Peroxisome Proliferator-Activated Receptor alpha (PPAR alpha) down-regulation in cystic fibrosis lymphocytes

Background: PPARs exhibit anti-inflammatory capacities and are potential modulators of the inflammatory response. We hypothesized that their expression and/or function may be altered in cystic fibrosis (CF), a disorder characterized by an excessive host inflammatory response. Methods: PPARα, β and γ mRNA levels were measured in peripheral blood cells of CF patients and healthy subjects via RT-PCR. PPARα protein expression and subcellular localization was determined via western blot and immunofluorescence, respectively. The activity of PPARα was analyzed by gel shift assay. Results: In lymphocytes, the expression of PPARα mRNA, but not of PPARβ, was reduced (-37%; p < 0.002) in CF patients compared with healthy persons and was therefore further analyzed. A similar reduction of PPARα was observed at protein level (-26%; p < 0.05). The transcription factor was mainly expressed in the cytosol of lymphocytes, with low expression in the nucleus. Moreover, DNA binding activity of the transcription factor was 36% less in lymphocytes of patients (p < 0.01). For PPARα and PPARβ mRNA expression in monocytes and neutrophils, no significant differences were observed between CF patients and healthy persons. In all cells, PPARγ mRNA levels were below the detection limit. Conclusion: Lymphocytes are important regulators of the inflammatory response by releasing cytokines and antibodies. The diminished lymphocytic expression and activity of PPARα may therefore contribute to the inflammatory processes that are observed in CF

Changes in Seizure Frequency and Test-Retest Scores on the Wechsler Adult Intelligence Scale

Test-retest performance on the Wechsler Adult Intelligence Scale (WAIS) of two groups of adult epilepsy patients are presented and compared. In one group, Seizures Improved (SI) group, seizure frequency had decreased during the test-retest interval, and in the other group, Seizures Unimproved (SU) group, the number of seizures had either increased or stayed the same over the test-retest interval. The SI group showed a significant test-retest improvement on WAIS Verbal IQ, Performance 1Q, and Full Scale IQ, as well as on eight of 11 WAIS subtests. In comparison, the SU group showed significant increases only on the Performance IQ and Object Assembly subtest. Furthermore, differences between the two groups were observed in the pattern of test-retest changes seen on the Performance measures relative to the Verbal measures. The results suggest that change in seizure frequency is one of the factors associated with test-retest changes in the intellectual functioning of epilepsy patients. RÉSUMÉ Les rÉsultats obtenus À I‘Échelle de WAIS (Wechsler Adults Intelligence Scale) a partir d'une passation I (test) et d'une passation II (retest) chez deux groupes d'Épileptiques adultes sont prÉsentÉs et compares: (a) Dans un groupe la frequence des crises a diminue dur-ant I'intervalle “test-retest” (c'est a dire dans I'inter-valle separant la passation I (test) de la passation II (retest): Groupe des crises ameliorees (SI: seizures improved), (b) Dans l'autre groupe le nombre des crises au contraire a augmente ou bien est reste iden-tique au cours de I'intervalle “test-retest”: Groupe des crises non ameliorees (SU: seizures unimproved). Le groupe des “crises ameliorees” montre une amelioration significative tant sur le plan du QIV (quotient de I'echelle verbale), que du QIP (quotient de I'echelle performance) et du QIG (quotient global), ainsi que de 8 des subtests parmi les onze que contien I'echelle. En comparaison le groupe des “crises non ameliorees” ne montre une amelioration significative qu'au niveau du QIP et en particulier sur le subtest d'assemblage d'ob-jets (celui-ci faisant partie de I'echelle performance). De plus, on observe entre les deux groupes des differences du “type” des modifications entrainees par la situation “test-retest”, sur les rÉsultats obtenus a I'echelle performance et ceux obtensus a I'echelle verbale. Ces rÉsultats permettent de suggerer que, dans le fonctionnement intellectuel des sujets epileptiques, les changements dans la frequence des crises sont un des facteurs a mettre en correlation avec les changements observes a partir de la situation “test-retest”. RESUMEN Se compararon dos grupos de adultos con epilepsia por medio del rendimiento en dos tests de WAIS. En un grupo, la frecuencia de los ataques habia disminuido en el intervalo entre el primer test y el segundo [grupo con mejoria (SI)], mientras que en el otro el mimero de crisis no habia variado o habia au-mentado [grupo sin mejoria (SU)]. El grupo SI mostro una mejoria en laescala verbal CI, en la realizacion CI, en la escala total de CI y en los subtests WAIS. En comparacion, el grupo SU solo mostro un aumento significativo en la realizacion CI y en el subtest de Reunion de Objetos. Ademas, se observaron diferen-cias entre los dos grupos en lo que respecta a la prim-era y a la segunda prueba en la realizacion de las medidas verbales. Los resultados sugieren que los cambios en la frecuencia de los ataques juegan un papel en lo que respecta a funciÓn intelectual cuando se compara el primer WAIS con el segundo. ZUSAMMENFASSUNG Test und Retest Ergebnisse im WAIS von 2 Gruppen erwachsener Epileptiker werden dargestellt und ver-glichen. In einer Gruppe hatte die Anfallshaufigkeit wahrend des Test-Retest-Intervalls abgenommen– verbesserte Gruppe (SI)–und in einer anderen Gruppe war die Anfallshaufigkeit entweder gestiegen oder gleich geblieben wahrend des Test-Retest-Intervalls– unveranderte Gruppe (SU). Die SI-Gruppe zeigte signifikante Verbesserung zwischen Test und Retest im Verbal-IQ des WAIS, im Handlungsteil und im Gesamt-IQ ebenso wie in 8 von 11 WAIS Subtests. Im Vergleich hierzu zeigte die SU-Gruppe signifikante Verbesserung nur im Handlungs-IQ und im Objekte-zuordnungs-Subtest. Weiterhin wurden Unterschiede zwischen den beiden Gruppen im Muster der Test-Retest-Veranderungen im Verhaltnis des Handlung-steils zum Verbalteil bemerkt. Die Ergebnisse lassen vermuten, dalJ die Veranderung der Anfallshaufigkeit einer der Faktoren ist, der hinsichtlich der in-tellektuellen Funktion anfallskranker Patienten Bezie-hungen zu den Veranderungen des Test-Retest-Ergeb-nis aufweist.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65457/1/j.1528-1157.1981.tb04334.x.pd

