Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (, ), telomeropathies (, ,), ribosome disorders (, ,), and DNA repair deficiency (). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as and (N = 16 of the 86 patients, 18.6%), (N = 6, 7.0%), and (N = 7, 8.1%), each of which was associated with a distinct natural history; and patients often experienced transient aplasia and monosomy 7, whereas patients presented early-onset severe aplastic anemia, and patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.

This single-center retrospective study analyzed 85 consecutive patients who underwent allogeneic stem cell transplantation (allo-SCT) with the aim to assess whether there is a correlation between exposure to cyclosporine-A (CsA; as measured by CsA concentrations during the first month after allo-SCT) and the risk for developing severe grade III-IV acute graft-versus-host disease (aGVHD). The median concentrations of CsA in the blood at 1, 2, 3, and 4 weeks after allo-SCT were 348 (range: 172-733), 284 (range: 137-535), 274 (range: 107-649), and 247 (range: 37-695) ng/mL, respectively. Overall, grade II-IV aGVHD occurred in 36 patients (42%) at a median of 29 (range: 6-100) days after allo-SCT. The incidence of grade III-IV aGVHD (n = 20) was 23% (95% confidence interval [CI], 14%-32%). In univariate analysis, patients receiving allo-SCT from an HLA-matched unrelated donor had a higher risk of grade III-IV aGVHD, and patients having the lowest CsA concentration in the first and second weeks after allo-SCT had a significantly higher risk of grade III-IV aGVHD. In a multivariate logistic regression analysis, a higher CsA concentration measured during the first week following graft infusion was the strongest parameter significantly associated with a reduced risk of severe grade II-IV aGVHD (P = .012; relative risk [RR] = 0.24; 95% CI, 0.08-0.73). Of note, when adjusted by donor type, CsA concentration in week 1 remained significantly associated with risk of severe grade II-IV aGVHD (P = .014). We conclude that precise monitoring of CsA concentrations and adjustment of CsA dose early after allo-SCT may be effective to prevent onset of severe aGVHD.

An experimental study of shear stability of several high-molecular-weight polymers used as mobility control agents in EOR projects has been performed in well-controlled conditions. The shearing device was made of a capillary tube with ID of 125 μm, through which polymer solution was injected at controlled rate. The set-up enables a precise measurement of the shear rate to which the polymer macromolecule is submitted. The degradation rate was measured by the viscosity loss induced by the passage into the capillary tube. The shear rate was gradually increased up to 106 sec-1 while checking degradation rate at each stage. Different commercial EOR polymer products were submitted to the test with polyacrylamide backbone and different substitution monomer groups. All macromolecules behave as flexible coils in solution. The parameters investigated were: Molecular weight (between 6 and 20x106)Nature of substitution group (Acrylate, ATBS/sulfonate, nVP/Vinyl-Pyrrolidone)Salinity Polymer shear degradation increases with molecular weight and salinity, but decreases with the presence of Acrylate, ATBS and nVP. All results can be interpreted in terms of chain flexibility. The highly flexible polyacrylamide homopolymer is the most sensitive to shear degradation. Introduction of acrylate groups in the polymer chain induces some stability because of the rigidity provided by charge repulsion, which vanishes in the presence of high salinity (due to the screening of acrylate negative charges). ATBS and VP groups, which are larger in size, provide significant chain rigidity thus better shear stability. It is also shown that some very-high molecular-weight polymers, after passing the shearing device, attain a final viscosity lower than lower-molecular-weight products with the same chemical composition. This factor has to be taken into account in the final choice of a polymer for a given field application. As a comparison, although less popular today than two decades ago, xanthan gum, which behaves like a semi-rigid rod, is shown to be much less sensitive to the shear degradation test than the coiled polyacrylamides.

Background: There is still a need for simple, noninvasive, and inexpensive methods to diagnose the causes of cognitive impairment and dementia. In this study, contemporary statistical methods were used to classify the clinical cases of cognitive impairment based on electroencephalograms (EEG). Methods: An EEG database was established from seven different groups of subjects with cognitive impairment and dementia as well as healthy controls. A classifier was created for each possible pair of groups using statistical pattern recognition (SPR). Results: A good-to-excellent separation was found when differentiating cases of degenerative disorders from controls, vascular disorders, and depression but this was less so when the likelihood of comorbidity was high. Conclusions: Using EEG with SPR seems to be a reliable method for diagnosing the causes of cognitive impairment and dementia, but comorbidity must betaken into account.

Major ABO incompatibility between donor and recipient is not considered a barrier to successful allogeneic hematopoietic stem cell transplantation (HSCT), even if it can be associated with several immunohematologic complications. Nevertheless, conflicting data still exist as to its influence on graft-versus-host disease (GVHD) incidence, relapse rate, and survival. To further investigate the relevance of ABO major mismatch on transplantation outcome, we retrospectively analyzed results from 414 patients with major or major/minor ABO-mismatched bone marrow (BM), peripheral blood (PB), and cord blood (CB) allogeneic HSCT. Transplantation outcome was assessed by comparison with results from a 395-patient ABO-compatible population with similar characteristics. Median time to red cell transfusion independence was significantly longer in ABO-incompatible BM recipients (median time, 63 days vs 41 days; P =.001), with faster disappearance of antidonor IgM hemagglutinins in unrelated recipients (median time, 36 days vs 44 days; P = .03) and in patients with grade > or =II acute GVHD (aGVHD) (median time, 35 days vs 59 days ; P = .001). In PB stem cell (PBSC) and CB transplantation, erythroid reconstitution was not significantly delayed, regardless of donor type or presence of aGVHD. A slight correlation between ABO incompatibility and GVHD incidence was found in PBSC recipients when considering grade > or =II aGVHD incidence (63% in ABO-matched HSCT vs 83% in ABO-mismatched HSCT; P = .055), but this was not confirmed in multivariate analysis. In patients with acute leukemia, multivariate analysis revealed an association between major ABO mismatch and decreased relapse rate with borderline statistical significance (hazard ratio, 0.65; P = .04). Major ABO incompatibility mainly, if not exclusively, affects red blood cell engraftment after BM transplantation. Somewhat surprisingly, the graft-versus-plasma cell effect seems to be confined to this stem cell source.

