Identification of indole inhibitors of human hematopoietic prostaglandin D2 synthase (hH-PGDS).

Human H-PGDS has shown promise as a potential target for anti-allergic and anti-inflammatory drugs. Here we describe the discovery of a novel class of indole inhibitors, identified through focused screening of 42,000 compounds and evaluated using a series of hit validation assays that included fluorescence polarization binding, 1D NMR, ITC and chromogenic enzymatic assays. Compounds with low nanomolar potency, favorable physico-chemical properties and inhibitory activity in human mast cells have been identified. In addition, our studies suggest that the active site of hH-PGDS can accommodate larger structural diversity than previously thought, such as the introduction of polar groups in the inner part of the binding pocket.

Computer game-based upper extremity training in the home environment in stroke persons: a single subject design.

BACKGROUND: The objective of the present study was to assess whether computer game-based training in the home setting in the late phase after stroke could improve upper extremity motor function. METHODS: Twelve subjects with prior stroke were recruited; 11 completed the study. DESIGN: The study had a single subject design; there was a baseline test (A1), a during intervention test (B) once a week, a post-test (A2) measured directly after the treatment phase, plus a follow-up (C) 16-18 weeks after the treatment phase. Information on motor function (Fugl-Meyer), grip force (GrippitR) and arm function in activity (ARAT, ABILHAND) was gathered at A1, A2 and C. During B, only Fugl-Meyer and ARAT were measured. The intervention comprised five weeks of game-based computer training in the home environment. All games were designed to be controlled by either the affected arm alone or by both arms. Conventional formulae were used to calculate the mean, median and standard deviations. Wilcoxon's signed rank test was used for tests of dependent samples. Continuous data were analyzed by methods for repeated measures and ordinal data were analyzed by methods for ordered multinomial data using cumulative logistic models. A p-value of < 0.05 was considered statistically significant. RESULTS: Six females and five males, participated in the study with an average age of 58 years (range 26-66). FMA-UE A-D (motor function), ARAT, the maximal grip force and the mean grip force on the affected side show significant improvements at post-test and follow-up compared to baseline. No significant correlation was found between the amount of game time and changes in the outcomes investigated in this study. CONCLUSION: The results indicate that computer game-based training could be a promising approach to improve upper extremity function in the late phase after stroke, since in this study, changes were achieved in motor function and activity capacity.

Radiographic airway abnormalities in untreated early rheumatoid arthritis are associated with peripheral neutrophil activation.

BACKGROUND: The role of the lung for the initiation and progression of rheumatoid arthritis (RA) is still unclear. Up to 10% of RA patients develop interstitial lung disease which remains a clinical challenge. Understanding early disease mechanisms is of great importance. The objective of this study was to determine whether there is an association between peripheral neutrophil phenotypes and presence of pulmonary abnormalities (PA) on chest high-resolution computed tomography (HRCT) in untreated early RA (ueRA). METHODS: Clinical data and blood were collected, and HRCT performed at diagnosis on 30 consecutive anti-citrullinated protein antibody (ACPA) and/or rheumatoid factor (RF) positive ueRA patients. HRCTs were evaluated for the presence of RA-associated parenchymal, airway and/or pleural abnormalities. Expression of phenotype markers on neutrophils were determined by flow cytometry. Levels of calprotectin, ACPA and RF were measured using immunoassays. RESULTS: The frequency of having any PA was 60%. Airway abnormalities were present in 50%, parenchymal nodules in 43% and interstitial lung abnormalities (ILA) in 10%. Unsupervised multivariate data analysis showed clustering of any PA with neutrophil activation, parameters of inflammation and RF titres. In univariate analysis, the patients with PA displayed significantly increased CD11b and decreased CD62L expression on neutrophils (1.2-fold, p = 0.014; 0.8-fold, p = 0.012) indicating activation and significantly increased RF IgM titre and CRP (5.7-fold, p = 0.0025; 2.3-fold, p = 0.0035) as compared to no PA. Titres of RF, but not ACPA, correlated with expression of the neutrophil activation marker CD11b. A stratified analysis demonstrated that airway involvement was the PA subtype with the strongest association with neutrophil activation. CONCLUSION: We report a strong association between radiographic airway findings and activation of circulating neutrophils in early RA supporting a role of innate immunity and the lung at disease onset. Our results also indicate different contributions of RF and ACPA in the RA pathogenesis.

