Biodistribution of synthetic thymosin β4 in the serum,urine, and major organs of mice

Thymosin β₄ (Tβ₄) is a peptide of 43 amino acids that was first isolated from the thymus gland and subsequently found to be ubiquitous in nature. Tβ₄ functions mainly as an actin-sequestering molecule in non-muscle cells, where its primary role is to maintain the large pool of unpolymerized G-actin in the cell. Studies on the pharmacokinetics of Tβ₄ in human and other mammals have not been reported so far. In the present study, we have measured Tβ₄ concentrations in serum, urine, and 10 major organs of female Swiss-Webster mice following intraperitoneal administration of 400 μg synthetic Tβ₄. Using a modified enzymatic immu-noassay, our data show a significant increase of Tβ₄ in serum starting 2 min after injection and lasting for 40 min (average: 2.34±0.54μg/ml). High concentrations were found in urine (59.3 ± 7.54μg/ml) at three different time points after injection (20 min, 40 min, and 2 h). Of the 400 μg Tβ₄ administered to mice 83 % was recovered at the end of the study, 44.6% of which corresponded to urine, 1.4% to serum, and 37.5% to the organs. In 50% of the tested organs, the wet weight concentrations of Tβ₄ increased significantly from the first 40 min to 2 h after injection in comparison to their baseline wet weight concentrations. These organs were: the brain (72 μg/g vs 42 μg/g), heart (80 μg/g vs 37 μg/g), liver (15 μg/g vs 9 μg/g), kidneys (65 μg/g vs 28 μg/g), and peritoneal fat (47 μg/g vs 13 μg/g). Wet weight concentrations increased in the thymus (196 μg/g vs 147 μg/g) and muscle (45 μg/g vs 0 μg/g) after 6 h of injection. The spleen showed an increase in wet weight concentrations at the 2 min timepoint (267 μg/g vs 161 μg/g). Ovaries had a biphasic increase at 40 min(72 μg/g vs 62 μg/g) and 24 h (92 μg/g vs 62 μg/g) after Tβ₄ administration. In lungs, the highest wet weight increase after injection (149 μg/g at timepoint 6h) was not higher than its basal wet weight concentration (153 μg/g). These phar-macokinetic studies of Tβ₄ in mice have established that high levels of Tβ₄ are found in the blood following I.P. administration and the kidney rapidly removes the peptide from the circulation. The kinetics of this response should help define the proper scheduling of administration of Tβ₄ during clinical trials in disorders, such as the acute respiratory distress syndrome (ARDS), associated with actin toxicity.     

Effects of β-carotene and aspartame on clustogenic activity of cyclophosphamide and dioxidine in mice

Antimutagenic effects of combination of aspartame (0.4 and 4 mg/kg) and -carotene (0.15-15 mg/kg) were studied by estimation of chromosome aberrations in bone marrow cells of C57Bl/6 mice. Single and 5-day treatment with this combination decreased the clastogenic effects of dioxidine and cyclophosphamide and produced a more potent and universal antimutagenic effect than its constituents.     

Effects of β-carotene and aspartame on clustogenic activity of cyclophosphamide and dioxidine in mice

Antimutagenic effects of combination of aspartame (0.4 and 4 mg/kg) and β-carotene (0.15–15 mg/kg) were studied by estimation of chromosome aberrations in bone marrow cells of C57Bl/6 mice. Single and 5-day treatment with this combination decreased the clastogenic effects of dioxidine and cyclophosphamide and produced a more potent and universal antimutagenic effect than its constituents. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 130, No. 11, pp. 570–573, November, 2000     

Morphological analysis of the trachea and pattern of breathing in βENaC-Tg mice

Cystic fibrosis (CF) is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene which is a Cl- channel and a regulator of the epithelial Na+ channel (ENaC). We have recently shown that newborn CFTR-deficient mice exhibit abnormalities of the tracheal cartilage leading to altered ventilation (Bonvin et al., 2008). However, the mechanism by which a lack of CFTR causes tracheal cartilage defects remains unknown. The main goal of the present study was to determine whether the development of airway cartilage defects is related to ENac channel dysfunction. We thus performed macroscopic analysis of the trachea and explored ventilatory function in adult βENaC-overexpressing (βENaC-Tg) mice with airway Na+ hyperabsorption and "CF-lung" lung disease, at 2 and 5 month of age. Only minor cartilaginous abnormalities were observed in 8 out of 16 βENaC-Tg mice and in 2 out of 20 littermate controls. Breathing pattern was progressively altered in βENaC-Tg mice as evidenced by a significant decrease in respiratory frequency. Our results suggest that Na+ hyperabsorption alone is not a major contributor to the development of tracheal malformation observed in CF mice and that breathing pattern changes in βENaC-Tg mice likely reflect airflow limitation due to airway mucus obstruction.     

