Applicability of IG/TCR gene rearrangements as targets for minimal residual disease assessment in a population‐based cohort of Swedish childhood acute lymphoblastic leukaemia diagnosed 2002–2006

Minimal residual disease (MRD) detection during the early treatment phase has become an important stratification parameter in many childhood acute lymphoblastic leukaemia (ALL) treatment protocols. Here, we aimed to address the applicability of rearranged antigen‐receptor genes as potential MRD markers using real‐time quantitative polymerase chain reaction (RQ‐PCR) in a Swedish population‐based cohort. From 334 childhood ALL cases diagnosed during 2002–2006, we analysed 279 diagnostic samples (84%) by screening for rearranged immunoglobulin (IG) and T‐cell receptor (TCR) genes. Allele‐specific oligonucleotides were designed, and the sensitivity and quantitative level was determined for each target. Overall, clonal IG/TCR rearrangements were detected in 97% (236/244) of B‐cell precursor ALL (BCP ALL) and 94% (33/35) of T‐ALL. A sensitive RQ‐PCR analysis (≤10^?4) was obtained in 89% (216/244) of BCP ALL and in 74% (26/35) of T‐ALL, whereas two sensitive targets were only available in 47% (115/244) of BCP ALL and 29% (10/35) of T‐ALL cases. With the stratification threshold of ≥10^?3, which is applied in the current Nordic treatment protocol (NOPHO‐ALL 2008) for the identification of high‐risk patients, 93% of BCP ALL and 86% of T‐ALL reached this quantitative range by at least one target gene. Taken together, this national retrospective study demonstrates that an IG/TCR target for MRD monitoring can be identified in the majority of childhood ALL cases, whereas identification of a second sensitive target gene needs to be improved.     

A prospective study of sicca symptoms in patients with rheumatoid arthritis

OBJECTIVE: To investigate sicca symptoms in patients with rheumatoid arthritis (RA) with respect to constancy, temporal changes of prevalence, and possible risk factors. METHODS: A prospective cohort study of 70 patients with RA was conducted over 5 years. The main variables of interest were the 6 questions on sicca symptoms used in the preliminary European criteria for Sj?gren's syndrome. RESULTS: Fourteen patients were lost to followup. We found that 84.2% (95% confidence interval [95% CI] 59.5-95.8) of the patients reporting sicca symptoms at baseline also reported them at followup. During the study period, sicca symptoms increased by 52.6% in general (P = 0.02) and by 80.0% for the ocular components (P = 0.04). Sicca symptoms (odds ratio [OR] = 8.35, 95% CI 1.91-36.49) and pain (OR = 1.03, 95% CI 1.00-1.07) at baseline were identified as independent predictive factors for sicca symptoms at followup. CONCLUSIONS: Sicca symptoms in patients with RA are remarkably constant over time. There is also a substantial time-dependent increase in the prevalence of such symptoms. As the prevalence of ocular sicca symptoms in general populations tend to level out with age, there seems to be a disease-related increase of ocular symptoms over time in patients with RA. Present pain and sicca symptoms constitute risk factors for future sicca symptoms.     

Foraging trade-offs,flagellar arrangements,and flow architecture of planktonic protists

Unicellular flagellated protists are a key element in aquatic microbial food webs. They all use flagella to swim and to generate feeding currents to encounter prey and enhance nutrient uptake. At the same time, the beating flagella create flow disturbances that attract flow-sensing predators. Protists have highly diverse flagellar arrangements in terms of number of flagella and their position, beat pattern, and kinematics, but it is unclear how the various arrangements optimize the fundamental trade-off between resource acquisition and predation risk. Here we describe the near-cell flow fields produced by 15 species and demonstrate consistent relationships between flagellar arrangement and swimming speed and between flagellar arrangement and flow architecture, and a trade-off between resource acquisition and predation risk. The flow fields fall in categories that are qualitatively described by simple point force models that include the drag force of the moving cell body and the propulsive forces of the flagella. The trade-off between resource acquisition and predation risk varies characteristically between flow architectures: Flagellates with multiple flagella have higher predation risk relative to their clearance rate compared to species with only one active flagellum, with the exception of the highly successful dinoflagellates that have simultaneously achieved high clearance rates and stealth behavior due to a unique flagellar arrangement. Microbial communities are shaped by trade-offs and environmental constraints, and a mechanistic explanation of foraging trade-offs is a vital part of understanding the eukaryotic communities that form the basis of pelagic food webs.

