Systematic evaluation of risk factors for diagnostic delay in inflammatory bowel disease.

The diagnosis of inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), continues to present difficulties due to unspecific symptoms and limited test accuracies. We aimed to determine the diagnostic delay (time from first symptoms to IBD diagnosis) and to identify associated risk factors. A total of 1591 IBD patients (932 CD, 625 UC, 34 indeterminate colitis) from the Swiss IBD cohort study (SIBDCS) were evaluated. The SIBDCS collects data on a large sample of IBD patients from hospitals and private practice across Switzerland through physician and patient questionnaires. The primary outcome measure was diagnostic delay. Diagnostic delay in CD patients was significantly longer compared to UC patients (median 9 versus 4 months, P < 0.001). Seventy-five percent of CD patients were diagnosed within 24 months compared to 12 months for UC and 6 months for IC patients. Multivariate logistic regression identified age <40 years at diagnosis (odds ratio [OR] 2.15, P = 0.010) and ileal disease (OR 1.69, P = 0.025) as independent risk factors for long diagnostic delay in CD (>24 months). In UC patients, nonsteroidal antiinflammatory drug (NSAID intake (OR 1.75, P = 0.093) and male gender (OR 0.59, P = 0.079) were associated with long diagnostic delay (>12 months). Whereas the median delay for diagnosing CD, UC, and IC seems to be acceptable, there exists a long delay in a considerable proportion of CD patients. More public awareness work needs to be done in order to reduce patient and doctor delays in this target population.

Modifiable and nonmodifiable risk factors for postoperative delirium after cardiac surgery with cardiopulmonary bypass.

Postoperative delirium after cardiac surgery is associated with increased morbidity and mortality as well as prolonged stay in both the intensive care unit and the hospital. The authors sought to identify modifiable risk factors associated with the development of postoperative delirium in elderly patients after elective cardiac surgery in order to be able to design follow-up studies aimed at the prevention of delirium by optimizing perioperative management. A post hoc analysis of data from patients enrolled in a randomized controlled trial was performed. A single university hospital. One hundred thirteen patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass. None. MEASUREMENTS AND MAINS RESULTS: Screening for delirium was performed using the Confusion Assessment Method (CAM) on the first 6 postoperative days. A multivariable logistic regression model was developed to identify significant risk factors and to control for confounders. Delirium developed in 35 of 113 patients (30%). The multivariable model showed the maximum value of C-reactive protein measured postoperatively, the dose of fentanyl per kilogram of body weight administered intraoperatively, and the duration of mechanical ventilation to be independently associated with delirium. In this post hoc analysis, larger doses of fentanyl administered intraoperatively and longer duration of mechanical ventilation were associated with postoperative delirium in the elderly after cardiac surgery. Prospective randomized trials should be performed to test the hypotheses that a reduced dose of fentanyl administered intraoperatively, the use of a different opioid, or weaning protocols aimed at early extubation prevent delirium in these patients.

Factors influencing emergency delays in acute stroke management.

Early admission to hospital with minimum delay is a prerequisite for successful management of acute stroke. We sought to determine our local pre- and in-hospital factors influencing this delay. Time from onset of symptoms to admission (admission time) was prospectively documented during a 6-month period (December 2004 to May 2005) in patients consecutively admitted for an acute focal neurological deficit presented at arrival and of presumed vascular origin. Mode of transportation, patient's knowledge and correct recognition of stroke symptoms were assessed. Physicians contacted by the patients or their relatives were interviewed. The influence of referral patterns on in-hospital delays was further evaluated. Overall, 331 patients were included, 249 had an ischaemic and 37 a haemorrhagic stroke. Forty-five patients had a TIA with neurological symptoms subsiding within the first hours after admission. Median admission time was 3 hours 20 minutes. Transportation by ambulance significantly shortened admission delays in comparison with the patient's own means (HR 2.4, 95% CI 1.6-3.7). The only other factor associated with reduced delays was awareness of stroke (HR 1.9, 95% CI 1.3-2.9). Early in-hospital delays, specifically time to request CT-scan and time to call the neurologist, were shorter when the patient was referred by his family or to a lesser extent by an emergency physician than by the family physician (p < 0.04 and p < 0.01, respectively) and were shorter when he was transported by ambulance than by his own means (p < 0.01). Transportation by ambulance and referral by the patient or family significantly improved admission delays and early in-hospital management. Correct recognition of stroke symptoms further contributed to significant shortening of admission time. Educational programmes should take these findings into account.

