Permanent anosmia and ageusia after resection of a left temporoinsular low-grade glioma: anatomofunctional considerations

Five percent of the general population has olfactory or gustatory disorders, although most do not complain about it. However, in some cases, these symptoms can be disabling and may affect quality of life. Anosmia was reported as a possible complication following head injury and neurosurgical procedures, particularly after the resection of tumors located in the anterior fossa and the treatment of aneurysms in the anterior circulation. Nonetheless, in all of these situations, olfactory dysfunction could be explained by damage to the peripheral olfactory system. Here, the authors report a case of complete anosmia associated with ageusia following awake resection of a low-grade glioma involving the left temporoinsular region, with no recovery during a follow-up of 3 years. The frontal lobe was not retracted, and the olfactory tract was not visualized during surgery; therefore, postoperative anosmia and ageusia are likely explained by damage to the cortex and central pathways responsible for these senses. The authors suggest that the patient might have had a subclinical right hemianosmia before surgery, which is a common condition. After resection of the central structures critical for smell and taste processing in the left hemisphere, the patient could have finally had bilateral and complete olfactory and gustatory loss. This is the first known report of permanent anosmia and ageusia following glioma surgery. Because these symptoms might have been underestimated, more attention should be devoted to olfaction and taste, especially with regard to possible subclinical preoperative deficit. (http://thejns.org/doi/abs/10.3171/2012.2.JNS111982)

Influence of Mid-Trimester Amniotic Fluid on Endogenous and Lipopolysaccharide-Mediated Responses of Mononuclear Lymphoid Cells

Problem We evaluated the influence of amniotic fluid (AF) on immune mediator production by mononuclear leukocytes. Method of study Thirty mid-gestation AFs were incubated with peripheral blood mononuclear cells (PBMCs) in the presence or absence of lipopolysaccharide (LPS). Supernatants were tested for interleukin (IL) -6, 10, 12, 23, tumor necrosis factor-alpha (TNF-alpha) and monocyte chemotactic protein (MCP)-1. Results Endogenous mediator production was minimal or non-detectable. AF stimulated endogenous MCP-1, IL-6 and TNF-alpha release. In the presence of LPS, production of MCP-1 and IL-10 by PBMCs was enhanced eightto ninefold by AF. Release of IL-6 and IL-23 was enhanced less than twofold by the addition of AF while TNF-alpha production was unchanged. AF-stimulated mediator production was similar irrespective of pregnancy outcome. Conclusion Selective AF stimulation of LPS-mediated MCP-1 and IL-10 release may be a mechanism to promote antibody production and the influx of phagocytic cells to engulf pathogens while downregulating the production of pro-inflammatory cytokines.

New insights about host response to smallpox using microarray data

Abstract Background Smallpox is a lethal disease that was endemic in many parts of the world until eradicated by massive immunization. Due to its lethality, there are serious concerns about its use as a bioweapon. Here we analyze publicly available microarray data to further understand survival of smallpox infected macaques, using systems biology approaches. Our goal is to improve the knowledge about the progression of this disease. Results We used KEGG pathways annotations to define groups of genes (or modules), and subsequently compared them to macaque survival times. This technique provided additional insights about the host response to this disease, such as increased expression of the cytokines and ECM receptors in the individuals with higher survival times. These results could indicate that these gene groups could influence an effective response from the host to smallpox. Conclusion Macaques with higher survival times clearly express some specific pathways previously unidentified using regular gene-by-gene approaches. Our work also shows how third party analysis of public datasets can be important to support new hypotheses to relevant biological problems.

