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91.
Kaufmann GR Zaunders J Murray J Kelleher AD Lewin SR Solomon A Smith D Cooper DA 《AIDS research and human retroviruses》2001,17(2):147-159
A major goal of antiretroviral HIV-1 therapy is the reversal of HIV-1-associated immunological dysfunction. However, the pathogenetic mechanisms involved and their significance are largely unknown. On the basis of the life cycle of naive, activated, and memory CD4(+) T cell subsets, a mathematical model of immune reconstitution was developed and applied to data for T cell subsets in individuals with acute or chronic HIV-1 infection receiving antiretroviral therapy. The final model that most accurately fitted the data, and resulted in realistic estimates for CD4(+) T cell turnover, considered three pathways of immune reconstitution for naive cells, including thymic production, peripheral expansion, and redistribution of naive cells from lymphoid tissue. The reconstitution of the memory compartment was fitted through differentiation and expansion of naive cells and peripheral expansion of memory cells as well as redistribution of memory cells trapped in the lymphoid tissue. Estimated median half-lives for naive and memory CD4(+) T cells were 114 and 21 days, while total production rates were 9.1 x 10(7) and 2.4 x 10(9) cells/day, respectively. Peripheral expansion and thymic production contributed equally to the regeneration of naive cells, but peripheral expansion of memory cells was larger than production of these cells by differentiation of naive cells. A comparison of immune reconstitution in acute and chronic HIV-1 infection revealed that, after adjustment for age, the main difference was the more rapid release of a larger number of naive cells in treated acute HIV-1 infection. Thymic function and peripheral expansion rates, however, were similar in both cohorts. 相似文献
92.
Background
With mental ill-health on the rise globally, it is crucial to investigate whether the needs of individuals with mental ill-health are fully addressed. Attempts to measure negative consequences of unmet needs have been limited by the use of cross-sectional study designs or self-report measures. We aimed to investigate the interplay between perceived mental ill-health and unmet need in relation to mental health on a population level.Methods
A record linkage methodology was implemented drawing information from the 2011 Northern Ireland Census returns and a population-wide prescribing database (n=286?717). Chronic mental ill-health was assessed through the Census self-reported mental health question (presence of an emotional, psychological, or mental health condition that has lasted or is expected to last at least 12 months) and compared with regular psychotropic medication use (monthly dosage of antidepressant, anxiolytic, antipsychotic, or antimania medication) in the 6 and 12 months after the Census. Logistic regression models adjusted for demography (age, sex, ethnicity, marital status, educational attainment, occupational social class), household (tenure, car availability), and area variables (urbanicity, deprivation).Findings
Overall, 23?803 individuals (8%) aged 25–74 years reported a chronic mental health condition, with low rates among ethnic minorities (129 [3%] of 3897 non-White individuals in receipt of medication). Of the individuals with self-reported mental ill-health, 5246 (22%) did not use psychotropic medication over the following 6 months, and 4412 (19%) did not use them by 12 months. Lower uptake was noted among men (odds ratio 0·56, 95% CI 0·52–0·60), non-white ethnic minorities (0·38, 0·26–0·54), and individuals separated, divorced, or widowed (0·75, 0·68–0·82) or unemployed (0·65, 0·53–0·81).Interpretation
Discrepancies between population mental ill-health and uptake of pharmacological treatment were more evident among men, ethnic minorities, and the economically disadvantaged. This study indicates that administrative data linkages can provide a valuable resource to define population characteristics, and inform policy and practice. However, the findings might be limited by availability of data on psychosocial and non-pharmacological interventions, use of proxy measures of mental health treatment, and the self-reported nature of the Census. Further research should explore whether this variation is due to stigma or lack of understanding or knowledge of available health-care services.Funding
None. 相似文献93.
