Reduced brain serotonergic activity after repeated treatment with β-adrenoceptor antagonists

Rats were treated subchronically (14 days) or acutely (single dose) with the ₁-selective adrenoceptor antagonist metoprolol or the ₂-selective adrenoceptor antagonist ICI 118,551. Metoprolol (350 mg/kg/day for 14 days, orally) significantly reduced the 5-hydroxytryptophan (5-HTP) accumulation when measured 30 min after inhibition of L-amino acid decarboxylase by NSD 1015 (100 mg/kg IP) in the limbic forebrain, the corpus striatum, the cerebral cortex, the brain stem, and in the cerebellum. ICI 118,551 (0.5 mg/kg, twice daily for 14 days, SC) also significantly reduced the 5-HTP accumulation in the same brain regions except in the corpus striatum and the brain stem. Simultaneously assayed tryptophan levels were largely unaffected. Thus sustained -adrenoceptor blockade causes a decrease in the in vivo rate of tryptophan hydroxylation in various rat brain regions. The subchronic treatments with metoprolol or ICI 118,551 also significantly reduced the endogenous levels of 5-hydroxytryptamine (5-HT) in the various rat brain regions studied. Acute treatment with either metoprolol (2 mg/kg SC) or ICI 118,551 (0.5 mg/kg SC) did not affect the 5-HTP accumulation or the endogenous 5-HT levels in the brain regions studied. This inhibitory effect on brain 5-HT systems produced by sustained -adrenoceptor blockade may be of significance both for the long-term cardiovascular action and for occasional neuropsychiatric side effects during -blocking therapy.     

Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: no difference in related compared with unrelated transplant in first complete remission.

PURPOSE: The role of unrelated allogeneic stem-cell transplantation in acute lymphoblastic leukemia (ALL) patients is still not clear, and only limited data are available from the literature. We analyzed factors affecting clinical outcome of ALL patients receiving a related or unrelated stem-cell graft from matched donors. PATIENTS AND METHODS: The total study population was 264 adult patients receiving a myeloablative allogeneic stem-cell transplant for ALL at nine bone marrow transplantation centers between 1990 and 2002. Of these, 221 patients receiving a matched related or unrelated graft were analyzed. One hundred forty-eight patients received transplantation in complete remission; 62 patients were in relapse; and 11 patients were refractory to chemotherapy before transplant. Fifty percent of patients received bone marrow, and 50% received peripheral blood stem cell from a human leukocyte antigen-identical related (n = 103), or matched unrelated (n = 118) donor. RESULTS: Disease-free survival (DFS) at 5 years was 28%, with 76 patients (34%) still alive (2.2 to 103 months post-transplantation), and 145 deceased (65 relapses, transplant-related mortality, 45%). We observed an advantage regarding DFS in favor of patients receiving transplantation during their first complete remission (CR) in comparison with patients receiving transplantation in or after second CR (P =.014) or who relapsed (P <.001). We observed a clear trend toward improved survival in favor of B-lineage ALL patients compared with T-lineage ALL patients (P =.052), and Philadelphia chromosome-positive patients had no poorer outcome than Philadelphia chromosome-negative patients. Total-body irradiation-based conditioning improved DFS in comparison with busulfan (P =.041). CONCLUSION: Myeloablative matched related or matched unrelated allogeneic hematopoietic stem-cell transplantation in ALL patients should be performed in first CR.     

