Administration of interleukin-7 increases CD4 T cells in idiopathic CD4 lymphocytopenia.

Idiopathic CD4 lymphopenia (ICL) is a rare syndrome defined by low CD4 T-cell counts (<300/µL) without evidence of HIV infection or other known cause of immunodeficiency. ICL confers an increased risk of opportunistic infections and has no established treatment. Interleukin-7 (IL-7) is fundamental for thymopoiesis, T-cell homeostasis, and survival of mature T cells, which provides a rationale for its potential use as an immunotherapeutic agent for ICL. We performed an open-label phase 1/2A dose-escalation trial of 3 subcutaneous doses of recombinant human IL-7 (rhIL-7) per week in patients with ICL who were at risk of disease progression. The primary objectives of the study were to assess safety and the immunomodulatory effects of rhIL-7 in ICL patients. Injection site reactions were the most frequently reported adverse events. One patient experienced a hypersensitivity reaction and developed non-neutralizing anti-IL-7 antibodies. Patients with autoimmune diseases that required systemic therapy at screening were excluded from the study; however, 1 participant developed systemic lupus erythematosus while on study and was excluded from further rhIL-7 dosing. Quantitatively, rhIL-7 led to an increase in the number of circulating CD4 and CD8 T cells and tissue-resident CD3 T cells in the gut mucosa and bone marrow. Functionally, these T cells were capable of producing cytokines after mitogenic stimulation. rhIL-7 was well tolerated at biologically active doses and may represent a promising therapeutic intervention in ICL. This trial was registered at www.clinicaltrials.gov as #NCT00839436.

Decreases in colonic and systemic inflammation in chronic HIV infection after IL-7 administration.

Despite antiretroviral therapy (ART), some HIV-infected persons maintain lower than normal CD4(+) T-cell counts in peripheral blood and in the gut mucosa. This incomplete immune restoration is associated with higher levels of immune activation manifested by high systemic levels of biomarkers, including sCD14 and D-dimer, that are independent predictors of morbidity and mortality in HIV infection. In this 12-week, single-arm, open-label study, we tested the efficacy of IL-7 adjunctive therapy on T-cell reconstitution in peripheral blood and gut mucosa in 23 ART suppressed HIV-infected patients with incomplete CD4(+) T-cell recovery, using one cycle (consisting of three subcutaneous injections) of recombinant human IL-7 (r-hIL-7) at 20 µg/kg. IL-7 administration led to increases of both CD4(+) and CD8(+) T-cells in peripheral blood, and importantly an expansion of T-cells expressing the gut homing integrin α4ß7. Participants who underwent rectosigmoid biopsies at study baseline and after treatment had T-cell increases in the gut mucosa measured by both flow cytometry and immunohistochemistry. IL-7 therapy also resulted in apparent improvement in gut barrier integrity as measured by decreased neutrophil infiltration in the rectosigmoid lamina propria 12 weeks after IL-7 administration. This was also accompanied by decreased TNF and increased FOXP3 expression in the lamina propria. Plasma levels of sCD14 and D-dimer, indicative of systemic inflammation, decreased after r-hIL-7. Increases of colonic mucosal T-cells correlated strongly with the decreased systemic levels of sCD14, the LPS coreceptor - a marker of monocyte activation. Furthermore, the proportion of inflammatory monocytes expressing CCR2 was decreased, as was the basal IL-1ß production of peripheral blood monocytes. These data suggest that administration of r-hIL-7 improves the gut mucosal abnormalities of chronic HIV infection and attenuates the systemic inflammatory and coagulation abnormalities that have been linked to it.

A road map for designing and implementing a biological monitoring program.

Designing and implementing natural resource monitoring is a challenging endeavor undertaken by many agencies, NGOs, and citizen groups worldwide. Yet many monitoring programs fail to deliver useful information for a variety of administrative (staffing, documentation, and funding) or technical (sampling design and data analysis) reasons. Programs risk failure if they lack a clear motivating problem or question, explicit objectives linked to this problem or question, and a comprehensive conceptual model of the system under study. Designers must consider what "success" looks like from a resource management perspective, how desired outcomes translate to appropriate attributes to monitor, and how they will be measured. All such efforts should be filtered through the question "Why is this important?" Failing to address these considerations will produce a program that fails to deliver the desired information. We addressed these issues through creation of a "road map" for designing and implementing a monitoring program, synthesizing multiple aspects of a monitoring program into a single, overarching framework. The road map emphasizes linkages among core decisions to ensure alignment of all components, from problem framing through technical details of data collection and analysis, to program administration. Following this framework will help avoid common pitfalls, keep projects on track and budgets realistic, and aid in program evaluations. The road map has proved useful for monitoring by individuals and teams, those planning new monitoring, and those reviewing existing monitoring and for staff with a wide range of technical and scientific skills.

