The effect of peri-operative dexmedetomidine on the incidence of postoperative delirium in cardiac and non-cardiac surgical patients: a randomised, double-blind placebo-controlled trial.

Delirium occurs commonly following major non-cardiac and cardiac surgery and is associated with: postoperative mortality; postoperative neurocognitive dysfunction; increased length of hospital stay; and major postoperative complications and morbidity. The aim of this study was to investigate the effect of peri-operative administration of dexmedetomidine on the incidence of postoperative delirium in non-cardiac and cardiac surgical patients. In this randomised, double-blind placebo-controlled trial we included 63 patients aged ≥ 60 years undergoing major open abdominal surgery or coronary artery bypass graft surgery with cardiopulmonary bypass. The primary outcome was the incidence of postoperative delirium, as screened for with the Confusion Assessment Method. Delirium assessment was performed twice daily until postoperative day 5, at the time of discharge from hospital or until postoperative day 14. We found that dexmedetomidine was associated with a reduced incidence of postoperative delirium within the first 5 postoperative days, 43.8% vs. 17.9%, p = 0.038. Severity of delirium, screened with the Intensive Care Delirium Screening Checklist, was comparable in both groups, with a mean maximum score of 1.54 vs. 1.68, p = 0.767. No patients in the dexmedetomidine group died while five (15.6%) patients in the placebo group died, p = 0.029. For patients aged ≥ 60 years undergoing major cardiac or non-cardiac surgery, we conclude that the peri-operative administration of dexmedetomidine is associated with a lower incidence of postoperative delirium.

Effect of hyperextension of the neck (rose position) on cerebral blood oxygenation in patients who underwent cleft palate reconstructive surgery: prospective cohort study using near-infrared spectroscopy.

OBJECTIVES: To facilitate the best approach during cleft palate surgery, children are positioned with hyperextension of the neck. Extensive head extension may induce intraoperative cerebral ischemia if collateral flow is insufficient. To evaluate and monitor the effect of cerebral blood flow on cerebral tissue oxygenation, near-infrared spectroscopy has proved to be a valuable method. The aim of this study was to evaluate and quantify whether hyperextension affects the cerebral tissue oxygenation in children during cleft palate surgery. MATERIALS AND METHODS: This prospective study included children (ASA 1 and 2) under the age of 3 years old who underwent cleft palate repair at the Wilhelmina Children's Hospital, in The Netherlands. Data were collected for date of birth, cleft type, date of cleft repair, and physiological parameters (MAP, saturation, heart rate, expiratory CO2 and O2, temperature, and cerebral blood oxygenation) during surgery. The cerebral blood oxygenation was measured with NIRS. RESULTS: Thirty-four children were included in this study. The majority of the population was male (61.8%, n = 21). The mixed model analyses showed a significant drop at time of Rose position of - 4.25 (69-74 95% CI; p < 0.001) and - 4.39 (69-74 95% CI; p < 0.001). Postoperatively, none of the children displayed any neurological disturbance. CONCLUSION: This study suggests that hyperextension of the head during cleft palate surgery leads to a significant decrease in cerebral oxygenation. Severe cerebral desaturation events during surgery were uncommon and do not seem to be of clinical relevance in ASA 1 and 2 children. CLINICAL RELEVANCE: There was a significant drop in cerebral oxygenation after positioning however it is not clear whether this drop is truly significant physiologically in ASA 1 and 2 patients.

Ambient temperature and solar insolation are associated with decreased prevalence of SSRI-treated psychiatric disorders.