儿童皮下和网膜脂肪组织瘦素表达水平及其临床意义

【目的】　对不同年龄儿童皮下和网膜脂肪组织中瘦素 (leptin)mRNA表达水平进行调查。 　【方法】　配对的皮下和网膜脂肪组织从腹部择期手术患儿 ( 3 7例 ,3月～ 12岁 )和成人 ( 9名 )获取。应用real timeRT PCR方法测定不同部位脂肪组织中leptinmRNA表达水平 ,并探讨其与体块指数 (BMI)、腰围、臀围及腰臀围比 (WHR )、年龄、性别及肥胖的相互关系。　【结果】　与成人相一致 ,儿童leptin的表达亦有明显的部位性差异 ,皮下脂肪组织中leptinmRNA水平显著高于网膜 (P <0 .0 0 1)。皮下脂肪组织leptinmRNA表达水平与BMI呈显著正相关 (r =0 .69,P <0 .0 0 1) ,而网膜leptin与BMI呈较弱的正相关 (r =0 .3 2 ,P <0 .0 5 ) ;皮下和网膜leptin与WHR的均无显著相关 ,但网膜leptin与腰围呈较弱的正相关 (r =0 .3 3 ,P <0 .0 5 )。不同年龄组中脂肪组织的leptin表达水平差异有显著性(P <0 .0 1) ,6～ 12岁组皮下和网膜脂肪组织leptinmRNA表达均高于 1～ 5岁组 (P <0 .0 5 ) ,与成人水平相比 ,则差异无显著性 (P >0 .0 5 )。过重和肥胖儿童脂肪组织leptinmRNA表达水平显著高于非肥胖儿童。 　【结论】　儿童不同部位脂肪组织leptinmRNA表达水平在一定程度上反映了脂肪组织的生长和分布。肥胖儿童脂肪组织leptin的     

Results of two or five years of adjuvant tamoxifen correlated to steroid receptor and S-phase levels

A Swedish cooperative trial demonstrated that 5 years of adjuvant tamoxifen was more beneficial than 2 years of tamoxifen in the treatment of postmenopausal women with estrogen receptor (ER) positive, early stage, invasive breast cancer. The main aim of the present study was to investigate the importance of progesterone receptor (PgR) and ER concentration levels for patients participating in the trial and still distant recurrence free two years after the primary operation. Subgroup analyses revealed that only patients with ER positive and PgR positive breast cancer had improved distant recurrence free survival (DRFS) by prolonged tamoxifen therapy (p=0.0016). Patients with ER negative and PgR negative as well as ER positive and PgR negative tumors showed no significant effect of prolonged tamoxifen (p=0.53 and p=0.80, respectively). The percentage of ER negative and PgR positive breast cancers was too small (2.2%) for any meaningful subgroup analysis. There was a significant positive trend that the concentration level of PgR (high positive vs. low positive vs. negative) decreased the recurrence rate for those with prolonged therapy. No corresponding pattern was found for the ER content. S-phase fraction did not correlate to the recurrence rate of PgR positive breast cancers. Patients recurring during tamoxifen therapy had receptor negative tumors to a greater extent than those recurring after tamoxifen treatment.In conclusion, prolonged tamoxifen therapy for 5 years instead of 2 years was found to be beneficial for patients with ER positive and PgR positive breast cancer, whereas three extra years of tamoxifen had little or no effect for patients with ER positive but PgR negative tumors as well as for steroid receptor negative patients.     

Presence of bacteria and innate immunity of intestinal epithelium in childhood celiac disease

OBJECTIVES: Exposure to gliadin and related prolamins and appropriate HLA-DQ haplotype are necessary but not sufficient for contracting celiac disease (CD). Aberrant innate immune reactions could be contributing risk factors. Therefore, jejunal biopsies were screened for bacteria and the innate immune status of the epithelium investigated. METHODS: Children with untreated, treated, challenged CD, and controls were analyzed. Bacteria were identified by scanning electron microscopy. Glycocalyx composition and mucin and antimicrobial peptide production were studied by quantitative RT-PCR, antibody and lectin immunohistochemistry. RESULTS: Rod-shaped bacteria were frequently associated with the mucosa of CD patients, with both active and inactive disease, but not with controls. The lectin Ulex europaeus agglutinin I (UEAI) stained goblet cells in the mucosa of all CD patients but not of controls. The lectin peanut agglutinin (PNA) stained glycocalyx of controls but not of CD patients. mRNA levels of mucin-2 (MUC2), alpha-defensins HD-5 and HD-6, and lysozyme were significantly increased in active CD and returned to normal in treated CD. Their expression levels correlated to the interferon-gamma mRNA levels in intraepithelial lymphocytes. MUC2, HD-5, and lysozyme proteins were seen in absorptive epithelial cells. beta-defensins hBD-1 and hBD-2, carcinoembryonic antigen (CEA), CEA cell adhesion molecule-1a (CEACAM1a), and MUC3 were not affected. CONCLUSIONS: Unique carbohydrate structures of the glycocalyx/mucous layer are likely discriminating features of CD patients. These glycosylation differences could facilitate bacterial adhesion. Ectopic production of MUC2, HD-5, and lysozyme in active CD is compatible with goblet and Paneth cell metaplasia induced by high interferon-gamma production by intraepithelial lymphocytes.     