Developing a national certification pathway for genetic counselors in Sweden-a short report.

There is no Master's level education for genetic counseling in Sweden, meaning that genetic counselor professionals have very different backgrounds. Hence, there is a need to harmonize the quality of genetic counseling and introduce standards for practice. The Swedish Society for Genetic Counselors and the Swedish Society of Medical Genetics and Genomics collaborated to determine professional requirements and a career pathway, defining three vocational levels within the genetic counselor profession. We report here an individual educational pathway leading up to eligibility for certification as a genetic counselor in Sweden.

Reflecting on and managing the emotional impact of prosthetic joint infections on orthopaedic surgeons-a qualitative study.

AIMS: To investigate the experience and emotional impact of prosthetic joint infection (PJI) on orthopaedic surgeons and identify holistic strategies to improve the management of PJI and protect surgeons' wellbeing. METHODS: In total, 18 prosthetic joint surgeons in Sweden were recruited using a purposive sampling strategy. Content analysis was performed on transcripts of individual in-person interviews conducted between December 2017 and February 2018. RESULTS: PJI had a negative emotional impact on Swedish surgeons. Many felt guilt, stress, and a sense of failure, and several aspects of PJI management were associated with psychosocial challenges. Peer support was reported as the most important coping strategy as was collaborating with infectious disease specialists. CONCLUSION: Our study affirms that there is a negative emotional impact of PJI on surgeons which can be minimized by improved peer support and working in multidisciplinary teams. Based on the surgeons' experiences we have identified desired improvements that may facilitate the management of PJI. These may also be applicable within other surgical specialties dealing with postoperative infections, but need to be evaluated for their efficacy. Cite this article: Bone Joint J 2020;102-B(6):736-743.

Exchange of Modular Components Improves Success of Debridement, Antibiotics, and Implant Retention: An Observational Study of 575 Patients with Infection After Primary Total Hip Arthroplasty.

Debridement, antibiotics, and implant retention (DAIR) is a surgical treatment for periprosthetic joint infection (PJI). DAIR is a desirable treatment option from an economic and patient perspective, if successful. The aim of this observational study was to compare the rates of success, defined as no additional reoperations due to PJI, between DAIR with exchange of modular components and DAIR without exchange in patients who had first-time PJI after primary total hip arthroplasty (THA). METHODS: Patients with PJI at the site of a primary THA who were treated with DAIR in Sweden between January 1, 2009, and December 31, 2016, were identified in the Swedish Hip Arthroplasty Register. Supplementary questionnaires were sent to orthopaedic departments for additional variables of interest related to PJI. The primary end point was another reoperation due to PJI within 2 years after the first-time DAIR. DAIR with exchange was compared with DAIR without exchange using Kaplan-Meier survival analysis and Cox regression analysis. RESULTS: A total of 575 patients treated with DAIR for a first-time PJI at the site of a primary THA were analyzed; 364 underwent component exchange and 211 did not. The exchange of components was associated with a lower rate of reoperations due to PJI after DAIR (28.0%) compared with non-exchange (44.1%). The Kaplan-Meier implant survival estimate for exchange was 71.4% (95% confidence interval [CI] = 66.9% to 76.3%) compared with 55.5% (95% CI = 49.1% to 62.7%) for non-exchange. With the analysis adjusted for confounders, DAIR with exchange was associated with a significantly decreased risk of another reoperation due to PJI compared with non-exchange (hazard ratio [HR] = 0.51 [95% CI = 0.38 to 0.68]). CONCLUSIONS: In patients with a first-time PJI at the site of a primary THA, DAIR with exchange of modular components was superior to non-exchange DAIR. Surgeons should strive to exchange components when they perform DAIR, but there is a need to further identify how DAIR best should be practiced and which patients benefit from it. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Inhibition of cyclooxygenase-2 and EP1 receptor antagonism reduces human colonic longitudinal muscle contractility in vitro.

