The impacts of changing climate and streamflow on nutrient speciation in a large Prairie reservoir.

Climate mediated warming water temperature, drought and extreme flooding are projected to shift the phenology of nutrients in receiving lakes and reservoirs further intensifying eutrophication and algal blooms, especially in temperate reservoirs. An emerging issue in reservoir management is the prediction of climate change impacts, a necessity for sound decision making and sustainable management. Lake Diefenbaker is a large multipurpose reservoir in the Canadian Prairies. In this study, the impact of climate change on nutrient speciation in Lake Diefenbaker is examined using loosely linked SpAtially Referenced Regression On Watershed attributes (SPARROW) and CE-QUAL-W2 models. Two climate mediated scenarios, RCP 8.5 representing the most extreme climate change, and climate induced streamflow were modelled. Nutrient levels are anticipated to double under the climate change and streamflow scenarios. Winter and spring were identified as hot moments for nitrogen pollution with a plausible saturation of nitrous oxides in the future. Of concern is a plausible recycling of nitrate through dissimilatory nitrate reduction to ammonium. Summer and fall on the other hand represent the period for phosphorus enrichment and internal loading with a probable succession of cyanobacteria in the summer.

From Waldenström's macroglobulinemia to aggressive diffuse large B-cell lymphoma: a whole-exome analysis of abnormalities leading to transformation.

Transformation of Waldenström's macroglobulinemia (WM) to diffuse large B-cell lymphoma (DLBCL) occurs in up to 10% of patients and is associated with an adverse outcome. Here we performed the first whole-exome sequencing study of WM patients who evolved to DLBCL and report the genetic alterations that may drive this process. Our results demonstrate that transformation depends on the frequency and specificity of acquired variants, rather than on the duration of its evolution. We did not find a common pattern of mutations at diagnosis or transformation; however, there were certain abnormalities that were present in a high proportion of clonal tumor cells and conserved during this transition, suggesting that they have a key role as early drivers. In addition, recurrent mutations gained in some genes at transformation (for example, PIM1, FRYL and HNF1B) represent cooperating events in the selection of the clones responsible for disease progression. Detailed comparison reveals the gene abnormalities at diagnosis and transformation to be consistent with a branching model of evolution. Finally, the frequent mutation observed in the CD79B gene in this specific subset of patients implies that it is a potential biomarker predicting transformation in WM.

Implementation of a 3D ocean model to understand upland lake wind-driven circulation.

A community numerical ocean model is used to extend the understanding of wind-driven circulation in small upland lakes. A 3D model of a case study lake (Llyn Conwy, Wales, UK) is calibrated against measured velocity profiles via adjustment of the bottom roughness coefficient. Validation against a separate set of measured velocity profiles confirms the ability of the model to resolve key features of the flow field. Sensitivity analysis shows that the velocity field responds rapidly to changes in the wind forcing. Analysis of the gross circulation using Empirical Orthogonal Functions reveals a persistent two-gyre circulation pattern in the upper half layer of the water column driven by the interaction of wind and bathymetry. At the bottom, the flow is characterised by locally strong currents and analysis of vertical circulation over short time scales shows strong currents in the deepest parts of the lake basin and the responsiveness of the water column to changes in wind speed and direction. Even in small lakes, the assumption of uniform wind stress across the water surface is not always justified and topographic sheltering or other catchment roughness effects give rise to heterogeneity in the wind field. An idealized experiment for the case study lake shows that differences in circulation emerge if the wind stress is allowed to vary across the lake. Energetic wind forcing in upland areas can drive an energetic lake circulation that has important implications for mixing and sediment dynamics. 3D numerical modelling of wind-driven circulation should be more widely used to provide insights into physical limnology to support a wide range of ecological, biogeochemical and palaeoenvironmental studies.

MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström's macroglobulinemia.

We evaluated the MYD88 L265P mutation in Waldenström's macroglobulinemia (WM) and B-cell lymphoproliferative disorders by specific polymerase chain reaction (PCR) (sensitivity ∼10(-3)). No mutation was seen in normal donors, while it was present in 101/117 (86%) WM patients, 27/31 (87%) IgM monoclonal gammapathies of uncertain significance (MGUS), 3/14 (21%) splenic marginal zone lymphomas and 9/48 (19%) non-germinal center (GC) diffuse large B-cell lymphomas (DLBCLs). The mutation was absent in all 28 GC-DLBCLs, 13 DLBCLs not subclassified, 35 hairy cell leukemias, 39 chronic lymphocytic leukemias (16 with M-component), 25 IgA or IgG-MGUS, 24 multiple myeloma (3 with an IgM isotype), 6 amyloidosis, 9 lymphoplasmacytic lymphomas and 1 IgM-related neuropathy. Among WM and IgM-MGUS, MYD88 L265P mutation was associated with some differences in clinical and biological characteristics, although usually minor; wild-type MYD88 cases had smaller M-component (1.77 vs 2.72 g/dl, P=0.022), more lymphocytosis (24 vs 5%, P=0.006), higher lactate dehydrogenase level (371 vs 265 UI/L, P=0.002), atypical immunophenotype (CD23-CD27+ +FMC7+ +), less Immunoglobulin Heavy Chain Variable gene (IGHV) somatic hypermutation (57 vs 97%, P=0.012) and less IGHV3-23 gene selection (9 vs 27%, P=0.014). These small differences did not lead to different time to first therapy, response to treatment or progression-free or overall survival.

