The 5‐HT4 receptor levels in hippocampus correlates inversely with memory test performance in humans

The cerebral serotonin (5‐HT) system is involved in cognitive functions such as memory and learning and animal studies have repeatedly shown that stimulation of the 5‐HT type 4 receptor (5‐HT₄R) facilitates memory and learning and further that the 5‐HT₄R modulates cellular memory processes in hippocampus. However, any associations between memory functions and the expression of the 5‐HT₄R in the human hippocampus have not been investigated. Using positron emission tomography with the tracer [¹¹C]SB207145 and Reys Auditory Verbal Learning Test we aimed to examine the individual variation of the 5‐HT4R binding in hippocampus in relation to memory acquisition and consolidation in healthy young volunteers. We found significant, negative associations between the immediate recall scores and left and right hippocampal BP_ND, (p = 0.009 and p = 0.010 respectively) and between the right hippocampal BP_ND and delayed recall (p = 0.014). These findings provide evidence that the 5‐HT₄R is associated with memory functions in the human hippocampus and potentially pharmacological stimulation of the receptor may improve episodic memory. Hum Brain Mapp 34:3066–3074, 2013. © 2012 Wiley Periodicals, Inc.     

Cannabis Use and Deliberate Self-Harm in Adolescence: A Comparative Analysis of Associations in England and Norway

The objective of this study was to test hypotheses on causality and selection regarding associations between cannabis use and deliberate self-harm (DSH) among adolescents. School surveys were conducted among 9,800 adolescents in England and Norway applying identical measures on deliberate self-harm, suicidal thoughts, cannabis use, and various potential confounders. Cannabis use was more prevalent in England than in Norway. It was associated with DHS, suicidal thoughts and various risk factors for DSH. However, these associations were stronger in Norway than in England. The adjusted associations between cannabis use and suicidal thoughts were non-significant in both countries. The adjusted cannabis–DSH association was non-significant in England but significant in Norway. Elevated risk of DSH in adolescent cannabis users seems to be mainly due to selection mechanisms. Thus the association is not likely to be direct but due to other shared contributory factors.     

Double-hit BCL2/MYC translocations in a consecutive cohort of patients with large B-cell lymphoma - a single centre's experience

Concurrent BCL2 and MYC translocations, so called double hit (DH), are a rare finding in large B-cell lymphoma (LBCL). Based on data from retrospective series, DH has been correlated with aggressive clinical behaviour and poor outcome. We conducted a consecutive study of DH incidence and correlation with pathologic and clinical characteristics, including response to Rituximab-containing chemotherapy and survival, in an unselected cohort of patients with LBCL. Translocations involving BCL2 and MYC loci were examined with fluorescent in situ hybridization (FISH) in 157 patients with diffuse large B-cell lymphoma (DLBCL) or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BCLU). The incidence of DH was 11% in the total cohort, 7% of primary LBCL and 21% of transformed LBCL. DH lymphomas were all GCB immunophenotype and were more often BCLU. No clinical characteristics were correlated with the presence of DH, which also had no impact on overall response rate (ORR), relapse rate or overall survival (OS). However, sub-stratification of DH lymphomas by FISH indicated a possible inferior survival related to immunoglobulin MYC translocation partner gene. Screening of patients with BCLU and DLBCL of GCB type for DH BCL2/MYC translocation including MYC translocation partner gene may provide important prognostic information.     

Pneumocystis jiroveci pneumonia prophylaxis during maintenance therapy influences methotrexate/6-mercaptopurine dosing but not event-free survival for childhood acute lymphoblastic leukemia

Trimethoprim-sulfamethoxazole (TMP/SMX) is used in children with acute lymphoblastic leukemia (ALL) to prevent Pneumocystis pneumonia (PCP). We explored to which extent TMP/SMX influenced methotrexate (MTX)/6-mercaptopurine (6MP) dosage, myelosuppression, and event-free survival (EFS) during maintenance therapy. Of 447 study patients treated by the NOPHO ALL92 protocol, 120 patients received TMP/SMX continuously for 2-7 d/wk (TMP/SMX(2-7) ) and 287 patients never received TMP/SMX (TMP/SMX(never) ). Ten patients (all TMP/SMX(never) ) developed PCP, eight of which occurred within 7 months from the start of maintenance therapy. The TMP/SMX(2-7) group received lower oral 6MP doses than TMP/SMX(never) patients (50.6 vs. 63.9 mg/m(2) /d; P<0.001) but had lower absolute neutrophil counts (ANC) (median 1.7 vs. 2.0 × 10(9) /L; P<0.001). In Cox multivariate analysis, higher ANC levels (P=0.04) and male gender (P=0.06) were related to reduced EFS. ANC had no effect on EFS among TMP/SMX(2-7) patients (P=0.40) but did for TMP/SMX(never) patients (P=0.02). The difference in the effect on EFS between TMP/SMX(2-7) and TMP/SMX(never) patients was not significant (P=0.46). EFS did not differ between TMP/SMX(2-7) and TMP/SMX(never) patients (0.83 vs. 0.83; P=0.82). These results suggest that TMP/SMX is effective in preventing PCP and may have an antileukemic effect. TMP/SMX should be given the entire duration of maintenance therapy.     

