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Secondary Loss (secondary + loss)
Selected AbstractsPhenotypic and genetic analysis of the cerebellar mutant tmgc26, a new ENU-induced ROR-alpha alleleEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2010Douglas J. Swanson Abstract ROR-alpha is an orphan nuclear receptor, inactivation of which cell-autonomously blocks differentiation of cerebellar Purkinje cells with a secondary loss of granule neurons. As part of our ENU mutagenesis screen we isolated the recessive tmgc26 mouse mutant, characterized by early-onset progressive ataxia, cerebellar degeneration and juvenile lethality. Detailed analysis of the tmgc26,/, cerebella revealed Purkinje cell and granule cell abnormalities, and defects in molecular layer interneurons and radial glia. Chimera studies suggested a cell-autonomous effect of the tmgc26 mutation in Purkinje cells and molecular layer interneurons, and a non-cell-autonomous effect in granule cells. The mutation was mapped to a 13-Mb interval on chromosome 9, a region that contains the ROR-alpha gene. Sequencing of genomic DNA revealed a T-to-A transition in exon 5 of the ROR-alpha gene, resulting in a nonsense mutation C257X and severe truncation of the ROR-alpha protein. Together, our data identify new roles for ROR-alpha in molecular layer interneurons and radial glia development and suggest tmgc26 as a novel ROR-alpha allele that may be used to further delineate the molecular mechanisms of ROR-alpha action. [source] Acute retinal necrosis six years after herpes simplex encephalitis: An elusive immune deficit suggested by insufficient test sensitivityJOURNAL OF MEDICAL VIROLOGY, Issue 2 2004W. Preiser Abstract A patient presented with acute retinal necrosis of the left eye. Demonstration of herpes simplex virus (HSV) DNA in the aqueous humour confirmed the diagnosis. Negative results of HSV type-specific antibody tests based on gG antigens suggested a primary HSV infection. However, the patient had a past history of laboratory-confirmed herpes simplex encephalitis 6 years ago. Using antibody tests based on whole viral lysate antigens, he was seropositive from the onset, and immunoblot testing confirmed a lack of anti-gG reactivity. To be able to assess whether this might be related to the apparent inability of his immune system to suppress clinically symptomatic HSV infection, serial samples were tested by an HSV neutralisation test and a whole-blood flow cytometric assay to determine the frequency of HSV-specific CD4 lymphocytes. However, this did not yield evidence of obvious immunodeficiency; the patient reacted similarly to known positive controls by both assays. Although type-specific HSV serological tests based on gG are generally more specific than those based on whole viral lysate antigens, they have a somewhat lower sensitivity, as a certain percentage of HSV-infected individuals do not develop antibodies against gG, and others may suffer a secondary loss of anti-gG reactivity. Thus there is a risk of missing individual infected patients. Unless this potential problem is recognised, serious consequences might possibly result. We therefore urge virologists and clinicians to exercise great care if highly specific antibody assays based on recombinant proteins are employed. J. Med. Virol. 73:250,255, 2004. © 2004 Wiley-Liss, Inc. [source] Loss of pro-apoptotic BH3-only Bcl-2 family member bim does not protect mutant Lurcher mice from neurodegenerationJOURNAL OF NEUROSCIENCE RESEARCH, Issue 5 2003Philippe Bouillet Abstract Lurcher (lc) mice have a semi-dominant mutation in the gene encoding the ,2 glutamate receptor (GRID2). The resulting constitutive activity of this receptor in heterozygous +/lc (grid+/lc) and homozygous (gridlc/lc) mice leads to the death of all cerebellar Purkinje cells and most afferent granule neurons. Some studies have indicated that the death of Purkinje cells occurs by apoptosis, and the secondary loss of granule neurons has been shown to require the pro-apoptotic Bcl-2 family member Bax. The BH3-only protein Bim has been shown to contribute to cytokine withdrawal-induced apoptosis of sympathetic neurons and to be responsible for the kidney degeneration in mice lacking the pro-survival protein Bcl-2. Because Bim is expressed strongly in cerebellar Purkinje cells, we have examined whether it has a role in their death in mutant Lurcher mice. Our studies show that Bim deficiency does not modify the Lurcher phenotype, ruling out an indispensable role for Bim in this neurodegenerative disease. © 2003 Wiley-Liss, Inc. [source] Experience of maintenance infliximab therapy for refractory ulcerative colitis from six centres in EnglandALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2009E. A. RUSSO Summary Background, Infliximab is used for treatment of Crohn's disease and, following the Active Ulcerative Colitis Trials (ACT) 1 and 2, it has been used as rescue and maintenance therapy in moderate and severe ulcerative colitis (UC). Aim, To report on English experience with maintenance infliximab