Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain

As shown by analyses of morphology, gene expression, antigen-presenting function, and Flt3 dependence, the steady-state mouse brain contains a population of DCs that exhibits similarities to splenic DCs and differences from microglia

Quality Improvement Toward Decreasing High-Risk Medications for Older Veteran Outpatients

To examine the effectiveness of a quality improvement program to decrease prescribing of high-risk medications. DESIGN : Single cohort, pre- and postintervention. SETTING : Regional network of Department of Veterans Affairs medical facilities. PARTICIPANTS : Outpatient veterans aged 65 and older who received one or more high-risk medications and the prescribing clinicians. INTERVENTION : A two-stage intervention was implemented. First, a real-time warning message to prescribers appeared whenever one of the high-risk drugs was ordered; second, a personally addressed letter from the Chief Medical Officer asking prescribers to consider discontinuing the high-risk medication along with a copy of the Beers criteria article, a list of suggested alternatives to high-risk medications, and a list of older patients receiving the high-risk medications who had upcoming appointments with these prescribers. MEASUREMENTS : The primary outcome was the absence of prescribed high-risk medications for all patients in the cohort during the postintervention period. For a subgroup of the cohort whose prescribers received the second-stage intervention, an additional outcome was the absence of prescribed high-risk medications within the subgroup. RESULTS : Two thousand seven hundred fifty-three unique patients were identified in the cohort; 1,396 (50.7%) had high-risk medications discontinued, resulting in a significant decrease in the number of patients prescribed high-risk medications from the preintervention period to the postintervention period ( P <.001). Of the 801 patients in the subgroup, 72.0% (n=577) had high-risk medications discontinued ( P <.001). CONCLUSION : This multimethod intervention significantly decreased prescribing of high-risk medications to older patients. Further studies are needed to confirm the findings.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65236/1/j.1532-5415.2008.01772.x.pd

What’s in a Name? Use of Brand versus Generic Drug Names in United States Outpatient Practice

BACKGROUND: The use of brand rather than generic names for medications can increase health care costs. However, little is known at a national level about how often physicians refer to drugs using their brand or generic names. OBJECTIVE: To evaluate how often physicians refer to drugs using brand or generic terminology. DESIGN AND PARTICIPANTS: We used data from the 2003 National Ambulatory Medical Care Survey (NAMCS), a nationally representative survey of 25,288 community-based outpatient visits in the United States. After each visit, patient medications were recorded on a survey encounter form by the treating physician or transcribed from office notes. MEASUREMENTS: Our main outcome measure was the frequency with which medications were recorded on the encounter form using their brand or generic names. RESULTS: For 20 commonly used drugs, the median frequency of brand name use was 98% (interquartile range, 81–100%). Among 12 medications with no generic competition at the time of the survey, the median frequency of brand name use was 100% (range 92–100%). Among 8 medications with generic competition at the time of the survey (“multisource” drugs), the median frequency of brand name use was 79% (range 0–98%; P < .001 for difference between drugs with and without generic competition). CONCLUSIONS: Physicians refer to most medications by their brand names, including drugs with generic formulations. This may lead to higher health care costs by promoting the use of brand-name products when generic alternatives are available

Classical Flt3L-dependent dendritic cells control immunity to protein vaccine

DCs are critical for initiating immunity. The current paradigm in vaccine biology is that DCs migrating from peripheral tissue and classical lymphoid-resident DCs (cDCs) cooperate in the draining LNs to initiate priming and proliferation of T cells. Here, we observe subcutaneous immunity is Fms-like tyrosine kinase 3 ligand (Flt3L) dependent. Flt3L is rapidly secreted after immunization; Flt3 deletion reduces T cell responses by 50%. Flt3L enhances global T cell and humoral immunity as well as both the numbers and antigen capture capacity of migratory DCs (migDCs) and LN-resident cDCs. Surprisingly, however, we find immunity is controlled by cDCs and actively tempered in vivo by migDCs. Deletion of Langerin+ DC or blockade of DC migration improves immunity. Consistent with an immune-regulatory role, transcriptomic analyses reveals different skin migDC subsets in both mouse and human cluster together, and share immune-suppressing gene expression and regulatory pathways. These data reveal that protective immunity to protein vaccines is controlled by Flt3L-dependent, LN-resident cDCs.</jats:p

Absence of MHC class II on cDCs results in microbial-dependent intestinal inflammation.

