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1.  Impact of information letters on the reporting rate of adverse drug reactions and the quality of the reports: a randomized controlled study 
Background
Spontaneous reporting of adverse drug reactions (ADRs) is an important method for pharmacovigilance, but under-reporting and poor quality of reports are major limitations. The aim of this study was to evaluate if repeated one-page ADR information letters affect (i) the reporting rate of ADRs and (ii) the quality of the ADR reports.
Methods
All 151 primary healthcare units in the Region Västra Götaland, Sweden, were randomly allocated (1:1) to an intervention (n = 77) or a control group (n = 74). The intervention consisted of one-page ADR information letters administered at three occasions during 2008 to all physicians and nurses in the intervention units. The number of ADR reports received from the 151 units was registered, as was the quality of the reports, which was defined as high if the ADR was to be reported according to Swedish regulations, that is, if the ADR was (i) serious, (ii) unexpected, and/or (iii) related to the use of new drugs and not labelled as common in the Summary of Product Characteristics. A questionnaire was administered to evaluate if the ADR information letter had reached the intended recipient.
Results
Before the intervention, no significant differences in reporting rate or number of high quality reports could be detected between the randomization groups. In 2008, 79 reports were sent from 37 intervention units and 52 reports from 30 control units (mean number of reports per unit ± standard deviation: 1.0 ± 2.5 vs. 0.7 ± 1.2, P = 0.34). The number of high quality reports was higher in intervention units than in control units (37 vs. 15 reports, 0.5 ± 0.9 vs. 0.2 ± 0.6, P = 0.048). According to the returned questionnaires (n = 1,292, response rate 57%), more persons in the intervention than in the control group had received (29% vs. 19%, P < 0.0001) and read (31% vs. 26%, P < 0.0001) an ADR information letter.
Conclusions
This study suggests that repeated ADR information letters to physicians and nurses do not increase the ADR reporting rate, but may increase the number of high quality reports.
doi:10.1186/1472-6904-11-14
PMCID: PMC3182972  PMID: 21899766
2.  Activation of endosomal dynein motors by stepwise assembly of Rab7–RILP–p150Glued, ORP1L, and the receptor βlll spectrin 
The Journal of Cell Biology  2007;176(4):459-471.
The small GTPase Rab7 controls late endocytic transport by the minus end–directed motor protein complex dynein–dynactin, but how it does this is unclear. Rab7-interacting lysosomal protein (RILP) and oxysterol-binding protein–related protein 1L (ORP1L) are two effectors of Rab7. We show that GTP-bound Rab7 simultaneously binds RILP and ORP1L to form a RILP–Rab7–ORP1L complex. RILP interacts directly with the C-terminal 25-kD region of the dynactin projecting arm p150Glued, which is required for dynein motor recruitment to late endocytic compartments (LEs). Still, p150Glued recruitment by Rab7–RILP does not suffice to induce dynein-driven minus-end transport of LEs. ORP1L, as well as βIII spectrin, which is the general receptor for dynactin on vesicles, are essential for dynein motor activity. Our results illustrate that the assembly of microtubule motors on endosomes involves a cascade of linked events. First, Rab7 recruits two effectors, RILP and ORP1L, to form a tripartite complex. Next, RILP directly binds to the p150Glued dynactin subunit to recruit the dynein motor. Finally, the specific dynein motor receptor Rab7–RILP is transferred by ORP1L to βIII spectrin. Dynein will initiate translocation of late endosomes to microtubule minus ends only after interacting with βIII spectrin, which requires the activities of Rab7–RILP and ORP1L.
doi:10.1083/jcb.200606077
PMCID: PMC2063981  PMID: 17283181
3.  The Oxysterol-binding Protein Homologue ORP1L Interacts with Rab7 and Alters Functional Properties of Late Endocytic Compartments 
Molecular Biology of the Cell  2005;16(12):5480-5492.