We investigated the contribution of cyclo-oxygenase enzyme inhibition and prostamide agonism on human colonic contractility in vitro. The effects of the non-specific COX inhibitor diclofenac were compared against selective COX-2 inhibition via nimesulide, the prostanoid EP(1) receptor antagonist SC19220 or the prostaglandin prodrug/prostamide receptor agonist bimatoprost, on potency of contraction to acetylcholine in human colonic circular and longitudinal muscle strips. Pre-treatment with either nimesulide (10(-5)M) or diclofenac (10(-6)M) caused a significant decrease in the potency of acetylcholine-evoked longitudinal muscle contraction, but did not inhibit acetylcholine-evoked circular muscle contraction. Pre-treatment with the EP(1) receptor antagonist SC19220 (10(-5)M) similarly decreased cholinergic potency in longitudinal muscle, without influence on circular muscle contraction. The prostamide agonist bimatoprost (10(-6)M) increased basal circular and longitudinal muscle tone, but did not alter cholinergic potency in either muscle layer. In conclusion, colonic longitudinal muscle contraction is augmented by COX-2 activity, most likely via PGE(2) acting at EP(1) receptors. While colonic contraction is tonically modulated by bimatoprost, it does not share the same functional properties attributed to other endogenous COX-2 metabolites on colonic contractile function.

Low gastric acid and high plasma gastrin in high-anxiety Wistar Kyoto rats.

OBJECTIVE: Wistar Kyoto (WKY) rats are more susceptible to stress-evoked ulcerations than Sprague-Dawley (SPD) rats. We have already demonstrated that gastrin cells are more active and ghrelin cells less active in WKY rats than in SPD rats. The purpose of this study was to compare endocrine cell activity and gastric acid output in WKY and SPD rats. MATERIAL AND METHODS: Gastric acid output was determined in conscious rats with gastric fistula. Plasma gastrin and ghrelin levels were measured after an overnight fast. Acid secretagogues (gastrin, histamine and carbachol) were given by continuous subcutaneous infusion. RESULTS: The volume of gastric juice, and the acidity and acid output were all significantly lower (p <0.05) in fasted WKY rats than in fasted SPD rats. Gastrin evoked a 4-fold (p <0.01) and 3-fold (p <0.05) increase in gastric acid output in SPD rats and WKY rats, respectively. Histamine raised the acid output 1.6-fold in SPD rats (p=0.06) and 3-fold in WKY rats (p <0.05), while carbachol failed to affect the acid output (weak increase, p >0.05). Fasting plasma ghrelin levels were 2-fold higher in SPD rats than in WKY rats (p <0.01) while fasting gastrin levels were 10-fold higher in WKY rats than in SPD rats (p <0.05). Neither the parietal-cell density nor the oxyntic mucosal thickness differed between the two strains. CONCLUSIONS: The results of the present study suggest that a high gastrin cell activity in WKY rats is secondary to a low gastric acidity. Whether the high gastrin cell activity is linked to susceptibility to stress ulcer in WKY rats warrants further investigation.

Similar Risk of Re-Revision in Patients after One- or Two-Stage Surgical Revision of Infected Total Hip Arthroplasty: An Analysis of Revisions in the Swedish Hip Arthroplasty Register 1979⁻2015.

Late chronic infection is a devastating complication after total hip arthroplasty (THA) and is often treated with surgery. The one-stage surgical procedure is believed to be the more advantageous from a patient and cost perspective, but there is no consensus on whether the one- or two-stage procedure is the better option. We analysed the risk for re-revision in infected primary THAs repaired with either the one- or two-stage method. Data was obtained from the Swedish Hip Arthroplasty Register and the study groups were patients who had undergone a one-stage (n = 404) or two-stage (n = 1250) revision due to infection. Risk of re-revision was analysed using Kaplan-Meier analysis with log-rank test and Cox regression analysis. The cumulative survival rate was similar in the two groups at 15 years after surgery (p = 0.1). Adjusting for covariates, the risk for re-revision due to all causes did not differ between patients who were operated on with the one- or two-stage procedure (Hazard Ratio (HR) = 0.9, 95% Confidence Interval (C.I.) = 0.7-1.2, p = 0.5). The risk for re-revision due to infection (HR = 0.7, 95% C.I. = 0.4-1.1, p = 0.2) and aseptic loosening (HR = 1.2, 95% C.I. = 0.8-1.8, p = 0.5) was similar. This study could not determine whether the one-stage method was inferior in cases when the performing surgeons chose to use the one-stage method.

