Vesicoureteral reflux (VUR) is the most common underlying etiology responsible for febrile urinary tract infections (UTIs) or pyelonephritis in children. Along with the morbidity of pyelonephritis, long-term sequelae of recurrent renal infections include renal scarring, proteinuria, and hypertension. Treatment is directed toward the prevention of recurrent infection through use of continuous antibiotic prophylaxis during a period of observation for spontaneous resolution or by surgical correction. In children, bowel and bladder dysfunction (BBD) plays a significant role in the occurrence of UTI and the rate of VUR resolution. Effective treatment of BBD leads to higher rates of spontaneous resolution and decreased risk of UTI.
Objective: To report on the response to therapy in a patient with autoimmune autonomic ganglionopathy with a high titer of an autoantibody directed against the α-3 subunit of the nicotinic acetylcholine receptor (nAChR) of the autonomic ganglia. Design: Case report. Setting: University-based referral center for autonomic dysfunction. Patient: Patient with prior indolent B-cell lymphoma who presented with symptomatic orthostatic hypotension and autonomic failure and was found to have a high titer of nAChR antibody. Intervention: Plasma exchange and rituximab therapy (both initial 4-week therapy and maintenance therapy). Main Outcome Measures: Autonomic ganglionic antibody titer; the autonomic assessments were the presence of orthostatic hypotension, the concentration of plasma norepinephrine, and quantitative sweat testing. Results: Treatment with rituximab followed by plasma exchange significantly decreased the nAChR antibody titers for a short time, and then the titers increased. The titers suppressed to almost undetectable levels once regular maintenance therapy with rituximab was initiated. Reduction in nAChR antibody titer resulted in a decrease in orthostatic hypotension, an increased concentration of upright plasma norepinephrine, improvement in some sweat function, and improvement in symptoms. Conclusions: Long-term rituximab therapy suppressed autoantibody production to undetectable levels over the course of 2 years and resulted in sustained clinical improvement in this patient with debilitating autoimmune autonomic ganglionopathy. More data are needed before rituximab therapy can be recommended as routine therapy for this disorder.
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Vineshkumar Thidil Puliyappadamba;
Sharmistha Chakraborty;
Sandili S. Chauncey;
Li Li;
Kimmo J. Hatanpaa;
Bruce Mickey;
Shayan Noorani;
Hui-Kuo Shu;
Sandeep Burma;
David A. Boothman;
Amyn A. Habib
RIP1 is a central mediator of cell death in response tocell stress but can also mediate cell survival by activating NF-κB. Here, we show that RIP1 acts as a switch in EGFR signaling. EGFRvIII is an oncogenic mutant that does not bind ligand and is coexpressed with EGFRWT in glioblastoma multiforme (GBM). EGFRvIII recruits ubiquitin ligases to RIP1, resultingin K63-linked ubiquitination of RIP1. RIP1 binds toTAK1 and NEMO, forming an EGFRvIII-RIP1 signalosome that activates NF-κB. RIP1 is essential for EGFRvIII-mediated oncogenicity and correlates with NF-κB activation in GBM. Surprisingly, activation of EGFRWT with EGF results in a negative regulation of EGFRvIII, with dissociation of the EGFRvIII-RIP1 signalosome, loss of RIP1 ubiquitination and NF-κB activation, and association of RIP1 with FADD and caspase-8. If EGFRWT is overexpressed with EGFRvIII, the addition of EGF leads to a RIP1 kinase-dependent cell death. The EGFRWT-EGFRvIII-RIP1 interplay may regulate oncogenicity and vulnerability to targeted treatment in GBM
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Karen L. Kaul;
Linda M. Sabatini;
Gregory J. Tsongalis;
Angela M. Caliendo;
Randall J. Olsen;
Edward R Ashwood;
Sherri Bale;
Robert Benirschke;
Dean Carlow;
Birgit H Funke;
Wayne W. Grody;
Randall T. Hayden;
Madhuri Hegde;
Elaine Lyon;
Kazunori Murata;
Melissa Pessin;
Richard D. Press;
Richard B. Thomson
An explosion of knowledge and technology is revolutionizing medicine and patient care. Novel testing must be brought to the clinic with safety and accuracy, but also in a timely and cost-effective manner, so that patients can benefit and laboratories can offer testing consistent with current guidelines. Under the oversight provided by the Clinical Laboratory Improvement Amendments, laboratories have been able to develop and optimize laboratory procedures for use in-house. Quality improvement programs, interlaboratory comparisons, and the ability of laboratories to adjust assays as needed to improve results, utilize new sample types, or incorporate new mutations, information, or technologies are positive aspects of Clinical Laboratory Improvement Amendments oversight of laboratory-developed procedures. Laboratories have a long history of successful service to patients operating under Clinical Laboratory Improvement Amendments. A series of detailed clinical examples illustrating the quality and positive impact of laboratory-developed procedures on patient care is provided. These examples also demonstrate how Clinical Laboratory Improvement Amendments oversight ensures accurate, reliable, and reproducible testing in clinical laboratories.