Region-specific distribution of β-amyloid peptide and cytokine expression in TgCRND8 mice

Alzheimer's disease (AD) is a multifactorial disease that results in progressive neurodegeneration. Brain regions are differentially affected in AD. There is also an age-dependent effect on amyloid-beta peptide (Aβ) accumulation and neuroinflammation as disease progresses. In the TgCRND8 APP transgenic mouse model, levels of Aβ species and cytokines were examined as a function of brain region and age. A temporal sequence was observed whereby Aβ accumulation is followed by expression of IL-1β and eventually, of CXCL1, in the hippocampus and olfactory bulb but not the cortex. We have shown for the first time, in an APP mouse model, age and regional differences in Aβ accumulation and cytokine expression.     

Region-specific distribution of β-amyloid peptide and cytokine expression in TgCRND8 mice

It has recently become clear that alcohol addiction might be related to a brain dysfunction, in which a genetic background and environmental factors shape brain mechanisms involved with alcohol consumption. Craving, a major component determining relapses in alcohol abuse has been linked to abnormal activity in the orbitofrontal cortex, dorsal anterior cingulated cortex (dACC) and amygdala. We report the results of a patient who underwent rTMS targeting the dACC using a double cone coil in an attempt to suppress very severe intractable alcohol craving. Functional imaging studies consisting of fMRI and resting state EEG were performed before rTMS, after successful rTMS and after unsuccessful rTMS with relapse. Craving was associated with EEG beta activity and connectivity between the dACC and PCC in the patient in comparison to a healthy population, which disappeared after successful rTMS. Cue induced worsening of craving pre-rTMS activated the ACC-vmPFC and PCC on fMRI, as well as the nucleus accumbens area, and lateral frontoparietal areas. The nucleus accumbens, ACC-vmPFC and PCC activation disappeared on fMRI following successful rTMS. Relapse was associated with recurrence of ACC and PCC EEG activity, but in gamma band, in comparison to a healthy population. On fMRI nucleus accumbens, ACC and PCC activation returned to the initial activation pattern. A pathophysiological approach is described to suppress alcohol craving temporarily by rTMS directed at the anterior cingulate. Linking functional imaging changes to craving intensity suggests this approach warrants further exploration.     

Immunolocalization of β-catenin and Lef-1 during postnatal hair follicle development in mice

It is well recognized that the Wnt pathway, in which β-catenin and Lef-1 are important factors, is associated with many physiological processes, including embryogenesis and postnatal development. The Wnt pathway also plays a critical role in the development of skin. It regulates the formation of the dorsal dermis and epidermal appendages in the skin and the activity of epithelial stem cells. In this study, we investigated the presence and localization of β-catenin and Lef-1 in murine hair follicles through the first postnatal month, which encompasses the first hair cycle in mice, using Western blotting and immunohistochemistry. Our results show that β-catenin and Lef-1 are expressed during all stages in a hair cycle, most strongly in the anagen and weakly in the catagen and telogen phases. The results also suggest that the β-catenin-Lef-1 complex may regulate hair follicle cycling. This process will be of considerable interest to future studies.     

Pattern Recognition of EEG Signals and Applications in Robotics

With the rapid development of brain computer interface (simply called BCI),electroencephalography (EEG) will be another interesting bio-electrical signal applied in robotics after EMG.In order to realize it finally,the accurate measurement and pattern recognition of EEG signal must be a very important and elementary research objective.Based on our current researches and some reports from the other international colleagues in the field,we deeply discuss the basic characteristics of EEG signal,the development and selection of EEG measurement system,feature extraction and recognition methods of EEG signal,and then review EEG‘s applications in robotics as well as the future research trends in this paper.     