Influence of socioeconomic factors on delays, management and outcome amongst patients with acute myocardial infarction undergoing primary percutaneous coronary intervention.

The outcome after primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI) is strongly affected by time delays. In this study, we sought to identify the impact of specific socioeconomic factors on time delays, subsequent STEMI management and outcomes in STEMI patients undergoing pPCI, who came from a well-defined region of the French part of Switzerland. A total of 402 consecutive patients undergoing pPCI for STEMI in a large tertiary hospital were retrospectively studied. Symptom-to-first-medical-contact time was analysed for the following socioeconomic factors: level of education, origin and marital status. Main exclusion criteria were: time delay beyond 12 hours, previous treatment with fibrinolytic agents or patients immediately referred for coronary artery bypass graft surgery. Therefore, 222 patients were finally included. At 1 year, there was no difference in mortality between the different socioeconomic groups. Furthermore, there was no difference in management characteristics between them. Symptom-to-first-medical-contact time was significantly longer for patients with a low level of education, Swiss citizens and unmarried patients, with median differences of 23 minutes, 18 minutes and 13 minutes, respectively (p <0.05). Nevertheless, no difference was found regarding in-hospital management and clinical outcome. This study demonstrates that symptom-to-first-medical-contact time is longer amongst people with a lower educational level, Swiss citizens and unmarried people. Because of the low mortality rate in general, these differences in delays did not affect clinical outcomes. Still, tertiary prevention measures should particularly focus on these vulnerable populations.

Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome.

The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual disabilities. Here, we show that during mouse synaptogenesis and in human FXS fibroblasts, a dual dysregulation of APP and the α-secretase ADAM10 leads to the production of an excess of soluble APPα (sAPPα). In FXS, sAPPα signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPα levels, restoring translational control, synaptic morphology, and behavioral plasticity. Thus, proper control of ADAM10-mediated APP processing during a specific developmental postnatal stage is crucial for healthy spine formation and function(s). Downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating FXS phenotypes.

Desensitization of thermal hyperemia in the skin is reproducible.

OBJECTIVE: Local heating increases skin blood flow SkBF (thermal hyperemia). In a previous study, we reported that a first local thermal stimulus could attenuate the hyperemic response to a second one applied later on the same skin spot, a phenomenon that we termed desensitization. However, other studies found no evidence for desensitization in similar conditions. The aim of the present work was to test whether it was related to differences in instrumentation. METHODS: Twenty-eight healthy young males were studied. Two pairs of heating chambers, one custom-made (our study) and one commercial (other groups), were affixed to forearm skin. SkBF was measured with single-point laser-Doppler flowmetry (LDF) (780nm) in one pair, and laser-Doppler imaging (LDI) (633nm) in the other. A temperature step from 34 to 41°C, was applied for 30minutes and repeated after two hours. RESULTS: During the second thermal challenge, the plateau SkBF was lower than during the first thermal and was observed with each of the four combinations of SkBF measurement techniques and heating equipment (p<0.05 for all conditions, range -9% to -16% of the initial value). CONCLUSION: Desensitization of thermal hyperemia is not specific to peculiar operating conditions.

Inbreeding avoidance through kin recognition: choosy females boost male dispersal.

Inbreeding avoidance is predicted to induce sex biases in dispersal. But which sex should disperse? In polygynous species, females pay higher costs to inbreeding and thus might be expected to disperse more, but empirical evidence consistently reveals male biases. Here, we show that theoretical expectations change drastically if females are allowed to avoid inbreeding via kin recognition. At high inbreeding loads, females should prefer immigrants over residents, thereby boosting male dispersal. At lower inbreeding loads, by contrast, inclusive fitness benefits should induce females to prefer relatives, thereby promoting male philopatry. This result points to disruptive effects of sexual selection. The inbreeding load that females are ready to accept is surprisingly high. In absence of search costs, females should prefer related partners as long as delta<r/(1+r) where r is relatedness and delta is the fecundity loss relative to an outbred mating. This amounts to fitness losses up to one-fifth for a half-sib mating and one-third for a full-sib mating, which lie in the upper range of inbreeding depression values currently reported in natural populations. The observation of active inbreeding avoidance in a polygynous species thus suggests that inbreeding depression exceeds this threshold in the species under scrutiny or that inbred matings at least partly forfeit other mating opportunities for males. Our model also shows that female choosiness should decline rapidly with search costs, stemming from, for example, reproductive delays. Species under strong time constraints on reproduction should thus be tolerant of inbreeding.

