Total Parenteral Nutrition Causes Circumferential Intestinal Atrophy,Remodeling of the Intestinal Wall,and Redistribution of Eosinophils in the Rat Gastrointestinal Tract

Total parenteral nutrition (TPN) is held to cause intestinal atrophy and weaken mechanical and immunological barriers. To monitor the degree of atrophy caused by TPN, female Sprague-Dawley rats were, for 8 days, maintained on TPN (n = 6) and compared to identically housed controls given food and water ad libitum (n = 6). Specimens from jejunum, ileum, and colon were taken for histology and morphometric analysis. Topographic distribution and presence of eosinophils, by eosinophil peroxidase (EPO) staining, were examined in the gastric fundus, jejunum, ileum, and colon. Atrophy in terms of a markedly reduced circumference was noted throughout the intestinal tract in all rats subjected to TPN. The width of jejunal and ileal villi was narrowed and the length of jejunal villi was decreased. Furthermore, submucosal thickness in the jejunum and ileum increased. The height of ileal enterocytes remained unaltered. The number of goblet cells decreased in jejunal but not in ileal villi. The Paneth cells, suggested to play important roles in innate defense, increased in size. In the gastric fundus a marked increase in eosinophils was revealed predominantly in the mucosa and submucosa. The number and distribution of jejunal and ileal eosinophils were identical to those of controls. In colon from TPN rats, a redistribution of eosinophils was noted, causing a “band-like” accumulation of eosinophils in the basal portion of the mucosa. In conclusion, TPN causes gut atrophy and an increase in Paneth cell size. Eosinophils increase in number in the gastric fundus and a topographic redistribution occurs in the colon.     

Murine models of acute neuronopathic Gaucher disease

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the glucosidase, beta, acid (GBA) gene that encodes the lysosomal enzyme glucosylceramidase (GCase). GCase deficiency leads to characteristic visceral pathology and, in some patients, lethal neurological manifestations. Here, we report the generation of mouse models with the severe neuronopathic form of GD. To circumvent the lethal skin phenotype observed in several of the previous GCase-deficient animals, we genetically engineered a mouse model with strong reduction in GCase activity in all tissues except the skin. These mice exhibit rapid motor dysfunction associated with severe neurodegeneration and apoptotic cell death within the brain, reminiscent of neuronopathic GD. In addition, we have created a second mouse model, in which GCase deficiency is restricted to neural and glial cell progenitors and progeny. These mice develop similar pathology as the first mouse model, but with a delayed onset and slower disease progression, which indicates that GCase deficiency within microglial cells that are of hematopoietic origin is not the primary determinant of the CNS pathology. These findings also demonstrate that normal microglial cells cannot rescue this neurodegenerative disease. These mouse models have significant implications for the development of therapy for patients with neuronopathic GD.     

A putative role for cytokines in the impaired appetite in depression

Impaired appetite and weight changes are commonly seen in patients with depression, but the pathophysiology behind this imbalance between energy intake and energy expenditure remains largely unknown. The aim of this paper is to review the literature regarding a possible role for cytokines in the regulation of appetite and body weight, with special emphasis on depression. There now exists a substantial amount of evidence that depressed patients show signs of immune activation including increased levels of proinflammatory cytokines. Cytokines, which by themselves have anorectic properties, stimulate the release of the cytokine-like anorexogenic peptide leptin. In addition to their anorectic properties, both proinflammatory cytokines and leptin interact with the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system (SNS) and the immune system. In turn, these systems regulate energy balance as well as they are dysfunctional in depression. Furthermore, both proinflammatory cytokines and leptin can induce anhedonia, one of the cardinal symptoms of depression. In view of the different effects on appetite and/or body weight observed in melancholic versus atypical depression, we suggest that cytokines are differentially altered in these subtypes of depression, and that this may explain some of the inconsistency in the reported findings of cytokine as well as leptin levels in depressed patients. Finally, we propose that the immune system uses the interoceptive pathway projecting to the insular cortex, a brain region where cytokine-induced changes in appetite could be partly mediated, and that this pathway is activated in depression.     