Evolution of soluble forms of CD86, CD95 and CD95L molecules in liver transplant recipients.

Co-stimulatory factors such as CD86 and apoptotic molecules such as CD95 and CD95L required to start and to turn off the allogenic immune response may also be present as soluble proteins. To determine the role of the soluble forms of CD86 (sCD86), CD95 (sCD95) and CD95L (sCD95L) in the outcome of liver transplants, we analyzed the circulating levels of these molecules in patients subjected to liver transplantation in the pre-operative period and during the first month post-transplantation. Serum samples were obtained from sixty-nine first orthotopic liver transplants (OLT). The patients were classified into acute rejection (AR=24) and not acute rejection (NAR=45), or considering the presence of chronic active hepatitis B or C (VP=30) or other primary liver diseases (VN=39). The levels of sCD86, sCD95 and sCD95L were analyzed by solid phase sandwich enzyme-linked immunoabsorbent assays. Our results first showed that the pre-transplantation serum levels of sCD86 in the AR group were significantly higher than in the NAR group (1007±82U/mL vs. 739±46U/mL, p=0.006), and in the post-transplantation period these levels decreased sharply. Second, the levels of sCD95L and sCD95 in the pre-transplantation period did not point to statistically significant differences between the AR and NAR groups. Considering primary liver disease, the pre-transplantation levels of sCD86 and sCD95L in the VP group were significantly higher than those of the VN group (VP, 977±69U/mL vs. VN, 722±51U/mL, p<0.002, and VP, 482±78pg/mL vs. VN, 221±31pg/mL, p=0.002, respectively). Multivariate analysis revealed that only the pre-transplantation levels of sCD86 were independently associated with the development of episodes of acute rejection (p=0.005, OR=2.1, IC 95%=1.27-3.47). In conclusion, the present work shows that primary liver disease could influence the pre-transplantation levels of sCD86 and sCD95L. High pre-transplantation serum levels of sCD86 could favor the development of episodes of acute rejection.

Study of Fas (CD95) and FasL (CD178) polymorphisms in liver transplant recipients.

The Fas receptor is capable of transducing apoptotic cell death upon interaction with their ligand (FasL). Recent studies suggest that the Fas/FasL system is involved both in graft rejection and in transplantation tolerance. In this study, we analyzed the effect of Fas and FasL polymorphisms in liver allograft outcome. Fas and FasL polymorphisms were analyzed in 151 primary liver graft recipients. The Fas (-670 A/G) and the FasL (IVS2nt -124 A/G and IVS3nt 169 T/delT) polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Fas -1377 G/A polymorphism was determined by allele-specific amplification. Fas and FasL polymorphisms were not associated with acute and chronic rejection in liver transplant. In contrast, those recipients bearing the AA -670 Fas genotype showed significantly lower graft survival rate (S = 40%) than those bearing the GA genotype (S = 63.1%). These differences were detected from the first year post-transplant. Multivariate analysis confirmed that the AA genotype increased the risk of liver graft loss. This work suggests for the first time a possible harmful effect of Fas -670 AA genotype on liver graft survival, whereas the Fas and FasL polymorphisms are not associated with acute or chronic rejection in liver graft recipients.

Evaluation of CD86 gene polymorphism at +1057 position in liver transplant recipients.

BACKGROUND: Efficient T cell-APC interaction requires the participation of primary and co-stimulatory signals. The main co-stimulatory pathway involves the interaction of CD80 and CD86, expressed on the APCs, with their T cell counter-receptor, CD28 and CTLA-4. Recently, a G to A transition has been described at position +1057 of the CD86 gene, located in their cytoplasmic tail. METHODS: CD86 polymorphism was analyzed by sequence based typing in DNA samples obtained from 205 liver transplant recipients. Acute rejection and chronic rejection were diagnosed based upon conventional clinical, biochemical and histological criteria. RESULTS: The study of CD86 +1057 (G/A) polymorphism revealed that recipients bearing the A allele or the AA genotype have a reduced risk of acute rejection. In fact, the AA genotype was absent in the group of patients showing acute rejection episodes, whereas its frequency in those patients without acute rejection episodes was 8.8% (P=0.009, OR=0.07). This polymorphism did not reveal any association with the incidence of chronic rejection, but patients bearing the AA genotype showed a higher graft survival rate (83.3%) than those bearing the GA genotype (49.3%) or GG genotype (56.5%). CONCLUSIONS: The results of the present report suggest that the CD86 AA genotype at +1057 position could be involved in liver transplant acceptance, given that its presence is related to a decrease of acute rejection frequency and to a graft survival increase.