ORP1L is a member of the human oxysterol-binding protein (OSBP) family. ORP1L localizes to late endosomes (LEs)/lysosomes, colocalizing with the GTPases Rab7 and Rab9 and lysosome-associated membrane protein-1. We demonstrate that ORP1L interacts physically with Rab7, preferentially with its GTP-bound form, and provide evidence that ORP1L stabilizes GTP-bound Rab7 on LEs/lysosomes. The Rab7-binding determinant is mapped to the ankyrin repeat (ANK) region of ORP1L. The pleckstrin homology domain (PHD) of ORP1L binds phosphoinositides with low affinity and specificity. ORP1L ANK- and ANK+PHD fragments induce perinuclear clustering of LE/lysosomes. This is dependent on an intact microtubule network and a functional dynein/dynactin motor complex. The dominant inhibitory Rab7 mutant T22N reverses the LE clustering, suggesting that the effect is dependent on active Rab7. Transport of fluorescent dextran to LEs is inhibited by overexpression of ORP1L. Overexpression of ORP1L, and in particular the N-terminal fragments of ORP1L, inhibits vacuolation of LE caused by Helicobacter pylori toxin VacA, a process also involving Rab7. The present study demonstrates that ORP1L binds to Rab7, modifies its functional cycle, and can interfere with LE/lysosome organization and endocytic membrane trafficking. This is the first report of a direct connection between the OSBP-related protein family and the Rab GTPases.
doi:10.1091/mbc.E05-03-0189
PMCID: PMC1289395  PMID: 16176980
4.  Adhesion of the probiotic bacterium Lactobacillus plantarum 299v onto the gut mucosa in critically ill patients: a randomised open trial 
Critical Care  2005;9(3):R285-R293.
Introduction
To achieve any possible positive effect on the intestinal mucosa cells it is important that probiotics adhere tightly onto the intestinal mucosa. It has been shown in healthy volunteers that Lactobacillus plantarum 299v (Lp 299v) (DSM 9843), a probiotic bacterium, given orally in a fermented oatmeal formula adheres onto the intestinal mucosa, but whether this also occurs in critically ill patients is unknown.
Methods
After randomisation, nine enterally fed, critically ill patients treated with broad-spectrum antibiotics received an oatmeal formula fermented with Lp 299v throughout their stay in the intensive care unit; eight patients served as controls. Biopsies of the rectal mucosa were made at admission and then twice a week, and the biopsies were analysed blindly.
Results
Four patients in the control group were colonised with Lp 299v at admission but thereafter all their biopsies were negative (Lp 299v is an ingredient in a common functional food, ProViva®, in Sweden). Of the treated patients none was colonised at admission but three patients had Lp 299v adhered on the mucosa from the second or third biopsy and in the following samples.
Conclusion
This study shows that Lp 299v could survive the passage from the stomach to the rectum and was able adhere onto the rectal mucosa also in critically ill, antibiotic-treated patients.
doi:10.1186/cc3522
PMCID: PMC1175894  PMID: 15987403
5.  The Two Variants of Oxysterol Binding Protein-related Protein-1 Display Different Tissue Expression Patterns, Have Different Intracellular Localization, and Are Functionally Distinct 
Molecular Biology of the Cell  2003;14(3):903-915.
Oxysterol binding protein (OSBP) homologs comprise a family of 12 proteins in humans (Jaworski et al., 2001; Lehto et al., 2001). Two variants of OSBP-related protein (ORP) 1 have been identified: a short one that consists of the carboxy-terminal ligand binding domain only (ORP1S, 437 aa) and a longer N-terminally extended form (ORP1L, 950 aa) encompassing three ankyrin repeats and a pleckstrin homology domain (PHD). We now report that the two mRNAs show marked differences in tissue expression. ORP1S predominates in skeletal muscle and heart, whereas ORP1L is the most abundant form in brain and lung. On differentiation of primary human monocytes into macrophages, both ORP1S and ORP1L mRNAs were induced, the up-regulation of ORP1L being >100-fold. The intracellular localization of the two ORP1 variants was found to be different. Whereas ORP1S is largely cytosolic, the ORP1L variant localizes to late endosomes. A significant amount of ORP1S but only little ORP1L was found in the nucleus. The ORP1L ankyrin repeat region (aa 1–237) was found to localize to late endosomes such as the full-length protein. This localization was even more pronounced for a fragment that additionally includes the PHD (aa 1–408). The amino-terminal region of ORP1L consisting of the ankyrin repeat and PHDs is therefore likely to be responsible for the targeting of ORP1L to late endosomes. Interestingly, overexpression of ORP1L was found to enhance the LXRα-mediated transactivation of a reporter gene, whereas ORP1S failed to influence this process. The results suggest that the two forms of ORP1 are functionally distinct and that ORP1L is involved in control of cellular lipid metabolism.
doi:10.1091/mbc.E02-08-0459
PMCID: PMC151568  PMID: 12631712

Results 1-5 (5)