Modification of pro- and antiinflammatory cytokines and vascular-related molecules by tumor necrosis factor-a blockade in patients with rheumatoid arthritis

OBJECTIVE: Analysis of serum concentrations and modifications of tumor necrosis factor-a (TNF-a), its soluble receptors (TNFR), interleukin 10 (IL-10), and vascular related molecules [soluble vascular cell adhesion molecule 1 (sVCAM-1), vascular endothelial growth factor (VEGF)] after therapy with methotrexate (MTX) and anti-TNF (infliximab) in patients with rheumatoid arthritis (RA). METHODS: Thirty-six patients with RA and 20 healthy controls were included. Patients had been orally taking a stable dose of MTX of at least 12.5 mg/week for a minimum of 6 months before inclusion in the study. Twenty-five patients had shown a clinical response to MTX (MTX Group). The other 11 had shown an unsatisfactory response and presented with active RA; they were selected for additional treatment with infliximab (MTX + IFM Group). Disease activity score (DAS28), hemoglobin concentration, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum levels of TNF-a, soluble TNFR, IL-10, sVCAM-1 and VEGF were determined at baseline and prior to every infusion of infliximab (3 mg/kg) at 2, 6, 14, 22, and 30 weeks. RESULTS: Although serum levels of TNF-a were similar in patients and controls, patients showed significantly higher concentrations of both soluble TNFR (sTNFR55 and sTNFR75), IL-10, sVCAM-1, and VEGF than healthy individuals. Significantly higher levels of sVCAM-1 and VEGF, but not of the other tested molecules, were detected in those with active disease. After infliximab treatment (MTX + IFM Group) there was a significant decrease in DAS28 and modified Health Assessment Questionnaire scores and ESR and CRP levels. Serum concentration of VEGF showed a significant decrease after infliximab, with levels comparable to those of patients with inactive RA, although VEGF continued to present higher values than in healthy controls. CONCLUSION: Increased levels of vascular related molecules sVCAM-1 and VEGF are serum markers of active RA. The absence of normalization of levels of these molecules in patients with inactive RA could be one of the reasons response to therapy is only temporary.     

Intestinal alterations in patients with a medullary lesion

Loss of bowel control is distressing for persons with a medullary lesion and affects their quality of life. The present study aims to provide an updated review of the topic. Impaired neural control of continence and defecation after a medullary lesion provokes bowel dysfunction, with a high prevalence of two main symptoms: fecal incontinence and constipation. The physiopathology of these disorders is correlated with the neurological characteristics of the lesion, and various physiopathologic patterns have been established that correlate with the clinical manifestations. Evaluation of bowel dysfunction in these patients is normally exclusively clinical and complementary examinations are rarely used, although they seem promising. Treatment is based on establishing a program of evacuation. However, despite correct application, the results can be unsatisfactory and consequently other therapeutic alternatives should be developed.     

Epigenetics in Adipose Tissue,Obesity, Weight Loss,and Diabetes

Given the role that diet and other environmental factors play in the development of obesity and type 2 diabetes, the implication of different epigenetic processes is being investigated. Although it is well known that external factors can cause cell type-dependent epigenetic changes, including DNA methylation, histone tail modifications, and chromatin remodeling, the regulation of these processes, the magnitude of the changes and the cell types in which they occur, the individuals more predisposed, and the more crucial stages of life remain to be elucidated. There is evidence that obese and diabetic people have a pattern of epigenetic marks different from nonobese and nondiabetic individuals. The main long-term goals in this field are the identification and understanding of the role of epigenetic marks that could be used as early predictors of metabolic risk and the development of drugs or diet-related treatments able to delay these epigenetic changes and even reverse them. But weight gain and insulin resistance/diabetes are influenced not only by epigenetic factors; different epigenetic biomarkers have also been identified as early predictors of weight loss and the maintenance of body weight after weight loss. The characterization of all the factors that are able to modify the epigenetic signatures and the determination of their real importance are hindered by the following factors: the magnitude of change produced by dietary and environmental factors is small and cumulative; there are great differences among cell types; and there are many factors involved, including age, with multiple interactions between them.     

Comparison of chemotherapy to radiotherapy as consolidation of complete or good partial response after six cycles of chemotherapy for patients with advanced Hodgkin's disease: results of the groupe d'études des lymphomes de l'Adulte H89 trial