The production and regulation of IGF and IGFBPs in human adipose tissue cultures

BackgroundAdipocytes express and secrete IGFs and IGFBPs; proteins with important effects on adipocyte homeostasis. However, the factors that control adipocyte generation of IGFs and IGFBPs are not clarified.AimTo identify regulators of the synthesis of IGFs and IGFBs in adipose tissue.MethodsSubcutaneous adipose tissue fragments (500 mg) from 7 healthy lean women were incubated for 48 h following addition of GH (50 μg/l), dexamethasone (DXM, 20 nM), insulin (100 nM), interleukin (IL)-1β (50 ng/l), IL-6 (50 ng/l) and tumor-necrosis factor (TNF)-α (10 ng/l). Outcome parameters included tissue mRNA and culture media IGF and IGFBP levels.ResultsAdipose tissue cultures secreted more IGF-II than IGF-I protein (1.14 ± 0.41 vs. 0.26 ± 0.09 μg/l [mean ± SEM]; P < 0.02). IGF-I mRNA and protein levels were stimulated by GH (to 340% [153; 477] (median [interquartiles]) and 270 ± 26%, respectively; P < 0.003), and inhibited by IL-1β (to 28% [21; 77] and 68 ± 11%, respectively; P < 0.003). TNF-α reduced IGF-I and IGF-II protein levels to 51 ± 8% and 69 ± 8%, respectively (P ≤ 0.002), without affecting mRNA levels. IGF protein levels were unaffected by DXM, insulin and IL-6. All IGFBPs IGFBP-1 were expressed. IGFBP-4 was by far the most predominant IGFBP by immunoassay and WLB revealed two bands at 28 and 24 kDa, most likely representing glycosylated and non-glycosylated IGFBP-4.ConclusionAdipose tissue cultures secrete more IGF-II than IGF-I, and predominantly IGFBP-4. The secretion of IGF-I is affected by GH, IL-1β and TNF-α, whereas IGF-II is affected by TNF-α only. Hence, cytokines may control adipocyte homeostasis by affecting local IGF-generation.     

Functional late outgrowth endothelial progenitors isolated from peripheral blood of burned patients

Background

Bioengineered skin substitutes are increasingly considered as a useful option for the treatment of full thickness burn injury. Their viability following grafting can be enhanced by seeding the skin substitute with late outgrowth endothelial progenitor cells (EPCs). However, it is not known whether autologous EPCs can be obtained from burned patients shortly after injury.

Methods

Late outgrowth EPCs were isolated from peripheral blood sampled obtained from 10 burned patients (extent 19.6 ± 10.3% TBSA) within the first 24 h of hospital admission, and from 7 healthy subjects. Late outgrowth EPCs were phenotyped in vitro.

Results

In comparison with similar cells obtained from healthy subjects, growing colonies from burned patients yielded a higher percentage of EPC clones (46 versus 17%, p = 0.013). Furthermore, EPCs from burned patients secreted more vascular endothelial growth factor (VEGF) into the culture medium than did their counterparts from healthy subjects (85.8 ± 56.2 versus 17.6 ± 14 pg/mg protein, p = 0.018). When injected to athymic nude mice 6 h after unilateral ligation of the femoral artery, EPCs from both groups of subjects greatly accelerated the reperfusion of the ischaemic hindlimb and increased the number of vascular smooth muscle cells.

Conclusions

The present study supports that, in patients with burns of moderate extension, it is feasible to obtain functional autologous late outgrowth EPCs from peripheral blood. These results constitute a strong incentive to pursue approaches based on using autotransplantation of these cells to improve the therapy of full thickness burns.     

Rinsing of allograft bone does not improve implant fixation

Background and purpose Impacted morselized allograft bone is a well-established method for reconstructing bone defects at revision surgery. However, the incorporation of bone graft is not always complete, and a substantial volume of fibrous tissue has been found around grafted implants. We hypothesized that rinsing the bone graft may improve graft incorporation by removing the majority of immunogenic factors present in blood, marrow, and fat.

Methods We implanted a cylindrical (10- × 6-mm) porous-coated Ti implant into each proximal tibia of 12 dogs. The implants were surrounded by a 2.5-mm gap into which morselized fresh frozen allograft bone was impacted. The bone graft was either (1) untreated or (2) rinsed in 37°C saline for 3 × 1 min. After 4 weeks, the animals were killed and implant fixation was evaluated by mechanical push-out and histomorphometry.

Results The groups (rinsed vs. control) were similar regarding mechanical implant fixation (mean (SD)): shear strength (MPa) 2.7 (1.0) vs. 2.9 (1.2), stiffness (MPa/mm) 15 (6.7) vs. 15 (5.6), and energy absorption (kJ/m²) 0.5 (0.2) vs. 0.6 (0.4), The same was evident for the new bone formation on the implant surface and around the implant: ongrowth (%) 6 vs. 7 and ingrowth (%) 9 vs. 9. Although not statistically significant, a 61% reduction in fibrous tissue ongrowth and 50% reduction in ingrowth were found in the rinsed group.

Interpretation Within the limits of this experimental model, we did not detect any benefits of rinsing morselized allograft bone prior to impaction grafting.