Deletion of the dominant autoantigen in NZB mice with autoimmune hemolytic anemia: effects on autoantibody and T-helper responses

The mechanisms underlying apparently spontaneous autoimmune diseases, such as autoimmune hemolytic anemia (AIHA) in New Zealand Black (NZB) mice, are unknown. Here, we determine the contribution of the dominant red blood cell (RBC) autoantigen, the anion exchanger protein Band 3, to the development of NZB autoimmune responses. The approach was to prevent Band 3 expression in NZB mice by disrupting the AE1 gene. AE1(-/-) NZB mice produced RBC autoantibodies at the same levels as the wild-type strain, but they differed in recognizing antigens that correspond to glycophorins, rather than Band 3. Splenic T-helper (Th) cells from wild-type NZB mice proliferated strongly against multiple Band 3 peptides, particularly the dominant epitope within aa861-874. This helper response was severely attenuated in AE1(-/-) animals, leaving only weak proliferation to peptide aa861-874. The results demonstrate that the defect in self-tolerance in NZB AIHA is directed to the RBC type, and is not specific for, or dependent on, Band 3. However, the predisposition to RBC autoimmunity may be focused onto Band 3 by weak Th cell cross-reactivity between the helper dominant epitope and an exogenous antigen. The redundancy of the major autoantigen illustrates the requirement for specific therapy to induce dominant forms of tolerance, such as T-cell regulation.     

The effect of chemotherapy on Ki-67, Bcl-2 and Bak expression in primary tumors and lymph node metastases of breast cancer

The aim of this study was the analysis of Ki-67, Bcl-2 and Bak expression in primary tumor and axillary lymph node metastases of breast cancer as well as an attempt to assess preoperative chemotherapy influence on the mentioned markers with regard to changes in the morphological appearance of the primary tumor and its metastases. Immunohistochemical examinations of Ki-67, Bcl-2 and Bak expression were conducted on sections collected from 135 patients treated surgically on invasive ductal breast cancer. Sixty-four of these patients were administered preoperative chemotherapy, whilst on 71 patients the surgery was performed without initial chemotherapy. In the group of patients without preoperative chemotherapy positive correlation in Ki-67 and Bcl-2 expression between primary tumors and lymph node metastases (p<0.0001, r=0.707; p<0.0001, r=0.604, respectively) was observed. In the group of patients after chemotherapy positive correlation between primary tumors and lymph node metastases in case of Bcl-2 and Bak proteins (p<0.04, r=0.424; p<0.02, r=0.478, respectively) was observed. It was also found that preoperative chemotherapy has an influence on the expression of proteins connected with proliferation and apoptosis and thus, it can influence neoplastic process biology. It does not have any significant impact on the proapoptotic Bak protein expression either in primary tumor or in lymph node metastases of breast cancer. However, it is related to lower expression of antiapoptotic Bcl-2 protein (p<0.0005) and of Ki-67 proliferation marker (p<0.03) in primary tumors, which indirectly indicates a beneficial influence of preoperative chemotherapy on the primary tumor. Concurrently, the influence of neoadjuvant therapy on lymph node metastases seems to be relatively small, which can limit its effectiveness.     

Acute and chronic treatment with mianserin differentially affects the anticonvulsant activity of conventional antiepileptic drugs in the mouse maximal electroshock model

Rationale Epilepsy often coexists with depression. Therefore, the probability of simultaneous treatment with antiepileptics and antidepressants and the possibility of interactions between them are relatively high. Objective The effects of acute and chronic administration of mianserin on the protective activity of valproate (VPA), carbamazepine, phenytoin, and phenobarbital were evaluated in the maximal electroshock in mice. Materials and methods Animals were subjected to electroconvulsions. Undesired effects were evaluated in the chimney test (motor impairment) and passive-avoidance task (memory deficit). Brain concentrations of antiepileptic drugs were assessed by immunofluorescence. Results When given acutely, mianserin (at doses greater than or equal to 20 mg/kg) significantly raised the electroconvulsive threshold. The antidepressant, at the subanticonvulsant doses, enhanced the anticonvulsant action of carbamazepine, phenytoin, and VPA. Mianserin administered chronically at 30 mg/kg significantly decreased the electroconvulsive threshold. In contrast to acute treatment, the antidepressant at subeffective doses diminished the anticonvulsant activity of VPA and phenytoin. Mianserin given either acutely or chronically did not affect the brain concentrations of antiepileptic drugs, so a pharmacokinetic contribution to the observed interactions is not probable. Acute and chronic treatment with mianserin and its combinations with antiepileptic drugs did not impair either motor coordination or long-term memory. Conclusion Although acute application of mianserin may potentiate the anticonvulsant action of some antiepileptics, its chronic administration can lead to the opposite effect. Therefore, as far as the presented results can be transferred to clinical conditions, the antidepressant therapy with mianserin should be limited or even avoided in epileptic patients.     

