.07393233478069305,
0.012107097543776035
] |
[
0.4945170283317566,
0.4915842115879059,
0.0040076435543596745,
0.009891080670058727
] |
en
| 0.999996 |
Statistical analysis: Data was analyzed using distribution analysis and χ 2 tests to investigate the association between categorized variables. Student's t tests were used to analyze continuous variables. The analysis was performed using the SPSS package.
|
15298721_p15
|
15298721
|
Methods
| 2.743478 |
biomedical
|
Study
|
[
0.9979801774024963,
0.0004978278884664178,
0.001521922880783677
] |
[
0.9755959510803223,
0.023324014618992805,
0.0007941430667415261,
0.0002859292726498097
] |
en
| 0.999996 |
During the study period there were 359 ED visits that were eligible to be included in the study (table 1 , flow chart 1). . 214 (59.6%) visited the ED during the "working hours" of primary care clinics, 28 (7.8% of all visits) were recurrent visits to the ED.
|
15298721_p16
|
15298721
|
Results
| 2.240404 |
biomedical
|
Study
|
[
0.947452187538147,
0.04947128891944885,
0.0030765633564442396
] |
[
0.9837943911552429,
0.013087935745716095,
0.0005369472783058882,
0.0025808345526456833
] |
en
| 0.999995 |
Out of all ED visits only 196 (54.6%) patients had a referral letter, the rest were self-referrals. Referral letters were mainly from the family practitioner (147/196, 75%), 14 (7%) from other practitioners in the community, and 35 (18%) of referrals were by ambulance. The referral letters from the community were legible in 43.4% (70/161), 46.5% (75/161) were barely legible and 10% (16/161) illegible. In only 25/161 letters (15.7% of the referrals) a specific question was asked by the referring physician and in another 32 (20.2%) there was only a general question.
|
15298721_p17
|
15298721
|
Results
| 2.26808 |
clinical
|
Study
|
[
0.1622265875339508,
0.8268420100212097,
0.010931371711194515
] |
[
0.7379497289657593,
0.2021840512752533,
0.004907415248453617,
0.054958783090114594
] |
en
| 0.999998 |
The main diagnostic groups according to the ICPC were: respiratory (15.7%), digestive system (18.1%), musculo-skeletal (15.2%) and cardio-vascular (11%). In 9.6% of the cases the discharge letter did not contain a specific diagnosis and the diagnosis fell in the "general" category. The most common specific diagnoses were: chest pain (5.9%), abdominal pain (3.9%), other respiratory tract infections (3.7%), asthma (3.1%), back pain (2.8%), COPD exacerbation (2.8%) headache (2.5%), nephrolithiasis (2.5%), vertigo or dizziness (2.5%) and gastroenteritis (2.3%).
|
15298721_p18
|
15298721
|
Results
| 3.364472 |
biomedical
|
Study
|
[
0.9284786581993103,
0.07026349753141403,
0.0012578294845297933
] |
[
0.9462819695472717,
0.04534188657999039,
0.0028528948314487934,
0.005523323081433773
] |
en
| 0.999997 |
The "out of hours" visitors tended to be younger (52.2 ± 17.5 vs. 55.4 ± 19.5, p = NS) (table 1 ). A third of the "working hours" visits (71/214) were self referrals as opposed to 63.5% (92/145) of "out of hours" visits . Table 2 compares the referring practitioners according to ED visiting hours.
|
15298721_p19
|
15298721
|
Results
| 2.258134 |
biomedical
|
Study
|
[
0.8864549398422241,
0.10570171475410461,
0.00784338265657425
] |
[
0.9819877743721008,
0.014339422807097435,
0.000741174619179219,
0.0029316849540919065
] |
en
| 0.999997 |
In 147 cases the reffering physician was the family physician, documentation of the ED referral was found in 32% (47/147) of primary care files. The ED discharge letter was found in 50% (179/359) of the primary care files. A follow-up visit was documented in only 31% (111/359). Neither follow up visits nor discharge letters were found in 43% of the files (153/359). No associations between clinic characteristics (size, place) or family practitioner qualification and ED visit documentation was found.