The treatment of advanced Hodgkin's disease (HD) with chemotherapy (CTx) alone or combined modality treatments has been controversial. In 1989, we designed a randomized study to compare 2 cycles of CTx to (sub)total nodal irradiation (RTx) as consolidation treatments for patients with stage IIIB/IV HD in complete remission (CR) or good partial response after 6 cycles of CTx. A total of 559 patients were randomized to receive 6 cycles of MOPP/ABV (mechlorethamine, vincristine, procarbazine, prednisone/Adriamycin [doxorubicin], bleomycin, vinblastine) hybrid (n = 266) or ABVPP (n = 267). After induction treatment, 418 patients could be evaluated for the consolidation phase. With a median follow-up of 48 months, the 5-year disease-free survival estimates were 80% for 8 cycles of MOPP/ABV, 82% for 6 cycles of MOPP/ABV plus RTx, 68% for 8 cycles of ABVPP, and 75% for 6 cycles of ABVPP plus RTx (P =.01). The 5-year disease-free survival estimates did not differ between CTx and RTx, 74% and 79%, respectively (P =.07). After MOPP/ABV, the 5-year overall survival estimates did not differ between CTx and RTx, 85% and 88%, respectively (P =.2). After ABVPP, the 5-year survival estimates were 94% for CTx and 78% for RTx (P =.002). These results showed that RTx was not superior to CTx consolidation after doxorubicin-induced CR for patients with advanced HD. Because of the uncertainty of obtaining a prolonged second remission for patients relapsing after CTx and RTx and the possible long-term effects of RTx, we prefer 8 cycles of CTx as standard treatment when a CR has been achieved after 6 cycles.     

Recovery of esophageal peristalsis after congenital tracheoesophageal fistula repair in an adult

Summary Congenital tracheoesophageal fistulas are usually recognized during early life and are associated with severe esophageal dysmotilities that supposedly persist after fistula repair. We present the case of a patient with abdominal distension diagnosed to result from congenital tracheoesophageal fistula at the age of 17 years. Prior to surgery, manometry showed aperistalsis in the esophageal body that gradually improved during the 14 months of post-operative follow-up. We hypothesized that the dysmotility was due to increased gastroesophageal reflux or to intragastric distension. Therefore, we studied: (1) the correlation between motility and gastroesophageal reflux before and after surgery, and (2) the effect of isotonic gastric distension on esophageal motility. Our studies demonstrated that one year after surgery gastroesophageal acid reflux remained abnormal and that acute experimental gastric distension had no effect on esophageal motility. In summary, esophageal dysmotility in congenital tracheoesophageal fistula may return to normal after surgical repair; neither acute gastric distension nor gastroesophageal reflux are responsible for the reversible esophageal motor abnormalities.     

Pharmacological inhibition of the chemokine receptor CX3CR1 attenuates disease in a chronic-relapsing rat model for multiple sclerosis

One hallmark of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is infiltration of leukocytes into the CNS, where chemokines and their receptors play a major mediatory role. CX3CR1 is a chemokine receptor involved in leukocyte adhesion and migration and hence a mediator of immune defense reactions. The role of CX3CR1 in MS and EAE pathogenesis however remains to be fully assessed. Here, we demonstrate CX3CR1 mRNA expression on inflammatory cells within active plaque areas in MS brain autopsies. To test whether blocking CNS infiltration of peripheral leukocytes expressing CX3CR1 would be a suitable treatment strategy for MS, we developed a selective, high-affinity inhibitor of CX3CR1 (AZD8797). The compound is active outside the CNS and AZD8797 treatment in Dark Agouti rats with myelin oligodendrocyte glycoprotein-induced EAE resulted in reduced paralysis, CNS pathology, and incidence of relapses. The compound is effective when starting treatment before onset, as well as after the acute phase. This treatment strategy is mechanistically similar to, but more restricted than, current very late antigen-4–directed approaches that have significant side effects. We suggest that blocking CX3CR1 on leukocytes outside the CNS could be an alternative approach to treat MS.Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and degenerative disease of the central nervous system (CNS). It was already discovered in the early 1900s that a similar disease could be induced in different animal species by injection of spinal cord extracts or myelin-derived proteins (1–3). This group of animal models for MS, called experimental autoimmune encephalomyelitis (EAE), has provided an experimental platform for building an extensive understanding of the pathology of MS, as well as discovering strategies for intervention of the disease. A typical feature of the pathogenesis in both MS and EAE is the infiltration of leukocytes from the blood stream into the CNS (3). Leukocyte adhesion and extravasation includes several well defined steps and various adhesion molecules, chemokines and their receptors are important mediators for this process. In line with this, the recently developed therapeutic drugs natalizumab and fingolimod, which broadly target leukocyte migration to the brain, exhibit efficacy in EAE models (4, 5), and they are now established therapies in MS (6).Natalizumab, blocking the interaction between very late antigen-4 (VLA-4) and CD106 (VCAM-1), is an effective treatment both on clinical endpoints and MRI biomarkers (7). Fingolimod, the first oral drug for relapsing remitting MS (RRMS), acts on S1P receptors preventing lymphocytes from moving out of lymphoid tissue (8). Natalizumab is only approved as a second-line monotherapy in RRMS or in patients with very active disease, because it carries increased risk of developing the often fatal progressive multifocal leukoencephalopathy (7, 9). Treatment with fingolimod is associated with side effects such as signs of immune suppression, including increased frequency of infections (8).Considering the pronounced presence of inflammatory cells in the brain of MS patients, the significant correlation between inflammation and axonal injury (10) and the efficiency of treatments that broadly block infiltration of immune cells, a similar but more restricted therapeutic approach is appealing. Chemokines are synthesized and released at sites of inflammation, where they act on specific receptors expressed by immune cells to mediate directed cell migration in synergy with adhesion molecules, such as VLA-4, from the blood stream and into the sites of inflammation. CX3CR1 is a unique member of the chemokine receptor family (11) and binds with high affinity to its ligand CX3CL1 [fractalkine (FKN)]. FKN is produced in a membrane bound form but can also be released following proteolytic cleavage, making it important for mediating both adhesion and migration of CX3CR1-expressing cells. In contrast to VLA-4, which is broadly expressed on most leukocytes except neutrophils (7, 12), the expression of CX3CR1 is restricted to subpopulations of monocytes, T lymphocytes, and natural killer (NK) cells (13–16). We have previously demonstrated intense accumulation of CX3CR1-expressing microglia/macrophages within inflammatory foci in the spinal cord of Dark Agouti (DA) rats with EAE induced by myelin oligodendrocyte glycoprotein (MOG) (17) and formed the hypothesis that CX3CR1 would be an attractive therapeutic target for treating MS.To test the hypothesis, we have developed a selective, high-affinity small-molecule inhibitor of CX3CR1 (AZD8797) (18). This molecule has the potential to be administered as an oral drug in humans. However, because of the decrease in potency to rat CX3CR1 and a modest oral bioavailability in rats (39%), we have chosen continuous s.c. dosing for the proof-of-concept studies in rats. The MOG_1-125–induced EAE model in DA rats was used, because it exhibits pathology very similar to MS with infiltration of inflammatory cells, demyelination, and axonal degeneration in the CNS, as well as a relapsing remitting disease course (19, 20). To further mimic the human treatment situation, we have not only treated rats before the onset of paralysis but also initiated treatment during ongoing disease. We present efficacy (reduced paralysis) versus exposure data, analysis of CNS pathology, and measurements of functional inhibition of CX3CR1. These data, in combination with an analysis for CX3CR1 expression within MS brain autopsy samples, clearly demonstrate the potential of CX3CR1 inhibition as an alternative and unique approach for treating MS.     