Relative CO2/NH3 permeabilities of human RhAG, RhBG and RhCG

Mammalian glycosylated rhesus (Rh) proteins include the erythroid RhAG and the nonerythroid RhBG and RhCG. RhBG and RhCG are expressed in multiple tissues, including hepatocytes and the collecting duct (CD) of the kidney. Here, we expressed human RhAG, RhBG and RhCG in Xenopus oocytes (vs. H2O-injected control oocytes) and used microelectrodes to monitor the maximum transient change in surface pH (ΔpHS) caused by exposing the same oocyte to 5 % CO2/33 mM HCO3 − (an increase) or 0.5 mM NH3/NH4 + (a decrease). Subtracting the respective values for day-matched, H2O-injected control oocytes yielded channel-specific values (*). (ΔpH∗S)CO2 and (−ΔpH∗S)NH3 were each significantly >0 for all channels, indicating that RhBG and RhCG—like RhAG—can carry CO2 and NH3. We also investigated the role of a conserved aspartate residue, which was reported to inhibit NH3 transport. However, surface biotinylation experiments indicate the mutants RhBGD178N and RhCGD177N have at most a very low abundance in the oocyte plasma membrane. We demonstrate for the first time that RhBG and RhCG—like RhAG—have significant CO2 permeability, and we confirm that RhAG, RhBG and RhCG all have significant NH3 permeability. However, as evidenced by (ΔpH∗S)CO2/(−ΔpH∗S)NH3 values, we could not distinguish among the CO2/NH3 permeability ratios for RhAG, RhBG and RhCG. Finally, we propose a mechanism whereby RhBG and RhCG contribute to acid secretion in the CD by enhancing the transport of not only NH3 but also CO2 across the membranes of CD cells.

Synaptic circuitry of ganglion cells in the mammalian retina

Before signals of the visual environment are transferred to higher brain areas via the optic nerve, they are processed and filtered in parallel pathways within the retina. In the past a plethora of functionally distinct ganglion cell types responding to certain aspects of the environment, such as direction of movement, contrast and colour have been described. Aim of this thesis was the anatomical investigation of the selectivity in retinal circuits underlying this diversity. For this purpose, mouse and macaque retinae were analysed. OFF-ganglion cells in the mouse retina received their excitatory drive unselectively from all bipolar cell types stratifying within the area of their dendritic trees. Only the input to direction-selective C6 ganglion cells and bistratified D2 ganglion cells appeared to be weighted. In primates the highly specialised midget-system forms a 1:1 connection from red- and green-sensitive cones onto midget bipolar- and ganglion cells, building the substrate for red/green colour vision. Here it was demonstrated that blue-sensitive (S-) cones also contact OFF-midget bipolars and are, thus, potential candidates to transfer blue-OFF signals to M1 intrinsically photosensitive ganglion cells (ipRGCs). M1 cells received glycinergic input from A8 amacrine cells and express GABAA receptors containing subunit alpha 3. M2 cells, in contrast, received less inhibitory input.

Retrospective comparison of maternal vs. HPA-matched donor platelets for treatment of fetal alloimmune thrombocytopenia

In fetal alloimmune thrombocytopenia (FAIT), transplacental maternal antibodies cause destruction of fetal platelets. FAIT is similar to fetal Rhesus haemolytic disease, but half of the affected fetuses are born to primiparous women. In 10-20% of cases, prenatal and perinatal intracranial haemorrhages are reported. Different therapeutic approaches have been described, including maternally administered high-dose intravenous immunoglobulin (high dose IVIG) without or with steroids or intrauterine transfusion (IUT) of compatible platelets. For the latter, the use of plasma-free maternal and donor platelets has been described, but a comparison of these two sources of platelets has not been reported.

Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression

Clinical, postmortem and preclinical research strongly implicates dysregulation of glutamatergic neurotransmission in major depressive disorder (MDD). Recently, metabotropic glutamate receptors (mGluRs) have been proposed as attractive targets for the discovery of novel therapeutic approaches against depression. The aim of this study was to examine mGluR2/3 protein levels in the prefrontal cortex (PFC) from depressed subjects. In addition, to test whether antidepressants influence mGluR2/3 expression we also studied levels of mGluR2/3 in fluoxetine-treated monkeys. Postmortem human prefrontal samples containing Brodmann's area 10 (BA10) were obtained from 11 depressed and 11 psychiatrically healthy controls. Male rhesus monkeys were treated chronically with fluoxetine (dose escalated to 3mg/kg, p.o.; n=7) or placebo (n=6) for 39 weeks. The mGluR2/3 immunoreactivity was investigated using Western blot method. There was a robust (+67%) increase in the expression of the mGlu2/3 protein in the PFC of depressed subjects relative to healthy controls. The expression of mGlu2/3 was unchanged in the PFC of monkeys treated with fluoxetine. Our findings provide the first evidence that mGluR2/3 is elevated in the PFC in MDD. This observation is consistent with reports showing that mGluR2/3 antagonists exhibit antidepressant-like activity in animal models and demonstrates that these receptors are promising targets for the discovery of novel antidepressants.