Unicellular flagellated protists play a key role in the biogeochemical cycles of the global ocean. Their photosynthetic activity and grazing on microbes are major processes in the microbial food web, and they may control the populations of bacteria and cyanobacteria (1). By being grazed, they transfer primary production to higher trophic levels (2–4). Thus, flagellates are both consumers and prey, but we do not understand how their resource acquisition trades off against predation mortality, or how this trade-off shapes their foraging behavior.In the low Reynolds number (Re) world of protists, viscosity impedes predator-prey contact. The physical mechanisms that nevertheless allow flagellates to daily clear a volume of water for prey that corresponds to approximately 10⁶ times their own cell volume (5, 6) are not well understood. Many marine flagellates are mixotrophic and can acquire resources both through photosynthesis and by eating other organisms (7). Their demand for inorganic mineral nutrients is also constrained by viscosity that retards the advective enhancement of diffusive uptake (8).To encounter prey and enhance advective transport of nutrients, protists may swim or create a feeding current through the beating of one or several flagella (9, 10). However, the beating of flagella produces fluid disturbances that exposes the flagellate to its rheotactic (flow-sensing) predators (11). Small flagellates are grazed by microzooplankton, many of which perceive their prey from the fluid disturbance that the prey generates (12, 13). Thus, there are fundamental foraging trade-offs. Such trade-offs are largely unexplored among the eukaryotic microbes that form the basis of aquatic food webs. This is crucial, because the diversity of microbial communities is determined by such trade-offs in concert with environmental constraints (14–17). Microbial diversity in turn governs the functionality and “services” of microbial communities, and hence also their role in ocean biogeochemistry (18, 19).Here we explore the trade-off between resource acquisition and predation risk in marine nanoflagellates and microflagellates by describing the flow fields produced by the action of their flagella. The quantification of near-cell feeding currents has been reported in only a few species of free-swimming protists (10, 20). The kinematics, wave patterns, and arrangement and number of flagella are highly diverse among flagellated protists (Fig. 1). Theoretical models suggest that the feeding currents and fluid signal generated by a swimming cell depends on the arrangement of the flagella (11, 13, 21, 22). We use microparticle image velocimetry (µPIV) to visualize and quantify the flow fields generated by free-swimming planktonic protists with diverse flagellar arrangements and beat patterns. We show how the different modes of swimming produce very different flow architectures and demonstrate a trade-off between resource acquisition and predation risk in flagellated protists.Open in a separate windowFig. 1.Schematic overview of the diverse flagellar arrangements and beat patterns represented in this study. Latin names below each taxonomic group indicate the species (or other taxonomic unit) examined. Flagellar hairs are drawn when feasible, but some flagellar morphologies (e.g., the dinoflagellates) are deliberately simplified (25, 63). Redrawn from several sources; not to scale.     

Gut Toxicity During Hemopoietic Stem Cell Transplantation May Predict Acute Graft-Versus-Host Disease Severity in Patients

Graft-versus-host disease (GVHD) is the primary complication of allogeneic, hemopoietic, stem cell transplantation (HSCT). Murine models suggest that gut toxicity, induced by the intensive chemotherapy preceding hematopoietic stem cell infusion, aggravates systemic GVHD. In HSCT patients gut toxicity correlates with chemotherapy intensity. The present study investigates acute GVHD severity and intestinal toxicity in patients undergoing allogeneic HSCT. In 38 patients intestinal permeability was assessed before and after chemotherapy (on days −1, +4, +7 and +14 as related to the stem cell infusion). Cumulative acute GVHD (days 0–100) and clinical intestinal toxicity (days 0–14) were evaluated in parallel. Patients with mild, acute GVHD (grades 0–I) had better-preserved intestinal barrier function (P=0.04) and less pronounced cumulative clinical intestinal toxicity (P=0.02) compared with patients with more severe acute GVHD (grades II–IV). Gut toxicity predicts acute GVHD severity. Therefore, gut protective strategies may diminish GVHD severity in allogeneic HSCT patients.     

Enterocolitis induced by autoimmune targeting of enteric glial cells: A possible mechanism in Crohn''s disease?

