Genetic polymorphism of KIR2DL4 (CD158d), a putative NK cell receptor for HLA-G, does not influence susceptibility to asthma.

Human leukocyte antigen (HLA)-G is upregulated on the bronchial epithelium of asthma patients and genetic polymorphism affecting expression of HLA-G has been reported to influence susceptibility to asthma. As the NK cell receptor KIR2DL4 has been reported to induce interferon gamma (IFNγ) secretion when ligated with HLA-G, we postulated that the 9A/10A genetic polymorphism of KIR2DL4 which influences receptor structure may influence susceptibility to asthma. KIR2DL4 genotypes were determined in two cohorts of children (n = 219 and n = 1356) in whom total serum IgE, allergen-specific IgE, atopy, bronchial reactivity and asthma symptoms had been studied between birth and 14 years. No reproducible associations with KIR2DL4 genotype were identified, leading us to conclude that the KIR2DL4 9A/10A polymorphism has no influence on susceptibility to asthma.

The genotype of the NK cell receptor, KIR2DL4, influences INFgamma secretion by decidual natural killer cells.

Natural killer (NK) cells are the predominant leukocyte in first trimester decidua and play a role in vascular remodelling through interferon gamma (IFNgamma) secretion. Membrane expression of the killer immunoglobulin-like receptor (KIR) KIR2DL4 on peripheral blood NK (pNK) cells is controlled by the 9A/10A transmembrane genetic polymorphism. On peripheral NK cells (pNK), KIR2DL4 can only be detected on the membrane of cells from individuals with at least one copy of the 10A allele and ligation of KIR2DL4 results in IFNgamma secretion. In this study, we assessed KIR2DL4 expression and IFNgamma secretion as a result of KIR2DL4 ligation, by decidual NK (dNK) cells. The 9A/10A transmembrane polymorphism was shown to control KIR2DL4 expression by dNK, as previously shown for pNK cells. Freshly isolated dNK cells from subjects with at least one 10A allele expressed KIR2DL4 whereas those from 9A homozygous subjects did not. Although freshly isolated dNK did not secrete IFNgamma in response to KIR2DL4 ligation regardless of KIR2DL4 genotype, activation by in vitro culture with IL-2 enabled dNK cells from individuals with at least one 10A allele, but not those without a 10A allele, to secrete IFNgamma in response to KIR2DL4 ligation. This study confirms that expression of KIR2DL4 by dNK is dependent on the 9A/10A polymorphism and that this polymorphism influences IFNgamma secretion by dNK cells.

Menopausal hormone therapy and irregular endometrial bleeding: a potential role for uterine natural killer cells?

CONTEXT: Irregular bleeding affects many users of combined menopausal hormone therapy (HT) and commonly leads to invasive and expensive investigations to exclude underlying malignancy. In most cases no abnormality is found. OBJECTIVE: The main objective of this study was to explore the role of uterine natural killer (uNK) cells and their regulatory cytokine IL-15 in irregular bleeding in HT users. DESIGN: This was a prospective observational study conducted between 2002 and 2004. SETTING: The study was conducted in a tertiary referral menopause clinic at King Edward Memorial Hospital, Western Australia. PATIENTS: Patients included 117 postmenopausal women taking combined HT. INTERVENTIONS: Outpatient endometrial biopsies were taken during and outside bleeding episodes. MAIN OUTCOME MEASURES: The relationship between endometrial uNK cells (CD56+) and bleeding patterns was measured. We also addressed the impact of HT exposure on uNK cell populations, the relationship between endometrial IL-15 expression and uNK cell populations, and killer Ig like receptor genotype in subjects with irregular bleeding. RESULTS: Endometrial CD56+ uNK cells were significantly increased in biopsies obtained during bleeding episodes (P < 0.001), compared with HT users with no bleeding. The highest level of IL-15 expression was also seen in biopsies taken during bleeding. No clear relationship between killer Ig like receptor genotype and bleeding on HT was observed. CONCLUSIONS: Little is known about the mechanisms underlying irregular bleeding in HT users. This is the first report of uNK cells and their association with regulating cytokines in postmenopausal endometrium and demonstrates a possible mechanism by which HT may induce irregular bleeding.

