Key points The locus coeruleus (LC) contains noradrenergic (NA) neurons that respond to novel stimuli in the environment with phasic activation to initiate an orienting response; phasic LC activation is also triggered by stimuli, representing the outcome of task‐related decision processes, to facilitate ensuing behaviours and help optimize task performance. Here, we report that LC‐NA neurons exhibit bursts of action potentials in vitro resembling phasic LC activation in vivo, and the activity is gated by inhibitory interneurons (I‐INs) located in the peri‐LC. We also observe that inhibition of peri‐LC I‐INs enhances prepulse inhibition and axons from cortical areas that play important roles in evaluating the cost/reward of a stimulus synapse on both peri‐LC I‐INs and LC‐NA neurons. The results help us understand the cellular mechanisms underlying the generation and regulation of phasic LC activation with a focus on the role of peri‐LC I‐INs. Abstract Noradrenergic (NA) neurons in the locus coeruleus (LC) have global axonal projection to the brain. These neurons discharge action potentials phasically in response to either novel stimuli in the environment to initiate an orienting behaviour or stimuli representing the outcome of task‐related decision processes to facilitate ensuing behaviours and help optimize task performance. Nevertheless, the cellular mechanisms underlying the generation and regulation of phasic LC activation remain unknown. We report here that LC‐NA neurons recorded in brain slices exhibit bursts of action potentials that resembled the phasic activation‐pause profile observed in animals. The activity was referred to as phasic‐like activity (PLA) and was suppressed and enhanced by blocking excitatory and inhibitory synaptic transmissions, respectively. These results suggest the existence of a local circuit to drive PLA, and the activity could be regulated by the excitatory–inhibitory balance of the circuit. In support of this notion, we located a population of inhibitory interneurons (I‐INs) in the medial part of the peri‐LC that exerted feedforward inhibition of LC‐NA neurons through GABAergic and glycinergic transmissions. Selective inhibition of peri‐LC I‐INs with chemogenetic methods could enhance PLA in brain slices and increase prepulse inhibition in animals. Moreover, axons from the orbitofrontal and prelimbic cortices, which play important roles in evaluating the cost/reward of a stimulus, synapse on both peri‐LC I‐INs and LC‐NA neurons. These observations demonstrate functional roles of peri‐LC I‐INs in integrating inputs of the frontal cortex onto LC‐NA neurons and gating the phasic LC output.

The association between cytomegalovirus (CMV)-specific reactivity of T cell subsets and development of CMV retinitis (CMV-R) was prospectively studied in 50 CMV-seropositive AIDS patients. The frequency of CMV-specific CD69 expression on CD8 T cells was similar in patients with and patients without CMV-R (median, 1.0% vs. 1.2%; P=.14). However, the frequency of CMV-specific CD69 expression on CD4 T cells was significantly lower in patients with CMV-R than in those without CMV-R (median, 0.4% vs. 2.25%; P<.001). CMV-specific CD4 T cell reactivity in patients who developed CMV-R shortly after starting highly active antiretroviral therapy (HAART) remained low, although the CD4 cell counts increased markedly. Therefore, development of CMV-R is associated with a poor CMV-specific reactivity of CD4 T cells but not with poor reactivity of CD8 T cells. Development of CMV-R after initiation of HAART is associated with a poor reconstitution of CMV-specific immune response, rather than with immune rebound.

Whether immunity against opportunistic pathogens can be fully restored by control of HIV-1 replication remains open to question. This longitudinal study was conducted to measure anti-tuberculosis (TB) cellular immunity in 13 HIV-1/TB-coinfected patients effectively treated by highly active antiretroviral therapy (HAART) in a period of 12 months. In this study, anti-TB cellular immunity was assessed by determining the frequencies of CD 69 expression on CD4+ and CD8+ T cells in response to purified protein derivative (PPD) stimulation (abbreviated as %CD4+CD69 to PPD and %CD8+CD69 to PPD). Here, we show that %CD4+CD69 to PPD correlated with the results of tuberculin skin tests and interferon-gamma (IFN-gamma) production from PPD-stimulated CD4+ T cells, and %CD8+CD69 to PPD also correlated with CD8+ T cell-mediated PPD-specific cytolysis. In overall analysis for these 13 patients, both %CD4+CD69 to PPD and %CD8+CD69 to PPD increased significantly during the 12 months (p =. 003 and p <.001, respectively). However, we found %CD4+CD69 to PPD or %CD8+CD69 to PPD failed to increase substantially in some patients (i.e., immunologic nonresponders). A significantly higher proportion of patients whose baseline CD4+ count was <50 cells/mm3 were considered to be CD4+ nonresponders compared with those whose baseline CD4+ count was >50 cells/mm3. Furthermore, baseline CD4+ cell count in nonresponders is significantly lower than that in responders, although the effectiveness of HAART did not differ between them. Our results indicate that PPD-specific frequencies of CD69 expression may be used as surrogate markers of anti-TB cellular immunity. By this method, we show that full reconstitution of anti-TB cellular immunity in HIV-1/TB coinfected patients may not necessarily be achieved by "successful" HAART and may be influenced by the baseline immune status when HAART is started. These data suggest that the decision to discontinue secondary prophylaxis for opportunistic infections should be cautiously made, even when the CD4+ cell count has significantly increased.

Dendritic cells (DCs), a critical component of innate immunity, are the most potent APCs. When DCs mature, they can elicit strong T cell responses. We studied the kinetics of Ag-induced phenotypic and functional maturation of human monocyte-derived DCs using an in vitro T cell-independent culture system. With this model, we herein show that an Ag that has recently or repetitively been exposed (“exposed Ag”) rapidly induces a high level of maturation; however, an Ag that has never or only remotely been exposed (“unexposed Ag”) slowly induces a low level of maturation. The kinetics of Ag-induced maturation of DCs possibly implies a novel mechanism for immunological memory that would provide maximal host protection from repetitively invading pathogens in the environment.

Ovarian hyperstimulation during IVF-embryo transfer treatment is a risk factor for developing adnexal torsion. Early diagnosis and prompt surgical intervention is the only way to protect the ovary and preserve the pregnancy. Laparoscopic surgery in early pregnancy causes no harm to the fetus and should be encouraged once the diagnosis is confirmed. Delaying surgery may induce serious infection and jeopardize the lives of both the fetus and mother.