Effects of Aerobic and Resistance Exercise in Older Adults With Rheumatoid Arthritis: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the effect of a moderate-to-high-intensity, aerobic and resistance exercise with person-centered guidance in older adults with rheumatoid arthritis (RA), through a randomized controlled multicenter trial. METHODS: Older adults (ages 65-75 years) with RA (n = 74) were randomized to either a 20-week exercise intervention at a gym (n = 36) or to home-based exercise of light intensity (n = 38). Assessments were performed at baseline, at 20 weeks, and at 12 months. The primary outcome was the difference in the Health Assessment Questionnaire disability index (HAQ DI) score, and the secondary outcomes were the differences in physical fitness assessed by a cardiopulmonary exercise test, an endurance test, the timed up and go test, the sit to stand test, and an isometric elbow flexion force measurement. RESULTS: No significant differences between the groups were found for the primary outcome, HAQ DI score. Within the intervention group there was a significant improvement in the HAQ DI score when compared to baseline (P = 0.022). Aerobic capacity (P < 0.001) and 3 of 4 additional performance-based tests of endurance and strength significantly improved (P < 0.05) in the intervention group when compared to the control group. In the intervention group, 71% of patients rated their health as much or very much improved compared to 24% of patients in the control group (P < 0.001). At the 12-month follow-up, there were no significant differences in change between the 2 groups on the HAQ DI score. A significant between-group difference was found for change in an endurance test (P = 0.022). CONCLUSION: Aerobic and resistance exercise with person-centered guidance improved physical fitness in terms of aerobic capacity, endurance, and strength in older adults with RA.

Functional characterization of Arabidopsis calreticulin1a: a key alleviator of endoplasmic reticulum stress.

The chaperone calreticulin plays important roles in a variety of processes in the endoplasmic reticulum (ER) of animal cells, such as Ca2+ signaling and protein folding. Although the functions of calreticulin are well characterized in animals, only indirect evidence is available for plants. To increase our understanding of plant calreticulins we introduced one of the Arabidopsis isoforms, AtCRT1a, into calreticulin-deficient (crt-/-) mouse embryonic fibroblasts. As a result of calreticulin deficiency, the mouse crt-/- fibroblasts have decreased levels of Ca2+ in the ER and impaired protein folding abilities. Expression of the AtCRT1a in mouse crt-/- fibroblasts rescued these phenotypes, i.e. AtCRT1a restored the Ca2+-holding capacity and chaperone functions in the ER of the mouse crt-/- fibroblasts, demonstrating that the animal sorting machinery was also functional for a plant protein, and that basic calreticulin functions are conserved across the Kingdoms. Expression analyses using a beta-glucuronidase (GUS)-AtCRT1a promoter construct revealed high expression of CRT1a in root tips, floral tissues and in association with vascular bundles. To assess the impact of AtCRT1a in planta, we generated Atcrt1a mutant plants. The Atcrt1a mutants exhibited increased sensitivity to the drug tunicamycin, an inducer of the unfolded protein response. We therefore conclude that AtCRT1a is an alleviator of the tunicamycin-induced unfolded protein response, and propose that the use of the mouse crt-/- fibroblasts as a calreticulin expression system may prove useful to assess functionalities of calreticulins from different species.

Mechanism of action of AZD0865, a K+-competitive inhibitor of gastric H+,K+-ATPase.