Serotonergic function is known to fluctuate in association with light and temperature. Serotonin-related behaviors and disorders similarly vary with climatic exposure, but the associations are complex. This complexity may reflect the importance of dose and timing of exposure, as well as acclimation. This cross-sectional study tests how average climate exposures (ambient temperature and solar insolation) vary with the prevalence of a group of SSRI-treated disorders. For comparison, we similarly studied a group of disorders not treated by SSRIs (i.e substance use disorders). Psychiatric prevalence data were obtained from the Collaborative Psychiatric Epidemiology Surveys (CPES). Average yearly solar insolation was obtained from NASA's NLDAS-2 Forcing Dataset Information. Average yearly temperature was obtained from NOAA's US Climate Normals. Logistic regression models were generated to assess the relationship between these two climatic factors and the prevalence of SSRI-treated and substance use disorders. Age, gender, race, income, and education were included in the models to control for possible confounding. Temperature and insolation were significantly associated with the SSRI-responsive group. For an average 1 GJ/m2/year increase, OR was 0.90 (95% CI 0.85-0.96, p = 0.001), and for an average 10 °F increase, OR was 0.93 (95% CI 0.88-0.97, p = 0.001). This relationship was not seen with substance use disorders (insolation OR: 0.97, p = 0.682; temperature OR: 0.96, p = 0.481). These results warrant further investigation, but they support the hypothesis that chronic exposure to increased temperature and light positively impact serotonin function, and are associated with reduced prevalence of some psychiatric disorders. They also support further investigation of light and hyperthermia treatments.

A preliminary overview of the corticioid Atractiellomycetes (Pucciniomycotina, Basidiomycetes).

The taxonomy of the corticioid fungi from the class Atractiellomycetes (Pucciniomycotina, Basidiomycetes) currently addressed to the genus Helicogloea, is revised based on morphological and nuclear ribosomal DNA (ITS and LSU) data. The genus is restricted to 25 species with semitranslucent, gelatinous basidiocarps lacking differentiated cystidia and clamps on hyphae, of which 11 are described as new to science. The asexual genus Leucogloea is placed as a synonym of Helicogloea s. str. Since the type species of Saccoblastia, S. ovispora, is combined to Helicogloea, a new genus, Saccosoma, is introduced to encompass Saccoblastia farinacea and six related species, one of which is described as new. In contrast to Helicogloea in the strict sense, the basidiocarps of Saccosoma are arid, not gelatinized, and hyphae are clamped. The third lineage of the corticioid Atractiellomycetes is represented by the Bourdotigloea vestita complex. Species of Bourdotigloea are devoid of clamps but often possess well-differentiated cystidia, as well as long, cylindrical-fusiform basidiospores. Bourdotigloea encompasses nine species, of which six are described here as new.

Impact of genomic risk factors on survival after haematopoietic stem cell transplantation for patients with acute leukaemia.

The EBMT risk score is an established tool successfully used in the prognosis of survival post-HSCT and is applicable for a range of haematological disorders. One of its main advantages is that score generation involves summation of clinical parameters that are available pretransplant. However, the EBMT risk score is recognized as not being optimal. Previous analyses, involving patients with various diagnoses, have shown that non-HLA gene polymorphisms influence outcome after allogeneic HSCT. This study is novel as it focuses only on patients having acute leukaemia (N = 458) and attempts to demonstrate how non-HLA gene polymorphisms can be added to the EBMT risk score in a Cox regression model to improve prognostic ability for overall survival. The results of the study found that three genetic factors improved EBMT risk score. The presence of MAL (rs8177374) allele T in the patient, absence of glucocorticoid receptor haplotype (consisting of rs6198, rs33389 and rs33388) ACT in the patient and absence of heat-shock protein 70-hom (+2437) (rs2227956) allele C in the patient were associated with decreased survival time. When compared to the EBMT risk score, the scores combining EBMT risk score with the genetic factors had an improved correlation with clinical outcome and better separation of risk groups. A bootstrapping technique, involving repeated testing of a model using multiple validation sets, also revealed that the newly proposed model had improved predictive value when compared to the EBMT risk score alone. Results support the view that non-HLA polymorphisms could be useful for pretransplant clinical assessment and provide evidence that polymorphisms in the recipient genotype may influence incoming donor cells, suppressing the initiation of the graft versus leukaemia effect and reducing survival.

