Allogeneic bone marrow transplantation with a fixed low number of T cells in the marrow graft [see comments]

Despite prophylaxis with immunosuppressive drugs, severe acute graft- versus-host disease (GVHD) remains a major cause of morbidity and mortality in patients transplanted with unmodified bone marrow (BM) grafts from HLA-identical siblings. Although T-cell depletion of the BM graft has evolved as the most effective method to prevent severe acute GVHD, this beneficial effect is counterbalanced by an increased rate of graft failure and relapse of the disease. To find an approach to T-cell depletion that may avoid these extreme risks, we gave BM recipients a fixed low number of 1 x 10(5) donor T cells per kilogram of recipient's body weight in the graft. This corresponds with 99% T-cell depletion and is achieved by the addition of T cells to the graft that was previously depleted of T cells. A total of 70 patients with hematologic malignancies or aplastic anemia, including 40 patients with standard- risk leukemias, received BM grafts, depleted of T cells according to this approach, from HLA-identical siblings. The preparative regimen consisted of cyclophosphamide and total body irradiation. The patients also received a short course of cyclosporine posttransplant. Graft failure did not occur. Acute GVHD, only grade I or II, was seen in 70% of the patients and was limited to the skin in all patients. Chronic GVHD occurred in 31% of the patients and, with the exception of 1 patient, was limited to the skin as well. Relapse occurred in 3 of 40 (8%) patients with standard-risk leukemias, resulting in a projected survival at 5 years of 80%. Patients with standard-risk diseases had a procedure-related mortality of 11%. Quality of life, determined 1 year after BM transplant, was good in almost all patients with standard-risk diseases. Thus, this approach of T-cell depletion may be an approach that avoids the development of severe acute and chronic GVHD without damaging the function or antileukemic effect of the graft and that has a low transplant-related morbidity and mortality.     

Stem cell factor and interleukin-7 synergize to enhance early myelopoiesis in vitro

Interleukin-7 (IL-7) has been shown to be a critical factor in murine lymphoid development. It stimulates pre-B cells to divide in the absence of stroma cells and it is an important growth regulator of immature and mature T cells. IL-7 has been shown to synergize with stem cell factor (SCF) to provide a potent growth stimulus for pre-B cells. However, the combined effects of IL-7 and SCF on murine primitive hematopoietic cells in vitro have not been established. In the present study, the effects of recombinant rat (rr) SCF and recombinant human (rh) IL-7 on primitive murine bone marrow progenitors (Lin-Sca1+) were investigated in single-cell cloning experiments. rhIL-7 alone had no proliferative effect on Lin-Sca1+ cells, but in a dose-dependent manner directly enhanced rrSCF-induced colony formation, with an average increase in colony numbers of 2.7-fold. Interestingly, the cells formed in response to SCF and IL-7 were predominantly mature granulocytes. Thus, SCF and IL-7 synergize to stimulate early myelopoiesis in vitro.     

Evidence for the physiological role of a rhodanese-like protein for the biosynthesis of the molybdenum cofactor in humans

Recent studies have identified the human genes involved in the biosynthesis of the molybdenum cofactor. The human MOCS3 protein contains an N-terminal domain similar to the Escherichia coli MoeB protein and a C-terminal segment displaying similarities to the sulfurtransferase rhodanese. The MOCS3 protein is believed to catalyze both the adenylation and the subsequent generation of a thiocarboxylate group at the C terminus of the smaller subunit of molybdopterin (MPT) synthase. The MOCS3 rhodanese-like domain (MOCS3-RLD) was purified after heterologous expression in E. coli and was shown to catalyze the transfer of sulfur from thiosulfate to cyanide. In a defined in vitro system for the generation of MPT from precursor Z, the sulfurated form of MOCS3-RLD was able to provide the sulfur for the thiocarboxylation of MOCS2A, the small MPT synthase subunit in humans. Mutation of the putative persulfide-forming active-site cysteine residue C412 abolished the sulfurtransferase activity of MOCS3-RLD completely, showing the importance of this cysteine residue for catalysis. In contrast to other mammalian rhodaneses, which are mostly localized within mitochondria, MOCS3 in addition to the subunits of MPT synthase are localized in the cytosol.     