Regulation of human neutrophil-mediated cartilage proteoglycan degradation by phosphatidylinositol-3-kinase.

The ability of neutrophils to degrade cartilage proteoglycan suggests that the neutrophils that accumulate in the joints of rheumatoid arthritis patients are mediators of tissue damage. The regulatory mechanisms which are relevant to the proteoglycan-degrading activity of neutrophils are poorly understood. Since phosphatidylinositol 3-kinase (PI3-K), protein kinase C (PKC), the extracellular signal-regulated protein kinase (ERK)1/ERK2 and cyclic adenosine monophosphate (cAMP) have been reported to regulate neutrophil respiratory burst and/or degranulation, a role for these signalling molecules in regulating proteoglycan degradation was investigated. Preincubation of human neutrophils with GF109203X (an inhibitor of PKC), PD98059 (an inhibitor of MEK, the upstream regulator of ERK1/ERK2) or with forskolin or dibutyryl cAMP, failed to suppress proteoglycan degradation of opsonized bovine cartilage. In contrast, preincubation of neutrophils with wortmannin or LY294002, specific inhibitors of PI3-K, inhibited proteoglycan degradation. Incubation of neutrophils with cartilage resulted in the activation of PI3-K in neutrophils, consistent with a role for PI3-K in proteoglycan degradation. Activation of PI3-K and proteoglycan degradation was enhanced by tumour necrosis factor-alpha. Degradation caused by neutrophils from the synovial fluid of rheumatoid arthritis patients was also inhibited by wortmannin. These data demonstrate that the proteoglycan degradative activity of neutrophils required PI3-K but not PKC or the ERK1/ERK2/ERK5 cascades and was insensitive to increases in intracellular cAMP concentrations.

[Humoral immune response to the proteins of an antimeningococcal BC vaccine in a trial carried out in Antioquia, Colombia]. / Respuesta inmune humoral a las proteínas de una vacuna antimeningocócica BC en un ensayo realizado en Antioquia, Colombia.

This study evaluated the humoral response to protein components of the Cuban-produced vaccine against serogroups B and C meningococcus, VA-MENGOC-BC, in adults and children 1 to 5 years old. The trial was conducted in an area of the Department of Antioquia, Colombia, in which an elevated incidence of meningococcal disease had been recorded. The serum anti-vaccine-protein response was studied before (T0) and after (T1) vaccination by means of enzyme-linked immunosorbent assay (ELISA), and lytic capacity was evaluated through the bactericidal antibodies test (BAT). The ELISA was performed before and after vaccination on the sera of 407 adults and 213 children. Lytic capacity against Cuban meningococcal strain B:4:P1.15 was studied with BAT in paired sera from 90 adults and 114 children. The two techniques showed a statistically significant response (P < 0.01) to the vaccine, in both adults and children. Of the total number of subjects tested with ELISA, 81% showed an immune response to the vaccine (T1/T0 > or = 2) (95% confidence interval, CI95%: 78% to 84%); among children, immune response was 91% (CI95%: 87% to 94%). All the children 1 year of age (n = 7) responded. Seroconversion (T1/T0 > or = 4), as shown by ELISA, was 80% among adults (CI95%: 73% to 86%) and 90% among children (CI95%: 83% to 100%). BAT demonstrated seroconversion in 85% (CI95%: 78% to 92%) of subjects who had been seronegative before vaccination, 85% of the adults (CI95%: 76% to 95%) and 84% of the children (CI95%: 72% to 96%). Seroconversion among children 3 and 4 years of age was 80%. The group of sera from children 1, 2, and 5 years old available for study with BAT was too small for meaningful statistical analysis; all of them seroconverted. In 20 sera chosen randomly for study of their bactericidal activity against all the strains isolated from patients in Colombia (B:4:P1.15, B:8:P1.nt, and two strains of serogroup C), seroconversion was found in all 20 cases. These results give reason to think that vaccination in this group produced an effective immune response, as measured serologically, and this belief is corroborated in practice by the lack of any cases of meningococcal disease through September 1994 among the people vaccinated.

[Humoral immune response to the capsular polysaccharide of Neisseria meningitidis serogroup C in an antimeningococcal BC vaccination trial in Antioquia, Colombia]. / Respuesta inmune humoral al polisacárido capsular de Neisseria meningitidis serogrupo C en un ensayo de vacunación antimeningocócica BC en Antioquia, Colombia.