|
15298721_p20
|
15298721
|
Results
| 2.465519 |
clinical
|
Study
|
[
0.21308131515979767,
0.7801569700241089,
0.006761718075722456
] |
[
0.9000518918037415,
0.06292856484651566,
0.0046300445683300495,
0.032389476895332336
] |
en
| 0.999996 |
The Emergency Department (ED) acts as a link between community and hospital based medicine. In Israel a patient who needs non elective admission to a hospital unit must pass through the ED, either with a referral note from a medical practitioner, or as a self referral. Most ED visits, however, do not result in hospitalization, and many could be regarded as primary health care problems . These patients are discharged directly from the ED to the community and further care of the family practitioner. A visit to the ED is generally not prompted by a benign complaint; The most common reasons for referral include, chest pain, asthma exacerbations and nephrolithiasis, subsequent follow up by the family practitioner can be vital. It was found that most children do not have outpatient follow-up after an ED asthma visit . However, those patients that present for outpatient follow-up have an increased likelihood for repeat ED asthma visits, and this visit should be a key opportunity to prevent future ED asthma visits.
|
15298721_p21
|
15298721
|
Discussion
| 3.765301 |
biomedical
|
Other
|
[
0.8321376442909241,
0.16166314482688904,
0.006199167110025883
] |
[
0.07639610767364502,
0.9048073291778564,
0.012334010563790798,
0.0064625004306435585
] |
en
| 0.999997 |
The increasing role played by the ED in treating primary care problems has been discussed in a number of recent articles .
|
15298721_p22
|
15298721
|
Discussion
| 1.391012 |
biomedical
|
Other
|
[
0.8647931814193726,
0.03256141394376755,
0.10264544934034348
] |
[
0.007582893129438162,
0.9739799499511719,
0.01554123219102621,
0.002896005054935813
] |
en
| 0.999996 |
One aspect, which is important to the ED team, is the logistics and manpower needed to optimize the treatment of these non-urgent patients in ways that will not interfere with emergencies yet providing them adequate care. It is unclear whether the capability and quality of primary care services in the ED should be improved and compete with the community family physicians. This is true especially in Israel where there is a universal national health insurance and every patient can have a personal family practitioner.
|
15298721_p23
|
15298721
|
Discussion
| 1.695924 |
biomedical
|
Other
|
[
0.39762958884239197,
0.36234983801841736,
0.24002057313919067
] |
[
0.003909815568476915,
0.9935688972473145,
0.0005780193023383617,
0.001943291281349957
] |
en
| 0.999997 |
The continuity of comprehensive management is expected from the family practitioner, and is gaining importance nowadays . To achieve this goal the communication between health care providers who treat the patient is mandatory. In the case of the ED visit, where we found many self referrals and referrals from other physicians, it becomes even more important.
|
15298721_p24
|
15298721
|
Discussion
| 1.57917 |
biomedical
|
Other
|
[
0.5319512486457825,
0.3868234157562256,
0.08122535049915314
] |
[
0.002221449976786971,
0.9927230477333069,
0.0007490204297937453,
0.004306403454393148
] |
en
| 0.999997 |
The modes of communication are the referral letter and the discharge letter. We have found that the referral letter can be improved both in style (printed instead of illegible hand writing) and content (the referring physician should define and clarify the reasons for referral and his expectations). These problems exist in discharge letters as well .
|
15298721_p25
|
15298721
|
Discussion
| 1.408025 |
clinical
|
Other
|
[
0.24381907284259796,
0.39715978503227234,
0.3590211570262909
] |
[
0.004874975886195898,
0.9903505444526672,
0.0012141373008489609,
0.0035602704156190157
] |
en
| 0.999999 |
Documentation in the primary care file was poor, only one third of referrals were documented and less than 60% of discharges. This figure is between the 27%–77% that was found by others . A possible bias is that some follow-up visits were to specialists. But in the case of discharge from the general medicine ED we presume that most patients were advised to return to their family physicians.