Preferential use of the landmark navigational system by head direction cells in rats.

Previous studies have identified a population of cells recorded in the postsubiculum and the anterior thalamic nucleus (ATN) that discharge as a function of an animal's head direction (HD) in the horizontal plane. The present experiments monitored HD cell activity when rats were confronted with a situation in which directional information from internal sensory sources (e.g., proprioceptive, vestibular, or motor efference copy) conflicted with directional information derived from familiar, external landmarks. Results showed that when a salient, familiar cue was reintroduced to rat's environment into a position that conflicted with the cell's current firing direction, HD cells in both the ATN and the postsubiculum shifted their preferred direction to reflect their originally established orientation with this cue. This finding suggests that sensory inputs onto HD cells from external landmark cues are capable of overriding spatial information developed through internal sensory cues.

Cue control and head direction cells.

Previous research has shown that head direction (HD) cells in both the anterior dorsal thalamus (ADN) and the postsubiculum (PoS) in rats discharge in relation to familiar, visual landmarks in the environment. This study assessed whether PoS and ADN HD cells would be similarly responsive to nonvisual or unfamiliar environmental cues. After visual input was eliminated by blindfolding the rats, HD cells maintained direction-specific discharge, but their preferred firing directions became less stable. In addition, rotations of the behavioral apparatus indicated that some nonvisual cues (presumably tactile, olfactory, or both) exerted above chance stimulus control over a cell's preferred firing direction. However, a prominent auditory cue was not effective in exerting stimulus control over a cell's preferred direction. HD cell activity also was assessed after rotation of a novel visual cue exposed to the rat for 1, 3, or 8 min. An 8-min exposure was enough time for a novel visual cue to gain control over a cell's preferred direction, whereas an exposure of 1 or 3 min led to control in only about half the sessions. These latter results indicate that HD cells rely on a rapid learning mechanism to develop associations with landmark cues.

Effects of repeated disorientation on the acquisition of spatial tasks in rats: dissociation between the appetitive radial arm maze and aversive water maze.

This study examined the effects of disorientation on the acquisition of different spatial reference memory tasks. In an appetitively motivated radial arm maze task in which 1 arm was consistently baited, rats that were disoriented before each trial were impaired in their ability to acquire the task relative to rats placed in a clear container and not disoriented. However, disoriented rats were able to learn a Morris water maze and a water version of the radial arm maze under similar training conditions, suggesting that the effects of disorientation may interact with the quality or quantity of motivation involved in a given task. These results suggest that appetitive and aversive spatial tasks are dissociable, and that any impairment that is due to disorientation is specific to the appetitive radial arm maze task.

Processing the head direction cell signal: a review and commentary.

Animals require information about their location and directional heading in order to navigate. Directional information is provided by a population of cells in the postsubiculum and the anterior thalamic nuclei that encode a very accurate, continual representation of the animal's directional heading in the horizontal plane, which is independent of the animal's location. Recent studies indicate that this signal 1) arises either in the anterior thalamic nuclei or in structures upstream from it; 2) is not dependent on an intact hippocampus; 3) receives sensory inputs from both idiothetic and landmark systems; and 4) correlates well with the animal's behavior in a spatial reference memory task. Furthermore, HD cells in the anterior thalamic nuclei appear to encode what the animal's directional heading will be about 40 ms in the future, while HD cells in the postsubiculum encode the animal's current directional heading. Both the electrophysiological and anatomical data suggest that the anterior thalamic nuclei and/or the lateral mammillary nuclei may be the sites of convergence for spatial information derived from landmarks and internally-generated cues. Current evidence also indicates that the vestibular system plays a crucial role in the generation of the HD cell signal. However, the notion that the vestibular system is the sole contributor to the signal generator is difficult to reconcile with several findings; these latter findings are better accounted for with a motor efference copy signal.

Roentgenographic documentation of atlanto-occipital sidebending.