Sexual dimorphism in resource acquisition and deployment: both size and timing matter.

Background and Aims The males and females of many dioecious plant species differ from one another in important life-history traits, such as their size. If male and female reproductive functions draw on different resources, for example, one should expect males and females to display different allocation strategies as they grow. Importantly, these strategies may differ not only between the two sexes, but also between plants of different age and therefore size. Results are presented from an experiment that asks whether males and females of Mercurialis annua, an annual plant with indeterminate growth, differ over time in their allocation of two potentially limiting resources (carbon and nitrogen) to vegetative (below-and above-ground) and reproductive tissues.Methods Comparisons were made of the temporal patterns of biomass allocation to shoots, roots and reproduction and the nitrogen content in the leaves between the sexes of M. annua by harvesting plants of each sex after growth over different periods of time.Key Results and Conclusions Males and females differed in their temporal patterns of allocation. Males allocated more to reproduction than females at early stages, but this trend was reversed at later stages. Importantly, males allocated proportionally more of their biomass towards roots at later stages, but the roots of females were larger in absolute terms. The study points to the important role played by both the timing of resource deployment and the relative versus absolute sizes of the sinks and sources in sexual dimorphism of an annual plant.

Cells with neuronal characteristics differentiate and persist for one year in rat optic nerve explants cultures.

Evidence concerning the presence or absence of common neuronglia lineages in the postnatal mammalian central nervous system is still a matter of speculation. We address this problem using optic nerve explants, which show an extremely long survival in culture. Morphological, immunocytochemical and immunochemical methods were applied. The results obtained from in vitro tissue were compared with optic nerves (ONs) and whole-brain samples from animals of different ages. Newborn rat ONs represented the starting material of our tissue culture; they are composed of unmyelinated axons, astrocytes and progenitor cells but devoid of neuronal cell bodies. At this age, Western blots of ONs were positively stained by neurofilament and synapsin I specific antibodies. These bands increased in intensity during postnatal in situ development. In explant cultures, the glia cells reach a stage of functional differentiation and they maintain, together with undifferentiated cells, a complex histotypic organization. After 6 days in vitro, neurofilaments and synapsin I could not be detected on immunoblots, indicating that 1) axonal degeneration was completed, and 2) neuronal somata were absent at the time. Surprisingly, after about 4-5 weeks in culture, a new cell type appeared, which showed characteristics typical of neurons. After 406 days in vitro, neurofilaments and synapsin I were unequivocally detectable on Western blots. Furthermore, both immunocytochemical staining and light and electron microscopic examinations corroborated the presence of this earlier-observed cell type. These in vitro results clearly show the high developmental plasticity of ON progenitor cells, even late in development. The existence of a common neuron-glia precursor, which never gives rise to neurons in situ, is suggested.

CD8 kinetically promotes ligand binding to the T-cell antigen receptor.

The mechanism of CD8 cooperation with the TCR in antigen recognition was studied on live T cells. Fluorescence correlation measurements yielded evidence of the presence of two TCR and CD8 subpopulations with different lateral diffusion rate constants. Independently, evidence for two subpopulations was derived from the experimentally observed two distinct association phases of cognate peptide bound to class I MHC (pMHC) tetramers and the T cells. The fast phase rate constant ((1.7 +/- 0.2) x 10(5) M(-1) s(-1)) was independent of examined cell type or MHC-bound peptides' structure. Its value was much faster than that of the association of soluble pMHC and TCR ((7.0 +/- 0.3) x 10(3) M(-1) s(-1)), and close to that of the association of soluble pMHC with CD8 ((1-2) x 10(5) M(-1) s(-1)). The fast binding phase disappeared when CD8-pMHC interaction was blocked by a CD8-specific mAb. The latter rate constant was slowed down approximately 10-fold after cells treatment with methyl-beta-cyclodextrin. These results suggest that the most efficient pMHC-cell association route corresponds to a fast tetramer binding to a colocalized CD8-TCR subpopulation, which apparently resides within membrane rafts: the reaction starts by pMHC association with the CD8. This markedly faster step significantly increases the probability of pMHC-TCR encounters and thereby promotes pMHC association with CD8-proximal TCR. The slow binding phase is assigned to pMHC association with a noncolocalized CD8-TCR subpopulation. Taken together with results of cytotoxicity assays, our data suggest that the colocalized, raft-associated CD8-TCR subpopulation is the one capable of inducing T-cell activation.

Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells.

NKG2D is an activation receptor that allows natural killer (NK) cells to detect diseased host cells. The engagement of NKG2D with corresponding ligand results in surface modulation of the receptor and reduced function upon subsequent receptor engagement. However, it is not clear whether in addition to modulation the NKG2D receptor complex and/or its signaling capacity is preserved. We show here that the prolonged encounter with tumor cell-bound, but not soluble, ligand can completely uncouple the NKG2D receptor from the intracellular mobilization of calcium and the exertion of cell-mediated cytolysis. However, cytolytic effector function is intact since NKG2D ligand-exposed NK cells can be activated via the Ly49D receptor. While NKG2D-dependent cytotoxicity is impaired, prolonged ligand exposure results in constitutive interferon gamma (IFNgamma) production, suggesting sustained signaling. The functional changes are associated with a reduced presence of the relevant signal transducing adaptors DNAX-activating protein of 10 kDa (DAP-10) and killer cell activating receptor-associated protein/DNAX-activating protein of 12 kDa (KARAP/DAP-12). That is likely the consequence of constitutive NKG2D engagement and signaling, since NKG2D function and adaptor expression is restored to normal when the stimulating tumor cells are removed. Thus, the chronic exposure to tumor cells expressing NKG2D ligand alters NKG2D signaling and may facilitate the evasion of tumor cells from NK cell reactions.

β-Arrestin2 influences the response to methadone in opioid-dependent patients.

β-Arrestin2 (ARRB2) is a component of the G-protein-coupled receptor complex and is involved in μ-opioid and dopamine D(2) receptor signaling, two central processes in methadone signal transduction. We analyzed 238 patients in methadone maintenance treatment (MMT) and identified a haplotype block (rs34230287, rs3786047, rs1045280 and rs2036657) spanning almost the entire ARRB2 locus. Although none of these single nucleotide polymorphisms (SNPs) leads to a change in amino-acid sequence, we found that for all the SNPs analyzed, with exception of rs34230287, homozygosity for the variant allele confers a nonresponding phenotype (n=73; rs1045280C and rs2036657G: OR=3.1, 95% CI=1.5-6.3, P=0.004; rs3786047A: OR=2.5, 95% CI=1.2-5.1, P=0.02) also illustrated by a 12-fold shorter period of negative urine screening (P=0.01). The ARRB2 genotype may thus contribute to the interindividual variability in the response to MMT and help to predict response to treatment.

Appropriateness criteria for surgery improve clinical outcomes in patients with low back pain and/or sciatica.