|
15298721_p26
|
15298721
|
Discussion
| 1.719163 |
clinical
|
Other
|
[
0.27520230412483215,
0.7023813724517822,
0.022416360676288605
] |
[
0.43245476484298706,
0.5090755820274353,
0.005137226544320583,
0.053332455456256866
] |
en
| 0.999998 |
It is well known that medical notes are poor in other areas, Miller et al found documentation of only 15% of prescriptions given by family practitioners. They explained one of the causes for this discrepancy as the need of double writing (both the prescription itself and in the medical notes). By introducing carbon copy prescriptions, they achieved an 82% documentation rates in patients' files. Opila found documentation in out patient medical records greatly improved after employing quality control and a feedback system.
|
15298721_p27
|
15298721
|
Discussion
| 2.866442 |
biomedical
|
Study
|
[
0.9755086898803711,
0.015404356643557549,
0.00908701028674841
] |
[
0.8058580756187439,
0.12597575783729553,
0.06440108269453049,
0.0037650694139301777
] |
en
| 0.999996 |
With the introduction of computerized medical files in primary care clinics in our region, the need of "double writing" will disappear, and this in turn should dramatically improve documentation rate of referrals and discharges to the ED; particularly if a computerized reminder system is used to encourage follow up of referrals by the family practitioner.
|
15298721_p28
|
15298721
|
Discussion
| 1.642676 |
biomedical
|
Other
|
[
0.5280465483665466,
0.3300231695175171,
0.14193028211593628
] |
[
0.002730040578171611,
0.9945610165596008,
0.0004191039188299328,
0.002289901953190565
] |
en
| 0.999999 |
Israeli health care system works in regard to ED use quite different from the US and other countries. Likewhise these results may not automatically be generalized to other health care systems. This study described the written communication between the emergency department and the primary care physician, which is the first and mandatory step in establishing continuation of care. This is only one of the four dimensions of continuity of care in family practice: chronological, geographical, interdisciplinary, and interpersonal . Each of these dimensions may influence the quality of care and be evaluated and studied. Further study is needed to prove the link between documantion of ED visit and good contuniuity of care. Large scale prospective intervention studies are needed to prove that continuity of care between ED and the primary care physician improves outcome and saves money.
|
15298721_p29
|
15298721
|
Limitations
| 3.208875 |
biomedical
|
Study
|
[
0.9849779605865479,
0.0094221793115139,
0.005599943455308676
] |
[
0.9651466608047485,
0.031859058886766434,
0.0021471953950822353,
0.0008471436449326575
] |
en
| 0.999996 |
ED visits may have important implications for the patient and his family practitioner. The high rate of ED self referrals together with low documentation rates of ED visits in the primary care charts result in poor continuity of care of ED visitors.
|
15298721_p30
|
15298721
|
Conclusion
| 1.674617 |
clinical
|
Other
|
[
0.3584132194519043,
0.606190025806427,
0.035396724939346313
] |
[
0.012119770981371403,
0.972055971622467,
0.0013586332788690925,
0.014465617947280407
] |
en
| 0.999998 |
None declared.
|
15298721_p31
|
15298721
|
Competing interests
| 0.828596 |
other
|
Other
|
[
0.19056588411331177,
0.00526782963424921,
0.804166316986084
] |
[
0.017649337649345398,
0.97890704870224,
0.0020668196957558393,
0.001376785570755601
] |
it
| 0.999996 |
All authors read and approved the final manuscript.