T-Cell Depletion in the Colonic Mucosa of Patients With Idiopathic CD4+ Lymphopenia.

Idiopathic CD4(+) lymphopenia (ICL) is a rare syndrome characterized by low peripheral CD4(+) T-cell counts that can lead to serious opportunistic infections. The pathogenesis of ICL remains unclear, and whether effector sites are also lymphopenic is unknown. In this study, rectosigmoid mucosal biopsy specimens from patients with ICL and healthy controls were evaluated. Significant T-cell lymphopenia was observed in the mucosal tissue of patients with ICL by flow cytometry and immunohistochemistry, compared with healthy controls. Functional capacity of T cells, assessed by production of interferon γ and interleukin 17, was preserved in the mucosa of patients with ICL. In contrast to T lymphocytes, the frequency of myeloid cells (neutrophils and macrophages) was elevated in the colonic mucosa of patients with ICL. Despite the observed mucosal abnormalities, plasma levels of intestinal fatty acid binding protein, a marker of enterocyte turnover and other inflammatory biomarkers, including interleukin 6, C-reactive protein, and tumor necrosis factor, were not elevated in patients with ICL, compared with healthy controls, whereas soluble CD14 levels were minimally elevated. These data suggest that patients with ICL, despite gut mucosal lymphopenia and local tissue inflammation, have preserved enterocyte turnover and T-helper type 17 cells with minimal systemic inflammation. These observations highlight differences from patients with human immunodeficiency virus infection, with or without AIDS, and may partially explain their distinct clinical prognosis.

Intracranial subdural hygroma after Le Fort I osteotomy.

Various intra- and postoperative complications have been well-documented after Le Fort I osteotomies; however, an intracranial subdural hygroma has not yet been reported in oral and maxillofacial studies. We report a unique case of an intracranial subdural hygroma requiring neurosurgical intervention after Le Fort I advancement.

Comprehensive analysis of unique cases with extraordinary control over HIV replication.

True long-term nonprogressors (LTNPs)/elite controllers (ECs) maintain durable control over HIV replication without antiretroviral therapy. Herein we describe 4 unique persons who were distinct from conventional LTNPs/ECs in that they had extraordinarily low HIV burdens and comparatively weak immune responses. As a group, typical LTNPs/ECs have unequivocally reactive HIV-1 Western blots, viral loads below the lower threshold of clinical assays, low levels of persistent viral reservoirs, an over-representation of protective HLA alleles, and robust HIV-specific CD8(+) T-cell responses. The 4 unique cases were distinguished from typical LTNPs/ECs based on weakly reactive Western blots, undetectable plasma viremia by a single copy assay, extremely low to undetectable HIV DNA levels, and difficult to isolate replication-competent virus. All 4 had at least one protective HLA allele and CD8(+) T-cell responses that were disproportionately high for the low antigen levels but comparatively lower than those of typical LTNPs/ECs. These unique persons exhibit extraordinary suppression over HIV replication, therefore, higher-level control than has been demonstrated in previous studies of LTNPs/ECs. Additional insight into the full spectrum of immune-mediated suppression over HIV replication may enhance our understanding of the associated mechanisms, which should inform the design of efficacious HIV vaccines and immunotherapies.

Sparing of spatial mental imagery in patients with hippocampal lesions.

In four experiments, we explored the capacity for spatial mental imagery in patients with hippocampal lesions, using tasks that minimized the role of learning and memory. On all four tasks, patients with hippocampal lesions performed as well as controls. Nonetheless, in separate tests, the patients were impaired at remembering the materials that had been used to assess mental imagery. The findings suggest that the hippocampus is not needed for constructing many forms of spatial imagery but is needed for the formation of long-term memory. In future studies of the neural organization of spatial mental imagery, it will be important to separate the contribution of spatial processing from the contribution of learning and memory.

Decreased interleukin 7 responsiveness of T lymphocytes in patients with idiopathic CD4 lymphopenia.