Platelet adhesion to collagen type IV under flow conditions

Collagen type IV is a sheet-forming collagen and a major constituent of the vessel wall. To find out which conditions are important for platelet adhesion to collagen type IV, we performed perfusion studies with anticoagulated blood in parallel plate perfusion chambers. The role of divalent cations was investigated by using plasmas with variable concentrations of Mg2+ and Ca2+ ions. When Mg2+ concentration was decreased from 2.00 mmol/L to 0.25 mmol/L at a fixed Ca2+ concentration of 1.25 mmol/L, platelet coverage on the collagen type IV surface decreased from 22.8% +/- 1.8% (n = 4) to 4.6% +/- 0.6% (n = 4) at a shear rate of 1,600 s-1. Also, platelet aggregate formation on collagen type IV was strongly impaired. A monoclonal antibody against the glycoprotein (Gp) Ib receptor and von Willebrand factor (vWF)- depleted plasma reduced the platelet coverage to collagen type IV to, respectively, 10% and 45% of the control value. Electron microscopy showed that vWF was only present between platelets and between the platelet and the collagen type IV surface, but did not bind elsewhere to collagen type IV. These data indicate that collagen type IV is a reactive collagen for platelets. Differences in physiologic plasma magnesium concentrations may in part explain the differences in platelet reactivity to collagen type IV between individuals, and perhaps contribute to differences in the risk for thrombosis.     

Platelet adhesion to collagen and endothelial cell matrix under flow conditions is not dependent on platelet glycoprotein IV

Platelet membrane glycoprotein IV (GPIV) is a cell-surface glycoprotein that has been proposed as a receptor for collagen. Recently, it has been shown that platelets with the Naka-negative phenotype lack GPIV on their surface, whereas donors with this phenotype are healthy and do not suffer from hematologic disorders. In this study, we compared Naka- negative platelets with normal platelets in adhesion to collagen types I, III, IV, and V and the extracellular matrix of endothelial cells (ECM) under static and flow conditions. No differences in platelet adhesion and subsequent aggregate formation on the collagens types I, III, and IV were observed under static and flow conditions. Adhesion of both homozygous and heterozygous Naka-negative platelets to collagen type V was strongly reduced under static conditions. Collagen type V was not adhesive under flow conditions. No difference in platelet adhesion to ECM was observed, which suggests that GPIV is not important in adhesion to subendothelium, for which ECM may serve as a model. These results indicate that GPIV is not a functional receptor for collagen under flow conditions.     

Characteristics and outcome of 16 periprosthetic shoulder joint infections

Purpose

Shoulder arthroplasties are increasingly performed, but data on periprosthetic joint infections (PJI) in this anatomical position are limited. We retrospectively investigated the characteristics and outcome of shoulder PJI after primary arthroplasty from 1998 to 2010 in a single centre.

Methods

Periprosthetic joint infection was defined as periprosthetic purulence, presence of sinus tract or microbial growth. A Kaplan–Meier survival method was used to estimate relapse-free survival of prosthesis.

Results

From 1,571 primary shoulder prostheses, we evaluated 16 patients with a PJI at different stages, i.e, early (n = 4), delayed (n = 6) and late (n = 6) infections. The median patient age was 67 (range 53–86) years, and 69 % were females. The most commonly isolated microorganism was Propionibacterium acnes in 38 % of patients (monobacterial in four and polymicrobial in two patients). In 14 of the 16 patients, surgical interventions consisting of debridement and implant retention (6 patients), exchange (7) and explantation (1) were performed. Four patients had a relapse of infection with P. acnes (n = 3) or Bacteroides fragilis (n = 1). The relapse-free survival of the prosthesis was 75 % (95 % confidence interval 46–90 %) after 1 and 2 years, 100 % in six patients following the treatment algorithm for hip and knee PJI and 60 % in 10 patients not followed up. All but one of the relapses were previously treated without exchange of the prosthesis.

