Neural sources of focused attention in visual search

Previous studies of visual search in humans using event-related potentials (ERPs) have revealed an ERP component called 'N2pc' (180-280 ms) that reflects the focusing of attention onto potential target items in the search array. The present study was designed to localize the neuroanatomical sources of this component by means of magnetoencephalographic (MEG) recordings, which provide greater spatial precision than ERP recordings. MEG recordings were obtained with an array of 148 magnetometers from six normal adult subjects, one of whom was tested in multiple sessions so that both single-subject and group analyses could be performed. Source localization procedures revealed that the N2pc is composed of two distinct neural responses, an early parietal source (180-200 ms) and a later occipito-temporal source (220-240 ms). These findings are consistent with the proposal that parietal areas are used to initiate a shift of attention within a visual search array and that the focusing of attention is implemented by extrastriate areas of the occipital and inferior temporal cortex.     

高低通量血液透析膜清除溶质能力的比较

目的：比较高通量和低通量聚砜膜血液透析器对慢性肾功能衰竭维持性血液透析患者尿素氮、肌酐、血磷及β2-微球蛋白的清除能力. 方法：于2004-09/2005-01选择上海交通大学医学院附属新华医院血液透析中心维持性血液透析患者43例,血透时间1.5～5.0年.实验经医院伦理委员会审批,患者均知情同意.①实验分组：按随机数字表法分为高通量透析组23例和低通量透析组20例.②实验方法：高通量透析组采用F60聚砜膜血液透析器,超滤系数Kuf为40 mL/（h·mm Hg）.低通量透析组采用F6聚砜膜血液透析器,超滤系数Kuf为5.5 mL/（h·mm Hg）.所有患者透析3次/周,4 h/次,均采用Fresenius 4008S容量控制型透析机和超纯净水碳酸氢盐透析液,透析液流量500 mL/min,血流量190～250 mL/min,采用肝素抗凝,共5个月.③实验评估：两组患者透析前后常规检测血尿素氮、肌酐、血磷浓度;采用放射免疫方法测定血β2-微球蛋白含量,观察透析前后各种溶质含量变化,计算其溶质清除率. 结果：①血尿素氮、肌酐和血磷浓度变化：两组患者透析前后血尿素氮、肌酐和血磷浓度均显著下降.两组血尿素氮、肌酐和血磷的清除率差异无显著性意义（P＞0.05）,表明高通量和低通量血液透析均能有效清除维持性血液透析患者血液中的小分子溶质.②β2-微球蛋白含量变化：高通量透析组透析后β2-微球蛋白含量显著下降,低通量透析组透析前后β2-微球蛋白含量无显著变化.清除率组间差异有显著性意义（t=3.62,P＜0.05）. 结论：应用高通量F60聚砜膜血液透析器和低通量F6聚砜膜血液透析器均能有效清除维持性血液透析患者血液中的小分子溶质,但高通量F60聚砜膜血液透析器对β2-微球蛋白的清除能力显著优于低通量F6聚砜膜血液透析器.     

Immunoregulation of B lymphocyte colony formation by T cell subsets in patients with chronic lymphocytic leukemia