BACKGROUND: Elevated serum interleukin 7 (IL-7) levels are observed in lymphopenic conditions, including idiopathic CD4 lymphopenia (ICL), which is characterized by CD4 lymphopenia in the absence of human immunodeficiency virus infection or other known immunodeficiency. METHODS: To test whether defective IL-7 signaling could be an etiologic or contributing factor in ICL, peripheral blood mononuclear cells from patients with ICL (median CD4 T-cell count, 160 cells/µL) and healthy controls (median CD4 T-cell count, 582 cells/µL) were evaluated for expression of IL-7Rα chain (CD127) and intracellular phosphorylated STAT-5 (a marker of γc cytokine signaling) after cytokine stimulation. Gene expression was analyzed by real-time polymerase chain reaction following IL-7 stimulation. RESULTS: The percentage of CD4+CD127+ T cells was lower in patients with ICL, compared with controls (P < .001). Lower levels of STAT-5 phosphorylation after IL-7 stimulation were observed in both CD4 and CD8 T cells from patients with ICL, compared with controls (P < .001 and P = .017, respectively), that inversely correlated in CD4 T cells with serum IL-7 levels (r = -0.734, P = .013). Destabilization of p27(kip1), a critical step for IL-7-induced T-cell cycling, was decreased in patients with ICL, compared with controls (P = .004), after IL-7 stimulation. CONCLUSIONS: These data suggest that diminished responsiveness to IL-7 in CD4 and CD8 T cells during ICL may be contributing to the dysregulation of T-cell homeostasis.

CD4+ T cells, including Th17 and cycling subsets, are intact in the gut mucosa of HIV-1-infected long-term nonprogressors.

During acute human immunodeficiency virus (HIV) infection, there is a massive depletion of CD4(+) T cells in the gut mucosa that can be reversed to various degrees with antiretroviral therapy. Th17 cells have been implicated in mucosal immunity to extracellular bacteria, and preservation of this subset may support gut mucosal immune recovery. However, this possibility has not yet been evaluated in HIV-1-infected long-term nonprogressors (LTNPs), who maintain high CD4(+) T cell counts and suppress viral replication in the absence of antiretroviral therapy. In this study, we evaluated the immunophenotype and function of CD4(+) T cells in peripheral blood and gut mucosa of HIV-uninfected controls, LTNPs, and HIV-1-infected individuals treated with prolonged antiretroviral therapy (ART) (VL [viral load]<50). We found that LTNPs have intact CD4(+) T cell populations, including Th17 and cycling subsets, in the gut mucosa and a preserved T cell population expressing gut homing molecules in the peripheral blood. In addition, we observed no evidence of higher monocyte activation in LTNPs than in HIV-infected (HIV(-)) controls. These data suggest that, similar to nonpathogenic simian immunodeficiency virus (SIV) infection, LTNPs preserve the balance of CD4(+) T cell populations in blood and gut mucosa, which may contribute to the lack of disease progression observed in these patients.

Representations in mental imagery and working memory: evidence from different types of visual masks.

Although few studies have systematically investigated the relationship between visual mental imagery and visual working memory, work on the effects of passive visual interference has generally demonstrated a dissociation between the two functions. In four experiments, we investigated a possible commonality between the two functions: We asked whether both rely on depictive representations. Participants judged the visual properties of letters using visual mental images or pictures of unfamiliar letters stored in short-term memory. Participants performed both tasks with two different types of interference: sequences of unstructured visual masks (consisting of randomly changing white and black dots) or sequences of structured visual masks (consisting of fragments of letters). The structured visual noise contained elements of depictive representations (i.e., shape fragments arrayed in space), and hence should interfere with stored depictive representations; the unstructured visual noise did not contain such elements, and thus should not interfere as much with such stored representations. Participants did in fact make more errors in both tasks with sequences of structured visual masks. Various controls converged in demonstrating that in both tasks participants used representations that depicted the shapes of the letters. These findings not only constrain theories of visual mental imagery and visual working memory, but also have direct implications for why some studies have failed to find that dynamic visual noise interferes with visual working memory.

Two forms of spatial imagery: neuroimaging evidence.

