Background: The potential benefit of hyaluronans in alleviating pain associated with osteoarthritis (OA) in joints other than the knee is of increasing interest. This double-blind, randomized, ...controlled study examined the safety and efficacy of intra-articular sodium hyaluronate (Hyalgan®) in the treatment of pain associated with ankle OA. Materials and Methods: Thirty consecutive patients with ankle OA documented by X-ray were randomized to treatment with five weekly injections of either sodium hyaluronate 2 mL (HYL) or phosphate-buffered saline 2 mL (control) in the tibiotalar joint. The primary endpoint was pain on movement and weightbearing using the Ankle Osteoarthritis Scale (AOS) 3 months after injection (a 100-mm visual analog scale VAS). Additional measures included the Western Ontario and McMaster Universities (WOMAC) OA Index and patient global assessment through 6 months; the Short Form-12 (SF-12) Health Survey at 3 months and 6 months; and all reported adverse events (AEs). Results: The study groups differed only in age, baseline WOMAC pain, and AOS total scores; 80% of the HYL and 73% of the control patients completed the study. At Month 3, the primary endpoint of the study, the HYL group demonstrated a significantly greater improvement from baseline in AOS total score than did the control group (HYL: −17.4 ± 5.0 mm; Control: −5.1 ± 4.0 mm; p = 0.0407). The incidence of AEs was low, with no significant differences between the groups. There were no post-injection flares. Conclusion: Our study suggests that sodium hyaluronate may be a safe and effective option for pain associated with ankle OA, although larger studies are needed.
Objective The purpose of this study was to compare the risk of surgically treated stress urinary incontinence (SUI) and pelvic organ prolapse (POP) in relation to mode of delivery and age at first ...childbirth. Study Design This was a cohort study. Data from the Swedish Medical Birth Register on women with only cesarean delivery (n = 30,880 women) or only vaginal delivery (n = 59,585 women) were compared with the Swedish Patient Register to calculate incidence rates and hazard ratios (95% confidence interval CI) for SUI and POP surgery. Results In analyses that were stratified by age, vaginal delivery consistently increased the risks of SUI and POP surgery. Among vaginally delivered women who were ≥30 years old, incidence rates of POP surgery were 13.8 (95% CI, 12.7–15.1), and for younger women were 6.4 (95% CI, 6.0–6.8) per 10,000 person-years. Exclusion of instrumental vaginal delivery did not alter the conclusions. Conclusion Increasing age at first delivery increased the risk of subsequent SUI and POP surgery after both vaginal and cesarean delivery.
To estimate the incidence of gestational trophoblastic disease in Nova Scotia and to evaluate the effect of time and maternal age on these rates.
Information on women with a pathologically confirmed ...diagnosis of gestational trophoblastic disease was extracted from the Nova Scotia Gestational Trophoblastic Disease Registry between 1990 and 2005. The total numbers of deliveries and pregnancies were determined from the Nova Scotia Atlee Perinatal Database and consensus data derived from Statistics Canada.
Four-hundred twenty-eight women were identified with gestational trophoblastic disease. Hydatidiform moles showed rates of 220/100,000 pregnancies, 264/100,000 total births, and 266/100,000 live births. Rates of partial mole were twofold higher than complete mole (P<.001). The rates of hydatidiform mole were highest in both younger (younger than 20 years old, P=.02) and older age groups (30-34 years old, P=.04, and at least 35 years old, P=.02). The rates of hydatidiform mole were highest in both younger (less than 20 years old, P=.02) and older age groups (30-34 years old, P .04, and 35 or more years old P=.02). The rates of partial moles were significantly higher in women older than 20 years of age (P<.001) and increased with increasing age (P<.001); the reverse trend was seen in complete mole (P<.001). There was no temporal change in rates or average age of hydatidiform mole during the study period.
The rates of hydatidiform mole in Nova Scotia estimated by this population-based study using comprehensive validated information, are higher than most previously reported. Maternal age was a significant factor in the risk for molar pregnancies.