Picture Recognition of Food by Macaques (Macaca silenus)

Pictorial representations of three-dimensional objects are often used to investigate animal cognitive abilities; however, investigators rarely evaluate whether the animals conceptualize the two-dimensional image as the object it is intended to represent. We tested for picture recognition in lion-tailed macaques by presenting five monkeys with digitized images of familiar foods on a touch screen. Monkeys viewed images of two different foods and learned that they would receive a piece of the one they touched first. After demonstrating that they would reliably select images of their preferred foods on one set of foods, animals were transferred to images of a second set of familiar foods. We assumed that if the monkeys recognized the images, they would spontaneously select images of their preferred foods on the second set of foods. Three monkeys selected images of their preferred foods significantly more often than chance on their first transfer session. In an additional test of the monkeys' picture recognition abilities, animals were presented with pairs of food images containing a medium-preference food paired with either a high-preference food or a low-preference food. The same three monkeys selected the medium-preference foods significantly more often when they were paired with low-preference foods and significantly less often when those same foods were paired with high-preference foods. Our novel design provided convincing evidence that macaques recognized the content of two-dimensional images on a touch screen. Results also suggested that the animals understood the connection between the two-dimensional images and the three-dimensional objects they represented.

Metabolomics reveals attenuation of the SLC6A20 kidney transporter in nonhuman primate and mouse models of type 2 diabetes mellitus

To enhance understanding of the metabolic indicators of type 2 diabetes mellitus (T2DM) disease pathogenesis and progression, the urinary metabolomes of well characterized rhesus macaques (normal or spontaneously and naturally diabetic) were examined. High-resolution ultra-performance liquid chromatography coupled with the accurate mass determination of time-of-flight mass spectrometry was used to analyze spot urine samples from normal (n = 10) and T2DM (n = 11) male monkeys. The machine-learning algorithm random forests classified urine samples as either from normal or T2DM monkeys. The metabolites important for developing the classifier were further examined for their biological significance. Random forests models had a misclassification error of less than 5%. Metabolites were identified based on accurate masses (<10 ppm) and confirmed by tandem mass spectrometry of authentic compounds. Urinary compounds significantly increased (p < 0.05) in the T2DM when compared with the normal group included glycine betaine (9-fold), citric acid (2.8-fold), kynurenic acid (1.8-fold), glucose (68-fold), and pipecolic acid (6.5-fold). When compared with the conventional definition of T2DM, the metabolites were also useful in defining the T2DM condition, and the urinary elevations in glycine betaine and pipecolic acid (as well as proline) indicated defective re-absorption in the kidney proximal tubules by SLC6A20, a Na(+)-dependent transporter. The mRNA levels of SLC6A20 were significantly reduced in the kidneys of monkeys with T2DM. These observations were validated in the db/db mouse model of T2DM. This study provides convincing evidence of the power of metabolomics for identifying functional changes at many levels in the omics pipeline.

