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61.
Koh AE Njoroge SW Feliu M Cook A Selig MK Latchman YE Sharpe AH Colvin RB Paul E 《Journal of autoimmunity》2011,37(1):48-57
Polymorphisms in the SLAM family of leukocyte cell surface regulatory molecules have been associated with lupus-like phenotypes in both humans and mice. The murine Slamf gene cluster lies within the lupus-associated Sle1b region of mouse chromosome 1. Non-autoreactive C57BL/6 (B6) mice that have had this region replaced by syntenic segments from other mouse strains (i.e. 129, NZB and NZW) are B6 congenic strains that spontaneously produce non-nephritogenic lupus-like autoantibodies. We have recently reported that genetic ablation of the SLAM family member CD48 (Slamf2) drives full-blown autoimmune disease with severe proliferative glomerulonephritis (CD48GN) in B6 mice carrying 129 sequences of the Sle1b region (B6.129CD48−/−). We also discovered that BALB/c mice with the same 129-derived CD48-null allele (BALB.129CD48−/−) have neither nephritis nor anti-DNA autoantibodies, indicating that strain specific background genes modulate the effects of CD48 deficiency. Here we further examine this novel model of lupus nephritis in which CD48 deficiency transforms benign autoreactivity into fatal nephritis. CD48GN is characterized by glomerular hypertrophy with mesangial expansion, proliferation and leukocytic infiltration. Immune complexes deposit in mesangium and in sub-endothelial, sub-epithelial and intramembranous sites along the glomerular basement membrane. Afflicted mice have low-grade proteinuria, intermittent hematuria and their progressive renal injury manifests with elevated urine NGAL levels and with uremia. In contrast to the lupus-like B6.129CD48−/− animals, neither BALB.129CD48−/− mice nor B6 × BALB/c F1.129CD48−/− progeny have autoimmune traits, indicating that B6-specific background genes modulate the effect of CD48 on lupus nephritis in a recessive manner. 相似文献
62.
Liang SC Greenwald RJ Latchman YE Rosas L Satoskar A Freeman GJ Sharpe AH 《European journal of immunology》2006,36(1):58-64
To compare the roles of programmed death 1 ligand 1 (PD-L1) and PD-L2 in regulating immunity to infection, we investigated responses of mice lacking PD-L1 or PD-L2 to infection with Leishmania mexicana. PD-L1(-/-) and PD-L2(-/-) mice exhibited distinct disease outcomes following infection with L. mexicana. In comparison to susceptible WT mice, PD-L1(-/-) mice showed resistance to L. mexicana, as demonstrated by reduced growth of cutaneous lesions and parasite burden. In contrast, PD-L2(-/-) mice developed exacerbated disease with increased parasite burden. Host resistance to L. mexicana is partly associated with the development of a Th1 response and down-regulation of the Th2 response. Both PD-L1(-/-) and PD-L2(-/-) mice produced levels of IFN-gamma similar to WT mice. However, the development of IL-4-producing cells was reduced in PD-L1(-/-) mice, demonstrating a role for PD-L1 in regulating Th cell differentiation. This inadequate Th2 response may explain the increased resistance of PD-L1(-/-) mice. Although no alterations in Th1/Th2 skewing were observed in PD-L2(-/-) mice, PD-L2(-/-) mice exhibited a marked increase in L. mexicana-specific antibody production. Increased Leishmania-specific IgG production may suppress the healing response through FcgammaR ligation on macrophages. Taken together, our results demonstrate that PD-L1 and PD-L2 have distinct roles in regulating the immune response to L. mexicana. 相似文献
63.
Papageorgiou T Guibert J Goffinet F Patrat C Fulla Y Janssens Y Zorn JR 《Human reproduction (Oxford, England)》2002,17(11):2846-2850
BACKGROUND: High, normal and poor responders are usually defined by reference to subjectively selected estradiol E2 levels at days 4-6 and the day of hCG administration (d-hCG). The purpose of this study was to use E2 percentile curves from day 5 until d-hCG to determine high, normal and poor responders, and to predict IVF outcome. METHODS: In this retrospective study, 762 patients underwent 905 cycles with a GnRH agonist/recombinant FSH short protocol. They were divided into three groups according to their age. Percentile E2 curves according to E2 levels were plotted. High responders were those patients with E2 levels above the 90th percentile, normal responders had E2 between the 10th and 90th percentiles, and poor responders had E2 below the 10th percentile. RESULTS: IVF outcome, expressed as number of oocytes, total embryos obtained and number of high grade embryos, was significantly better for patients with E2 above the 90th percentile at d-hCG for the three age groups and at day 5 for group A (<35 years). Pregnancy rates were higher for high responders, but the difference did not reach statistical significance. CONCLUSIONS: Percentile curves can be useful in controlled ovarian stimulation cycles to define high, normal and poor responders, and also to predict IVF outcome. 相似文献
64.
