The human side of microglia Smith, Amy M; Dragunow, Mike
Trends in neurosciences (Regular ed.),
03/2014, Volume:
37, Issue:
3
Journal Article
Peer reviewed
Highlights • There are key differences between human and rodent microglia. • Established protocols are available for primary human microglial cell culture. • Human cell models of brain disease and ...neuroinflammation are expanding. • New technologies bridge the gap between in vitro human cell and in vivo animal research. • These can be used to gain insight into human brain microglial cell physiology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The U.S. government has recently spent several hundred million dollars to promote healthy relationships in new parents. The influx of money implies that relationships of new parents are at elevated ...risk for declining satisfaction and dissolution. This meta-analysis aggregates data from 37 studies that track couples from pregnancy to after the birth of the first child and 4 studies that track childless newlywed couples over time and compare couples who do and do not become parents. Results indicate significant, small declines in relationship satisfaction for both men and women from pregnancy to 11 months postbirth; 5 studies that followed couples for 12-14 months found moderate-sized declines. Seven variables moderated the decrease in relationship satisfaction from pregnancy to early parenthood. However, the decrease in satisfaction may not indicate anything unique about the transition to parenthood; the 4 studies following newlyweds indicated that those who do not become parents experience a decrease in relationship satisfaction similar to that of parents across a comparable span of time. Implications for prevention and future directions are discussed.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
Although previous research has shown a negative relation between partner support and posttraumatic stress disorder (PTSD) symptom severity among military service members following deployment, the ...mediating mechanisms of this effect remain poorly understood. This study examined willingness to disclose deployment- and combat-related experiences as a mediating mechanism underlying the linkage between intimate partner support and PTSD symptom severity in a sample of 76 U.S. Air Force service members deployed to Iraq in a year-long, high-risk mission. Airmen's reports of overall social support, and partner support specifically, significantly predicted concurrent postdeployment PTSD symptom severity. Subsequent mediation analyses demonstrated that level of disclosure of deployment- and combat-related experiences by service members to their intimate partners accounted for a significant portion of the relation between partner support and postdeployment PTSD symptom severity. The level of Airmen's disclosure was also inversely related to levels of relationship distress. Implications of these findings for prevention and intervention strategies and for further research are discussed.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
OBJECTIVE:To 1) determine, using contemporary recombinant antigen–based assays, the aquaporin-4 (AQP4)–immunoglobulin G (IgG) detection rate in sequential sera of patients assigned a clinical ...diagnosis of neuromyelitis optica (NMO) but initially scored negative by tissue-based indirect immunofluorescence (IIF) assay; and 2) evaluate the impact of serostatus on phenotype and outcome.
METHODS:From Mayo Clinic records (2005–2011), we identified 163 patients with NMO; 110 (67%) were seropositive by IIF and 53 (33%) were scored seronegative. Available stored sera from 49 “seronegative” patients were tested by ELISA, AQP4-transfected cell-based assay, and in-house fluorescence-activated cell sorting assay. Clinical characteristics were compared based on final serostatus.
RESULTS:Thirty of the 49 IIF-negative patients (61%) were reclassified as seropositive, yielding an overall AQP4-IgG seropositivity rate of 88% (i.e., 12% seronegative). The fluorescence-activated cell sorting assay improved the detection rate to 87%, cell-based assay to 84%, and ELISA to 79%. The sex ratio (female to male) was 1:1 for seronegatives and 9:1 for seropositives (p < 0.0001). Simultaneous optic neuritis and transverse myelitis as onset attack type (i.e., within 30 days of each other) occurred in 32% of seronegatives and in 3.6% of seropositives (p < 0.0001). Relapse rate, disability outcome, and other clinical characteristics did not differ significantly.
CONCLUSIONS:Serological tests using recombinant AQP4 antigen are significantly more sensitive than tissue-based IIF for detecting AQP4-IgG. Testing should precede immunotherapy; if negative, later-drawn specimens should be tested. AQP4-IgG–seronegative NMO is less frequent than previously reported and is clinically similar to AQP4-IgG–seropositive NMO.
Background Although peanut oral immunotherapy (OIT) has been conclusively shown to cause desensitization, it is currently unknown whether clinical protection persists after stopping therapy. ...Objective Our primary objective was to determine whether peanut OIT can induce sustained unresponsiveness after withdrawal of OIT. Methods We conducted a pilot clinical trial of peanut OIT at 2 US centers. Subjects age 1 to 16 years were recruited and treated for up to 5 years with peanut OIT. The protocol was modified over time to permit dose increases to a maximum of 4000 mg/d peanut protein. Blood was collected at multiple time points. Clinical end points were measured with 5000-mg double-blinded, placebo-controlled food challenges once specific criteria were met. Results Of the 39 subjects originally enrolled, 24 completed the protocol and had evaluable outcomes. Twelve (50%) of 24 successfully passed a challenge 1 month after stopping OIT and achieved sustained unresponsiveness. Peanut was added to the diet. At baseline and the time of challenge, such subjects had smaller skin test results, as well as lower IgE levels specific for peanut, Ara h 1, and Ara h 2 and lower ratios of peanut-specific IgE/total IgE compared with subjects not passing. There were no differences in peanut IgG4 levels or functional activity at the end of the study. Conclusions This is the first demonstration of sustained unresponsiveness after peanut OIT, occurring in half of subjects treated for up to 5 years. OIT favorably modified the peanut-specific immune response in all subjects completing the protocol. Smaller skin test results and lower allergen-specific IgE levels were predictive of successful outcome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The movement of evidence-based practices (EBPs) into routine clinical usage is not spontaneous, but requires focused efforts. The field of implementation science has developed to facilitate the ...spread of EBPs, including both psychosocial and medical interventions for mental and physical health concerns.