Identification and validation of biomarkers associated with acute and chronic graft versus host disease.

Graft versus host disease (GVHD) is a major complication of haematopoietic SCT (HSCT). A number of inflammatory cytokines/chemokines are implicated in GVHD and have been identified in numerous single centre studies as potential biomarkers for acute and/or chronic GVHD. In this study, we analysed candidate inflammatory biomarkers (B-cell activating factor (BAFF), interleukin 33 (IL-33), CXCL10 and CXCL11) in a two-centre study. Biomarkers were evaluated pre-transplant and at serial time points post transplant in acute and chronic GVHD patient sera with time-matched control samples from patients without GVHD. Further validation was performed using the human skin explant assay, clinical GVHD biopsies and mRNA expression analysis. BAFF was significantly increased pre-transplant. BAFF, IL-33, CXCL10 and CXCL11 showed increased levels in acute GVHD patient sera and high protein expression in grades II-III of the in vitro skin explant graft versus host reaction (GVHR) group. BAFF, CXCL10 and CXCL11 also showed increased mRNA expression levels in clinical biopsies compared with the no/low-grade GVHD group. BAFF, CXCL10 and CXCL11 levels were increased in chronic GVHD patient sera. The results identify BAFF and CXCL10 as predictive biomarkers for acute GVHD and BAFF, CXCL10 and CXCL11 as useful diagnostic biomarkers for acute GVHD and chronic GVHD.

Predicting survival using clinical risk scores and non-HLA immunogenetics.

Previous studies of non-histocompatibility leukocyte antigen (HLA) gene single-nucleotide polymorphisms (SNPs) on subgroups of patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) revealed an association with transplant outcome. This study further evaluated the association of non-HLA polymorphisms with overall survival in a cohort of 762 HSCT patients using data on 26 polymorphisms in 16 non-HLA genes. When viewed in addition to an already established clinical risk score (EBMT-score), three polymorphisms: rs8177374 in the gene for MyD88-adapter-like (MAL; P=0.026), rs9340799 in the oestrogen receptor gene (ESR; P=0.003) and rs1800795 in interleukin-6 (IL-6; P=0.007) were found to be associated with reduced overall survival, whereas the haplo-genotype (ACC/ACC) in IL-10 was protective (P=0.02). The addition of these non-HLA polymorphisms in a Cox regression model alongside the EBMT-score improved discrimination between risk groups and increased the level of prediction compared with the EBMT-score alone (gain in prediction capability for EBMT-genetic-score 10.8%). Results also demonstrated how changes in clinical practice through time have altered the effects of non-HLA analysis. The study illustrates the significance of non-HLA genotyping prior to HSCT and the importance of further investigation into non-HLA gene polymorphisms in risk prediction.

Non-HLA genomics: does it have a role in predicting haematopoietic stem cell transplantation outcome?

Haematopoietic stem cell transplantation (HSCT) remains the only cure for many haematological neoplasms; however, the mortality rate remains high, at around 30-80%. Complications after HSCT include relapse, graft-versus-host disease, graft rejection and infection. High-resolution HLA matching has improved survival in HSCT over recent years; however, GVHD still remains a serious complication. Single nucleotide polymorphisms (SNPS) within genes that are involved with an individual's capability to mount an immune response to infectious pathogens, residual leukaemia, alloantigens or genes involved in drug metabolism have been studied for their association with HSCT outcome. Indeed, over the last 15 years, several groups, including ourselves, have demonstrated that non-HLA gene polymorphisms can be predictive of HSCT outcome. Can genetic characteristics of the patient and donor be used in the future to tailor HSCT protocols and determine GVHD prophylaxis? This review summarizes some of the recent SNP association studies in HSCT and highlights some of the disparities therein, discussing the integral problems of performing genetic association studies on diseases with complex outcomes using heterogeneous cohorts. The review will comment on recent genomewide association studies (GWAS) and discuss their relevance in this field, and it will also comment on recent meta-analysis combining GWAS studies with other studies such as gene expression micro array data in the field of autoimmune disease and solid organ transplantation. It will mention possible novel candidate gene polymorphisms, for example SNPS in microRNAs. In addition, it will discuss some of the inherent problems associated with gene association studies including the GRIPs (genetic risk prediction studies) recommendations. In summary, this review will assess the usefulness of non-HLA genomic studies in HSCT with regard to predicting outcome and modifying therapy.