Co-ordinated Gene Expression in the Liver and Spleen during Schistosoma japonicum Infection Regulates Cell Migration

Determining the molecular events induced in the spleen during schistosome infection is an essential step in better understanding the immunopathogenesis of schistosomiasis and the mechanisms by which schistosomes modulate the host immune response. The present study defines the transcriptional and cellular events occurring in the murine spleen during the progression of Schistosoma japonicum infection. Additionally, we compared and contrasted these results with those we have previously reported for the liver. Microarray analysis combined with flow cytometry and histochemistry demonstrated that transcriptional changes occurring in the spleen were closely related to changes in cellular composition. Additionally, the presence of alternatively activated macrophages, as indicated by up-regulation of Chi3l3 and Chi3l4 and expansion of F4/80+ macrophages, together with enhanced expression of the immunoregulatory genes ANXA1 and CAMP suggests the spleen may be an important site for the control of S. japonicum-induced immune responses. The most striking difference between the transcriptional profiles of the infected liver and spleen was the contrasting expression of chemokines and cell adhesion molecules. Lymphocyte chemokines, including the homeostatic chemokines CXCL13, CCL19 and CCL21, were significantly down-regulated in the spleen but up-regulated in the liver. Eosinophil (CCL11, CCL24), neutrophil (CXCL1) and monocyte (CXCL14, CCL12) chemokines and the cell adhesion molecules VCAM1, NCAM1, PECAM1 were up-regulated in the liver but unchanged in the spleen. Chemokines up-regulated in both organs were expressed at significantly higher levels in the liver. Co-ordinated expression of these genes probably contributes to the development of a chemotactic signalling gradient that promotes recruitment of effector cells to the liver, thereby facilitating the development of hepatic granulomas and fibrosis. Together these data provide, for the first time, a comprehensive overview of the molecular events occurring in the spleen during schistosomiasis and will substantially further our understanding of the local and systemic mechanisms driving the immunopathogenesis of this disease

The unfolded protein response and its relevance to connective tissue diseases

The unfolded protein response (UPR) has evolved to counter the stresses that occur in the endoplasmic reticulum (ER) as a result of misfolded proteins. This sophisticated quality control system attempts to restore homeostasis through the action of a number of different pathways that are coordinated in the first instance by the ER stress-senor proteins IRE1, ATF6 and PERK. However, prolonged ER-stress-related UPR can have detrimental effects on cell function and, in the longer term, may induce apoptosis. Connective tissue cells such as fibroblasts, osteoblasts and chondrocytes synthesise and secrete large quantities of proteins and mutations in many of these gene products give rise to heritable disorders of connective tissues. Until recently, these mutant gene products were thought to exert their effect through the assembly of a defective extracellular matrix that ultimately disrupted tissue structure and function. However, it is now becoming clear that ER stress and UPR, because of the expression of a mutant gene product, is not only a feature of, but may be a key mediator in the initiation and progression of a whole range of different connective tissue diseases. This review focuses on ER stress and the UPR that characterises an increasing number of connective tissue diseases and highlights novel therapeutic opportunities that may arise

A search for quantitative trait loci controlling within-individual variation of physical activity traits in mice