Conclusions

As recommended for hip and knee PJI, we suggest treating shoulder PJI with a low-grade infection by microorganisms such as P. acnes with an exchange of the prosthesis. Cohort studies are needed to verify our results.     

On the nature of personal narratives of high quality

This investigation explores the discourse devices associated with high-quality personal narratives. The study examined normative characteristics of 11 high-quality personal narratives of a frightening experience identified (from a larger set of 72 narratives) for their effectiveness in engaging the audience. Lay ratings and an ethnographic interview with seven of the excellent storytellers further characterized the stories and validated their selection. Narratives of both African Americans and Caucasians were represented, and were similar in nature. The excellent narratives were longer, conveyed more fearful topics, and were more dramatic than average narratives. Drama was achieved through direct speech, prosodic shifts, voice changes, inclusion of multiple characters, repetition, and syntactic and semantic parallelism. Illustrative narrative excerpts are provided. This study illustrates the potential in pairing holistic and analytical approaches to narrative analysis.     

Repeated Radionuclide therapy in metastatic paraganglioma leading to the highest reported cumulative activity of 131I-MIBG

Objective

To examine the efficacy of different radiation doses after achievement of a complete response to chemotherapy in diffuse large B-cell lymphoma (DLBCL).

Methods

Patients with stage I-IV DLBCL treated from 1995?C2009 at Duke Cancer Institute who achieved a complete response to chemotherapy were reviewed. In-field control, event-free survival, and overall survival were calculated using the Kaplan-Meier method. Dose response was evaluated by grouping treated sites by delivered radiation dose.

Results

105 patients were treated with RT to 214 disease sites. Chemotherapy (median 6 cycles) was R-CHOP (65%), CHOP (26%), R-CNOP (2%), or other (7%). Post-chemotherapy imaging was PET/CT (88%), gallium with CT (1%), or CT only (11%). The median RT dose was 30?Gy (range, 12?C40?Gy). The median radiation dose was higher for patients with stage I-II disease compared with patients with stage III-IV disease (30 versus 24.5?Gy, p?<?0.001). Five-year in-field control, event-free survival, and overall survival for all patients was 94% (95% CI: 89-99%), 84% (95% CI: 77-92%), and 91% (95% CI: 85-97%), respectively. Six patients developed an in-field recurrence at 10 sites, without a clear dose response. In-field failure was higher at sites????10?cm (14% versus 4%, p?=?0.06).

Conclusion

In-field control was excellent with a combined modality approach when a complete response was achieved after chemotherapy without a clear radiation dose response.     

The role of the Child Health Services in the identification of children with possible Attention Deficit Hyperactivity Disorder/Deficits in Attention, Motor Control and Perception (ADHD/DAMP)

Literature concerning the role of the Child Health Services in the identification of children with possible Attention Deficit Hyperactivity Disorder/Deficits in Attention, Motor Control and Perception (ADHD/DAMP) is summarized in order to establish a background for evaluation, discussion and conclusion.     

Nutritional and genetic contributions to serum cholesterol concentration in a children's follow-up study

In the Finnish multicentre study of cardiovascular risk in young Finns in 1980, 1983 and 1986, 2429, 2052 and 1841 9 to 18-year-old children and adolescents participated. In 1980, subjects of eastern origin living in the west had, despite their western diet, higher serum cholesterol concentrations than subjects both residing in and originating from the west. In males, eastern origin increased the eastlwest difference in serum cholesterol concentrations. Between 1980 and 1986 the mean serum total cholesterol of the study cohorts decreased by 5.5% and simultaneously the east/west differences in serum cholesterol concentrations disappeared in boys. The study suggests that genetic background is a separate factor determining serum total cholesterol level, but with declining serum cholesterol concentrations the effect of the genetic factor does not become manifest.