|
15298721_p32
|
15298721
|
Authors' contributions
| 0.878058 |
other
|
Other
|
[
0.054435282945632935,
0.0028271148912608624,
0.9427375793457031
] |
[
0.002803728450089693,
0.9938488602638245,
0.002403399208560586,
0.0009439752320758998
] |
en
| 0.999998 |
VS Conceived and designed the study, participated in the collection, analysis and interpretation of data and drafted the manuscript. KE Participated in the statistical analysis, interpretation of data and draft of the manuscript.OY participated in the design of the study, data collection and interpretetio hand draft of the manuscript. SN participated in the design of the study, interpretation of data and draft of the manuscript. All authors have read and approved the final manuscript.
|
15298721_p33
|
15298721
|
Authors' contributions
| 0.911753 |
other
|
Other
|
[
0.06652779132127762,
0.0017213267274200916,
0.9317508339881897
] |
[
0.0031614264007657766,
0.9958667755126953,
0.0006076523568481207,
0.0003640811482910067
] |
en
| 0.999997 |
The pre-publication history for this paper can be accessed here:
|
15298721_p34
|
15298721
|
Pre-publication history
| 1.031347 |
other
|
Other
|
[
0.013091348111629486,
0.0014214670518413186,
0.9854872226715088
] |
[
0.0015875872923061252,
0.997281551361084,
0.0006836647517047822,
0.0004471398133318871
] |
en
| 0.999997 |
The type 1 diabetes, previously called insulin-dependent diabetes mellitus (IDDM), is the consequence of progressive and selective destruction of pancreatic β cells by an immune-mediated process , resulting in an absolute lack of insulin . It is well established that this self-destruction is primarily provoked by the activation of the autoreactive T lymphocytes by the production of T-helper 1 cytokines . In addition, the difference of the epidemiological data from one region to another could largely explain why the release of the autoimmunity is stimulated under the influence of one or more environmental factors , in genetically predisposed subjects. It is currently obvious that the strongest genetic susceptibility of predisposition is allotted to the IDDM1 alleles located in the HLA locus of the chromosome 6p21 , and the non-HLA alleles, particularly the IDDM2 polymorph gene located in the region 5' of the insulin gene ( INS ) promoter situated on the chromosome 11p15 . Other regions of the genome were identified as IDDM3, coding for the IGF1 receptor, IDDM4, located near the fibroblast growth factor 3 gene, IDDM5, near the estrogens receptor gene etc. The majority of these regions have no possible statistical criteria allowing them to be clearly linked to the disease . In all cases, it is mainly HLA alleles that present a high risk of contracting the disease compared to non-HLA alleles . Due to this, they are qualified as high genetic predictive markers of developing type 1 diabetes in families having a type 1 diabetic member. Interestingly, the disease prediction offered with success the possibility of clinical trials to delay, or even prevent the appearance of type 1 diabetes.
|
15331022_p0
|
15331022
|
Background
| 4.717209 |
biomedical
|
Review
|
[
0.996845543384552,
0.0017465408891439438,
0.0014079140964895487
] |
[
0.22216178476810455,
0.002946047345176339,
0.7737118005752563,
0.001180383376777172
] |
en
| 0.999996 |
However, the different HLA types associated with diabetes depend also on the population. The purpose of our study is to measure HLA DR3 and/or DR4 antigen frequencies and their association in diabetic and nondiabetic subjects originating from the west-Algerian region of Tlemcen. Using a case-control retrospective study design, we attempt to determine which is the greatest HLA DR susceptibility contributing to developing type 1 diabetes. Ninety-one (91) eligible subjects (thirty-nine (39) type 1 diabetics and fifty-two (52) nondiabetics with relatives with type 1 diabetes as controls), were recruited at the Internal Medicine Board of the Medical Centre University of Tlemcen.
|
15331022_p1
|
15331022
|
Background
| 4.021485 |
biomedical
|
Study
|
[
0.9994056224822998,
0.00036159134469926357,
0.0002327941620023921
] |
[
0.9995015859603882,
0.00022978067863732576,
0.00020055114873684943,
0.00006811706407461315
] |
en
| 0.999997 |
Table 1 summarizes HLA DR3, DR4 and DR3DR4 antigen frequencies in type 1 diabetics and their nondiabetic relatives.