Nutrition impact symptoms and body composition in patients with COPD.

BACKGROUND/OBJECTIVES: Anorexia or lack of appetite is common in chronic obstructive pulmonary disease (COPD) and may be caused or augmented by several symptoms affecting appetite and eating. We aimed to investigate and quantify the extent of nutrition impact symptoms (NIS) in patients with COPD and to explore relationships between NIS and fat-free mass depletion. SUBJECTS/METHODS: The results in this cross-sectional study are based on 169 COPD patients (62% female subjects). Body composition was assessed using bioelectrical impedance spectroscopy and the patients reported NIS by two newly developed questionnaires: the Eating Symptoms Questionnaire (ESQ) and the Disease-Related Appetite Questionnaire (DRAQ). RESULTS: Symptoms with the highest prevalence were dry mouth (71%), stomach ache (39%), pain or aches affecting appetite (36%) and constipation (35%). Problems with diarrhoea and feeling affected by smells were more severe among women compared with men (P<0.05). Thirty-six percent of the patients were depleted (fat-free mass index (FFMI) <15 kg/m2 for women and FFMI<16 kg/m2 for men). Depleted patients had more NIS (P<0.05) and also rated appetite and taste of food as worse compared with non-depleted patients (P<0.05). CONCLUSIONS: NIS are common in patients with COPD, and depleted patients have more severe symptoms. To investigate how these symptoms are best prevented and/or managed and whether NIS prevention/treatment can affect development of malnutrition in patients with COPD is a challenge for the future.

RAGE blockade and hepatic microcirculation in experimental endotoxaemic liver failure.

BACKGROUND: Activation of the receptor for advanced glycation endproducts (RAGE) causes sustained activation of multiple inflammatory pathways. Therefore, RAGE has potential as a new therapeutic target in sepsis. The aim of this study was to analyse whether RAGE blockade in vivo prevents microcirculatory dysfunction and subsequent tissue injury in endotoxaemic liver failure. METHODS: The hepatic microcirculation was analysed using intravital fluorescence microscopy in murine livers exposed to galactosamine/lipopolysaccharide (G/L) and treated with an anti-RAGE antibody (abRAGE) either 12 h before or h after exposure to G/L. Blood and liver tissue samples were harvested for analysis of leucocyte tissue infiltration, apoptotic and necrotic damage as well as RAGE downstream pathway signalling. RESULTS: Sinusoidal perfusion failure in livers exposed to G/L was reduced significantly by both pretreatment and post-treatment with abRAGE. Hepatic inflammation induced by exposure to G/L was also attenuated by abRAGE administration, as shown by a 55 per cent reduction in sinusoidal leucocyte stasis, a 65 per cent decrease in venular leucocyte rolling and adhesion, and an 85 per cent reduction in leucocyte tissue infiltration. Treatment with abRAGE markedly reduced hepatocellular apoptosis and necrosis in livers exposed to G/L, and blunted the rise in plasma high-mobility group protein B1 levels. Finally, G/L-induced activation of the mitogen-activated protein kinase cascade was also reduced significantly by blockade of RAGE. CONCLUSION: RAGE plays an important role in mediating endotoxaemic liver damage. RAGE blockade may have potential therapeutic value. SURGICAL RELEVANCE: The innate immune response to endoxaemia is initiated by a group of pattern recognition receptors, including the receptor for advanced glycation endproducts (RAGE). As RAGE is well known for perpetuation of inflammatory processes, blockade of this receptor might be of particular value in reducing or even halting endoxaemia-related organ disorders. Using intravital fluorescence microscopy this study demonstrated in vivo that pretreatment, but also post-treatment, with a RAGE-blocking antibody attenuated hepatic microcirculatory deterioration and leucocyte recruitment, and thus diminished liver injury in a murine model of endotoxaemic organ failure. These data underline the important role of RAGE in the innate immune response and support the potential therapeutic value of blocking this pattern recognition receptor.