Extensive acute deep vein thrombosis of the iliocaval segment: midterm results of thrombolysis and stent placement

PURPOSE: To evaluate patency and clinical outcome in patients treated with catheter-directed thrombolysis and stent placement for acute extensive thrombosis affecting the iliocaval segment. MATERIALS AND METHODS: During a 10-year period (1994-2005), 37 patients with 44 limbs (26 female, median age 31 years) with acute extensive venous thrombosis affecting the iliocaval segment were treated with catheter-directed thrombolysis. Angioplasty and stent placement was performed in 36 limbs (82%) for underlying stenosis or residual thrombosis. A prospectively registered database was analyzed in combination with a telephone interview about clinical symptoms. RESULTS: Technical success was achieved in all 44 limbs and clinical success in 42 of 44 (96%) limbs. Primary patency after a median imaging follow-up interval of 16 months was 34 of 44 (77%) limbs, assisted primary patency was 38 of 44 (86%) limbs, and secondary patency was 39 of 44 (89%) limbs. Thirty of 44 (68%) limbs were asymptomatic after a median clinical follow-up of 27 months, eight (18%) limbs were moderately improved, two (5%) limbs were unchanged, two (5%) limbs were moderately worse, and two (5%) limbs had no clinical follow-up. Complications occurred in six (16%) patients, three (8%) of which were major complications. No patient developed symptomatic pulmonary embolism. CONCLUSIONS: Catheter-directed thrombolysis and stent placement is a safe and effective treatment for acute iliocaval thrombosis. Clinical midterm results are encouraging. Thrombolyzed and stented segments remain patent in the vast majority of patients after 16 months. Primary and aggressive stent placement in the iliocaval vein segments can prevent rethrombosis and ensure patency.     

CD40 expression identifies a prognostically favourable subgroup of diffuse large B-cell lymphoma

In order to confirm our earlier findings of the prognostic effects of CD23 and CD40 expression in diffuse large B-cell lymphoma (DLBCL), possibly due to association with the germinal center (GC) phenotype and/or an increased autologous tumour response, tumour specimens from 125 patients with de novo DLBCL were investigated for immunohistochemical expression of CD23, CD40, BCL6, CD10, MUM1, CD4 and CD8. CD40 was positive in 64% and was associated with improved overall survival (p = 0.03). A GC phenotype was present in 47%, and was also associated with a better overall survival (p = 0.006) but did not correlate with CD40-expression. There was no correlation between amount of tumour infiltrating T-cells and CD40-positivity. CD23 was positive in 10% and expression did not correlate with prognosis. In conclusion, the prognostic effect of CD40 expression was confirmed, but did not correlate with GC-phenotype or T-cell infiltration.     

Phenylbutyrate sensitizes human glioblastoma cells lacking wild-type p53 function to ionizing radiation

PURPOSE: Histone deacetylase (HDAC) inhibitors induce growth arrest, differentiation, and apoptosis in cancer cells. Phenylbutyrate (PB) is a HDAC inhibitor used clinically for treatment of urea cycle disorders. Because of its low cytotoxicity, cerebrospinal fluid penetration, and high oral bioavailability, we investigated PB as a potential radiation sensitizer in human glioblastoma cell lines. METHODS AND MATERIALS: Four glioblastoma cell lines were selected for this study. Phenylbutyrate was used at a concentration of 2 mM, which is achievable in humans. Western blots were used to assess levels of acetylated histone H3 in tumor cells after treatment with PB. Flow cytometry was used for cell cycle analysis. Clonogenic assays were performed to assess the effect of PB on radiation sensitivity. We used shRNA against p53 to study the role of p53 in radiosensitization. RESULTS: Treatment with PB alone resulted in hyperacetylation of histones, confirmed by Western blot analysis. The PB alone resulted in cytostatic effects in three cell lines. There was no evidence of G(1) arrest, increase in sub-G(1) fraction or p21 protein induction. Clonogenic assays showed radiosensitization in two lines harboring p53 mutations, with enhancement ratios (+/- SE) of 1.5 (+/- 0.2) and 1.3 (+/- 0.1), respectively. There was no radiopotentiating effect in two cell lines with wild-type p53, but knockdown of wild-type p53 resulted in radiosensitization by PB. CONCLUSIONS: Phenylbutyrate can produce p21-independent cytostasis, and enhances radiation sensitivity in p53 mutant human glioblastoma cells in vitro. This suggests the potential application of combined PB and radiotherapy in glioblastoma harboring mutant p53.     

