374 research outputs found
Cellular maturation defects in Bruton's tyrosine kinase-deficient immature B cells are amplified by premature B cell receptor expression and reduced by receptor editing
In the mouse, Bruton's tyrosine kinase (Btk) is essential for efficient
developmental progression of CD43(+)CD2(-) large cycling into
CD43(-)CD2(+) small resting pre-B cells in the bone marrow and of
IgM(high) transitional type 2 B cells into IgM(low) mature B cells in the
spleen. In this study, we show that the impaired induction of cell surface
changes in Btk-deficient pre-B cells was still noticeable in kappa(+)
immature B cells, but was largely corrected in lambda(+) immature B cells.
As lambda gene rearrangements are programmed to follow kappa
rearrangements and lambda expression is associated with receptor editing,
we hypothesized that the transit time through the pre-B cell compartment
or receptor editing may affect the extent of the cellular maturation
defects in Btk-deficient B cells. To address this issue, we used 3-83 mu
delta transgenic mice, which prematurely express a complete B cell
receptor and therefore manifest accelerated B cell development. In
Btk-deficient 3-83 mu delta mice, the IgM(+) B cells in the bone marrow
exhibited a very immature phenotype (pre-BCR(+)CD43(+)CD2(-)) and were
arrested at the transitional type 1 B cell stage upon arrival in the
spleen. However, these cellular maturation defects were largely restored
when Btk-deficient 3-83 mu delta B cells were on a centrally deleting
background and therefore targeted for receptor editing. Providing an
extended time window for developing B cells by enforced expression of the
antiapoptotic gene Bcl-2 did not alter the Btk dependence of their
cellular maturation. We conclude that premature B cell receptor expression
amplifies the cellular maturation defects in Btk-deficient B cells, while
extensive receptor editing reduces these defects
Btk at the Pre-B Cell Receptor Checkpoint
Signalling from the BCR or its immature form, the pre-BCR, was shown to be crucial for B
cell development. Gene-targeted mice have defined differential roles of components of the
(pre-) BCR complex or its downstream signalling pathways. One of the proteins involved in
(pre-) BCR signalling is the cytoplasmic protein Bruton’s tyrosine kinase (Btk). Mice deficient
in Btk have B cell differentiation defects resulting in an X-linked immunodefi ciency (xid)
phenotype. The xid phenotype is characterized by a reduction in the number of peripheral
B cells and the residual B cell have an immature phenotype, indicating that the lack of Btk
causes a block in peripheral B cell
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Knowledge, attitudes and practices of medical staff towards obesity management in patients with spinal cord injuries: an International survey of four western European countries
Objective: To (1) examine the opinions of medical staff working in spinal cord injury (SCI) centres (SCICs); (2) evaluate their knowledge, attitudes and practices towards obesity prevention and management; (3) report the number of beds and dietitians available at each SCIC. Methods: A 37-item questionnaire was sent to 23 SCICs in the UK, the Netherlands, Belgium and the Republic of Ireland between September 2012 and January 2013. Results: Eighteen SCICs returned the questionnaires for analysis. All respondents stated that they had an interest in obesity treatment but only 2.3% of the respondents received training in obesity management. Sixty-one percent of staff did not consider body mass index (BMI) to be appropriate for use in SCI patients and subsequently less than half of the respondents use BMI routinely. The majority of respondents reported that they are confident in dealing with overweight (74.5%) and obese (66.1%) SCI adults, less than half (44.1%) are confident in treating overweight and obese SCI children. Respondents also indicated the need for nationally adopted guidelines and a lack of physical activity provision. There were 17.5 whole-time equivalent (WTE) dietitians recorded in 22 SCICs, equivalent to 47.8 beds per WTE dietitians (range 10–420). Non-UK SCIC dietitians are significantly better resourced than in UK SCICs (beds per WTE dietitian: 36 vs 124, P=0.035). Conclusion: Medical staff expressed the need to participate in obesity prevention and management. Appropriate training should be considered for all medical staff and the development of specific weight management guidelines and dietetic provision should be considered
Impaired precursor B cell differentiation in Bruton's tyrosine kinase-deficient mice
Bruton's tyrosine kinase (Btk) is a cytoplasmic signaling molecule that is
crucial for precursor (pre-B) cell differentiation in humans. In this
study, we show that during the transition of large cycling to small
resting pre-B cells in the mouse, Btk-deficient cells failed to
efficiently modulate the expression of CD43, surrogate L chain, CD2, and
CD25. In an analysis of the kinetics of pre-B cell differentiation in
vivo, Btk-deficient cells manifested a specific developmental delay within
the small pre-B cell compartment of about 3 h, when compared with
wild-type cells. Likewise, in in vitro bone marrow cultures, Btk-deficient
large cycling pre-B cells showed increased IL-7 mediated expansion and
reduced developmental progression into noncycling CD2(+)CD25(+) surrogate
L chain-negative small pre-B cells and subsequently into Ig-positive B
cells. Furthermore, the absence of Btk resulted in increased proliferative
responses to IL-7 in recombination-activating gene-1-deficient pro-B
cells. These findings identify a novel role for Btk in the regulation of
the differentiation stage-specific modulation of IL-7 responsiveness in
pro-B and pre-B cells. Moreover, our results show that Btk is critical for
an efficient transit through the small pre-B cell compartment, thereby
regulating cell surface phenotype changes during the developmental
progression of cytoplasmic mu H chain expressing pre-B cells into immature
IgM(+) B cells
Can verbal suggestions strengthen the effects of a relaxation intervention?