Routine assessment of amniotic fluid alpha-Fetoprotein in early second-trimester amniocentesis is no longer justified

BACKGROUND: Open fetal neural tube defects are often followed by an increase in alpha-Fetoprotein concentration in amniotic fluid. For over 25 years there has been a routine to measure amniotic fluid alpha-Fetoprotein in conjunction with early genetic amniocentesis. The efficacy of such a screening test in a low-risk population has been questioned but never evaluated in a Swedish population. METHODS: Data were reviewed retrospectively from all consecutive early second-trimester genetic amniocenteses from two hospitals during the years 1993-2003. Indications for the genetic amniocenteses were maternal age > or = 35 years, maternal anxiety or a history of fetal aneuploidy. A questionnaire was sent to all obstetric clinics in Sweden regarding current common policy and experience of routine amniotic fluid alpha-Fetoprotein measurements, in the detection of open fetal neural tube defects. RESULTS: A total of 1,813 samples were included. In eight cases (0.4%) the amniotic fluid alpha-Fetoprotein concentrations were > or = 3 multiples of median, but five of them were false positive (63%). Out of the three true positive cases, one had clinical relevance. In the other two cases the detection of open fetal neural tube defects was of subordinate importance. In Sweden, during 2004, 91% of the obstetric clinics performed routine assessment of amniotic fluid alpha-Fetoprotein at second-trimester genetic amniocentesis, but only 9% regarded the analysis useful in clinical practice. CONCLUSIONS: According to our results, routine measurement of amniotic fluid alpha-Fetoprotein in early second-trimester genetic amniocentesis, to rule out a risk of open fetal neural tube defects, does not seem justified. The clinical usefulness seems to be limited.     

Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma

Anti-CD20-containing chemotherapy regimens have become the standard of care for patients with follicular lymphoma needing cytotoxic therapy. Four randomized trials demonstrated a clinical benefit for patients treated with rituximab. However, no long-term follow up (i.e. > 5 years) of these trials is yet available. Between May 2000 and May 2002, 358 newly diagnosed patients with high tumor burden follicular lymphoma were randomized to receive cyclophosphamide, adriamycin, etoposide and prednisolone plus interferon-α2a or a similar chemotherapy-based regimen plus rituximab, and outcome was up-dated. With a median follow up of 8.3 years, addition of rituximab remained significantly associated with prolonged event-free survival (primary end point) (P=0.0004) with a trend towards a benefit for overall survival (P=0.076). The Follicular Lymphoma International Prognostic Index score was strongly associated with outcome for both event-free and overall survival in univariate analysis and its prognostic value remained highly significant after adjusting for other significant covariates in multivariate models (P<0.0001 and P=0.001, respectively). Considering long-term toxicity, the addition of rituximab in the first-line setting was confirmed as safe with regards to development of secondary malignancies. Long-term follow up of patients with follicular lymphoma treated in the FL2000 study confirms the sustained clinical benefit of rituximab without long-term toxicity. This study was registered at ClinicalTrials.gov (Identifier:00136552).