AZD0865 is a member of a drug class that inhibits gastric H(+),K(+)-ATPase by K(+)-competitive binding. The objective of these experiments was to characterize the mechanism of action, selectivity and inhibitory potency of AZD0865 in vitro. In porcine ion-leaky vesicles at pH 7.4, AZD0865 concentration-dependently inhibited K(+)-stimulated H(+),K(+)-ATPase activity (IC(50) 1.0+/-0.2 microM) but was more potent at pH 6.4 (IC(50) 0.13+/-0.01 microM). The IC(50) values for a permanent cation analogue, AR-H070091, were 11+/-1.2 microM at pH 7.4 and 16+/-1.8 microM at pH 6.4. These results suggest that the protonated form of AZD0865 inhibits H(+),K(+)-ATPase. In ion-tight vesicles, AZD0865 inhibited H(+),K(+)-ATPase more potently (IC(50) 6.9+/-0.4 nM) than in ion-leaky vesicles, suggesting a luminal site of action. AZD0865 inhibited acid formation in histamine- or dibutyryl-cAMP-stimulated rabbit gastric glands (IC(50) 0.28+/-0.01 and 0.26+/-0.003 microM, respectively). In ion-leaky vesicles at pH 7.4, AZD0865 (3 microM) immediately inhibited H(+),K(+)-ATPase activity by 88+/-1%. Immediately after a 10-fold dilution H(+),K(+)-ATPase inhibition was 41%, indicating reversible binding of AZD0865 to gastric H(+),K(+)-ATPase. In contrast to omeprazole, AZD0865 inhibited H(+),K(+)-ATPase activity in a K(+)-competitive manner (K(i) 46+/-3 nM). AZD0865 inhibited the process of cation occlusion concentration-dependently (IC(50) 1.7+/-0.06 microM). At 100 microM, AZD0865 reduced porcine renal Na(+),K(+)-ATPase activity by 9+/-2%, demonstrating a high selectivity for H(+),K(+)-ATPase. Thus, AZD0865 potently, K(+)-competitively, and selectively inhibits gastric H(+),K(+)-ATPase activity and acid formation in vitro, with a fast onset of effect.

The endocannabinoids anandamide and 2-arachidonoylglycerol inhibit cholinergic contractility in the human colon.

The effects of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) were determined on cholinergic contractility in strips of human colonic longitudinal muscle and circular muscle in vitro, in the presence of nitric oxide synthase blockade with N-nitro-l-arginine (10(-4) M). Anandamide and 2-AG inhibited longitudinal muscle and circular muscle contractile responses to acetylcholine (10(-9)-10(-4) M) in a concentration-dependent manner. This was unaltered following pretreatment with the cannabinoid CB(1) receptor-selective antagonist AM251 (10(-7) M), however in isolation AM251 elicited a significant rightward shift in the potency of acetylcholine-evoked contraction in both longitudinal muscle and circular muscle preparations. Pretreatment with an inhibitor of anandamide catabolism, arachidonoyl trifluoromethyl ketone (10(-5) M), alone caused a significant decrease in the potency of acetylcholine-evoked contraction in both longitudinal and circular muscle, but had no significant additional effect on the anandamide-induced (10(-5) M) suppression of contraction. Pretreatment with the cannabinoid CB(2) receptor inverse agonist JTE 907 (10(-6) M) neither influenced the potency of acetylcholine-evoked contraction alone nor prevented the potency shift in acetylcholine-evoked contraction in the presence of anandamide (10(-5) M). The findings of the present study indicate that the endocannabinoids anandamide and 2-arachidonoylglycerol suppress colonic cholinergic contractility via a non conventional cannabinoid or non-cannabinoid receptor-mediated pathway. Cholinergic contraction may be tonically modulated by endocannabinoids and/or products of arachidonate metabolism unrelated to endocannabinoid production. The extent of anandamide metabolism is not sufficient to influence the functional effects of its exogenous administration in human colonic tissue in vitro.

The morphologic characteristics and range of motion in the hips of athletes and non-athletes.