A Test of Absolute Numerousness Judgments in Lion-Tailed Macaques (Macaca Silenus)

Numerous studies have shown that animals have a sense of quantity and can distinguish between relative amounts. The concepts of relative numerousness, estimation, and subitizing are well established in species as diverse as chimpanzees and salamanders. Mobile animals have practical use for an understanding of number in common situations such as predation, mating, and competition. However, the ability to identify discrete quantities has only been firmly established in humans. The purpose of this study was to test for such “absolute numerousness” judgments in three lion-tailed macaques (Macaca silenus), a non-human primate. The three macaques tested had previously been trained on a computerized matchto- sample (MTS) task using geometric shapes. In this study, they were introduced to a MTS task containing a numerical cue, which required the monkeys to match stimuli containing either one or two items for rewards. If monkeys were successful at the initial matching task, they were tested with stimuli in which the position of the items and then the surface area of the items was controlled. If the monkeys could match successfully without using these non-numerical cues, they would demonstrate the capability to make absolute numerousness judgments. None of the monkeys matched successfully using the numerical cue, so no evidence of absolute numerosity was found. Each macaque progressed through the experiment in an individualized manner, attempting a variety of strategies to obtain rewards. These included side preferences and an alternating-side strategy that were unrelated to the numerical cues in the stimuli. When it became clear that the monkeys were not matching based on a stimulus-based cue, they were tested again on matching geometric shapes. All three macaques stopped using their alternate strategies and were able to match shapes successfully, demonstrating that they were still capable of completing the matching task. The data suggest that the monkeys could not transfer this ability to the numerical stimuli. This indicates that the macaques lack a sense of exact quantity, or that they could not recognize the numerical cues in the stimuli as being relevant to the task.

Investigation of Rudimentary Meta-Cognition in Lion-Tailed Macaques and Tufted Capuchins

Meta-cognition, or "thinking about thinking," has been studied extensively in humans, but very little is known about the process in animals. Although great apes and rhesus macaques (Macaca mulatta) have demonstrated multiple apparently meta-cognitive abilities, other species have either been largely ignored or failed to convincingly display meta-cognitive traits. Recent work by Marsh, however, raised the possibility that some species may possess rudimentary or partial forms of meta-cognition. This thesis sought to further investigate this possibility by running multiple comparative experiments. The goal of the first study was to examine whether lion-tailed macaques, a species that may have a rudimentary form of meta-cognition, are able to use an uncertainty response adaptively, and if so, whether they could use the response flexibly when the stimuli for which the subjects should be uncertain changed. The macaques' acquisition of the initial discrimination task is ongoing, and as such there were not yet data to support a conclusion either way. In the second study, tufted capuchins were required to locate a food reward hidden beneath inverted cups that sat on a Plexiglas tray. In some conditions the capuchins were shown where the food was hidden, in others they could infer its location, and in yet others they were not given information about the location of the food. On all trials, however, capuchins could optionally seek additional information by looking up through the Plexiglas into the cups. In general, capuchins did this less often when they were shown the food reward, but not when they could infer the reward's location. These data suggest capuchins only meta-cognitively control their information seeking in some conditions, and thus, add support to the potential for a rudimentary form of meta-cognition. In convergence with other studies, these results may represent early models for rudimentary meta-cognition, although viable alternative explanations still remain.

In-frame triplet deletions in RHD alter the D antigen phenotype

BACKGROUND: The deletion of three adjacent nucleotides in an exon may cause the lack of a single amino acid, while the protein sequence remains otherwise unchanged. Only one such in-frame deletion is known in the two RH genes, represented by the RHCE allele ceBP expressing a "very weak e antigen." STUDY DESIGN AND METHODS: Blood donor samples were recognized because of discrepant results of D phenotyping. Six samples came from Switzerland and one from Northern Germany. The molecular structures were determined by genomic DNA nucleotide sequencing of RHD. RESULTS: Two different variant D antigens were explained by RHD alleles harboring one in-frame triplet deletion each. Both single-amino-acid deletions led to partial D phenotypes with weak D antigen expression. Because of their D category V-like phenotypes, the RHD(Arg229del) allele was dubbed DVL-1 and the RHD(Lys235del) allele DVL-2. These in-frame triplet deletions are located in GAGAA or GAAGA repeats of the RHD exon 5. CONCLUSION: Partial D may be caused by a single-amino-acid deletion in RhD. The altered RhD protein segments in DVL types are adjacent to the extracellular loop 4, which constitutes one of the most immunogenic parts of the D antigen. These RhD protein segments are also altered in all DV, which may explain the similarity in phenotype. At the nucleotide level, the triplet deletions may have resulted from replication slippage. A total of nine amino acid positions in an Rhesus protein may be affected by this mechanism.

