Postnatal synapse elimination plays a critical role in sculpting and refining neural connectivity throughout the central and peripheral nervous systems, including the removal of supernumerary axonal ...inputs from neuromuscular junctions (NMJs). Here, we reveal a novel and important role for myelinating glia in regulating synapse elimination at the mouse NMJ, where loss of a single glial cell protein, the glial isoform of neurofascin (Nfasc155), was sufficient to disrupt postnatal remodeling of synaptic circuitry. Neuromuscular synapses were formed normally in mice lacking Nfasc155, including the establishment of robust neuromuscular synaptic transmission. However, loss of Nfasc155 was sufficient to cause a robust delay in postnatal synapse elimination at the NMJ across all muscle groups examined. Nfasc155 regulated neuronal remodeling independently of its canonical role in forming paranodal axo-glial junctions, as synapse elimination occurred normally in mice lacking the axonal paranodal protein Caspr. Rather, high-resolution proteomic screens revealed that loss of Nfasc155 from glial cells was sufficient to disrupt neuronal cytoskeletal organization and trafficking pathways, resulting in reduced levels of neurofilament light (NF-L) protein in distal axons and motor nerve terminals. Mice lacking NF-L recapitulated the delayed synapse elimination phenotype observed in mice lacking Nfasc155, suggesting that glial cells regulate synapse elimination, at least in part, through modulation of the axonal cytoskeleton. Together, our study reveals a glial cell-dependent pathway regulating the sculpting of neuronal connectivity and synaptic circuitry in the peripheral nervous system.
BACKGROUND
The distribution of drug samples is both permitted and a common practice in Canada and the US. The impact of this strategy on healthcare workers’ opinions and habits is a reason for ...concern.
OBJECTIVE
To evaluate the perceived advantages and disadvantages of using drug samples in a university hospital center.
METHOD
An observational, descriptive case study was conducted in a 500-bed university hospital center between October 18 and November 1, 2007. To obtain feedback from the healthcare staff, our research team, which was made up of a physician, pharmacy resident, 2 pharmacists, and a student in health administration, designed a 26-question survey using a Likert scale (fully agree, partially agree, partially disagree, totally disagree, do not know). The questions focused on 8 different variables (rapid treatment initiation, free cost and availability, practicality of use, patient risk, pharmacist's role, impact on choice of treatment, storage and stock management, risk of pilfering).
RESULTS
In total, 39 physicians, 18 medical residents, 17 medical clerks, 83 nurses, and 23 pharmacists working in various healthcare units and outpatient clinics (N = 180) agreed to take part in the survey and fill out the questionnaire. Generally speaking, there was a high degree of variation among the professional groups in their levels of agreement with the statements on the questionnaire. For example, 71% of the nurses, 43% of the physicians, 71% of the medical residents, and 36% of the medical clerks believed that drug samples encouraged treatment adherence, whereas only 17% of the pharmacists were of this opinion.
CONCLUSIONS
Our results show that the perceived advantages and risks of using drug samples vary by healthcare provider group and in terms of exposure or nonexposure to their use. Concerned professionals must be provided with this information and strict measures must be instituted to ensure patient security.
The recent characterization of human homologs of Toll may be the missing link for the transduction events leading to nuclear factor‐κB (NF‐κB) activity and proinflammatory gene transcription during ...innate immune response. Mammalian cells may express as many as 10 distinct Toll‐like receptors (TLRs), although TLR2 is a key receptor for recognizing cell wall components of Gram‐positive bacteria. The present study investigated the effects of circulating bacterial cell wall components on the expression of the gene‐encoding TLR2 across the mouse brain. Surprisingly, while Gram‐negative components caused a robust increase in TLR2 transcription within the cerebral tissue, peptidoglycan (PGN) and lipoteichoic acid (LTA), either alone or combined, failed to modulate the receptor transcript. Indeed, the mRNA levels for TLR2 in the choroid plexus and few other regions of the brain remained similar between vehicle‐, LTA‐, PGN‐, and LTA/PGN‐administered mice at all the times evaluated (i.e. 30 min to 24 h post‐intraperitoneal injection). This contrasts with the profound de novo expression of TLR2 following a single systemic injection of the lipopolysaccharide (LPS). The signal was first detected in regions devoid of blood–brain barrier and few blood vessels and microcapillaries. A second wave of TLR2 expression was also detected from these structures to their surrounding parenchymal cells that stained for a microglial marker iba1. The rapid induction of IκBα (index of NF‐κB activity) and up‐regulation of the adaptor protein MyD88 suggest that LPS‐induced TLR2 transcription may be dependent on the NF‐κB pathway. These data provide the evidence that TLR2 is not only present in the brain, but its encoding gene is regulated by cell wall components derived from Gram‐negative, not Gram‐positive, bacteria. The robust wave of TLR2‐expressing microglial cells may have a determinant impact on the innate immune response that occurs in the brain during systemic infection by Gram‐negative, not Gram‐positive, bacteria.
How do effector CD4 T cells escape cell death during the contraction of the immune response (IR) remain largely unknown. CD47, through interactions with thrombospondin-1 (TSP-1) and SIRP-α, is ...implicated in cell death and phagocytosis of malignant cells. Here, we reported a reduction in SIRP-α-Fc binding to effector memory T cells (T(EM)) and in vitro TCR-activated human CD4 T cells that was linked to TSP-1/CD47-induced cell death. The reduced SIRP-α-Fc binding (CD47(low) status) was not detected when CD4 T cells were stained with two anti-CD47 mAbs, which recognize distinct epitopes. In contrast, increased SIRP-α-Fc binding (CD47(high) status) marked central memory T cells (T(CM)) as well as activated CD4 T cells exposed to IL-2, and correlated with resistance to TSP-1/CD47-mediated killing. Auto-aggressive CD4 effectors, which accumulated in lymph nodes and at mucosal sites of patients with Crohn's disease, displayed a CD47(high) status despite a high level of TSP-1 release in colonic tissues. In mice, CD47 (CD47(low) status) was required on antigen (Ag)-specific CD4 effectors for the contraction of the IR in vivo, as significantly lower numbers of Ag-specific CD47(+/+)CD4 T cells were recovered when compared to Ag-specific CD47(-/-) CD4 T cells. In conclusion, we demonstrate that a transient change in the status of CD47, i.e. from CD47(high) to CD47(low), on CD4 effectors regulates the decision-making process that leads to CD47-mediated cell death and contraction of the IR while maintenance of a CD47(high) status on tissue-destructive CD4 effectors prevents the resolution of the inflammatory response.
Introduction Malignant rhabdoid tumor (MRT) is defined as a high-grade sarcoma derived from an uncertain cell of origin. Its diagnosis is associated with poor prognosis and patient's life expectancy ...is greatly reduced. Material and method Here, we describe a unique case of 9-month-old boy who presented with a large MRT arising from the soft tissue of the neck. Following intensive multimodal treatment, the patient benefited from a 25 years' remission until the discovery of multiple liver metastases. Conclusion MRT of soft tissue needs to be distinguished from other soft tissue neoplasms, as MRT is highly aggressive and is usually associated with a poor outcome. In addition, this is the longest remission time reported in a patient with soft tissue MRT and this might be related to the use of early intensive multimodal treatments.
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