The authors aim to introduce implementation science principles to non-specialist investigators, administrators, and policymakers seeking to become familiar with this emerging field. This introduction is based on published literature and the authors' experience as researchers in the field, as well as extensive service as implementation science grant reviewers. Implementation science is "the scientific study of methods to promote the systematic uptake of research findings and other EBPs into routine practice, and, hence, to improve the quality and effectiveness of health services." Implementation science is distinct from, but shares characteristics with, both quality improvement and dissemination methods. Implementation studies can be either assess naturalistic variability or measure change in response to planned intervention. Implementation studies typically employ mixed quantitative-qualitative designs, identifying factors that impact uptake across multiple levels, including patient, provider, clinic, facility, organization, and often the broader community and policy environment. Accordingly, implementation science requires a solid grounding in theory and the involvement of trans-disciplinary research teams. The business case for implementation science is clear: As healthcare systems work under increasingly dynamic and resource-constrained conditions, evidence-based strategies are essential in order to ensure that research investments maximize healthcare value and improve public health. Implementation science plays a critical role in supporting these efforts.
The fibroblast growth factor receptor (FGFR) signaling pathway is aberrantly activated in approximately 15% to 20% of patients with intrahepatic cholangiocarcinoma. Currently, several FGFR kinase ...inhibitors are being assessed in clinical trials for patients with FGFR-altered cholangiocarcinoma. Despite evidence of initial responses and disease control, virtually all patients eventually develop acquired resistance. Thus, there is a critical need for the development of innovative therapeutic strategies to overcome acquired drug resistance. Here, we present findings from a patient with FGFR2-altered metastatic cholangiocarcinoma who enrolled in a phase II clinical trial of the FGFR inhibitor, infigratinib (BGJ398). Treatment was initially effective as demonstrated by imaging and tumor marker response; however, after 8 months on trial, the patient exhibited tumor regrowth and disease progression. Targeted sequencing of tumor DNA after disease progression revealed the
kinase domain p.E565A and p.L617M single-nucleotide variants (SNV) hypothesized to drive acquired resistance to infigratinib. The sensitivities of these
SNVs, which were detected post-infigratinib therapy, were extended to include clinically relevant FGFR inhibitors, including AZD4547, erdafitinib (JNJ-42756493), dovitinib, ponatinib, and TAS120, and were evaluated
Through a proteomics approach, we identified upregulation of the PI3K/AKT/mTOR signaling pathway in cells harboring the
p.E565A mutation and demonstrated that combination therapy strategies with FGFR and mTOR inhibitors may be used to overcome resistance to FGFR inhibition, specific to infigratinib. Collectively, these studies support the development of novel combination therapeutic strategies in addition to the next generation of FGFR inhibitors to overcome acquired resistance in patients.
Retrieval practice protects memory against acute stress Smith, Amy M.; Floerke, Victoria A.; Thomas, Ayanna K.
Science (American Association for the Advancement of Science),
11/2016, Volume:
354, Issue:
6315
Journal Article
Peer reviewed
More than a decade of research has supported a robust consensus: Acute stress impairs memory retrieval. We aimed to determine whether a highly effective learning technique could strengthen memory ...against the negative effects of stress. To bolster memory, we used retrieval practice, or the act of taking practice tests. Participants first learned stimuli by either restudying or engaging in retrieval practice. Twenty-four hours later, we induced stress in half of the participants and assessed subsequent memory performance. Participants who learned by restudying demonstrated the typical stress-related memory impairment, whereas those who learned by retrieval practice were immune to the deleterious effects of stress. These results suggest that the effects of stress on memory retrieval may be contingent on the strength of the memory representations themselves.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Abstract Purpose (1) To assess prevalence of physical dating aggression and victimization among high school students; (2) to assess prevalence of mutual and exclusive aggression; (3) to determine ...whether aggression differs across ethnic groups and relationship type; and (4) to ascertain the likelihood of injury and breakup in individuals who reported that they were the recipients of physical aggression. Methods Students (N = 2363) from seven multiethnic high schools participated. Because males in high school date females younger than they and the reverse for females, and because males and females may underreport aggression, only within gender comparisons were conducted. Results More females reported engaging in physical aggression (40%) than reported being victims of aggression (30%). Fewer males reported engaging in physical aggression (24%) than reported being victims of physical aggression (31%). If physical aggression occurred, typically both partners were aggressive. For females, exclusive engagement in physical aggression (perpetration) was reported at higher rates than exclusively being the recipient of physical aggression (victimization) and vice versa for males. Dating aggression was less prevalent among male Asian students than other ethnic groups. Engaged males and females reported the highest rates of physical aggression. Injury was reported by over 25% of males and females who reported being the recipients of physical aggression. Conclusions Dating aggression intervention programs should address physical aggression of both males and females. Because approximately 30% of the high school males and females reported being the recipients of physical aggression by their partners, primary prevention efforts should occur before high school.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
This exploratory study was designed to address how multiple factors drawn from varying focal models and ecological levels of influence might operate relative to each other to predict partner ...aggression, using data from 453 representatively sampled couples. The resulting cross-validated models predicted approximately 50% of the variance in men's and women's partner aggression. The 3 strongest direct predictors of partner aggression for men and women were dominance/jealousy, marital adjustment, and partner responsibility attributions. Three additional direct paths to aggression for men were exposure to family-of-origin aggression, anger expression, and perceived social support. The 1 additional direct path for women was a history of their own aggression as a child or teenager. Implications for more integrative theories and intervention are discussed.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
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