Ihuoma U. Eneli Reena Oza-Frank Kathryn Grover Rick Miller Kelly Kelleher 《American journal of public health》2014,104(10):1822-1825
Sugar-sweetened beverage (SSB) consumption is linked to increased weight and obesity in children and remains the major source of added sugar in the typical US diet across all age groups. In an effort to improve the nutritional offerings for patients and employees within our institution, Nationwide Children’s Hospital in Columbus, Ohio, implemented an SSB ban in 2011 in all food establishments within the hospital. In this report, we describe how the ban was implemented. We found that an institutional SSB ban altered beverage sales without revenue loss at nonvending food locations. From a process perspective, we found that successful implementation requires excellent communication and bold leadership at several levels throughout the hospital environment.Sugar-sweetened beverage (SSB) consumption is linked to increased weight and obesity in children and remains the major source of added sugar in the typical US diet across all age groups.1 For the purposes of this report, we define SSBs as soft drinks (soda or pop), fruit drinks, sports drinks, energy drinks, and any other beverages to which sugar, typically high fructose corn syrup or sucrose (table sugar), has been added.2 Although recent studies indicate an overall trending down of SSB intake, higher rates of consumption occur among low-income and minority children.1In 2010 the Ohio legislature passed the Healthy Choices for Healthy Children Act to help schools play an active role in decreasing the high childhood obesity rates.3 A component of this law includes an SSB ban in schools. In an effort to recognize the importance of and support this statewide initiative, Nationwide Children’s Hospital (NCH) partnered with leaders in the business community to gain bipartisan support for this legislation. To further emphasize support, NCH decided to lead by example and expand the hospital’s already existing Wellness Initiative to improve the nutritional offerings for patients and employees through implementation of an SSB ban in all food establishments within the hospital and approved catering companies. Such a ban would not only impact the food environment for children but also their families as well as hospital staff. In this report, we describe our implementation of an organizational SSB ban and report the beverage consumption and sales revenue for the years preceding and following the ban, as well as key steps to implementation. 相似文献
94.
Brenda J. Meyer John M. Gardiner Dermot M. Bowler 《Journal of autism and developmental disorders》2014,44(10):2514-2524
Rehearsal strategies of adults with autism spectrum disorders (ASDs) and demographically matched typically developed (TD) adults were strategically manipulated by cueing participants to either learn, or forget each list word prior to a recognition task. Participants were also asked to distinguish between autonoetic and noetic states of awareness using the Remember/Know paradigm. The ASD group recognised a similar number of to-be-forgotten words as the TD group, but significantly fewer to-be-learned words. This deficit was only evident in Remember responses that reflect autonoetic awareness, or episodic memory, and not Know responses. These findings support the elaborative encoding deficit hypothesis and provide a link between the previously established mild episodic memory impairments in adults with high functioning autism and the encoding strategies employed. 相似文献
95.
Gabriel Duette Bonnie Hiener Hannah Morgan Fernando G. Mazur Vennila Mathivanan Bethany A. Horsburgh Katie Fisher Orion Tong Eunok Lee Haelee Ahn Ansari Shaik Rmi Fromentin Rebecca Hoh Charline Bacchus-Souffan Najla Nasr Anthony L. Cunningham Peter W. Hunt Nicolas Chomont Stuart G. Turville Steven G. Deeks Anthony D. Kelleher Timothy E. Schlub Sarah Palmer 《The Journal of clinical investigation》2022,132(7)
Despite long-term antiretroviral therapy (ART), HIV-1 persists within a reservoir of CD4+ T cells that contribute to viral rebound if treatment is interrupted. Identifying the cellular populations that contribute to the HIV-1 reservoir and understanding the mechanisms of viral persistence are necessary to achieve an effective cure. In this regard, through Full-Length Individual Proviral Sequencing, we observed that the HIV-1 proviral landscape was different and changed with time on ART across naive and memory CD4+ T cell subsets isolated from 24 participants. We found that the proportion of genetically intact HIV-1 proviruses was higher and persisted over time in effector memory CD4+ T cells when compared with naive, central, and transitional memory CD4+ T cells. Interestingly, we found that escape mutations remained stable over time within effector memory T cells during therapy. Finally, we provided evidence that Nef plays a role in the persistence of genetically intact HIV-1. These findings posit effector memory T cells as a key component of the HIV-1 reservoir and suggest Nef as an attractive therapeutic target. 相似文献
96.