Yvette van Ierland Gijs Elshout Henri?tte A Moll Ruud G Nijman Yvonne Vergouwe Johan van der Lei Marjolein Y Berger Rianne Oostenbrink 《The British journal of general practice》2014,64(618):e1-e9
Background
The diagnostic value of alarm features of serious infections in low prevalence settings is unclear.Aim
To explore to what extent alarm features play a role in referral to the emergency department (ED) by GPs who face a febrile child during out-of-hours care.Design and setting
Observational study using semi-structured, routine clinical practice data of febrile children (<16 years) presenting to GP out-of-hours care.Method
Logistic regression analyses were performed to assess the association between alarm features of serious infections (selected from two guidelines and one systematic review) and referral to the ED. Adherence to the guideline was explored by a 2×2 contingency table.Results
In total 794 (8.1%) of 9794 eligible patients were referred to the ED. Alarm signs most strongly associated with referral were ‘age <1 month’, ‘decreased consciousness’, ‘meningeal irritation’, and ‘signs of dehydration’. Nineteen percent of 3424 children with a positive referral indication according to the guideline were referred to the ED. The majority of those not referred had only one or two alarm features present. A negative referral indication was adhered to for the majority of children. Still, in 20% of referred children, alarm features were absent.Conclusion
In contrast to guidance, GPs working in primary out-of-hours care seem more conservative in referring febrile children to the ED, especially if only one or two alarm features of serious infection are present. In addition, in 20% of referred children, alarm features were absent, which suggests that other factors may be important in decisions about referral of febrile children to the hospital ED. 相似文献65.
Topical rather than intradermal application of the TLR7 ligand imiquimod leads to human dermal dendritic cell maturation and CD8+ T‐cell cross‐priming 下载免费PDF全文
Cynthia M. Fehres Sven C. M. Bruijns Astrid J. van Beelen Hakan Kalay Martino Ambrosini Erik Hooijberg Wendy W. J. Unger Tanja D. de Gruijl Yvette van Kooyk 《European journal of immunology》2014,44(8):2415-2424
Toll‐like receptor (TLR) ligands are attractive candidate adjuvants for therapeutic cancer vaccines, since TLR signaling stimulates and tunes both humoral and cellular immune responses induced by dendritic cells (DCs). Given that human skin contains a dense network of DCs, which are easily accessible via (intra‐)dermal delivery of vaccines, skin is actively explored as an antitumor vaccination site. Here we used a human skin explant model to explore the potential of TLR ligands as adjuvants for DC activation in their complex microenvironment. We show that topical application of Aldara skin cream, 5% of which comprises the TLR7 agonist imiquimod, significantly enhanced DC migration as compared with that resulting from intradermal injection of the TLR7/8 ligand R848 or the soluble form of imiquimod. Moreover, Aldara‐treated DCs showed highest levels of the costimulatory molecules CD86, CD83, CD40, and CD70. Topical Aldara induced the highest production of pro‐inflammatory cytokines in skin biopsies. When combined with intradermal peptide vaccination, Aldara‐stimulated DCs showed enhanced cross‐presentation of the melanoma antigen MART‐1, which resulted in increased priming and activation of MART‐1‐specific CD8+ T cells. These results point to advantageous effects of combining the topical application of Aldara with antitumor peptide vaccination. 相似文献
66.