This single centre study assessed the incidence, kinetics and predictive factors of Epstein-Barr Virus (EBV) reactivation and EBV-related lymphoproliferative diseases (LPDs) in 175 consecutive patients who received a reduced-intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HSCT). The cumulative incidence of EBV reactivation at 6 months after allo-HSCT defined as an EBV PCR load above 1000 copies of EBV DNA/10 5 cells was 15%, and none of these patients experienced any sign or symptom of LPD. A total of 17 patients, who had EBV DNA levels exceeding 1000 copies/10 5 cells on two or more occasions, were pre-emptively treated with rituximab. With a median follow-up of 655 (range, 92-1542) days post allo-HSCT, there was no statistically significant difference in term of outcome between those patients who experienced an EBV reactivation and those who did not. In multivariate analysis, the use of antithymocyte globulin as part of the RIC regimen was the only independent risk factor associated with EBV reactivation (relative risk ¼ 4.9; 95% confidence interval, 1.1-21.0; P ¼ 0.03). We conclude that patients undergoing RIC allo-HSCT using anti-thymocyte globulin as part of the preparative regimen are at higher risk for EBV reactivation. However, this did not impact on outcome, as quantitative monitoring of EBV viral load by PCR and preemptive rituximab therapy allowed for significantly reducing the risk of EBV-related LPD.

TX 75083-3836, U.S.A., fax 01-972-952-9435. AbstractLow-molecular-weight polyacrylamides crosslinked with chromium(III) acetate are widely used in the oilfield industry to seal off watered out zones in matricial reservoirs. These products are usually mixed in surface facilities, then pumped downhole through coiled tubing and injected into the formation over a depth of several feet. For the operators, gelation time and gel consistency after well shut-in are the two most important parameters to control. The pumping time cannot exceed the gelation time and the maximum pressure drawdown sustainable by the gel is related to gel consistency (as measured, for instance, by the yield stress). Both are known to depend on temperature, polymer concentration and structure (molecular weight, hydrolysis degree), and crosslinker concentration.A systematic screening of these parameters has been undertaken by means of rheological measurements using a cone-and-plate rheometer. The procedure for determining gelation time consisted in monitoring the viscosity of the polymer and crosslinker solutions mixed at time t=0 and then submitted to shearing at a constant rate. The gelation time, which corresponds to a sudden rise in the viscosity, was observed to be independent of the applied shear rate but to strongly vary with temperature and, to a lesser extent, with polymer hydrolysis degree, concentration and molecular weight and crosslinker concentration. From the set of data obtained, simple correlations or rules of thumb for the gelation time variations are given, which can be used to optimize the formulation for a given field application.To evaluate gel consistency, some yield stress measurements were performed after a resting (shut-in) time of about 10 hours. The yield stress is related to the maximum drawdown sustainable by the gel in a formation through a simple relationship.

Summary An experimental study of shear stability of several high-molecular-weight polymers used as mobility-control agents in EOR projects has been performed in well-controlled conditions. The shearing device was made of a capillary tube with an internal diameter (ID) of 125 μm, through which polymer solution was injected at a controlled rate. The setup enables a precise measurement of the shear rate to which the polymer macromolecule is submitted. The degradation rate was measured by the viscosity loss induced by the passage into the capillary tube. The shear rate was gradually increased up to 106 sec–1 while checking degradation rate at each stage. Different commercial EOR polymer products were submitted to the test with polyacrylamide backbone and different substitution monomer groups. All macromolecules behave as flexible coils in solution. The parameters investigated were Molecular weight (between 6 and 20×106)Nature of substitution group (acrylate, ATBS/sulfonate, nVP/ vinyl-pyrrolidone)Salinity Polymer shear degradation increases with molecular weight and salinity, but decreases with the presence of acrylate, ATBS, and nVP. All results can be interpreted in terms of chain flexibility. The highly flexible polyacrylamide homopolymer is the most sensitive to shear degradation. Introduction of acrylate groups in the polymer chain induces some stability because of the rigidity provided by charge repulsion, which vanishes in the presence of high salinity because of the screening of acrylate negative charges. ATBS and VP groups, which are larger in size, provide significant chain rigidity, and thus better shear stability. It is also shown that some very-high-molecular-weight polymers, after passing the shearing device, attain a final viscosity lower than lower-molecular-weight products with the same chemical composition. This factor has to be taken into account in the final choice of a polymer for a given field application. As a comparison, although less popular today than 2 decades ago, xanthan gum (XG), which behaves like a semirigid rod, is shown to be much less sensitive to the shear-degradation test than the coiled polyacrylamides (Sorbie 1991).