Association of vitamin D receptor polymorphisms with the outcome of allogeneic haematopoietic stem cell transplantation.

Recently, vitamin D receptor (VDR) polymorphism has been identified as an additional genetic factor associated with the outcome after allogeneic haematopoietic stem cell transplantation (HSCT) from HLA-matched sibling donors. In the present study, VDR ApaI, TaqI and FokI alleles were typed using single strand conformation polymorphism in 123 Polish recipients and their sibling or alternative donors to test the associations of VDR polymorphisms with HSCT outcome. Four VDR genotypes were identified as risk factors of acute graft-versus-host disease (aGVHD). Donor ApaI AA (OR = 7.245, P = 0.009), source of HSC (OR = 7.001, P = 0.007), transplantation from an alternative donor (OR = 6.630, P = 0.007) and donor FokI FF (OR = 4.473, P = 0.025) significantly contributed to the development of grades II-IV aGVHD, while recipient ApaI aa (OR = 3.233, P = 0.069), recipient FokI FF (OR = 2.558, P = 0.077) and female to male transplants (OR = 2.955, P = 0.099) were found to be less significant factors. In addition, the presence of ApaI aa genotype in the recipient was found to be associated with increased likelihood of death (P = 0.0228). The present study contributes to the studies demonstrating a role of VDR polymorphisms in HSCT outcome. In addition to previously described correlations of ApaI a allele and occurrence of severe grades III-IV aGVHD and (linked with ApaI aa) recipient TaqI TT genotype with aGVHD, the novel associations of recipient and donor FokI FF genotype and the increased aGVHD risk and recipient ApaI aa with survival were identified.

Oestrogen receptor alpha gene polymorphism associates with occurrence of graft-versus-host disease and reduced survival in HLA-matched sib-allo BMT.

Oestrogen receptors mediate the cellular response to oestrogens and related compounds and promote a wide range of effects on haemopoiesis. Polymorphisms of the oestrogen receptor genes have previously been associated with variation in bone mineral density, likelihood of fractures, risk of developing Alzheimer's disease, endometrial cancer and response to hormone replacement therapy. We examined the polymorphisms in both ERalpha and ERbeta genes in 108 patients receiving a bone marrow transplant from an HLA-matched sibling donor, and compared ER genotype with outcomes of occurrence of graft-versus-host disease (GVHD) and survival using logistic regression analysis. Polymorphism of ERalpha (presence of the PX haplotype (PvuII-XbaI RFLP) of intron 1), but not ERbeta, in the patient genotype associates with occurrence of acute GVHD and with lower overall survival, following correction for known clinical and genotypic risk features. Analysis of ER genotype prior to transplant might therefore inform on a patient's likelihood of developing post-transplant complications. Variation in transplant performance because of ER genotype suggests an underlying role for oestrogens in the pathophysiology of transplant-related complications, and suggests that oestrogen-related therapy may offer a new modality of post-transplant support.

Vitamin D receptor gene polymorphism associates with graft-versus-host disease and survival in HLA-matched sibling allogeneic bone marrow transplantation.