Immunogenicity and protective efficacy in mice and hamsters of a β-propiolactone inactivated whole virus SARS-CoV vaccine

The immunogenicity and efficacy of β-propiolactone (BPL) inactivated whole virion SARS-CoV (WI-SARS) vaccine was evaluated in BALB/c mice and golden Syrian hamsters. The vaccine preparation was tested with or without adjuvants. Adjuvant Systems AS01(B) and AS03(A) were selected and tested for their capacity to elicit high humoral and cellular immune responses to WI-SARS vaccine. We evaluated the effect of vaccine dose and each adjuvant on immunogenicity and efficacy in mice, and the effect of vaccine dose with or without the AS01(B) adjuvant on the immunogenicity and efficacy in hamsters. Efficacy was evaluated by challenge with wild-type virus at early and late time points (4 and 18 wk post-vaccination). A single dose of vaccine with or without adjuvant was poorly immunogenic in mice; a second dose resulted in a significant boost in antibody levels, even in the absence of adjuvant. The use of adjuvants resulted in higher antibody titers, with the AS01(B)-adjuvanted vaccine being slightly more immunogenic than the AS03(A)-adjuvanted vaccine. Two doses of WI-SARS with and without Adjuvant Systems were highly efficacious in mice. In hamsters, two doses of WI-SARS with and without AS01(B) were immunogenic, and two doses of 2 μg of WI-SARS with and without the adjuvant provided complete protection from early challenge. Although antibody titers had declined in all groups of vaccinated hamsters 18 wk after the second dose, the vaccinated hamsters were still partially protected from wild-type virus challenge. Vaccine with adjuvant provided better protection than non-adjuvanted WI-SARS vaccine at this later time point. Enhanced disease was not observed in the lungs or liver of hamsters following SARS-CoV challenge, regardless of the level of serum neutralizing antibodies.     

How organ-specific is the migration of ‘naive’ and ‘memory’ T cells?

The concept that ‘naive’ T cells (CD4⁺CD45RA^hi) selectively migrate into lymphoid organs and ‘memory’ T cells (CD4⁺CD45R0^hi) migrate into nonlymphoid organs has been enthusiastically taken up by the scientific community. However, even today, this premise is based mainly on indirect evidence obtained in one species. Here, Jürgen Westermann and Reinhard Pabst argue that, in the light of recent data, the generalization of this concept was too early.     

Differential expression of β1, β3 and β4 integrins in sarcomas of the small,round, blue cell category

Integrins are a large and complex family of membrane spanning heterodimeric cell surface glycoproteins mediating cell/cell and cell/matrix interactions. Small, round, blue cell sarcomas (SRBCS) are a group of poorly differentiated tumours of various and in part uncertain histogenesis displaying similar cytomorphology. Among them are rhabdomyosarcomas (RMS), ganglioneuroblastomas [(G)NB], primitive peripheral neuroectodermal tumours (pPNET) and Ewing's sarcomas (ES). Thirty-two SRBCS were studied immunohistochemically for the distribution of 1, 3 and 4 integrins in situ. We found complex and to some extent differential patterns of 1, 3 and 4 integrin subunit expression in different types of SRBCS: all of the sarcomas studied were consistently 1⁺, 4^–, 2^–. Four of nine RMS were completely negative for all other integrin subunits studied while one RMS was 5⁺ throughout and three RMS were focally 5⁺. Three RMS expressed the 6 and v chains. In contrast to RMS, pPNET and ES, all of which were 1^–, 3^–, (G)NB were 3⁺ and frequently co-expressed 1. The eight pPNET and seven ES studied showed a similarily restricted integrin profile that was limited to the expression of 1 and 5 in nearly all cases. In summary, RMS were 1⁺, 1^–, 3^– and heterogeneously expressed 5 and 6. (G)NB were generally 1⁺, 1⁺, 3⁺, 5^–, 6^–. pPNET and ES were 1⁺, 1^–, 3^–, 5⁺, 6^–. The data illustrate a complex expression pattern of various integrins in SRBCS, a differential expression pattern of some of the integrin subunits among different types of SRBCS and almost identical integrin profiles in pPNET and ES.This paper is dedicated to Prof. Dr. Dres. h.c. Wilhelm Doerr on the occasion of his 80^th birthday     

Impact of mothers’ experience and early-life stress on aggression and cognition in adult male mice