97.
Youren Tong Hiroo Yamaguchi Emilie Giaime Scott Boyle Raphael Kopan Raymond J. Kelleher III Jie Shen 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(21):9879-9884
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson''s disease. LRRK2 is a large protein containing a small GTPase domain and a kinase domain, but its physiological role is unknown. To identify the normal function of LRRK2 in vivo, we generated two independent lines of germ-line deletion mice. The dopaminergic system of LRRK2−/− mice appears normal, and numbers of dopaminergic neurons and levels of striatal dopamine are unchanged. However, LRRK2−/− kidneys, which suffer the greatest loss of LRRK compared with other organs, develop striking accumulation and aggregation of α-synuclein and ubiquitinated proteins at 20 months of age. The autophagy–lysosomal pathway is also impaired in the absence of LRRK2, as indicated by accumulation of lipofuscin granules as well as altered levels of LC3-II and p62. Furthermore, loss of LRRK2 dramatically increases apoptotic cell death, inflammatory responses, and oxidative damage. Collectively, our findings show that LRRK2 plays an essential and unexpected role in the regulation of protein homeostasis during aging, and suggest that LRRK2 mutations may cause Parkinson''s disease and cell death via impairment of protein degradation pathways, leading to α-synuclein accumulation and aggregation over time. 相似文献
98.
John V. Reynolds Narayanasamy Ravi Cian Muldoon John O. Larkin Suzanne Rowley Ken O’Byrne Donal Hollywood Dermot O’Toole 《World journal of surgery》2010,34(12):2821-2829
Background
Adenocarcinoma of the esophagogastric junction (AEG) as described by Siewert et al. is classified as one entity in the latest (7th Edition) American Joint Cancer Committee/International Union Against Cancer (AJCC/UICC) manual, compared with the previous mix of esophageal and gastric staging systems. The origin of AEG tumors, esophageal or gastric, and their biology remain controversial, particularly for AEG type II (cardia) tumors. 相似文献99.
Identification of circulating antigen-specific CD4+ T lymphocytes with a CCR5+, cytotoxic phenotype in an HIV-1 long-term nonprogressor and in CMV infection
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Zaunders JJ Dyer WB Wang B Munier ML Miranda-Saksena M Newton R Moore J Mackay CR Cooper DA Saksena NK Kelleher AD 《Blood》2004,103(6):2238-2247
Antigen-specific CD4+ effector T cells primarily provide help for B-cell antibody responses and CD8+ cytotoxic T-lymphocyte (CTL) responses. We have found an expanded population of HIV-1 p24-specific, T-cell receptor V beta 17+, CD4+ T lymphocytes, defined by in vitro proliferative and interferon-gamma responses to a 15-mer Gag peptide, in the peripheral blood of an individual with long-term nonprogressive HIV-1 infection. Ex vivo, these cells were CCR5+ and CCR7-, consistent with an effector/memory function. Surprisingly, these cells highly expressed several proteins characteristic of cytotoxic lymphocytes, including TIA-1 (T-cell intracellular antigen 1; GMP-17/NKG7), granzymes A and B, CD161 (NKRP-1), and CD244 (C1.7/2B4). Following in vitro peptide stimulation, these cells produced interleukin 2 (IL-2) and intracellular CD40L, suggesting possible helper function, in addition to induction of perforin and cytotoxicity. A subset of cytomegalovirus (CMV)-specific CD4+ T cells in healthy adults similarly expressed these CTL markers and CCR5, ex vivo. Furthermore, this distinct subset of CD4+ T cells was significantly elevated in healthy CMV-seropositive adults, compared with CMV-seronegative individuals. These results suggest that CCR5+ CD4+ CTL may be a major effector mechanism of the immune response to viral infections in humans. Moreover, expression of CCR5 may render them particularly susceptible to cytopathic effects during progressive HIV-1 infection. 相似文献
100.