Spatial imagery may be useful in such tasks as interpreting graphs and solving geometry problems, and even in performing surgery. This study provides evidence that spatial imagery is not a single faculty; rather, visualizing spatial location and mentally transforming location rely on distinct neural networks. Using 3-T functional magnetic resonance imaging, we tested 16 participants (8 male, 8 female) in each of two spatial imagery tasks--one that required visualizing location and one that required mentally rotating stimuli. The same stimuli were used in the two tasks. The location-based task engendered more activation near the occipito-parietal sulcus, medial posterior cingulate, and precuneus, whereas the transformation task engendered more activation in superior portions of the parietal lobe and in the postcentral gyrus. These differences in activation provide evidence that there are at least two different types of spatial imagery.

Training generalized spatial skills.

Spatial transformation skills are an essential aspect of cognitive ability. These skills can be improved by practice, but such improvement has usually been specific to tasks and stimuli. The present study investigated whether intensive long-term practice leads to change that transcends stimulus and task parameters. Thirty-one participants (14 male, 17 female) were tested on three cognitive tasks: a computerized version of the Shepard-Metzler (1971) mental rotation task (MRT), a mental paper-folding task (MPFT), and a verbal analogies task (VAT). Each individual then participated in daily practice sessions with the MRT or the MPFT over 21 days. Postpractice comparisons revealed transfer of practice gains to novel stimuli for the practiced task, as well as transfer to the other, nonpracticed spatial task. Thus, practice effects were process based, not instance based. Improvement in the nonpracticed spatial task was greater than that in the VAT; thus, improvement was not merely due to greater ease with computerized testing.

Improving inference for aerial surveys of bears: The importance of assumptions and the cost of unnecessary complexity.

Obtaining useful estimates of wildlife abundance or density requires thoughtful attention to potential sources of bias and precision, and it is widely understood that addressing incomplete detection is critical to appropriate inference. When the underlying assumptions of sampling approaches are violated, both increased bias and reduced precision of the population estimator may result. Bear (Ursus spp.) populations can be difficult to sample and are often monitored using mark-recapture distance sampling (MRDS) methods, although obtaining adequate sample sizes can be cost prohibitive. With the goal of improving inference, we examined the underlying methodological assumptions and estimator efficiency of three datasets collected under an MRDS protocol designed specifically for bears. We analyzed these data using MRDS, conventional distance sampling (CDS), and open-distance sampling approaches to evaluate the apparent bias-precision tradeoff relative to the assumptions inherent under each approach. We also evaluated the incorporation of informative priors on detection parameters within a Bayesian context. We found that the CDS estimator had low apparent bias and was more efficient than the more complex MRDS estimator. When combined with informative priors on the detection process, precision was increased by >50% compared to the MRDS approach with little apparent bias. In addition, open-distance sampling models revealed a serious violation of the assumption that all bears were available to be sampled. Inference is directly related to the underlying assumptions of the survey design and the analytical tools employed. We show that for aerial surveys of bears, avoidance of unnecessary model complexity, use of prior information, and the application of open population models can be used to greatly improve estimator performance and simplify field protocols. Although we focused on distance sampling-based aerial surveys for bears, the general concepts we addressed apply to a variety of wildlife survey contexts.

When is early visual cortex activated during visual mental imagery?

Although many neuroimaging studies of visual mental imagery have revealed activation in early visual cortex (Areas 17 or 18), many others have not. The authors review this literature and compare how well 3 models explain the disparate results. Each study was coded 1 or 0, indicating whether activation in early visual cortex was observed, and sets of variables associated with each model were fit to the observed results using logistic regression analysis. Three variables predicted all of the systematic differences in the probability of activation across studies. Two of these variables were identified with a perceptual anticipation theory, and the other was identified with a methodological factors theory. Thus, the variability in the literature is not random.

Brain areas underlying visual mental imagery and visual perception: an fMRI study.

We used functional magnetic resonance imaging (fMRI) to assess the maximal degree of shared neural processing in visual mental imagery and visual perception. Participants either visualized or saw faint drawings of simple objects, and then judged specific aspects of the drawings (which could only be evaluated properly if they used the correct stimulus). The results document that visual imagery and visual perception draw on most of the same neural machinery. However, although the vast majority of activated voxels were activated during both conditions, the spatial overlap was neither complete nor uniform; the overlap was much more pronounced in frontal and parietal regions than in temporal and occipital regions. This finding may indicate that cognitive control processes function comparably in both imagery and perception, whereas at least some sensory processes may be engaged differently by visual imagery and perception.

Visual cortex excitability increases during visual mental imagery--a TMS study in healthy human subjects.