The postnatal period is important for brain development and behavioral programming. Here, we hypothesized that females’ stressful experience early in life can lead to disruption of mother–offspring interactions with their own progeny. The objective of this study was to assess the effects of mothers’ stressful experience, early-life stress, or both on the behavior of adult male mice. In this study, female mice were allowed to raise their pups either without exposure to stress (normal rearing conditions, NC) or with exposure to maternal separation (3 hr/day, maternal separation, MS). Adult F1 female mice who had experienced MS (stressed mothers, SM) or had been reared normally (undisturbed mothers, UM) were used for generating F2 offspring, which was then exposed (or not exposed) to early-life stress. We assessed anxiety-like behavior, exploratory activity, locomotor activity, aggression, and cognition in four groups of adult F2 males (UM+NC, UM+MS, SM+NC, and SM+MS). We found that SM+MS males become more aggressive if agonistic contact is long enough; these results point to a change in their social coping strategy. Moreover, these aggressive males tended to show better long-term spatial memory. Overall, our findings suggest that mothers’ early-life experience may have important implications for the adult behavior of their offspring.     

Allergen-specific immunoglobulin,histamine and T-cell responses induced by soybean glycinin and β-conglycinin in BALB/c mice of oral sensitisation

Glycinin and β-conglycinin are major soybean allergens involved in food hypersensitivity. However, the mechanism of immune responses induced by glycinin and β-conglycinin has not been fully understood. Balb/c mice were oral sensitised with different doses (0.1, 1.0 and 10 mg/day) of soybean glycinin and β-conglycinin for five weeks. Allergen-specific immunoglobulin (Ig), serum histamine and T-cell responses were tested to assess the allergenic activity of glycinin and β-conglycinin. Mice sensitised with 0.1 or 1.0 mg/day allergens induced high levels of specific IgE, IgG1 and serum histamine compared with mice treated with saline. Furthermore, specific T-cell proliferation and significant up-regulation of interleukin (IL)-4, IL-5 and interferon (IFN)-γ were observed in splenocytes from mice gavaged with 0.1 or 1.0 mg/day soybean proteins. Low doses of glycinin or β-conglycinin can induce allergic reactions in BALB/c mice, which might be associated with increased IgE and cytokine production.     

Immune modulation of ovalbumin-induced lung injury in mice using β-glucosylceramide and a potential role of the liver

CD1d-restricted natural killer T (NKT) cells are implicated in the pathogenesis of asthma. β-Glucosylceramide (GC), a naturally occurring lipid, was previously shown to alter NKT cell distribution in the liver. We hypothesized that GC can affect lung and liver NKT cell distribution and ameliorate asthma. Mice were sensitized by intra-peritoneal injection of ovalbumin (OVA) for 2 weeks followed by repeated intranasal OVA challenges to induce lung injury mimicking asthma. OVA induced asthma groups were either treated by intranasal instillation of normal saline, intranasal instillation of GC or inhaled budesonide. To investigate the role of the liver, hepatic fibrosis was induced using carbon tetrachloride prior to asthma induction. Allergen induced bronchoconstriction was measured prior to sacrifice. Isolated lymphocytes from lungs, livers and spleens were analyzed for OVA induced proliferation and flow cytometry. Liver and lung histology, serum aminotransferase and anti-OVA antibodies level were assessed. Treatment with GC significantly reduced OVA induced airway responsiveness (p < 0.001) similar to inhaled budesonide. GC significantly reduced the peri-bronchial and peri-vascular inflammatory infiltration mainly through an effect on T cells, as suggested by decreased T cell proliferation (p = 0.009). Liver CD4 and NKT cells significantly increased after GC treatment suggesting liver involvement. Inducing hepatic fibrosis blunted the propagation of asthma in spite of sufficient increase of serum anti-OVA titers. GC has an immunomodulatory effect on a murine model of experimental asthma. We also suggest that the liver acts as an immunomodulatory organ and might have a regulatory effect on pulmonary diseases.     

Effects of oat soluble and insoluble β-glucan on 1,2-dimethylhydrazine-induced early colon carcinogenesis in mice

The study is aimed at studying the effects of soluble and insoluble oat β-glucan on colon carcinogenesis in mice. One hundred and twenty male Kunming mice were divided into normal control (NC), model control (MC), high doses (100?mg/kg body weight) of soluble (H-SOG) and insoluble β-glucan (H-IOG), and low doses (50?mg/kg body weight) of soluble (L-SOG) and insoluble β-glucan (L-IOG) groups. The mice except those in the NC group were given subcutaneous injections of DMH to induce colon cancer. The bile acid content was significantly reduced but the colonic short-chain fatty acid content was enhanced (p?p?相似文献   