It is assumed that the atlas (C1) glides superiorly and laterally along the occipital (C0) condyle during translatory motion of the head in the opposite direction. To provide roentgenographic documentation, a translatory test of atlanto-occipital (C0-C1) motion was performed to the left and to the right on a healthy, asymptomatic volunteer subject. Roentgenographic examination was made at the extreme in each direction. The films indicate the change in atlantal position relative to the occiput and support the assumption. A translation of the head in the coronal plane to test for atlanto-occipital joint mobility is described.

Modeling attractor deformation in the rodent head-direction system.

We present a model of the head-direction circuit in the rat that improves on earlier models in several respects. First, it provides an account of some of the unique characteristics of head-direction (HD) cell firing in the lateral mammillary nucleus and the anterior thalamus. Second, the model functions without making physiologically unrealistic assumptions. In particular, it implements attractor dynamics in postsubiculum and lateral mammillary nucleus without directionally tuned inhibitory neurons, which have never been observed in vivo, and it integrates angular velocity without the use of multiplicative synapses. The model allows us to examine the relationships among three HD areas and various properties of their representations. A surprising result is that certain combinations of purported HD cell properties are mutually incompatible, suggesting that the lateral mammillary nucleus may not be the primary source of head direction input to anterior thalamic HD cells.

Interaction between the postsubiculum and anterior thalamus in the generation of head direction cell activity.

Previous research has identified neurons in the postsubiculum (PoS) and anterior dorsal thalamic nucleus (AD) of the rat that discharge as a function of the animal's head direction. In addition, anatomical studies have shown that the AD and PoS are reciprocally connected with one another. The current study examined whether head direction (HD) cells in each of the two areas is dependent on input from the other structure. After both electrolytic or neurotoxic lesions of the AD, no cells were identified with direction-specific discharge in the PoS. In contrast, AD HD cell activity was still present after neurotoxic lesions to the PoS. However, AD HD cells in PoS-lesioned rats exhibited three important differences compared with AD HD cells in intact animals: (1) their directional firing range was significantly larger, (2) their firing predicted the animal's future head direction by a larger amount, and (3) their preferred firing direction was substantially less influenced by a prominent visual landmark within the recording environment. These results indicate that information critical for HD cell activity is conveyed in both directions between the AD and the PoS; whereas the AD is necessary for the presence of HD cell activity in the PoS, the PoS appears important in allowing visual landmarks to exert control over the preferred firing direction of AD HD cells. These findings have implications for several computational models that propose to account for the generation of the HD cell signal.

The effects of disorientation on visual landmark control of head direction cell orientation.

Head direction (HD) and place cells were recorded in rats that had previously exhibited significant acquisition deficits on a radial arm maze task following disorientation treatment. In this study we determined whether this behavioral impairment was associated with a lack of landmark stimulus control over the preferred orientations of HD and place cells. Neurons were recorded as animals retrieved food pellets in a cylindrical apparatus containing a single cue card. Some of these HD cells were also recorded while animals explored an eight-arm radial maze in a similar cue-controlled environment. The stimulus control of the landmarks in each environment was assessed by rotating the landmark and examining the subsequent preferred orientations of HD and place cells. Animals underwent disorientation treatment before and after each recording session. Despite this disorientation, rotation of the cue card in the cylindrical apparatus resulted in a corresponding shift in the preferred orientations of HD and place cells in 13 of 15 and 7 of 7 recording sessions, respectively. On the radial arm maze, rotation of the landmark cue was associated with a corresponding shift in the HD cell's preferred orientation in 7 of 9 sessions. These results suggest that a visual landmark's stimulus control may not require a learned association between that landmark and an animal's stable experience in an environment. Furthermore, instability in the HD cell system is unlikely to account for the impaired performance of the disoriented animals in the radial arm maze. Rather, these impairments may be due to the animal's inability to utilize stable representations of the environment provided by HD and place cells.

Growth in the presence of salicylate increases fluoroquinolone resistance in Staphylococcus aureus.

Salicylate and acetylsalicylate slightly increased fluoroquinolone resistance in ciprofloxacin-susceptible and -resistant Staphylococcus aureus. Salicylate allowed a greater number of cells from ciprofloxacin-susceptible and -resistant strains to survive on high fluoroquinolone concentrations. Salicylate also increased the frequency with which a susceptible strain mutated to become more resistant to ciprofloxacin.