The cam deformity may cause impingement and probably leads to osteoarthritis of the hip. The aetiology of the cam deformity is incompletely understood. Vigorous training during skeletal growth can lead to the development of cam and symptoms of femoro-acetabular impingement and subsequent osteoarthritis of the hip. The purpose of this study was to compare the radiographic characteristics and range of motion between a group of athletes and a non-athletic control group. Thirty-two male athletes (17 soccer players and 15 ice-hockey players) and thirty non-athletes, used as a control group, were examined clinically and radiographically. Hip range of motion was measured and the FADIR and FABER tests were performed. Standard radiographs of both hips were taken. The centre-edge angle, alpha angle, caput-collum-diaphysis angle, head-neck offset and Tönnis grade were registered. The athletes had a higher Tönnis grade (right P = 0.009, left P = 0.004), more pain on the FADIR test (right P = 0.006, left P = 0.001) and lower ROM in internal (right P = 0.003, left P = 0.025) and external rotation (P < 0.001). A superiorly placed cam deformity (seen on an AP pelvis view) was correlated with reduced external rotation (right P = 0.001, left P = 0.004) and mild osteoarthritis (Tönnis grade 1), (P = 0.015, left P = 0.020), while a more anteriorly placed cam deformity (seen on a modified Lauenstein view) was correlated with reduced internal rotation (right P = 0.029, left P = 0.013). A lower range of motion, more osteoarthritic changes and more pain were found in the athletes than the controls. The control group had more cam deformities than previously reported.

A quality control method enhancement concept-Continual improvement of regulatory approved QC methods.

Quality Control methods (QC-methods) play an important role in the overall control strategy for drug manufacturing. However, efficient life-cycle management and continual improvement are hindered due to a variety of post-approval variation legislations across territories and a lack of harmonization of the requirements. As a result, many QC-methods fall behind the technical development. Developing the QC-method in accordance with the Quality by Design guidelines gives the possibility to do continual improvements inside the original Method Operable Design Region (MODR). However, often it is necessary to do changes outside the MODR, e.g. to incorporate new technology that was not available at the time the original method was development. Here, we present a method enhancement concept which allows minor adjustments, within the same measuring principle, outside the original MODR without interaction with regulatory agencies. The feasibility of the concept is illustrated by a case study of a QC-method based on HPLC, assumed to be developed before the introduction of UHPLC, where the switch from HPLC to UHPLC is necessary as a continual improvement strategy. The concept relies on the assumption that the System Suitability Test (SST) and failure modes are relevant for other conditions outside the MODR as well when the same measuring principle is used. It follows that it should be possible to move outside the MODR as long as the SST has passed. All minor modifications of the original, approved QC-method must be re-validated according to a template given in the original submission and a statistical equivalence should be shown between the original and modified QC-methods. To summarize, revalidation is handled within the pharmaceutical quality control system according to internal change control procedures, but without interaction with regulating agencies.

A protein kinase Cbeta inhibitor attenuates multidrug resistance of neuroblastoma cells.

BACKGROUND: The acquisition of drug resistance is a major reason for poor outcome of neuroblastoma. Protein kinase C (PKC) has been suggested to influence drug resistance in cancer cells. The aim of this study was to elucidate whether inhibition of PKCbeta isoforms influences drug-resistance of neuroblastoma cells. METHODS: The effect of the PKCbeta inhibitor LY379196 on the growth-suppressing effects of different chemotherapeutics on neuroblastoma cells was analyzed with MTT assays. The effect of LY379196 on the accumulation of [3H]vincristine was also investigated RESULTS: The PKCbeta inhibitor LY379196 suppressed the growth of three neuroblastoma cell lines. LY379196 also augmented the growth-suppressive effect of doxorubicin, etoposide, paclitaxel, and vincristine, but not of carboplatin. The effect was most marked for vincristine and for the cell-line (SK-N-BE(2)) that was least sensitive to vincristine. No effect was observed on the non-resistant IMR-32 cells. Two other PKC inhibitors, Gö6976 and GF109203X, also enhanced the vincristine effect. The PKC inhibitors caused an increased accumulation of [3H]vincristine in SK-N-BE(2) cells. CONCLUSIONS: This indicates that inhibition of PKCbeta could attenuate multidrug resistance in neuroblastoma cells by augmenting the levels of natural product anticancer drugs in resistant cells.