Approximately 50% of rhesus macaques (RMs) expressing the major histocompatibility complex class I (MHC-I) allele
spontaneously control chronic-phase viremia after infection with the pathogenic ...simian immunodeficiency virus mac239 (SIVmac239) clone. CD8
T-cell responses in these animals are focused on immunodominant Mamu-B*08-restricted SIV epitopes in Vif and Nef, and prophylactic vaccination with these epitopes increases the incidence of elite control in SIVmac239-infected
-positive (
) RMs. Here we evaluated if robust vaccine-elicited CD8
T-cell responses against Vif and Nef can prevent systemic infection in
RMs following mucosal SIV challenges. Ten
RMs were vaccinated with a heterologous prime/boost/boost regimen encoding Vif and Nef, while six sham-vaccinated MHC-I-matched RMs served as the controls for this experiment. Vaccine-induced CD8
T cells against Mamu-B*08-restricted SIV epitopes reached high frequencies in blood but were present at lower levels in lymph node and gut biopsy specimens. Following repeated intrarectal challenges with SIVmac239, all control RMs became infected by the sixth SIV exposure. By comparison, four vaccinees were still uninfected after six challenges, and three of them remained aviremic after 3 or 4 additional challenges. The rate of SIV acquisition in the vaccinees was numerically lower (albeit not statistically significantly) than that in the controls. However, peak viremia was significantly reduced in infected vaccinees compared to control animals. We found no T-cell markers that distinguished vaccinees that acquired SIV infection from those that did not. Additional studies will be needed to validate these findings and determine if cellular immunity can be harnessed to prevent the establishment of productive immunodeficiency virus infection.
It is generally accepted that the antiviral effects of vaccine-induced classical CD8
T-cell responses against human immunodeficiency virus (HIV) are limited to partial reductions in viremia after the establishment of productive infection. Here we show that rhesus macaques (RMs) vaccinated with Vif and Nef acquired simian immunodeficiency virus (SIV) infection at a lower (albeit not statistically significant) rate than control RMs following repeated intrarectal challenges with a pathogenic SIV clone. All animals in the present experiment expressed the elite control-associated major histocompatibility complex class I (MHC-I) molecule Mamu-B*08 that binds immunodominant epitopes in Vif and Nef. Though preliminary, these results provide tantalizing evidence that the protective efficacy of vaccine-elicited CD8
T cells may be greater than previously thought. Future studies should examine if vaccine-induced cellular immunity can prevent systemic viral replication in RMs that do not express MHC-I alleles associated with elite control of SIV infection.
Identifying and characterizing Ag-specific CD8+ T cells are central to the study of immunological memory. Although powerful strategies such as MHC tetramers and peptide-induced cytokine production ...assays exist for identifying Ag-specific CD8+ T cells, alternate strategies that are not dependent upon a priori knowledge of the immunodominant and subdominant antigenic epitopes, as well as the MHC background of the animal are of obvious utility. In this study, we present a transgenic mouse model that uses Cre-loxP recombination to permanently mark all activated CD8+ T cells with beta-galactosidase. We used the lymphocytic choriomeningitis virus infection model to track the dynamics of the antiviral CD8+ T cell responses. We show that in this transgenic mouse model system, all of the antiviral effector and memory CD8+ T cells are contained within the beta-gal-marked CD8+ T cell population.
In early drug discovery, where chiral syntheses may not yet have been elucidated or enantiomeric separation is not feasible, screening of racemates in metabolic stability assays may offer a pragmatic ...approach. To assess the risk of incorrectly deprioritizing enantiomers due to misclassification of apparent in vitro intrinsic clearance (CLintapp), we evaluated (1) theoretical simulations; (2) literature on enantiomeric CLintapp differences; (3) historic MSD data; and (4) new data on enantiomers with high eudysmic ratios and low predicted three-dimensional similarity. Overall, the results suggested minimal risk of not progressing an enantiomer due to an appreciably different (>3-fold) racemate CLintapp.
Memory CD8+ T cells require CD28 costimulation Borowski, Annie B; Boesteanu, Alina C; Mueller, Yvonne M ...