In situ expression of β1, β3 and β4 integrin subunits in non-neoplastic endothelium and vascular tumours

Endothelial cells play an important role in adhesive interactions between circulating cells and extracellular matrix proteins. In vitro studies have shown that many of these processes are mediated by a superfamily of heterodimeric transmembrane glycoproteins called integrins. The distribution patterns of 1, 3 and 4 integrin subunits in endothelial cells (EC) in situ were examined immunohistochemically on serial forzen sections of a wide range of non-neoplastic tissues and of vascular tumours, both benign and malignant. Expression of the 1 subunit was a constitutive feature of EC. Among the 1-associated subunits, 5 and 6 were broadly distributed in EC, irrespective of vessel size and microenvironment. The 3 subunit displayed intermediate levels of expression with a slight preference for small vessel EC. Presence of 1 was confined to EC of capillaries and venules/small veins. Expression of 2 in EC was inconsistent. With rare exceptions, the 4 chain was absent in EC. The 3 and v subunits were expressed in most EC, though not always concomitantly. In contrast to the 1 chain, however, these integrin subunits were absent in EC of glomerular capillaries and were expressed variably in sinusoidal EC. The 4 chain was evenly present in the great majority of EC, except for those of large vessels. In vascular tumours, the patterns of 1 and 1 to 6 subunit expression generally corresponded to those found in their non-neoplastic counterparts. Expression of 3, v and 4 chains, however, decreased in neoplasia, especially in angiosarcomas. These data show that EC dispose of broad and at the same time differential repertoires of integrin subunits that presumably reflect vessel-type associated functional differences among these cells. In vascular tumours, the orthologous distribution patterns of 1 and 1 to 6 chains are conserved in most instances while the amounts of 3, v and 4 subunits expressed in EC tend to decrease in the course of malignant transformation.Dedicated to Prof. Dr. med. Dres. h.c. Wilhelm Doerr on the occasion of his 80th birthday     

Lead exposure increases levels of β-amyloid in the brain and CSF and inhibits LRP1 expression in APP transgenic mice

Lead (Pb) is an environmental factor suspected of contributing to neurodegenerative diseases such as Alzheimer's disease (AD). In AD, it has been postulated that increased production and/or decreased metabolism/clearance of β-amyloid (Aβ) may lead to amyloid plaque deposition as well as a cascade of other neuropathological changes. It has been suggested that Pb exposure may be associated with AD-like pathology and severe memory deficits in humans. Therefore, we investigated whether Pb exposure could induce Aβ accumulation in the brain. In this study, we demonstrated that acute Pb treatments lead to increased levels of Aβ in the cerebrospinal fluid (CSF) and brain tissues. Interestingly, Pb treatments did not affect Aβ production in brain neurons. Furthermore, Pb treatments significantly decreased LRP1 protein expression in the choroid plexus (CP). Our results suggest disrupted LRP1-mediated transport of Aβ in this region may be responsible for the Aβ accumulation in brain.     

A ‘Textbook Pattern’? Malaria Control and Eradication in Jamaica, 1910–65

In 1965 Jamaica was declared free of malaria by the World Health Organisation (WHO), thus ending centuries of death and suffering from the disease. This declaration followed the successful completion of the WHO’s Malaria Eradication Programme (MEP) on the island, initiated in 1958. This account first explores the antecedent control measures adopted by the government up to the MEP. These, as advocated by the previous malaria ‘experts’ who had reported on the disease on the island concentrated on controlling the vector and the administration of quinine for individual protection. Although Jamaica suffered no catastrophic epidemics of island-wide scope, malaria was a constant cause of mortality and morbidity. Major change came in the wake of the Second World War within the changing political context of national independence and international development. In 1957 the Jamaican government joined the global WHO programme to eradicate malaria. The Jamaican campaign exposes many of the problems noted in other studies of such top–down initiatives in their lack of attention to the particular circumstances of each case. Despite being described as ‘a textbook pattern’ of malaria eradication, the MEP in Jamaica suffered from a lack of sufficient preparation and field knowledge. This is most obviously illustrated by the fact that all literature on the programme sent to Jamaica in the first two years was in Spanish. That the MEP exploited the technological opportunity provided by dichlorodiphenyltrichloroethane (DDT) with advantage in Jamaica is not disputed but as this analysis illustrates this success was by no means guaranteed. Keywords : Jamaica, Malaria, Control, Eradication, World Health Organisation