We investigated the role of polymorphism of the vitamin D receptor (VDR) gene in HLA-matched sibling BMT for polymorphisms previously associated with human disease pathology. In intron 8 of the VDR gene, the B and A alleles of the BsmI and ApaI RFLPs were found to associate with reduced aGVHD when present in the patient's genotype. Logistic regression analysis demonstrated that patient VDR genotype, along with previously identified IL-10(-1064) and IFN-gamma genotype to be risk factors for severe acute GVHD. The A allele also associates with increased likelihood of death when present in the donor genotype (AA vs Aa or aa, hazard ratio 2.03, P = 0.0232). In patients who received increased prophylaxis with multi-agent therapy, patients whose graft was from a donor with an AA genotype had a substantially worse survival than patients whose graft was from a donor with a non-AA genotype (hazard ratio 12.93, P < 0.0001). Analysis of VDR genotype in prospective BMT recipients could indicate patients at risk of severe aGVHD. Analysis of VDR genotype in prospective BMT donors may identify individuals who have greater transplant-related mortality, and also allow appropriately restricted use of increased immunosuppressive prophylaxis.

Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation.

Proinflammatory cytokines including interferon-gamma (IFNgamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFalpha) are implicated in the pathogenesis of acute graft-versus-host disease (aGVHD). Cytokine gene polymorphism is associated with functional differences in cytokine regulation and altered clinical performance in a variety of diseases. Polymorphism in the IFNgammaIntron1 microsatellite (CA)n repeat has been linked with in vitro IFNgamma production and renal transplant rejection. The IL-6(-174)(G/C) single nucleotide polymorphism has been linked to in vitro and in vivo IL-6 production, juvenile chronic arthritis, and renal transplant rejection. This study examined the potential association of GVHD with IFNgamma and IL-6 polymorphisms in 80 sibling bone marrow transplant (BMT) donor/recipient pairs. Patients homozygous for the IFNgammaIntron1 allele 3 had more severe (grade III-IV) aGVHD. Patients possessing the IL-6(-174)G allele had a trend toward higher grades of aGVHD, and those homozygous for the IL-6(-174)G allele were more likely to develop chronic GVHD (cGVHD). The associations of previously identified aGVHD severity-associated cytokine gene polymorphisms (TNFd and IL-10(-1064)) with severe aGVHD were reconfirmed. Logistic regression analysis confirmed the association of severe aGVHD with recipient genotype at IFNgammaIntron1 (odds ratio [OR] 3.92; P =.02), IL-10(-1064) (OR 4.61; P =.026) and TNFd (OR 3.29; P =.039), and that of cGVHD with recipient IL-6(-174) genotype (OR 4.25; P =.007), in addition to age, gender mismatch, and underlying disease. Assessment of cytokine genotype may potentially allow more accurate prediction of GVHD and appropriate adjustment of GVHD prophylaxis, as well as indicating novel areas for future studies of GVHD pathogenesis.

Population-based study of the pattern of molecular markers of minimal residual disease in childhood and adult acute lymphoblastic leukemia: an assessment of the practical difficulty of representative sampling for trial purposes. Northern Region Haematology Group.

BACKGROUND: The prevalence, in unselected patients with acute lymphoblastic leukaemia (ALL), of clonal rearrangements suitable for minimal residual disease (MRD) studies has not been formally investigated. PROCEDURE: This was a prospective, demographic study of the frequency of molecular markers of MRD in all patients with ALL presenting over 5 years within the Northern Health Region of England (population 3.1 million). Presentation marrow samples were examined to detect informative markers. RESULTS: One hundred twenty-four children (age <15 years) developed non-Burkitt ALL. No material was available for study in 21. Eighty-six had clonal gene rearrangements (BCR/ABL, immunoglobulin heavy chain (IGH) and/or T cell receptor (TCR) gene rearrangements). All entered remission; 84 (68% of the original cohort) survived to become eligible for MRD studies. One hundred sixteen adults developed ALL, of whom 48 were not studied due to insufficient cellular material in the bone marrow aspirate or to logistical problems in central referral of samples from other hospitals. Material from elderly adults (age >55 years) was less likely to be sent for analysis, 36% vs. 59% (P = 0.024). Thirty-eight had BCR/ABL and/or IGH/TCR gene rearrangements. Thirty-one (27% of the original cohort) entered remission and became eligible for MRD studies. Informative gene rearrangements were more common in children than adults (83% vs. 63%, P < 0.003). CONCLUSIONS: The results reveal substantial potential, unintentional, selection bias. Large-scale multicentre studies of MRD in children may well produce clinically relevant and representative data. Those who mount similar studies in adults should not assume they will be similarly representative or as successful in accrual of material.