End-state comfort and joint configuration variance during reaching

This study joined two approaches to motor control. The first approach comes from cognitive psychology and is based on the idea that goal postures and movements are chosen to satisfy task-specific constraints. The second approach comes from the principle of motor abundance and is based on the idea that control of apparently redundant systems is associated with the creation of multi-element synergies stabilizing important performance variables. The first approach has been tested by relying on psychophysical ratings of comfort. The second approach has been tested by estimating variance along different directions in the space of elemental variables such as joint postures. The two approaches were joined here. Standing subjects performed series of movements in which they brought a hand-held pointer to each of four targets oriented within a frontal plane, close to or far from the body. The subjects were asked to rate the comfort of the final postures, and the variance of their joint configurations during the steady state following pointing was quantified with respect to pointer endpoint position and pointer orientation. The subjects showed consistent patterns of comfort ratings among the targets, and all movements were characterized by multi-joint synergies stabilizing both pointer endpoint position and orientation. Contrary to what was expected, less comfortable postures had higher joint configuration variance than did more comfortable postures without major changes in the synergy indices. Multi-joint synergies stabilized the pointer position and orientation similarly across a range of comfortable/uncomfortable postures. The results are interpreted in terms conducive to the two theoretical frameworks underlying this work, one focusing on comfort ratings reflecting mean postures adopted for different targets and the other focusing on indices of joint configuration variance.     

Immunological Abnormalities in a Child with Constitutional Aplastic Anemia

This case report describes a child with severe constitutional hypoplastic anemia and Seckel's syndrome. Immunological analysis on mononuclear peripheral blood cells revealed an abnormally low ratio of T-helper to T-suppressor/cytotoxic cells and a highly increased number of HLA-DR-positive T suppressor/cyiotoxic cells. Interferon-y and interleukin-2 production by mitogen-stimulated peripheral blood mononuclear cells was slightly reduced, and no spontaneous production of these lymphokines was seen. The immunological abnormalities demonstrated in this case of constitutional aplastic anemia may indicate common features with acquired aplastic anemia.     

Addition of oxiranes to the acids of phosphorus. Direction of ring opening

The proportion of the α- and β-ring opening in the addition of unsymmetrically substituted oxiranes to P? OH acids namely diethyl phosphoric acid, phosphorous acid, and phosphoric acid, was established. Ring opening of propylene oxide does not depend on the number of the P? OH groups in the acid and, for di- and trifunctional acids, does not depend on the degree of substitution. After this first reaction of addition the formed hydroxyl groups add the oxirane molecules and the phosphorus-containing polyethers are formed. All of the propylene oxide additions exhibit a ratio of α/β-ring openings of 1:1. For the higher substituted oxiranes the proportion of the attack on the least substituted carbon atom increases, reaching for 1,1-dimethyloxirane up to 90% of α-addition (almost exclusive formation of the tertiary alcohol).     

Intradialytic amino acids supplementation in hemodialysis patients with malnutrition: results of a multicenter cohort study.

OBJECTIVE: Prospective evaluation of the effect of 6-month-long intradialytic amino acids (AA) supplementation on selected nutritional variables in malnourished hemodialysis (HD) patients. DESIGN: Multicenter, prospective, (nonrandomized, noncontrolled) observational study. SETTING: Thirty-one HD units affiliated with academic centers and tertiary-care hospitals. PATIENTS: Adult patients treated by HD for at least 6 months. Inclusion criteria were: serum albumin concentration < or =39 g/L and at least 4% loss of body weight during the last 6 months in otherwise stable HD patients. From a cohort of 133 patients who were enrolled, 97 (54 men and 43 women) were eligible for the analysis. INTERVENTION: Intradialytic AA supplementation with 500 mL 10% solution per HD session for a period of 6 months. MAIN OUTCOME MEASURES: Serum albumin concentration, modified Subjective Global Assessment (SGA) score, body mass index (BMI), mid-arm circumference (MAC), and total lymphocyte count. Measurements were recorded at baseline and after 3 and 6 months of AA supplementation. RESULTS: Serum albumin concentration increased significantly from the mean 32.5 +/- 4.6g/L at baseline to 36.4 +/- 4.8 g/L at 3 months (P <.001) and 37.1 +/- 4.8 g/L at final observation (P <.001 versus baseline). Significant correlation was observed between frequency of AA supplementation and serum albumin increase (r = 0.41; P <.0001). Rate of improvement negatively correlated significantly with baseline concentration of serum albumin (r = - 0.42; P <.0001). SGA score significantly improved from median of 16 points at baseline to 12 points at 3 months (P <.01) and 11 points at 6 months (P <.01 versus baseline), and this improvement also correlated with the frequency of AA supplementation. Small yet significant increase of MAC was observed at 6 months (from baseline 24.1 +/- 4.3 to 24.8 +/- 4.8 cm; P <.01), whereas BMI remained unchanged. CONCLUSION: Intradialytic AA supplementation improves selected nutritional parameters of HD patients with malnutrition. The improvement depends on the intensity of supplementation.     

Stimulus specific adaptation in excited but not in inhibited cells in inferotemporal cortex of Macaque

Many cells in inferotemporal cortex respond more actively to a novel presentation than to a subsequent re-presentation of the same image, exhibiting stimulus specific adaptation (SSA). Previously, analysis of this adaptation was limited to visually excited cells, excluding visually inhibited cells. In the present experiment we studied 654 cells in four macaques performing visual tasks. Strong SSA (P < 0.0001) was observed in those cells which were excited by visual stimuli. This adaptation was also seen in the subset of such cells which, though excited by visual stimuli, failed to show visual specificity in their responses. Interestingly, no SSA (P > 0.1) was observed in the group of cells inhibited by visual stimuli. Furthermore, most inhibited cells failed to show visual specificity. This lack of visual specificity and SSA suggest that the visually inhibited cells have a limited role in the detailed information processing of visual perception and memory activated by the tasks used in the present experiments.