Previous neuroimaging studies provided evidence that visual mental imagery relies, in part, on the primary visual cortex. We hypothesized that, analogous to the finding that motor imagery increases the excitability of motor cortex, visual imagery should increase visual cortex excitability, as indexed by a decrease in the phosphene threshold (PT). In order to test visual cortex excitability, the primary visual cortex was stimulated with transcranial magnetic stimulation (TMS), so as to elicit phosphenes in the right lower visual quadrant. Subjects performed a visual imagery task and an auditory control task. We applied TMS with increasing intensity to determine the PT for each subject. Independent of the quadrant in which subjects placed their visual images, imagery decreased PT compared to baseline PT; in contrast, the auditory task did not change PT. These findings demonstrate for the first time a short-term, task-dependent modulation of PT. These results constitute evidence that early visual areas participate in visual imagery processing.

Visual imagery in cerebral visual dysfunction.

Many sorts of deficits in imagery follow brain damage, but the relation between the site of damage and the type of deficit is not simple or straightforward. The dissociations in performance after brain damage provide hints regarding the processing system underlying imagery, but difficulties in interpretation urge caution in mapping these findings to theoretic models. Neuroimaging techniques, such as PET and fMRI, open a window into the working brain and offer valuable information not easily accessible through the study of patients, who, as noted, may have deficits beyond those observable and may rely on compensation and neural reorganization. As we come to understand the mental imagery system more fully, such issues as the laterality of image generation are likely to prove too coarse and vague. The brain is an enormously intricate organ, and even within a circumscribed domain such as imagery it seems to process information in complex and subtle ways.

Visual memory and visual mental imagery recruit common control and sensory regions of the brain.

Separate lines of research have shown that visual memory and visual mental imagery are mediated by frontal-parietal control regions and can rely on occipital-temporal sensory regions of the brain. We used fMRI to assess the degree to which visual memory and visual mental imagery rely on the same neural substrates. During the familiarization/study phase, participants studied drawings of objects. During the test phase, words corresponding to old and new objects were presented. In the memory test, participants responded "remember," "know," or "new." In the imagery test, participants responded "high vividness," "moderate vividness," or "low vividness." Visual memory (old-remember) and visual imagery (old-high vividness) were commonly associated with activity in frontal-parietal control regions and occipital-temporal sensory regions. In addition, visual memory produced greater activity than visual imagery in parietal and occipital-temporal regions. The present results suggest that visual memory and visual imagery rely on highly similar--but not identical--cognitive processes.

Understanding the dorsal and ventral systems of the human cerebral cortex: beyond dichotomies.

Traditionally, characterizations of the macrolevel functional organization of the human cerebral cortex have focused on the left and right cerebral hemispheres. However, the idea of left brain versus right brain functions has been shown to be an oversimplification. We argue here that a top-bottom divide, rather than a left-right divide, is a more fruitful way to organize human cortical brain functions. However, current characterizations of the functions of the dorsal (top) and ventral (bottom) systems have rested on dichotomies, namely where versus what and how versus what. We propose that characterizing information-processing systems leads to a better macrolevel organization of cortical function; specifically, we hypothesize that the dorsal system is driven by expectations and processes sequences, relations, and movement, whereas the ventral system categorizes stimuli in parallel, focuses on individual events, and processes object properties (such as shape in vision and pitch in audition). To test this hypothesis, we reviewed over 100 relevant studies in the human neuroimaging and neuropsychological literatures and coded them relative to 11 variables, some of which characterized our hypothesis and some of which characterized the previous dichotomies. The results of forward stepwise logistic regressions supported our characterization of the 2 systems and showed that this model predicted the empirical findings better than either the traditional dichotomies or a left-right difference.

Inspecting visual mental images: can people "see" implicit properties as easily in imagery and perception?

Can people "see" previously unnoticed properties in objects that they visualize, or are they locked into the organization of the pattern that was encoded during perception? To answer this question, we first asked a group to describe letters of the alphabet and found that some properties (such as the presence of a diagonal line) are often mentioned, whereas others (such as symmetry) are rarely if ever mentioned. Then we showed not only that other participants could correctly detect both kinds of properties in visualized letters, but also that the relative differences in the ease of detecting these two types of properties are highly similar in perception (when the letters are actually visible) and imagery (when the letters are merely visualized). These findings provide support for the view that images can be reinterpreted in ways much like what occurs during perception and speak to the wider issue of the long-standing debate about the format of mental images.