<p>Abstract</p> <p>Background</p> <p>In recent years it has become increasingly apparent that physical inactivity can predispose individuals to a host of health problems. While many studies have analyzed the effect of various environmental factors on activity, we know much less about the genetic control of physical activity. Some studies in mice have discovered quantitative trait loci (QTL) influencing various physical activity traits, but mostly have analyzed inter-individual variation rather than variation in activity within individuals over time. We conducted a genome scan to identify QTLs controlling the distance, duration, and time run by mice over seven consecutive three-day intervals in an F₂population created by crossing two inbred strains (C57L/J and C3H/HeJ) that differed widely (average of nearly 300%) in their activity levels. Our objectives were (a) to see if we would find QTLs not originally discovered in a previous investigation that assessed these traits over the entire 21-day period and (b) to see if some of these QTLs discovered might affect the activity traits only in the early or in the late time intervals.</p> <p>Results</p> <p>This analysis uncovered 39 different QTLs, over half of which were new. Some QTLs affected the activity traits only in the early time intervals and typically exhibited significant dominance effects whereas others affected activity only in the later age intervals and exhibited less dominance. We also analyzed the regression slopes of the activity traits over the intervals, and found several QTLs affecting these traits that generally mapped to unique genomic locations.</p> <p>Conclusions</p> <p>It was concluded that the genetic architecture of physical activity in mice is much more complicated than has previously been recognized, and may change considerably depending on the age at which various activity measures are assessed.</p

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Development of a Management Algorithm for Post-operative Pain (MAPP) after total knee and total hip replacement: study rationale and design.

BACKGROUND: Evidence from clinical practice and the extant literature suggests that post-operative pain assessment and treatment is often suboptimal. Poor pain management is likely to persist until pain management practices become consistent with guidelines developed from the best available scientific evidence. This work will address the priority in healthcare of improving the quality of pain management by standardising evidence-based care processes through the incorporation of an algorithm derived from best evidence into clinical practice. In this paper, the methodology for the creation and implementation of such an algorithm that will focus, in the first instance, on patients who have undergone total hip or knee replacement is described. METHODS: In partnership with clinicians, and based on best available evidence, the aim of the Management Algorithm for Post-operative Pain (MAPP) project is to develop, implement, and evaluate an algorithm designed to support pain management decision-making for patients after orthopaedic surgery. The algorithm will provide guidance for the prescription and administration of multimodal analgesics in the post-operative period, and the treatment of breakthrough pain. The MAPP project is a multisite study with one coordinating hospital and two supporting (rollout) hospitals. The design of this project is a pre-implementation-post-implementation evaluation and will be conducted over three phases. The Promoting Action on Research Implementation in Health Services (PARiHS) framework will be used to guide implementation. Outcome measurements will be taken 10 weeks post-implementation of the MAPP. The primary outcomes are: proportion of patients prescribed multimodal analgesics in accordance with the MAPP; and proportion of patients with moderate to severe pain intensity at rest. These data will be compared to the pre-implementation analgesic prescribing practices and pain outcome measures. A secondary outcome, the efficacy of the MAPP, will be measured by comparing pain intensity scores of patients where the MAPP guidelines were or were not followed. DISCUSSION: The outcomes of this study have relevance for nursing and medical professionals as well as informing health service evaluation. In establishing a framework for the sustainable implementation and evaluation of a standardised approach to post-operative pain management, the findings have implications for clinicians and patients within multiple surgical contexts

Quality of Neonatal Healthcare in Kilimanjaro Region, Northeast Tanzania: Learning from Mothers' Experiences.

With a decline of infant mortality rates, neonatal mortality rates are striking high in development countries particularly sub Saharan Africa. The toolkit for high quality neonatal services describes the principle of patient satisfaction, which we translate as mother's involvement in neonatal care and so better outcomes. The aim of the study was to assess mothers' experiences, perception and satisfaction of neonatal care in the hospitals of Kilimanjaro region of Tanzania. A cross sectional study using qualitative and quantitative approaches in 112 semi structured interviews from 14 health facilities. Open ended questions for detection of illness, care given to the baby and time spent by the health worker for care and treatment were studied. Probing of the responses was used to extract and describe findings by a mix of in-depth interview skills. Closed ended questions for the quantitative variables were used to quantify findings for statistical use. Narratives from open ended questions were coded by colours in excel sheet and themes were manually counted. 80 mothers were interviewed from 13 peripheral facilities and 32 mothers were interviewed at a zonal referral hospital of Kilimanjaro region. 59 mothers (73.8%) in the peripheral hospitals of the region noted neonatal problems and they assisted for attaining diagnosis after a showing a concern for a request for further investigations. 11 mothers (13.8%) were able to identify the baby's diagnosis directly without any assistance, followed by 7 mothers (8.7%) who were told by a relative, and 3 mothers (3.7%) who were told of the problem by the doctor that their babies needed medical attention. 24 times mothers in the peripheral hospitals reported bad language like "I don't have time to listen to you every day and every time." 77 mothers in the periphery (90.6%) were not satisfied with the amount of time spent by the doctors in seeing their babies. Mothers of the neonates play great roles in identifying the illness of the newborn. Mother's awareness of what might be needed during neonatal support strategies to improve neonatal care in both health facilities and the communities