|
15331022_p2
|
15331022
|
Results
| 3.323708 |
biomedical
|
Study
|
[
0.9993128776550293,
0.0003135130100417882,
0.0003736251965165138
] |
[
0.9908305406570435,
0.008124638348817825,
0.0007997407810762525,
0.00024509982904419303
] |
en
| 0.999997 |
DR4 and DR3DR4 antigens showed an association with susceptibility to type 1 diabetes (DR4; OR = 2.10, DR3DR4; OR = 1.30, that is respectively OR confidence interval 1.04–4.24 and 0.60–2.80, 95% CI), in contrast, DR3 antigens showed no association with the disease (OR = 0.95, OR confidence interval 0.48–1.87, 95% CI). It is important to notice that the strongest association is found in DR4 phenotype as indicated in Figure 1 .
|
15331022_p3
|
15331022
|
Results
| 4.089699 |
biomedical
|
Study
|
[
0.9996095299720764,
0.00016886170487850904,
0.0002216001012129709
] |
[
0.9992986917495728,
0.0002465603465680033,
0.0004063418018631637,
0.00004840068140765652
] |
en
| 0.999995 |
In addition, the phenotypic frequency of DR4 or DR3DR4 molecules is higher in diabetic group than in the control one, although the difference did not reach significance level in DR3DR4 frequencies . On the contrary, the DR3 molecules frequency is slightly decreased in type 1 diabetic patients compared to the controls and presents no statistically significant difference ( p = 1.000). Furthermore, no incidence was related to the sex criteria for the frequencies of DR3 and DR3DR4 molecules ( p > 0.05). However, significant differences in HLA DR4 frequencies are linked to the female sex and present a value definitely higher in type 1 diabetic patients compared to those of nondiabetics for the same sex ( p < 0.05) .
|
15331022_p4
|
15331022
|
Results
| 4.113034 |
biomedical
|
Study
|
[
0.9994571805000305,
0.000221066948142834,
0.0003217953199055046
] |
[
0.9994408488273621,
0.0001580123062012717,
0.0003582823264878243,
0.00004280370194464922
] |
en
| 0.999998 |
Type 1 diabetes is a polygenic disease which results from the interaction between environmental (viral, toxic, nutritional, socioeconomic ) and genetic factors. It is the form of diabetes which occurs mainly in children and young adults .
|
15331022_p5
|
15331022
|
Discussion
| 2.635126 |
biomedical
|
Other
|
[
0.9966896772384644,
0.0019052264979109168,
0.001405074493959546
] |
[
0.006494355387985706,
0.976335346698761,
0.015031231567263603,
0.002139079151675105
] |
en
| 0.999996 |
Fortunately, molecular epidemiology offers the hope of the possibility of preventing the disease in the future, by evaluating the potential factors of risk of developing this pathology . Although almost 90 % of new cases of type 1 diabetes occur sporadically, studies of individuals with a diabetic relative in their family are essential .
|
15331022_p6
|
15331022
|
Discussion
| 3.061538 |
biomedical
|
Other
|
[
0.9980707764625549,
0.0009065070189535618,
0.001022794982418418
] |
[
0.022657034918665886,
0.9641552567481995,
0.012195383198559284,
0.000992283457890153
] |
en
| 0.999998 |
It is well established that associations between type 1 diabetes and certain HLA antigens largely facilitate the identification of the subjects having a potential risk to develop the disease. Among the putative HLA molecules known to confer a high susceptibility are DQA1 -DQB1 (= DQ8), DQA1 -DQB1 (= DQ2), DRA-DRB1 (= DR4) and DRA-DRB1 (= DR3) . However, epidemiological studies showed that the different HLA types associated with the diabetes depend also on the various populations. For instance, the risk of developing type 1 diabetes in Caucasians is greater if they are carrying the HLA A8 and B15, while DQ6 alleles are protectors . Among Japanese, it is the association with the HLA B54 that confers a higher susceptibility to develop the disease, while the strongest association was found with HLA DR and HLA DQ locus .