Spatial modulation of primate inferotemporal responses by eye position.

BACKGROUND: A key aspect of representations for object recognition and scene analysis in the ventral visual stream is the spatial frame of reference, be it a viewer-centered, object-centered, or scene-based coordinate system. Coordinate transforms from retinocentric space to other reference frames involve combining neural visual responses with extraretinal postural information. METHODOLOGY/PRINCIPAL FINDINGS: We examined whether such spatial information is available to anterior inferotemporal (AIT) neurons in the macaque monkey by measuring the effect of eye position on responses to a set of simple 2D shapes. We report, for the first time, a significant eye position effect in over 40% of recorded neurons with small gaze angle shifts from central fixation. Although eye position modulates responses, it does not change shape selectivity. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that spatial information is available in AIT for the representation of objects and scenes within a non-retinocentric frame of reference. More generally, the availability of spatial information in AIT calls into questions the classic dichotomy in visual processing that associates object shape processing with ventral structures such as AIT but places spatial processing in a separate anatomical stream projecting to dorsal structures.

THE ROLE OF MUCOSAL EPITHELIAL CELLS IN HIV-1 INFECTION

The predominant route of human immunodeficiency virus type 1 (HIV-1) transmission is infection across the vaginal mucosa. Epithelial cells, which form the primary barrier of protection against pathogens, are the first cell type at these mucosal tissues to encounter the virus but their role in HIV infection has not been clearly elucidated. Although mucosal epithelial cells express only low levels of the receptors required for successful HIV infection, productive infection does occur at these sites. The present work provides evidence to show that HIV exposure, without the need for productive infection, induces human cervical epithelial cells to produce Thymic Stromal Lymphopoietin (TSLP), an IL7-like cytokine, which potently activated human myeloid dendritic cells (mDC) to cause the homeostatic proliferation of autologous CD4+ T cells that serve as targets for HIV infection. Rhesus macaques inoculated with simian immunodeficiency virus (SIV) or with the simian-human immunodeficiency virus (SHIV) by the vaginal, oral or rectal route exhibited dramatic increases in: TSLP expression, DC and CD4+ T cell numbers, and viral replication, in the vaginal, oral, and rectal tissues, respectively within the first 2 weeks after virus exposure. Evidence obtained showed that HIV-mediated TSLP production by cervical cells is dependent upon the expression of the cell surface salivary agglutinin (SAG) protein gp340. Epithelial cells expressing gp340 exhibited HIV endocytosis and TSLP expression and genetic knockdown of gp340 or use of a gp340-blocking antibody inhibited TSLP expression by HIV. On the other hand, gp340-null epithelial cells failed to endocytose HIV and produce TSLP, but transfection of gp340 resulted in HIV-induced TSLP expression. Finally, HIV-induced TSLP expression was found to be mediated by TLR7/8 signaling and NF-kB activity because silencing these pathways or use of specific inhibitors abrogated TSLP expression in gp340-postive but not in gp340-null epithelial cells. Overall these studies identify TSLP as a key player in the acute phase of HIV-1 infection in permitting HIV to successfully maneuver the hostile vaginal mucosal microenvironment by creating a conducive environment for sustaining the small amount of virus that initially crosses the mucosal barrier allowing it to successfully cause infection and spread to distal compartments of the body

Of mice, macaques and men: scaling of virus dynamics and immune responses

In this Opinion piece, I argue that the dynamics of viruses and the cellular immune response depend on the body size of the host. I use allometric scaling theory to interpret observed quantitative differences in the infection dynamics of lymphocytic choriomeningitis virus (LCMV) in mice (Mus musculus), simian immunodeficiency virus (SIV) in rhesus macaques (Macaca mulatta) and human immunodeficiency virus (HIV) in humans.