STUDY DESIGN: Prospective, controlled, observational outcome study using clinical, radiographic, and patient/physician-based questionnaire data, with patient outcomes at 12 months follow-up. OBJECTIVE: To validate appropriateness criteria for low back surgery. SUMMARY OF BACKGROUND DATA: Most surgical treatment failures are attributed to poor patient selection, but no widely accepted consensus exists on detailed indications for appropriate surgery. METHODS: Appropriateness criteria for low back surgery have been developed by a multispecialty panel using the RAND appropriateness method. Based on panel criteria, a prospective study compared outcomes of patients appropriately and inappropriately treated at a single institution with 12 months follow-up assessment. Included were patients with low back pain and/or sciatica referred to the neurosurgical department. Information about symptoms, neurologic signs, the health-related quality of life (SF-36), disability status (Roland-Morris), and pain intensity (VAS) was assessed at baseline, at 6 months, and at 12 months follow-up. The appropriateness criteria were administered prospectively to each clinical situation and outside of the clinical setting, with the surgeon and patients blinded to the results of the panel decision. The patients were further stratified into 2 groups: appropriate treatment group (ATG) and inappropriate treatment group (ITG). RESULTS: Overall, 398 patients completed all forms at 12 months. Treatment was considered appropriate for 365 participants and inappropriate for 33 participants. The mean improvement in the SF-36 physical component score at 12 months was significantly higher in the ATG (mean: 12.3 points) than in the ITG (mean: 6.8 points) (P = 0.01), as well as the mean improvement in the SF-36 mental component score (ATG mean: 5.0 points; ITG mean: -0.5 points) (P = 0.02). Improvement was also significantly higher in the ATG for the mean VAS back pain (ATG mean: 2.3 points; ITG mean: 0.8 points; P = 0.02) and Roland-Morris disability score (ATG mean: 7.7 points; ITG mean: 4.2 points; P = 0.004). The ATG also had a higher improvement in mean VAS for sciatica (4.0 points) than the ITG (2.8 points), but the difference was not significant (P = 0.08). The SF-36 General Health score declined in both groups after 12 months, however, the decline was worse in the ITG (mean decline: 8.2 points) than in the ATG (mean decline: 1.2 points) (P = 0.04). Overall, in comparison to ITG patients, ATG patients had significantly higher improvement at 12 months, both statistically and clinically. CONCLUSION: In comparison to previously reported literature, our study is the first to assess the utility of appropriateness criteria for low back surgery at 1-year follow-up with multiple outcome dimensions. Our results confirm the hypothesis that application of appropriateness criteria can significantly improve patient outcomes.

Developmental expression of glial fibrillary acidic protein and glutamine synthetase in serum-free aggregating cell cultures of fetal rat telencephalon.

Serum-free aggregating cell cultures of fetal rat telencephalon were examined by a combined biochemical and double-labeling immunocytochemical study for the developmental expression of glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS). It was found that these two astroglial markers are co-expressed at different developmental stages in vitro. During the phase of cellular maturation (i.e. between days 14 and 34), GFAP levels and GS activity increase rapidly and in parallel. At the same time, the number of immunoreactive cells increase while the long and thick processes staining in early cultures gradually disappear. The present results demonstrate that in this particular cell culture system only one type of astrocytes develops which expresses both GFAP and GS and which attains a relatively high degree of maturation.

Men and women differ in their cardiovascular responses to affective pictures

Empirical evidence supports the hypothesis that emotional states might contribute to cardiovascular disease and health through multiple pathways. To the extent that the acute cardiovascular response to emotional events plays a role in cardiovascular health and disease, an essential step in order to understand this possible link is to define the hemodynamic response to affective challenges. This was the aim of the present study. We assessed blood pressure (BP), heart rate (HR), stroke volume (SV), cardiac output, and total peripheral resistance (TPR) in response to 13 picture series in 18 men and 19 women (mean age 26) in order to investigate their hemodynamic responses associated with activation of the appetitive and defensive motivational systems underlying emotional experience. The hemodynamic parameters were recorded by finger-cuff photoplethysmography with Finometer™ (FMS Finapres Medical Systems, Amsterdam) and electrocardiography with the Lifeshirt system (VivoMetrics Inc., Ventura, California). Participants rated self-perceived pleasantness and arousal for each series. In men, BP and SV, but not TPR, increased with increasing self-rated arousal both for appetitive and defensive activation, whereas in women these relationships were almost absent, especially, for defensive activation. HR decelerated more in response to negative than positive and neutral pictures, and more so in men than women. These findings indicate striking sex differences. In particular, it is suggested that the sympathetic inotropic effect to the heart increases with increasing self-rated arousal strongly in men but only weakly in women. Regardless of sex differences, the modulation of the cardiovascular response to affective pictures along the dimensions of pleasantness and arousal is primarily myocardial, and the pattern of cardiovascular response is consistent with a configuration of cardiac sympathetic-parasympathetic coactivation. One possible implication of the observed sex differences concerns the link between affective states and cardiovascular health and disease. Men have a higher incidence of cardiovascular diseases than premenopausal women, and exaggerated sympathetic reactivity to emotional events is a potential pathophysiological mechanism. These findings extend current knowledge showing that under several acute behavioral challenges men demonstrate stronger cardiovascular reactivity than women.