Conventional dendritic cells (cDCs) play an essential role in host immunity by initiating adaptive T cell responses and by serving as innate immune sensors. Although both innate and adaptive functions of cDCs are well documented, their relative importance in maintaining immune homeostasis is poorly understood. To examine the significance of cDC-initiated adaptive immunity in maintaining homeostasis, independent of their innate activities, we generated a cDC-specific Cre mouse and crossed it to a floxed MHC class II (MHCII) mouse. Absence of MHCII on cDCs resulted in chronic intestinal inflammation that was alleviated by antibiotic treatment and entirely averted under germ-free conditions. Uncoupling innate and adaptive functions of cDCs revealed that innate immune functions of cDCs are insufficient to maintain homeostasis and antigen presentation by cDCs is essential for a mutualistic relationship between the host and intestinal bacteria

Enduring Effects of Paternal Deprivation in California Mice (Peromyscus californicus): Behavioral Dysfunction and Sex-Dependent Alterations in Hippocampal New Cell Survival

Partial funding for Open Access provided by the UMD Libraries' Open Access Publishing Fund.Early-life experiences with caregivers can significantly affect offspring development in human and non-human animals. While much of our knowledge of parent-offspring relationships stem from mother-offspring interactions, increasing evidence suggests interactions with the father are equally as important and can prevent social, behavioral, and neurological impairments that may appear early in life and have enduring consequences in adulthood. In the present study, we utilized the monogamous and biparental California mouse (Peromyscus californicus). California mouse fathers provide extensive offspring care and are essential for offspring survival. Non-sibling virgin male and female mice were randomly assigned to one of two experimental groups following the birth of their first litter: (1) biparental care: mate pairs remained with their offspring until weaning; or (2) paternal deprivation (PD): paternal males were permanently removed from their home cage on postnatal day (PND) 1. We assessed neonatal mortality rates, body weight, survival of adult born cells in the dentate gyrus of the hippocampus, and anxiety-like and passive stress-coping behaviors in male and female young adult offspring. While all biparentally-reared mice survived to weaning, PD resulted in a ~35% reduction in survival of offspring. Despite this reduction in survival to weaning, biparentally-reared and PD mice did not differ in body weight at weaning or into young adulthood. A sex-dependent effect of PD was observed on new cell survival in the dentate gyrus of the hippocampus, such that PD reduced cell survival in female, but not male, mice. While PD did not alter classic measures of anxiety-like behavior during the elevated plus maze task, exploratory behavior was reduced in PD mice. This observation was irrespective of sex. Additionally, PD increased some passive stresscoping behaviors (i.e., percent time spent immobile) during the forced swim task—an effect that was also not sex-dependent. Together, these findings demonstrate that, in a species where paternal care is not only important for offspring survival, PD can also contribute to altered structural and functional neuroplasticity of the hippocampus. The mechanisms contributing to the observed sex-dependent alterations in new cell survival in the dentate gyrus should be further investigated

Polypharmacy, drug-drug interactions, and potentially inappropriate medications in older adults with human immunodeficiency virus infection.

ObjectivesTo describe the frequency of medication-related problems in older adults with human immunodeficiency virus (HIV) infection.DesignRetrospective chart review.SettingCommunity.ParticipantsHIV-positive individuals aged 60 and older and age- and sex-matched HIV-negative individuals.MeasurementsTotal number of medications, potentially inappropriate medications (PIMs) according to the modified Beers Criteria, anticholinergic drug burden according to the Anticholinergic Risk Scale (ARS), and drug-drug interactions using the Lexi-Interact online drug interactions database.ResultsOf 89 HIV-positive participants, most were Caucasian (91%) and male (94%), with a median age of 64 (range 60-82). Common comorbidities included hyperlipidemia, hypertension, and depression. Participants were taking a median of 13 medications (range 2-38), of which only a median of four were antiretrovirals. At least one PIM was prescribed in 46 participants (52%). Sixty-two (70%) participants had at least one Category D (consider therapy modification) drug-drug interaction, and 10 (11%) had a Category X (avoid combination) interaction. One-third of these interactions were between two nonantiretroviral medications. Fifteen participants (17%) had an ARS score of 3 or greater. In contrast, HIV-negative participants were taking a median of six medications, 29% had at least one PIM, and 4% had an ARS score of 3 or greater (P &lt; .05 for each comparison, except P = .07 for anticholinergic burden).ConclusionHIV-positive older adults have a high frequency of medication-related problems, of which a large portion is due to medications used to treat comorbid diseases. These medication issues were substantially higher than HIV-negative participants. Attention to the principles of geriatric prescribing is needed as this population ages in order to minimize complications from multiple medication use