The Journal of immunology (1950),
2007-Nov-15, Letnik:
179, Številka:
10
Journal Article
Recenzirano
Odprti dostop
CD8(+) T cells are a critical component of the adaptive immune response against infections and tumors. A current paradigm in immunology is that naive CD8(+) T cells require CD28 costimulation, ...whereas memory CD8(+) T cells do not. We show here, however, that during viral infections of mice, costimulation is required in vivo for the reactivation of memory CD8(+) T cells. In the absence of CD28 costimulation, secondary CD8(+) T cell responses are greatly reduced and this impairs viral clearance. The failure of CD8(+) T cells to expand in the absence of CD28 costimulation is CD4(+) T cell help independent and is accompanied by a failure to down-regulate Bcl-2 and by cell cycle arrest. This requirement for CD28 costimulation was shown in both influenza A and HSV infections. Thus, contrary to current dogma, memory CD8(+) T cells require CD28 costimulation to generate maximal secondary responses against pathogens. Importantly, this CD28 requirement was shown in the context of real infections were multiple other cytokines and costimulators may be up-regulated. Our findings have important implications for pathogens, such as HIV and measles virus, and tumors that evade the immune response by failing to provide CD28 costimulation. These findings also raise questions about the efficacy of CD8(+) T cell-based vaccines against such pathogens and tumors.
Certain major histocompatibility complex class I (MHC-I) alleles are associated with spontaneous control of viral replication in human immunodeficiency virus (HIV)-infected people and simian ...immunodeficiency virus (SIV)-infected rhesus macaques (RMs). These cases of "elite" control of HIV/SIV replication are often immune-mediated, thereby providing a framework for studying anti-lentiviral immunity. In this study, we examined how vaccination impacts SIV replication in RMs expressing the MHC-I allele
Approximately 21% of
and 50% of
RMs control chronic-phase viremia after SIVmac239 infection. Because CD8
T cells targeting Mamu-B*08-restricted SIV epitopes have been implicated in virologic suppression in
RMs, we investigated whether this might also be true for
RMs. Two groups of
RMs were vaccinated with genes encoding Mamu-B*17-restricted epitopes in Vif and Nef. These genes were delivered by themselves (group 1) or together with
(group 2). Group 3 included MHC-I-matched RMs and served as the control group. Surprisingly, the group 1 vaccine regimen had little effect on viral replication compared to group 3, suggesting that unlike
RMs, preexisting SIV-specific CD8
T cells alone do not facilitate long-term virologic suppression in
RMs. Remarkably, however, 5/8 group 2 vaccinees controlled viremia to <15 viral RNA copies/ml soon after infection. No serological neutralizing activity against SIVmac239 was detected in group 2, although vaccine-elicited gp140-binding antibodies correlated inversely with nadir viral loads. Collectively, these data shed new light on the unique mechanism of elite control in
RMs and implicate vaccine-induced, nonneutralizing anti-Env antibodies in the containment of immunodeficiency virus infection.
A better understanding of the immune correlates of protection against HIV might facilitate the development of a prophylactic vaccine. Therefore, we investigated simian immunodeficiency virus (SIV) infection outcomes in rhesus macaques expressing the major histocompatibility complex class I allele
Approximately 21% of
macaques spontaneously controlled chronic phase viremia after SIV infection, an effect that may involve CD8
T cells targeting Mamu-B*17-restricted SIV epitopes. We vaccinated
macaques with genes encoding immunodominant epitopes in Vif and Nef alone (group 1) or together with
(group 2). Although neither vaccine regimen prevented SIV infection, 5/8 group 2 vaccinees controlled viremia to below detection limits shortly after infection. This outcome, which was not observed in group 1, was associated with vaccine-induced, nonneutralizing Env-binding antibodies. Together, these findings suggest a limited contribution of Vif- and Nef-specific CD8
T cells for virologic control in
macaques and implicate anti-Env antibodies in containment of SIV infection.
The murine γ‐herpesvirus MHV‐68 causes an acute, transient pneumonitis, followed by an infectious mononucleosis (IM)‐like illness with splenomegaly, widespread latent infection of B lymphocytes and ...an expansion of Vβ4+ CD8+ T cells. CD8+ T cells specific for an H‐2Db‐restricted epitope were prominent during the acute respiratory infection, but their prevalence declined rapidly during the mononucleosis. In contrast, CD8+ T cells specific for an H‐2Kb‐restricted epitope, apparently expressed by virus‐infected B lymphocytes, were most numerous during the mononucleosis illness and were maintained at relatively high frequencies thereafter. The prevalence of all peptide‐specific CD8+ T cells decreased during the expansion of the Vβ4+ CD8+ population, which did not recognize any peptide epitopes identified and was apparent also in an MHC class I‐deficient environment. The CD8+ T cell population recognizing productively infected epithelial cells thus differed substantially from that responding during the IM illness.
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