|
15331022_p7
|
15331022
|
Discussion
| 4.204245 |
biomedical
|
Study
|
[
0.9993996620178223,
0.0002605085028335452,
0.00033978139981627464
] |
[
0.8822264671325684,
0.0012827684404328465,
0.11622001975774765,
0.00027083183522336185
] |
en
| 0.999999 |
In Algeria, and especially in its western region (Tlemcen), which is known for its history of consanguineous marriage, there is a high rate of consanguinity. This fact could increase the risk of developing type 1 diabetes by favouring the transmission of HLA haplotypes and recessive genes of susceptibility except for HLA antigens that are common in both parents. For these reasons, we were interested in checking whether phenotypically DR3DR4 antigens would involve less risk to develop the disease, in comparison with DR3 or DR4 antigens, knowing the fact that the presence of a probable consanguinity could reduce the frequency of DR3DR4 polymorph phenotype compared to that of DR3 or DR4 phenotype.
|
15331022_p8
|
15331022
|
Discussion
| 3.960315 |
biomedical
|
Study
|
[
0.9989131689071655,
0.0001758275757310912,
0.000911010371055454
] |
[
0.9990129470825195,
0.0008132066577672958,
0.0001276180992135778,
0.00004610909672919661
] |
en
| 0.999996 |
On a purely comparative basis, similarities seem to be found between our results and those of other investigators with regards to HLA DR4 or DR3DR4 frequencies, which are higher in the type 1 diabetic than the nondiabetic population. On the contrary, the HLA DR3 antigens showed comparable frequencies in both groups of our sample. Consequently, these observations associating DR3 phenotype to a protector effect against type 1 diabetes in our studied population are thus do not conform with those reported in the literature . However, DR4 and DR3DR4 antigens are obviously associated with susceptibility of developing the disease. It should also be noted that DR3DR4 antigens might represent a weaker predictive value of disease risk. We concluded from this that the non-excess of DR3DR4 antigens, or comparable frequencies of DR3 molecules between type 1 diabetic patients and ND relative controls, might be a strong indices of consanguinity in our sample. A recent study carried out in Sweden showed that HLA DR3 is associated to the development of type 1 diabetes and the incompatibility of blood group ABo . One can thus note that the role of the HLA DR3 antigens in conferring risk for type 1 diabetes can be masked in the homogeneous populations. Due to the restricted size of our sample, which may influence our interpretation, we should not consider the odds ratio of HLA DR3 antigens or the eventual consanguinity of our studied population. Moreover, many evidences incriminate DR3 and/or DR4 antigens in the susceptibility to type 1 diabetes and their association with the detected autoantibodies in this disease. Indeed, the marks of autoimmunity are much more observed in the diabetic patients carrying DR3 or DR4 antigens than in the diabetic patients where DR3 or DR4 antigens were absents . Furthermore, recent research indicates that a subject with HLA DR4 or DR3 alleles has three or four times more chance of developing type 1 diabetes compared to the general population; DR3DR4 is associated with the highest risk (20 to 40 times more) .
|
15331022_p9
|
15331022
|
Discussion
| 4.329071 |
biomedical
|
Study
|
[
0.9994276165962219,
0.0003284812846686691,
0.00024392458726651967
] |
[
0.9984468817710876,
0.000236462292377837,
0.0012299877125769854,
0.00008666650683153421
] |
en
| 0.999996 |
In Algeria, very few investigations have been undertaken to study the impact of the genetic background on the risk to develop type 1 diabetes in its population, where an annual average incidence of 4.7 per 100000 has already been listed . In a similar study carried out on Algerian unrelated type 1 diabetics (n = 50) and nondiabetics controls (n = 46), the presence of DR3-DQ2 (linkage disequilibrium) in 45 % of patients and in 13 % of controls was detected by molecular genotyping method using PCR (polymerase chain reaction) and SSO (sequence specific oligonucleotide). DR4-DQ8 was found in 37 % of diabetic cases and in 4 % of control groups . Finally, association with type 1 diabetes attributed to DR-B1*0405 (alleles of DR4 antigens expression) susceptibility showed a match with our results; however, the DR4 antigens were found to be linked to the female sex. According to the results showed in Table 1 , there is no difference between men and women patients with type 1 diabetes carrying DR4 antigens, but a significant difference was noticed in female sex, either women were contracted or not with diabetic disease.