The colonic mucosa provides a vital defensive barrier separating the body from the microbial populations residing in the intestinal lumen. Indeed, growing evidence shows that loss of this barrier may cause disease or exacerbate disease progression. The loss of barrier integrity increases the translocation of bacterial antigens and stimulates inflammation in the intestinal mucosa, which is the central pathological feature of inflammatory bowel diseases (IBDs). This review focuses on how intestinal mucus and intercellular tight junctions (TJs) act together to maintain the integrity of the colonic barrier and how barrier integrity is dysregulated in IBD.
Some pathogens are able to establish themselves within the host because they have evolved mechanisms to disrupt host innate immunity. For example, a number of pathogens secrete preformed effector proteins via type III secretion apparati that influence innate immune or apoptotic signaling pathways. One group of effector proteins that usurp innate immune signaling is the YopJ-like family of bacterial effector proteins, which includes AopP from Aeromonas salmonicida. Aeromonas species are known to cause gastrointestinal disease in humans, and are associated mainly with subcutaneous wound infections and septicemia in other metazoans, particularly fish. AopP has been reported to have inhibitory activity against the NF-κB pathway in cultured cells, although the pathological outcomes of AopP activity have not been examined. Here, we show that AopP has potent pro-apoptotic activity when expressed in cultured mammalian macrophage or epithelial cells, or when ectopically expressed in Drosophila melanogaster hemocytes or imaginal disk epithelial cells. Furthermore, apoptosis was significantly elevated upon concurrent AopP expression and TNF-α cellular stimulation. Together, our results demonstrate how the specificity of a YopJ-like protein toward signaling pathways directly governs cellular pathological outcome in disease.
Host signaling pathways play important roles in the replication of influenza virus, but their functional effects remain to be characterized at the molecular level. Here we identify two receptor tyrosine kinase inhibitors (RTKIs) of the tyrphostin class that exhibit robust antiviral activity against influenza A virus replication in cultured cells. One of these (AG879) is a selective inhibitor of the nerve growth factor receptor and human epidermal growth factor receptor 2 (TrkA/HER2) signaling; the other, tyrphostin A9 (A9), inhibits the platelet-derived growth factor receptor (PDGFR) pathway. We find that each inhibits at least three postentry steps of the influenza virus life cycle: AG879 and A9 both strongly inhibit the synthesis of all three influenza virus RNA species, block Crm1-dependent nuclear export, and also prevent the release of viral particles through a pathway that is modulated by the lipid biosynthesis enzyme farnesyl diphosphate synthase (FPPS). Tests of short hairpin RNA (shRNA) knockdown and additional small-molecule inhibitors confirmed that interventions targeting TrkA can suppress influenza virus replication. Our study suggests that host cell receptor tyrosine kinase signaling is required for maximal influenza virus RNA synthesis, viral ribonucleoprotein (vRNP) nuclear export, and virus release and that specific RTKIs hold promise as novel anti-influenza virus therapeutics.
Sialylated lipids serve as cellular receptors for polyomaviruses. Using pharmacological inhibitors and cell lines derived from knockout mice, we demonstrate that Abl family tyrosine kinases are required for replication of mouse polyomavirus and BK virus, a human polyomavirus associated with allograft failure following kidney transplantation. We show that decreasing Abl family kinase activity results in low levels of cell surface ganglioside receptors for mouse polyomavirus and that inhibition of sialidase activity promotes virion binding in the absence of Abl family kinase activity. These data provide evidence that Abl family kinases reduce ganglioside turnover in the plasma membrane by inhibiting host cell sialidase activity. Thus, Abl family kinases regulate the susceptibility of cells to polyomavirus infection by modulating gangliosides required for viral attachment.
Aberrant expression of regulatory receptors programmed death-1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) is linked with dysregulation and exhaustion of T lymphocytes during chronic human immunodeficiency virus type 1 (HIV-1) infection; however, less is known about whether a similar process impacts B-lymphocyte function during HIV-1 infection. We reasoned that disruption of the peripheral B cell compartment might be associated with decreased neutralizing antibody activity. Expression of markers that indicate dysregulation (BTLA and PD-1), immune activation (CD95), and proliferation (Ki-67) was evaluated in B cells from HIV-1-infected viremic and aviremic subjects and healthy subjects, in conjunction with immunoglobulin production and CD4 T cell count. Viral load and cross-clade neutralizing activity in plasma from viremic subjects were also assessed. Dysregulation of B lymphocytes was indicated by a marked disruption of peripheral B cell subsets, increased levels of PD-1 expression, and decreased levels of BTLA expression in viremic subjects compared to aviremic subjects and healthy controls. PD-1 and BTLA were correlated in a divergent fashion with immune activation, CD4 T cell count, and the total plasma IgG level, a functional correlate of B cell dysfunction. Within viremic subjects, the total IgG level correlated directly with cross-clade neutralizing activity in plasma. The findings demonstrate that even in chronically infected subjects in which B lymphocytes display multiple indications of dysfunction, antibodies that mediate cross-clade neutralization breadth continue to circulate in plasma.