Functional and Physiologic Assessment of the Colonic Reservoir or Side-to-End Anastomosis After Low Anterior Resection for Rectal Cancer: A Two-Year Follow-Up

PURPOSE Functional disturbances are common after anterior resection for rectal cancer. This study was designed to compare functional and physiologic outcome after low anterior resection and total mesorectal excision with a colonic J-pouch or a side-to-end anastomosis.METHODS Functional and physiologic variables were analyzed in patients randomized to a J-pouch (n = 36) or side-to-end anastomosis (n = 35). Postoperative functional outcome was investigated with questionnaires. Anorectal manometry was performed preoperatively and at six months, one year, and two years postoperatively.RESULTS There was no statistical difference in functional outcome between groups at two years. Maximum neorectal volume increased in both groups but was approximately 40 percent greater at two years in pouches compared with the side-to-end anastomosis. Anal sphincter pressures volumes were halved postoperatively and did not recover during follow-up of two years. Male gender, low anastomotic level, pelvic sepsis, and the postoperative decrease of sphincter pressures were independent factors for more incontinence symptoms.CONCLUSIONS Colonic J-pouch and side-to-end anastomosis gives comparable functional results two years after low anterior resection. Neorectal volume had no detectable influence on function. There was a pronounced and sustained postoperative decrease in sphincter pressures.Supported by the Stockholm County Council, Public Health and Medical Services Committee and the Swedish Research Council, grant #09101.Reprints are not available.     

Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model

Insulin-like growth factor 1 (IGF-1) plays a pleiotropic role in multiple myeloma (MM), that is, in survival, proliferation, chemotaxis, and angiogenesis. Strategies targeting the IGF-1 receptor (IGF-1R) may therefore be important to develop efficient anti-MM agents. In this work we investigated the effect of an IGF-1R tyrosine kinase (IGF-1RTK) inhibitor (picropodophyllin or PPP) in the 5T33MM mouse model. In vitro data showed that PPP reduced IGF-1R autophosphorylation and downstream ERK activation, leading to inhibition of IGF-1-stimulated proliferation and vascular endothelial growth factor (VEGF) secretion of MM cells. In an in vivo study, PPP reduced the bone marrow tumor burden and serum paraprotein in 5T33MM mice by 77% and 90%, respectively, compared to vehicle-treated animals. Angiogenesis was assessed by quantifying the microvessel density on CD31-stained paraffin sections and this was reduced by 60% in the PPP-treated group. In a separate survival experiment, Kaplan-Meier analysis demonstrated a significant increase in survival in PPP-treated 5T33MM animals compared to the vehicle controls (28 versus 18 days). These data suggest that the IGF-1RTK inhibitor PPP possesses a marked antitumor activity and strongly points to the possibility of using IGF-1R inhibitors in the treatment of MM.     

Which donor should be chosen for hematopoietic stem cell transplantation among unrelated HLA-A, -B, and -DRB1 genomically identical volunteers?

The aim of this study was to identify significant prognostic factors by using unrelated genomically HLA-A, -B and -DRB1-identical donors. Such data could help to choose the best donor. We studied 136 consecutive patients with hematologic malignancies and a median age of 32 years (range, 0-55 years) who received hematopoietic stem cell transplantation. Bone marrow grafts were given to 83 and peripheral blood stem cells to 53 patients. The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 30% and of chronic GVHD was 54%. At 5 years, the overall transplant-related mortality (TRM) was 34%, and patient survival was 50%. In Cox multivariate analysis, 32 potential risk factors were analyzed. Monoclonal antibody OKT-3 during conditioning was correlated with grade II to IV acute GVHD, chronic GVHD, and TRM. HLA-DP mismatch was associated with poor TRM and poor survival. Cytomegalovirus-seropositive patients with a seronegative donor had a decreased leukemia-free survival. Five-year TRM was 14% with no risk factor, 38% with 1 risk factor, and 87% with 2 risk factors. The 5-year survival was 72%, 48%, and 30% with 0, 1, and 2 risk factors, respectively. We concluded that unrelated hematopoietic stem cell transplantation may be improved if an optimal donor and immunosuppression are chosen.