Short stress management interventions such as relaxation therapy have demonstrated preliminary effectiveness in reducing stress-related problems. A promising tool to strengthen the effectiveness of relaxation-based interventions is the use of verbal suggestions, as previous research provided evidence that verbal suggestions can induce positive outcome expectancies, facilitate adaptive responses to stress and improve health outcomes. The present experimental proof-of-concept study aimed to investigate the effects of a brief relaxation intervention and specifically the role of verbal suggestions on stress-related outcomes assessed by self-report questionnaires and psychophysiological data. 120 participants (mean age = 22.1 years) were randomized to one of four intervention conditions: a brief relaxation intervention plus verbal suggestions condition, a brief relaxation intervention only condition, a verbal suggestions only condition, and a control condition. Afterwards, participants were subjected to a psychosocial stress challenge to assess reactivity to a stressful event. Immediately after both relaxation interventions (with and without verbal suggestions), lower self-reported state anxiety was found compared to the control condition, but no differences were observed in response to the stressor. The verbal suggestions only condition did not impact state anxiety. No significant effects were found for verbal suggestion interventions on cortisol, alpha amylase, heart rate and skin conductance. This is the first study investigating the role of verbal suggestions in the effectiveness of a brief relaxation intervention. Although this experimental proof-of-concept study provides support for the effectiveness of a brief relaxation intervention in lowering state anxiety directly after the intervention, the effects did not impact the response to a subsequent stressor and we did not observe any evidence for the add-on effectiveness of verbal suggestions. The effectiveness of brief relaxation interventions on stress responses should be investigated further in future research by incorporating interventions that are tailored to the specific stress challenge and various types of verbal suggestions
Function of Bruton's tyrosine kinase during B cell development is partially independent of its catalytic activity
The Tec family member Bruton's tyrosine kinase (Btk) is a cytoplasmic
protein tyrosine kinase that transduces signals from the pre-B and B cell
receptor (BCR). Btk is involved in pre-B cell maturation by regulating
IL-7 responsiveness, cell surface phenotype changes, and the activation of
lambda L chain gene rearrangements. In mature B cells, Btk is essential
for BCR-mediated proliferation and survival. Upon BCR stimulation, Btk is
transphosphorylated at position Y551, which promotes its catalytic
activity and subsequently results in autophosphorylation at position Y223
in the Src homology 3 domain. To address the significance of Y223
autophosphorylation and the requirement of enzymatic activity for Btk
function in vivo, we generated transgenic mice that express the
autophosphorylation site mutant Y223F and the kinase-inactive mutant
K430R, respectively. We found that Y223 autophosphorylation was not
required for the regulation of IL-7 responsiveness and cell surface
phenotype changes in differentiating pre-B cells, or for peripheral B cell
differentiation. However, expression of the Y223F-Btk transgene could not
fully rescue the reduction of lambda L chain usage in Btk-deficient mice.
In contrast, transgenic expression of kinase-inactive K430R-Btk completely
reconstituted lambda usage in Btk-deficient mice, but the defective
modulation of pre-B cell surface markers, peripheral B cell survival, and
BCR-mediated NF-kappaB induction were partially corrected. From these
findings, we conclude that: 1) autophosphorylation at position Y223 is not
essential for Btk function in vivo, except for regulation of lambda L
chain usage, and 2) during B cell development, Btk partially acts as an
adapter molecule, independent of its catalytic activity
Tumor suppressor function of Bruton tyrosine kinase is independent of its catalytic activity
During B-cell development in the mouse, Bruton tyrosine kinase (Btk) and
the adaptor protein SLP-65 (Src homology 2 [SH2] domain-containing
leukocyte protein of 65 kDa) limit the expansion and promote the
differentiation of pre-B cells. Btk is thought to mainly function by
phosphorylating phospholipase Cgamma2, which is brought into close
proximity of Btk by SLP-65. However, this model was recently challenged by
the identification of a role for Btk as a tumor suppressor in the absence
of SLP-65 and by the finding that Btk function is partially independent of
its kinase activity. To investigate if enzymatic activity is critical for
the tumor suppressor function of Btk, we crossed transgenic mice
expressing the kinase-inactive K430R-Btk mutant onto a Btk/SLP-65
double-deficient background. We found that K430R-Btk expression rescued
the severe developmental arrest at the pre-B-cell stage in Btk/SLP-65
double-deficient mice. Moreover, K430R-Btk co
Counterconditioning as Treatment to Reduce Nocebo Effects in Persistent Physical Symptoms: Treatment Protocol and Study Design.
Health and self-regulatio
Placebo effects of open-label verbal suggestions on itch
Placebo effects are positive outcomes that are not due to active treatment components, which may be elicited even when patients are aware of receiving an inert substance (open-label). This proof-of-principle study investigated for the first time whether open-label placebo effects on itch can be induced by verbal suggestions alone. Ninety-two healthy volunteers were randomized to experimental (open-label suggestions) or control (no suggestions) groups. Self-reported itch evoked by histamine iontophoresis was the primary study outcome. In addition, itch expectations, skin condition and affect were assessed. The experimental group expected lower itch than the control group, which was, in turn, related to less experienced itch in this group only, although no significantly different itch levels were reported between groups. The results illustrate a potential role for open-label placebo effects in itch, and suggest that further study of verbal suggestions through an extensive explanation of placebo effects might be promising for clinical practice
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