Rapid arrest of axon elongation by brefeldin A: a role for the small GTP-binding protein ARF in neuronal growth cones.

Members of the ADP-ribosylation factor (ARF) family of small guanosine triphosphate-binding proteins play an essential role in membrane trafficking which subserves constitutive protein transport along exocytic and endocytic pathways within eukaryotic cell bodies. In growing neurons, membrane trafficking within motile growth cones distant from the cell body underlies the rapid plasmalemmal expansion which subserves axon elongation. We report here that ARF is a constituent of axonal growth cones, and that application of brefeldin A to neurons in culture produces a rapid arrest of axon extension that can be ascribed to inhibition of ARF function in growth cones. Our findings demonstrate a role for ARF in growth cones that is coupled tightly to the rapid growth of neuronal processes characteristic of developmental and regenerative axon elongation, and indicate that ARF participates not only in constitutive membrane traffic within the cell body, but also in membrane dynamics within growing axon endings.

S100B, a neurotropic protein that modulates neuronal protein phosphorylation, is upregulated during lesion-induced collateral sprouting and reactive synaptogenesis.

Using light and electron microscopic immunocytochemistry, we examined the expression of the Ca2+-binding protein S100B in the dentate gyrus of adult rats during lesion-induced sprouting and reactive synaptogenesis. Nine days following unilateral lesioning of the entorhinal cortex, S100B was upregulated in cells primarily in the outer part of the molecular layer of the ipsilateral dentate gyrus. When examined with electron microscopy, numerous astrocytes and synapses containing S100B were identified. These data show that during lesion-induced sprouting and reactive synaptogenesis, S100B is upregulated in astrocytes and can be found in pre- and post-synaptic compartments where it might influence neuronal protein phosphorylation.

Up-regulation of fast-axonally transported proteins in retinal ganglion cells of adult rats with optic-peroneal nerve grafts.

Metabolic labeling and quantitative 2D gel fluorography were used to assess changes in the synthesis and transport of five fast-axonally transported and developmentally regulated proteins (GAP-43, SNAP-25, and proteins of 18, 22, and 23/24 kDa) after grafting of a peroneal nerve segment onto a transected optic nerve in adult rats. After optic nerve transection alone, only GAP-43 was up-regulated significantly compared to normal adult controls. The other proteins showed little change or were down-regulated following axotomy. By 4 weeks following optic nerve transection and peroneal nerve grafting, however, GAP-43, proteins 22 and 23/24 kDa showed a sustained up-regulation in synthesis and transport compared to normal controls; SNAP-25 and protein 18 kDa showed levels of expression similar to or slightly greater than normal controls. Increased expression of GAP-43 in retinal ganglion cells was also examined with immunocytochemistry. While a transient up-regulation of GAP-43 in retinal ganglion cells was observed following optic nerve transection, a sustained increase in GAP-43 immunoreactivity was present only in animals with nerve grafts. Backfilling of retinal ganglion cells from the grafts with horseradish peroxidase combined with GAP-43 immunocytochemistry revealed that all retinal ganglion cells with axons growing into the grafts were positive for GAP-43, but not all retinal ganglion cells showing GAP-43 immunoreactivity were extending axons into the grafts. We conclude that the presence of a nerve graft sustains the up-regulation of a number of proteins including GAP-43, and that this up-regulation is correlated with an increased potential for nerve growth, but other as yet unknown factors or conditions appear to play a role in determining if this growth potential will be realized.