Early pathological manifestations of Crohn's disease (CD) include vascular disruption, T cell infiltration of nerve plexi, neuronal degeneration, and induction of T helper 1 cytokine responses. This study demonstrates that disruption of the enteric glial cell network in CD patients represents another early pathological feature that may be modeled after CD8(+) T cell-mediated autoimmune targeting of enteric glia in double transgenic mice. Mice expressing a viral neoself antigen in astrocytes and enteric glia were crossed with specific T cell receptor transgenic mice, resulting in apoptotic depletion of enteric glia to levels comparable in CD patients. Intestinal and mesenteric T cell infiltration, vasculitis, T helper 1 cytokine production, and fulminant bowel inflammation were characteristic hallmarks of disease progression. Immune-mediated damage to enteric glia therefore may participate in the initiation and/or the progression of human inflammatory bowel disease.     

Bernard-Soulier syndrome Karlstad: Trp 498→Stop mutation resulting in a truncated glycoprotein Ibα that contains part of the transmembranous domain

In Bernard-Soulier syndrome, a hereditary bleeding disorder, the platelets are deficient in the glycoprotein (GP) Ib–IX–V complex, a major receptor for the von Willebrand factor. The components of the complex are encoded by separate genes. Patients with this syndrome have a variable expression level of the receptor protein on platelets depending on the specific genetic abnormality. We describe a patient with life-long bleeding symptoms, who is homozygous for a unique stop mutation, Trp 498→ Stop in the GPIbα gene, resulting in a truncated GPIbα polypeptide chain. In contrast to previously reported truncated forms of GPIbα, this form contains a portion of the transmembranous domain as well as the juxtamembranous cysteines engaged in a disulphide bond with GPIbβ. Flow cytometry with GPIbα antibodies demonstrated the presence of GPIb on the patient's platelets, although in reduced amounts compared to normal controls. GPIX was similarly detectable. Immunoblotting demonstrated that the patient synthesized a truncated GPIbα of the expected size of 130 K, which was, however, sensitive to proteolysis. These studies show that GPIbα lacking the intracytoplasmic tail can be expressed at the platelet surface provided elements of the transmembranous domain are present.     

Epoetin alfa and darbepoetin alfa for the treatment of chemotherapy-related anemia in cancer patients in Sweden: Comparative analysis of drug utilization, costs, and hematologic response

A retrospective chart review was performed at 3 Swedish hospitals to evaluate the utilization, outcomes, and cost of using epoetin alfa or darbepoetin alfa to treat cancer patients with chemotherapy-related anemia. Data on dosage, duration of treatment, hematologic response, red blood cell transfusions, and healthcare resource consumption were collected and analyzed at various time points following the initiation of drug therapy. A significantly faster hematologic response and increase in hemoglobin were observed in patients treated with epoetin alfa. Dosages used in clinical practice appeared to be lower than those recommended by Swedish treatment guidelines. There were no significant differences in resource utilization or healthcare costs between the 2 treatment groups. By day 112, the mean treatment cost per patient, in Swedish kronors (SEK), was SEK74,701 (~US$9800 or E8300) with epoetin alfa and SEK85,285 (~US$11,000 or E9500) with darbepoetin alfa. Drug acquisition and administration accounted for 81 % and 67% of the total cost of epoetin alfa and darbepoetin alfa therapy, respectively; the remainder of the total cost was for hospitalization and transfusions.     

Imaging breast adipose and fibroglandular tissue molecular signatures by using hybrid MRI-guided near-infrared spectral tomography

Magnetic resonance (MR)-guided near-infrared spectral tomography was developed and used to image adipose and fibroglandular breast tissue of 11 normal female subjects, recruited under an institutional review board-approved protocol. Images of hemoglobin, oxygen saturation, water fraction, and subcellular scattering were reconstructed and show that fibroglandular fractions of both blood and water are higher than in adipose tissue. Variation in adipose and fibroglandular tissue composition between individuals was not significantly different across the scattered and dense breast categories. Combined MR and near-infrared tomography provides fundamental molecular information about these tissue types with resolution governed by MR T1 images.     

Military walking blood bank and the civilian blood service

In most countries whole blood transfusions have been replaced by component therapy. This has allowed for both better usage of the blood donations and better quality during storage. While this strategy was initially motivated by the commercial need for plasma the plasma reduction also reduced the levels of low grade proteases and sialidase, hence minimizing the cellular storage lesion/microvesiculation during prolonged storage. Plasma reduction also reduces transfusion reactions associated with plasma. During special military conditions, however, blood transfusion is urgently needed without corresponding access to blood components, in particular platelets. Accordingly, new focus on whole blood has aroused and added a new challenge to the blood transfusion services. This special issue of "what is happening" highlights the planed efforts by Swedish and Norwegian groups in the developments of military walking blood bank, which is applicable to civil blood services.