Blood flow dynamics and sensitivity in breasts after reconstruction with DIEP-flap.

A method of breast reconstruction is based on the Deep Inferior Epigastric Perforator (DIEP) technique. Skin and fat are transplanted from the abdomen to the chest; blood vessels are reconnected through microsurgery. Nerves are, however, left unconnected. This study aims to evaluate the blood flow and reinnervation of blood vessels and skin in breasts reconstructed by DIEP flaps without neural repair. In all, DIEP flaps of 10 patients were tested at an average of 16.3 months postoperatively. Blood flow was assessed by PeriScan PIM II System, both before and after indirect heating. Tactile perception threshold was assessed by Semmes-Weinstein monofilament and thermal sensibility by SENSELab MSA Thermotest. The patients' contralateral breasts were used as controls. The blood flow of the flaps was statistically significantly lower than in the control breasts, both before and after indirect heating. The change in blood flow after indirect heating did, however, not significantly differ when comparing the breasts. All flaps regained deep pressure sensibility in all four quadrants. Five patients regained even better sensibility in one of their quadrants. Seven patients regained perception of cold stimuli, five perceived warmth. This study has shown that skin blood flow regulation is present in DIEP flaps 1 year after reconstruction. Blood flow dynamics are very similar to those in the normal breast. There is also a recovery of tactile and thermal sensibility, but this study has not shown any clear parallels between recovery blood flow, tactile sensibility and thermal sensibility.

Higher plant calreticulins have acquired specialized functions in Arabidopsis.

BACKGROUND: Calreticulin (CRT) is a ubiquitous ER protein involved in multiple cellular processes in animals, such as protein folding and calcium homeostasis. Like in animals, plants have evolved divergent CRTs, but their physiological functions are less understood. Arabidopsis contains three CRT proteins, where the two CRTs AtCRT1a and CRT1b represent one subgroup, and AtCRT3 a divergent member. METHODOLOGY/PRINCIPAL FINDINGS: Through expression of single Arabidopsis family members in CRT-deficient mouse fibroblasts we show that both subgroups have retained basic CRT functions, including ER Ca2+-holding potential and putative chaperone capabilities. However, other more general cellular defects due to the absence of CRT in the fibroblasts, such as cell adhesion deficiencies, were not fully restored. Furthermore, in planta expression, protein localization and mutant analyses revealed that the three Arabidopsis CRTs have acquired specialized functions. The AtCRT1a and CRT1b family members appear to be components of a general ER chaperone network. In contrast, and as recently shown, AtCRT3 is associated with immune responses, and is essential for responsiveness to the bacterial Pathogen-Associated Molecular Pattern (PAMP) elf18, derived from elongation factor (EF)-Tu. Whereas constitutively expressed AtCRT1a fully complemented Atcrt1b mutants, AtCRT3 did not. CONCLUSIONS/SIGNIFICANCE: We conclude that the physiological functions of the two CRT subgroups in Arabidopsis have diverged, resulting in a role for AtCRT3 in PAMP associated responses, and possibly more general chaperone functions for AtCRT1a and CRT1b.

Using semantic environment description as a tool to evaluate car interiors.

The semantic environment description (SMB) is a structured method used for evaluating the impression of an architectural environment. The SMB-method measures the impression with eight factors: pleasantness, complexity, unity, potency, social status, enclosedness, affection and originality. The SMB-method is also a useful tool for measuring the impression of a vehicle interior since the method is easy to administrate, has high reliability and validity, is easily adaptable for cross cultural comparisons and provides useful knowledge for design, engineering and marketing. The purpose of the present study was to more deeply investigate the feasibility of the SMB method for measuring the impression of vehicle interiors and to compare customers' and Volvo employees' assessments. The present study confirms that the SMB-method is easy to administer. The method is useful, even though it is not optimized for vehicle environments. If complemented with qualitative techniques the SMB-method provides more interesting results. Volvo employees and customers assessed the vehicle interiors slightly different. Thus it is recommended to use customer's assessments to acquire useful results.