in terms of response and colectomy rates and side-effect profile in UC. Methods, A retrospective audit conducted by using a web-based questionnaire filled in by 12 gastroenterologists from six English centres. Results, Of the 38 patients receiving induction with infliximab, 28 (73.6%) maintained an ongoing response (8-weekly infusions 5 mg/kg) for a mean duration of 16.8 months (range 4,59), with 21 (55.3%) being in remission. Three of 38 patients (7.9%) who also responded had a secondary loss of response after an average of 10 months (range 8,13); seven of 38 patients (18.4%) showed no response. The colectomy rate was seven of 38 (18.4%, five non-responders and two with secondary loss of response). Adverse effects occurred in five patients (13.2%). Two discontinued infliximab (alopecia, invasive breast cancer). The three less-severe adverse effects were acute and delayed-type hypersensitivity reactions and one persistent otitis media. Conclusion, Our experience suggests acceptable response rates, colectomy rates and side-effect profile of maintenance therapy with infliximab in moderate and severe UC. [source] Secondary Apoptosis of Spiral Ganglion Cells Induced by Aminoglycoside: Fas,Fas Ligand Signaling Pathway,THE LARYNGOSCOPE, Issue 9 2008Woo Yong Bae MD Abstract Objectives/Hypothesis: Hair cell loss results in the secondary loss of spiral ganglion neurons (SGNs), over a period of several weeks. The death of the SGNs themselves results from apoptosis. Previous studies have shown that several molecules are involved in the apoptosis of SGNs that occurred secondary to hair cell loss. However, the precise mechanism of apoptosis of the SGNs remains unclear. The aim of this study was to ascertain the secondary apoptosis of spiral ganglion cells induced by aminoglycoside and to investigate the role of the Fas,FasL signaling pathway using guinea pigs as an experimental animal model. Study Design: Laboratory study using experimental animals. Methods: Guinea pigs weighing 250 to 300 g (n = 21) from 3 to 4 weeks of age were used. Gentamicin (60 ,L) was injected through a cochleostomy site on their left side. At 1 (n = 7), 2 (n = 7), and 3 (n = 7) weeks after gentamicin treatment, their cochleas were obtained from their temporal bone. Hematoxylin and eosin and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling staining were performed to observe apoptosis. To investigate the involvement of the Fas,FasL signaling pathway in the secondary apoptosis of SGNs, we performed reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and immunohistochemistry. Results: A progressive loss of spiral ganglion cells with increasing time after gentamicin treatment was observed on light microscopic examination. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling staining demonstrated induction of apoptotic cell death in SGNs after gentamicin treatment. Expression of FasL increased over time after gentamicin treatment as determined by RT-PCR and western blotting. On immunohistochemical staining, we observed the localization of FasL in the SGNs. The proapoptotic molecules Bax and Bad were increased, but levels of the antiapoptotic molecule Bcl-2 were decreased at increasing survival times after gentamicin treatment on RT-PCR. The gentamicin-treated group displayed initial activation of caspase-8 and increased the cleavage of caspase-3, caspase-8, and PARP protein in a time-dependent manner. Conclusions: The secondary apoptosis of SGNs could be a result of the apoptotic Fas,FasL signaling pathway. Blocking the Fas,FasL signaling pathway could be considered as a method for preventing secondary degeneration of SGNs, and further studies are needed to confirm this. [source] Is ACCTRAN better than DELTRAN?CLADISTICS, Issue 6 2008Ingi Agnarsson When parsimony ancestral character reconstruction is ambiguous, it is often resolved in favour of the more complex character state. Hence, secondary loss (secondary "absence") of a complex feature is favoured over parallel gains of that feature as this preserves the stronger hypothesis of homology. We believe that such asymmetry in character state complexity is important information for understanding character evolution in general. However, we here point out an inappropriate link that is commonly made between this approach and the accelerated transformation (ACCTRAN) algorithm. In ACCTRAN, changes are assigned along branches of a phylogenetic tree as close to the root as possible. This has been taken to imply that ACCTRAN will minimize hypotheses of parallel origins of complex traits and thus that ACCTRAN is philosophically better justified than the alternatives, such as delayed transformation (DELTRAN), where changes are assigned along branches as close to the tips as possible. We provide simple examples to show that such views are mistaken and that neither ACCTRAN nor DELTRAN consistently minimize parallel gain of complex traits. We therefore do not see theoretical grounds for favouring the popular ACCTRAN algorithm. © The Willi Hennig Society 2008. [source] | |||||||||||||