|
15331022_p10
|
15331022
|
Discussion
| 4.134606 |
biomedical
|
Study
|
[
0.999535322189331,
0.00019552375306375325,
0.0002691104309633374
] |
[
0.9994076490402222,
0.00019721237185876817,
0.00034480495378375053,
0.000050414750148775056
] |
en
| 0.999997 |
It is certain that screening of HLA class II sub-types and determination of DNA coding sequences allows more precise characterization of ethnic groups, especially, because the same coded molecules can differ by the position of few amino acids. For example, it is well established that DQA1 and DQB1 alleles (sub-types of HLA DQ) code respectively for the alpha and beta chain of the DQ molecule . Thus, the combination of DQ alpha with Arg in position 52 (Arg-52) and DQ beta in position 57 without Asp (non-Asp 57) is called a diabetogenic heterodimer which is the biggest risk factor of type 1 diabetes in Caucasian. Nevertheless, among the Japanese population, type 1 diabetes is particularly associated with HLA DQ alpha Arg-52, but not with HLA DQ beta non-Asp 57 .
|
15331022_p11
|
15331022
|
Discussion
| 4.228935 |
biomedical
|
Study
|
[
0.9996883869171143,
0.00011918498785234988,
0.00019244813302066177
] |
[
0.9954628348350525,
0.0016654576174914837,
0.0027837541420012712,
0.00008802169759292156
] |
en
| 0.999999 |
Moreover, it is true that the search of an association with a candidate gene allows a better characterization for most of the frequent multifactorial diseases, because the candidate genes are directly implied in the pathological processes. Today, it is reported that the CTLA-4 (cytotoxic T-lymphocyte antigen-4) allele, localised on the chromosome 2p33, former IDDM12, is largely associated with the susceptibility of numerous common complex diseases, such as the common autoimmune disorders Graves' disease, the autoimmune hypothyroidism and type 1 diabetes . Combined, these pertinent observations still open new perspectives for debating this crucial subject concerning the public health.
|
15331022_p12
|
15331022
|
Discussion
| 4.082665 |
biomedical
|
Review
|
[
0.9993293285369873,
0.00028682983247563243,
0.00038381319609470665
] |
[
0.4882250428199768,
0.006094195414334536,
0.5050836801528931,
0.0005970451747998595
] |
en
| 0.999997 |
Type 1 diabetes, or youth diabetes, is a multifactorial disease occurring on a genetic ground of predisposition and starts under certain environmental conditions. The most effective preventive strategy must be designed at the pre-diabetes stage, since immune and/or genetic markers can easily indicate subjects with high risk before the clinical symptoms. Thus, the genetic analysis of HLA class II associations has allowed a screening of the contributing molecules to the type 1 diabetes development and the selection of subjects, which are likely to contract the disease.
|
15331022_p13
|
15331022
|
Conclusion
| 4.011594 |
biomedical
|
Study
|
[
0.9996399879455566,
0.0001580460520926863,
0.00020195591787341982
] |
[
0.9299721121788025,
0.021017730236053467,
0.048603784292936325,
0.0004063706146553159
] |
en
| 0.999997 |
In this study, we were confronted with difficulties in interpretation of our results which are mainly due to the presence of some indices of consanguinity in our studied population, showing a non excess of DR3DR4 phenotype compared to the DR3 or DR4 phenotype, and a no link of DR3 phenotype to the disease. This result could be due to an ethnic characteristic of Tlemcen population, a history of consanguineous marriages. Nevertheless, these preliminary results made it possible to answer the asked questions. Thus, the strongest type 1 diabetes association is statistically revealed with phenotypic expression of DR4 followed by DR3DR4 phenotype. Association studies between the disease and genetic polymorphisms should be carried out on the population having more limited consanguinity to reduce confusions in result interpretations.