Normal B lymphocytes are activated, proliferate, and then differentiate into plasma cells and secrete immunoglobulin (Ig). We have reported that chronic lymphocytic leukemia (CLL) T4 cells help and CLL T8 cells lack suppressor effects on Ig synthesis by normal B cells (Blood 62:767, 1983). We have now explored the earlier phase, proliferation, using B cell colony formation; in semisolid media. B lymphocyte colonies from normal individuals and from patients with CLL were grown in 0.3% agarose overlayed with T cells or T cell subsets and the B cell mitogen staphylococcal protein A. Enriched T cells, OKT4 or OKT8, were obtained either by sheep erythrocyte rosettes or depletion of OKT8 or OKT4 cells by monoclonal antibody or complement, respectively. Twenty thousand B cells from normal subjects yielded 65 +/- 9, 64 +/- 7, and 19 +/- 6 colonies with autologous unfractionated T-, OKT4-, or OKT8- positive cells, respectively. This compared to 29 +/- 11, 81 +/- 11, and 15 +/- 4 colonies from patients with CLL with added autologous unfractionated T-, OKT4-, or OKT8-positive cells. To determine whether the fewer number of colonies in both normal subjects and patients with CLL with OKT8-positive cells was due to suppression or lack of help, the number of OKT4-positive cells was held constant, and OKT8-positive cells were added in increasing numbers. No suppression of colony formation could be demonstrated. Furthermore, the addition of increasing numbers of concanavalin A (Con A)-activated OKT8-positive cells did not suppress colony formation. These results suggest that the CLL T cell subsets behave in a functionally similar manner to normal T cell subsets, namely, (1) that normal and CLL B cell colony growth is helped by OKT4 cells; and (2) in contrast to immunoglobulin secretion by B cells, neither normal nor CLL OKT8 cells, unstimulated or activated by Con A, suppress B cell colony growth.     

Reduction of cerebral infarct volume by apocynin requires pretreatment and is absent in Nox2-deficient mice

Background and purpose:

Reactive oxygen species (ROS) derived from Nox2-containing reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity is reportedly detrimental in cerebrovascular disease. However, ROS generation by other Nox isoforms may have a physiological role. No Nox2-selective inhibitors have yet been identified, and thus it is unclear whether isoform non-selective Nox inhibitors would necessarily improve outcome after stroke. We assessed the effect of apocynin on cerebrovascular ROS production and also on outcome following cerebral ischaemia when administered either before ischaemia or after cerebral reperfusion. The involvement of Nox2-containing NADPH oxidase in the effects of apocynin was assessed using Nox2^−/− mice.

Experimental approach:

Transient cerebral ischaemia was induced by 0.5 h middle cerebral artery occlusion followed by 23.5 h reperfusion. Mice received apocynin (2.5 mg·kg⁻¹, i.p.) either 0.5 h before ischaemia or 1 h after reperfusion. In situ superoxide production after cerebral ischaemia-reperfusion was measured in brain sections of wild-type mice at 24 h using dihydroethidium fluorescence.

Key results:

Treatment with apocynin 0.5 h before ischaemia reduced total infarct volume, neurological impairment and mortality in wild-type but not Nox2^−/− mice. Conversely, treatment with apocynin 1 h after initiation of reperfusion had no protective effect. Cerebral ischaemia and reperfusion increased superoxide production in the brain at 24 h, and pretreatment but not posttreatment with apocynin reduced superoxide levels.

Conclusions and implications:

Apocynin improves outcome following stroke when administered before ischaemia in wild-type but not Nox2^−/− mice.     

Determining the date of diagnosis – is it a simple matter? The impact of different approaches to dating diagnosis on estimates of delayed care for ovarian cancer in UK primary care

Background  

Studies of cancer incidence and early management will increasingly draw on routine electronic patient records. However, data may be incomplete or inaccurate. We developed a generalisable strategy for investigating presenting symptoms and delays in diagnosis using ovarian cancer as an example.     

Nonneoplastic hematopoietic myeloproliferative syndrome induced by dysregulated multi-CSF (IL-3) expression