Theresa Förg Christian T. Mayer Abdul Mannan Baru Catharina Arnold‐Schrauf Wendy W. J. Unger Hakan Kalay Yvette van Kooyk Tim Sparwasser 《European journal of immunology》2013,43(10):2543-2553
Vaccination is one of the oldest yet still most effective methods to prevent infectious diseases. However, eradication of intracellular pathogens and treatment of certain diseases like cancer requiring efficient cytotoxic immune responses remain a medical challenge. In mice, a successful approach to induce strong cytotoxic CD8+ T‐cell (CTL) reactions is to target antigens to DCs using specific antibodies against surface receptors in combination with adjuvants. A major drawback for translating this strategy into one for the clinic is the lack of analogous targets in human DCs. DC‐SIGN (DC‐specific‐ICAM3‐grabbing‐nonintegrin/CD209) is a C‐type lectin receptor with potent endocytic capacity and a highly restricted expression on human immature DCs. Therefore, DC‐SIGN represents an ideal candidate for DC targeting. Using transgenic mice that express human DC‐SIGN under the control of the murine CD11c promoter (hSIGN mice), we explored the efficacy of anti‐DC‐SIGN antibodies to target antigens to DCs and induce protective immune responses in vivo. We show that anti‐DC‐SIGN antibodies conjugated to OVA induced strong and persistent antigen‐specific CD4+ and CD8+ T‐cell responses, which efficiently protected from infection with OVA‐expressing Listeria monocytogenes. Thus, we propose DC targeting via DC‐SIGN as a promising strategy for novel vaccination protocols against intracellular pathogens. 相似文献
67.
68.
Maria Oden Yvette Mirabal Marc Epstein Rebecca Richards-Kortum 《Annals of biomedical engineering》2010,38(9):3031-3041
Recent reports have highlighted the need for educational programs to prepare students for careers developing and disseminating
new interventions that improve global public health. Because of its multi-disciplinary, design-centered nature, the field
of Biomedical Engineering can play an important role in meeting this challenge. This article describes a new program at Rice
University to give undergraduate students from all disciplines a broad background in bioengineering and global health and
provides an initial assessment of program impact. Working in partnership with health care providers in developing countries,
students in the Beyond Traditional Borders (BTB) initiative learn about health challenges of the poor and put this knowledge
to work immediately, using the engineering design process as a framework to formulate solutions to complex global health challenges.
Beginning with a freshman design project and continuing through a capstone senior design course, the BTB curriculum uses challenges
provided by partners in the developing world to teach students to integrate perspectives from multiple disciplines, and to
develop leadership, communication, and teamwork skills. Exceptional students implement their designs under the guidance of
clinicians through summer international internships. Since 2006, 333 students have designed more than 40 technologies and
educational programs; 28 have been implemented in sub-Saharan Africa, Latin America, the Caribbean, southeast Asia, and the
United States. More than 18,000 people have benefited from these designs. 95% of alumni who completed an international internship
reported that participation in the program changed or strengthened their career plans to include a focus on global health
medicine, research, and/or policy. Empowering students to use bioengineering design to address real problems is an effective
way to teach the new generation of leaders needed to solve global health challenges. 相似文献
69.
Detection and assignment of mutations and minihaplotypes in human DNA using peptide mass signature genotyping (PMSG): application to the human RDS/peripherin gene 下载免费PDF全文
Telmer CA Retchless AC Kinsey AD Conley Y Rigatti B Gorin MB Jarvik JW Retchless AR 《Genome research》2003,13(8):1944-1951
Peptide mass-signature genotyping (PMSG) is a scanning genotyping method that identifies mutations and polymorphisms by translating the sequence of interest in more than one reading frame and measuring the masses of the resulting peptides by mass spectrometry. PMSG was applied to the RDS/peripherin gene of 16 individuals from a family exhibiting autosomal dominant macular degeneration. The method revealed an A-->T transversion in the 5' splice site of intron 2 that is the likely cause of the disease. It also revealed four different minihaplotypes in exon 3 that represent particular combinations of SNPs at four different locations. This study demonstrates the utility of PMSG for identifying and characterizing point mutations and local minihaplotypes that are not readily analyzed by other approaches. 相似文献
70.
Brief report: breast-fed one-week-olds demonstrate superior neurobehavioral organization 总被引:5,自引:0,他引:5
OBJECTIVES: Following studies conducted during the immediate newborn stage, we investigated whether one-week-olds' neurobehavioral functioning was differentiated by feeding method. We also examined whether feeding-method effects differed among infants of adolescent mothers. METHOD: Participants were infants (N = 83) of breast-feeding (N = 41) and formula-feeding (N = 42) mothers. Approximately half of each group's participants had adolescent mothers and half were infants of adult mothers. Assessments on the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) were conducted on the infants when they were 8.95 days of age. RESULTS: Breast-fed infants surpassed formula-fed infants on items of the orientation, motor, range of state, and state regulation dimensions of the BNBAS. Breast-fed infants also exhibited fewer abnormal reflexes, signs of depression, and withdrawal. Infants of adolescent mothers did not differ from those of adult mothers, regardless of feeding method. CONCLUSION: These data provide compelling evidence that breast-feeding is advantageous to neonates' neurobehavioral organization. 相似文献