|
15331022_p14
|
15331022
|
Conclusion
| 4.042299 |
biomedical
|
Study
|
[
0.9994632601737976,
0.0002326145040569827,
0.0003042267053388059
] |
[
0.999575674533844,
0.00018656853353604674,
0.00019209180027246475,
0.00004563420225167647
] |
en
| 0.999995 |
The study was conducted on ninety-one first-degree related subjects (brothers, sisters and siblings), randomly recruited at the Internal Medicine Board of the Medical Centre University of Tlemcen (west-Algeria). The sample included thirty-nine patients with type 1 diabetes (15 males, 24 females), and fifty-two healthy subjects (21 males, 31 females) selected from diabetes relatives as controls. Prior medical histories and personal characteristics were obtained from participants via a questionnaire. The patients' mean (± Standard Deviation) age at clinical onset was 12.28 ± 5.97 years with range of 5 to 22 years and median of 11 years. Subjects who were not first degree related and who were not originating from Tlemcen region were excluded. The use of first-degree relatives eliminates exposures of environmental factors such as food items and viruses since first-degree relatives usually share the same milieu. For execution of the protocol, the informed consent was obtained from all the participating subjects to the designated study.
|
15331022_p15
|
15331022
|
Subjects
| 3.944613 |
biomedical
|
Study
|
[
0.9990401864051819,
0.0007026742678135633,
0.0002571103104855865
] |
[
0.9994508624076843,
0.000274154037469998,
0.00018358028319198638,
0.0000913566691451706
] |
en
| 0.999997 |
The applied serologic technique lies on the aptitude of the antibodies to recognize allotropic determinants of HLA molecules on cellular surface . This method is sensitized by a reaction of microlymphocytotoxicity , which uses specific anti-HLA DR antisera and rabbit complement of commercial typing tray (Biotest, Germany). Initially, the peripheral blood lymphocytes (PBL) were separated from the other illustrated elements of venous blood (collected in EDTA-containing tubes) by density gradient centrifugation on Ficoll-Hypaque . B lymphocytes were isolated by using nylon-wool-separated columns .
|
15331022_p16
|
15331022
|
HLA phenotyping (standard complement-dependent assay)
| 4.07206 |
biomedical
|
Study
|
[
0.9995598196983337,
0.00019587663700804114,
0.0002443042176309973
] |
[
0.992973804473877,
0.006227981764823198,
0.0006682745297439396,
0.00012990327377337962
] |
en
| 0.999996 |
The comparison of phenotypic frequencies was obtained by using chi-square analysis with Yates' correction or by Fisher's Exact test, whenever appropriate. The application of the observed χ 2 vs. expected χ 2 was employed to show significance of frequency differences with the sex ratio. A p value of less than 0.05 was considered statistically significant (two-by-two table: degrees of freedom (df) = 1, chi-square ≥ 3.84) . The association between HLA antigens and type 1 diabetes was performed by determination of odds ratio (OR) (confidence interval, 95 % CI). All statistical analyses were performed using the Epi Info 2000 Version 1.0 for Windows 95, 98, NT, and 2000 computers (Epi Info, Atlanta, Georgia, USA) and STATISTICA Version 5.0, '97 (STATISTICA, StatSoft, Paris, France).
|
15331022_p17
|
15331022
|
Statistical analysis
| 4.043839 |
biomedical
|
Study
|
[
0.9996176958084106,
0.00021883622684981674,
0.00016349891666322947
] |
[
0.998812198638916,
0.000580349937081337,
0.0005387747078202665,
0.00006872261292301118
] |
en
| 0.999998 |
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