Post 5-fluorouracil-treated murine marrow cells were infected with a retroviral vector (MPZen) bearing a multi-potential colony stimulating factor (Multi-CSF) cDNA insert and then transplanted into lethally irradiated syngeneic recipients to study the effects of autocrine production of Multi-CSF in normal hematopoietic cells. Extremely high levels (14,000 U/mL) of Multi-CSF were detected in the sera and in media conditioned by various hematopoietic tissues of the transplanted animals. While spleen, peritoneal, and peripheral blood cellularity increased approximately 10-fold, 10-fold, and 50-fold, respectively, bone marrow cellularity decreased twofold. Progenitor numbers were depressed twofold in the bone marrow but elevated more than 100-fold in the spleen and peritoneum. The majority (80%) of transplanted mice died within 5 weeks of transplantation and showed extensive neutrophilic infiltration of the spleen, lung, liver, and muscle, often with mast cell foci; a phenomenon also seen in the skin and intestine. Neither the infected cells from hematopoietic tissues of the primary mice, nor autonomous mast cell-lines that grew from these cells in liquid culture produced any overt disease when transplanted into normal or sublethally irradiated secondary recipients. In contrast, injection into mice of autonomous FDC-P1 cells transformed by the same retroviral construct led to tumor formation in vivo within 4 weeks. Thus, dysregulated Multi- CSF expression by normal hematopoietic cells produces a fatal but nonneoplastic myeloproliferative syndrome.     

Extracellular adenosine triphosphate increases cation permeability of chronic lymphocytic leukemic lymphocytes

Extracellular adenosine triphosphate (ATP) is known to reversibly increase the cation permeability of a variety of freshly isolated and cultured cell types. In this study the effects of extracellular ATP were studied using peripheral blood lymphocytes (PBL) isolated from both normal subjects and from patients with chronic lymphocytic leukemia (CLL). Changes in the permeability to Na+, Rb+, and Li+ ions were measured using conventional isotope and flame photometry techniques. In addition, changes in cytosolic (Ca2+) were fluorimetrically monitored to assess possible changes in net Ca2+ influx. ATP produced a 12-fold increase in 22Na+ influx into CLL cells but only a 3.5-fold increase in this flux in PBL cells. A maximal response was produced by 0.1 mmol/L ATP in the absence of Mg2+, while a twofold molar excess of Mg2+ over ATP abolished the response. ATP had no effect on the passive (ouabain-insensitive) 86Rb+ influx into PBL cells but stimulated this flux by fivefold in the CLL cells. Li+ influx into CLL cells was also stimulated threefold by ATP. Under these same conditions ATP also produced a net increase in total cell Na and a decrease in total cell K in the CLL cells. Exclusion of two normally impermeable dyes, trypan blue and ethidium bromide, was not altered in the ATP-treated CLL cells. Finally, extracellular ATP (3 mmol/L) produced no significant change in the cytosolic (Ca2+) of normal, monocyte-depleted populations of PBL. Conversely, this same concentration of ATP produced a very rapid (complete within 30 seconds) and a significant (an average threefold peak change) increase in the cytosolic (Ca2+) of cell preparations derived from five out of nine CLL patients. In these latter CLL cells, the ATP-induced elevation in cytosolic (Ca2+) appeared to be due to a net increase in Ca2+ influx, since no elevations were observed when the extracellular (Ca2+) was reduced to less than 0.1 mmol/L. These actions of ATP were specific in that equimolar concentrations of other nucleotides were without effect. These data indicate that treatment of CLL lymphocytes with extracellular ATP4 produces large increases in cation permeability. In contrast, there is less or no ATP-induced permeabilization of normal PBL.     

The role of MAP kinase kinase in interleukin-3 stimulation of proliferation

Expression of a dominant interfering mutant of MAP kinase kinase (MAPKK) inhibits interleukin-3 (IL-3) activation of MAP kinase in the murine bone marrow-derived cell line BAF3. This results in an increase in the level of IL-3 required to stimulate cell proliferation and suppress apoptosis. When apoptosis is constitutively inhibited by coexpression of bcl-2, the dominant interfering MAPKK inhibits IL-3 driven cell cycle progression. Thus, MAPKK function is necessary for optimal IL-3 inhibition of apoptosis and optimal IL-3 stimulation of entry into S phase. Expression of a constitutively activated mutant of MAPKK does not replace IL-3, but renders cells able to proliferate in a density-dependent manner. Cell contact is required to allow cell proliferation; such contact can be supplied by cells without activated MAPKK.