What drug policies cost: estimating drug policy expenditures in Sweden, 2002: work in progress

AIM: To estimate drug policy expenditures in Sweden for 2002. DATA AND METHOD: The various governmental agencies with drug policy responsibilities were identified and then requested to provide information on their actual spending on these activities. For most agencies additional information was obtained from special studies or expert opinion. FINDINGS: Drug policy expenditures are not easily identified in Swedish official statistics. The results have a very wide range between 500 and 1,400 million Euros during 2002, with 950 million Euros as a baseline estimate. Two items each account for almost 60% of the total-police (including customs and courts) and corrections-whereas treatment expenditures and income support represent about one-fifth, respectively. Comparison with the most recent previous estimate (1991) shows a substantial higher level in 2002. CONCLUSIONS: The findings suggest that a great deal of money is invested in drug policy measures in Sweden today and that it has most probably increased since the early 1990s. This development probably reflects the increase in number of problematic drug users in Sweden as well as increasing attention paid to the drug problem, foremost in the criminal justice system. More work is needed in developing a drug budget that is more easily available and in producing more reliable estimates both across sectors and across time. The need to develop the conceptualization of drug policy measures is also discussed.     

CD8+ T cell activation predominate early immune responses to hypercholesterolemia in Apoe -/- mice

Background

The adenosine/uridine-rich element (ARE)-binding protein AUF1 functions to regulate the inflammatory response through the targeted degradation of cytokine and other mRNAs that contain specific AREs in their 3' noncoding region (3' NCR). To investigate the role of AUF1 in the immune system, we characterized the lymphoid compartments of AUF1-deficient mice.

Results

Mice lacking AUF1 exhibit an altered proportion and size of splenic B cell subsets. We show prominent apoptosis in splenic B cell follicles and reduced expression of Bcl-2, A1, and Bcl-X_L correlate with increased turnover and significant reduction in the number and proportion of splenic FO B cells in AUF1-deficient mice. In addition, AUF1-deficient mice exhibit a sharp decrease in splenic size and lymphocyte cellularity. Bone marrow transfer studies demonstrate that AUF1 deficiency induces cell-autonomous defects in mature B cell subsets but not in the overall number of splenocytes. Reconstitution of irradiated adult AUF1-deficient mice with wild-type bone marrow restores the proportion of FO and marginal zone (MZ) B cells, but does not rescue the decrease in the number of splenocytes. Functionally, AUF1-deficient mice mount an attenuated response to T cell-independent (TI) antigen, which correlates with impaired MZ B cell function.

Conclusion

These data indicate that AUF1 is important in the maintenance of splenic FO B cells and adequate humoral immune responses.     

Studying interaction between children who do not use symbols in interaction and their parents within the family system--methodological challenges

Purpose. To parents of children with profound multiple disabilities who do not use symbols in interaction a successful outcome of dyadic interaction with their children consists of shared experiences, mutual joy and understanding. In the last two decades interaction intervention for these parents and their children has become an issue for research with the aim to identify factors that facilitate mutually rewarding parent-child interaction. Interaction patterns between the child and his/her caregivers must be studied, assessed and intervened within relation to the family system and how it changes over time. The aim of this article is to discuss the methodological challenges in studying parent-child interaction in the context of the family system.

Method. Research methods designed to handle complexity, multidimensionality, heterogeneity among research subjects and small number of participants in the analysis are described.

Conclusions. It is concluded that the theories and methods used must guide the researcher in how to delimit a manageable number of factors to include in the analysis, in how to analyse the interrelationships between the factors, and in how to study changes in patterns of factors over time. Prerequisites to meet the methodological challenges are that the constructs investigated have a sound theoretical base and that longitudinal data are collected.