As a complement to studying humoral immune response to the proteins of an antimeningococcal vaccine (VA-MENGOC-BC) against serogroups B and C, the humoral immune response to polysaccharide C of the vaccine was also evaluated in 142 children from 1 to 5 years of age in an area of the Department of Antioquia, Colombia. Paired pre-(T0) and post-vaccination (T1) sera were tested for IgG response by means of ELISA and for serum lytic capacity against a strain of serogroup C by means of the bactericidal antibodies test (BAT). Response to the vaccine was statistically significant (P < 0.01) by both techniques. PAB demonstrated seroconversion (T1/T0 > or = 4) in 88% (95% confidence interval, CI95%: 80% to 95%) of all those who were seronegative before vaccination. The proportion of seroconversion in children 2, 3, and 4 years of age was 86% or more. Of all the sera tested with ELISA, 93% (CI95%: 89% to 97%) showed response to the vaccine (T1/T0 > or = 2), and 98% (CI95%: 94% to 100%) of the subjects with T0 < or = 500 U/mL seroconverted. In this sample, the vaccine stimulated a specific and protective response as measured by ELISA and BAT, the latter test being utilized to evaluate protection status.

Coledocoduodenostomías: revisión de 11 años / Choledochoduodenostomy: eleven-year experience

Se revisa la casuistica del Hospital Universitario San Jorge de Pereira, desde el 1 de enero de 1978 hasta el 31 de diciembre de 1988; se encontro que, sobre un total de 1006 cirugias de vías biliares, se practicaron 27 coledocoduodenostomias y 10 coledocoyeyunostomias. Llama la atención que el primero de los procedimientos ha venido incrementándose a partir del año 1980, en la medida en que se ha tenido en cuenta como una buena opcion para derivar la corriente biliar con una tecnica relativamente sencilla, una incidencia de complicaciones baja y una mortalidad de cero, en nuestra serie.

Response of glioblastoma cell lines to low dose rate irradiation.

Glioblastoma U251 and U87 cells irradiated with single fraction high dose rate radiation (1.1 Gy/min) were relatively insensitive to inactivation of colony forming ability, similar to other glioblastoma cell lines. Initial rates of cell kill with continuous low dose rate irradiation (0.075 Gy/hr to 0.49 Gy/hr) were low, but at times greater than 20 hours and with dose rates of 0.25 Gy/hr or higher, the rate of cell kill increased. Population doubling times for these cell lines were about 24 hours, suggesting that cell cycle redistribution may be responsible for the increased sensitivity. DNA histograms obtained by flow cytometry support this hypothesis, with cells accumulating in the G2 and M phases of the cell cycle. These results suggest that low dose rate irradiation may be effective in treating glioblastomas. Optimization of time intervals between radiation treatments as well as dose rates used for glioblastoma patients may be influenced by these findings, resulting in better integration of continuous low-dose-rate irradiation (radioactive antibodies and implants) and high-dose-rate irradiation (fractionated external beam) into therapeutic programs.

Total skin electron irradiation for mycosis fungoides: relationship between acute toxicities and measured dose at different anatomic sites.

From June 1978 to June 1986, 50 patients with primary and recurrent mycosis fungoides were treated with total skin electron irradiation (TSEI), using the Stanford technique, to a total dose of 3600 cGy. TSEI was used alone, or in combination with low dose total body photon irradiation, or MOPP. Thermoluminescent dosimeter (TLD) measurements of the prescribed skin dose were obtained on twenty patients. The dorsum of the foot was 24% higher. The axillae, the bottom, and the arch of the foot were significantly underdosed. Frequencies of acute toxicities noted at 2000 cGy were: Skin, Grade I-II (RTOG) 80%. Partial epilation: scalp, 100%; eyebrows and at eyelashes, 20%. Nail dystrophy, 48%. Edema: hands and feet, 44%. Bullae: dorsum of feet, 8%; hands, 4%; and 3600 cGy: Skin, grade III 22%. Total epilation: scalp, 66%; eyebrows and eyelashes, 56%. Nail loss, 38%. Edema: hands and feet, 76%. Bullae: dorsum of feet, 34%; hands, 12%. Conjunctivitis, 4%. Large bullae, were more significant on the dorsum of the feet. Severe moist desquamation occurred in eight patients who had ulcerated lesions on initial presentation. Three patients were hospitalized due to ulceration and skin infection. All patients completed treatment after a short to moderate break. No patient developed skin necrosis, or corneal ulceration. No correlation exists between dose level, degree and onset of toxicity with previous chemotherapy or TBI. We conclude that the overall toxicity of TSEI is well tolerated.