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PubMed1993

The temporal and spatial expression of basic fibroblast growth factor during ocular development in the chicken.

PURPOSE: The authors determined the temporal and spatial localization of basic fibroblast growth factor (bFGF) during ocular development in the chick embryo in an attempt to elucidate its role in this process. METHODS: These studies used monospecific polyclonal rabbit anti-human bFGF immunoglobulin G in conjunction with immunohistochemical techniques and western blot analysis. Embryonic eyes at 5-20 days of development were studied. RESULTS: The bFGF was not detected by western blot analysis until embryonic day 12. However, low levels of bFGF-immunoreactive material were present in pigmented and neural retina and the lenses of 5-day embryos. Lens epithelial and fiber cells remained weakly stained throughout development; neuroepithelial cells, ganglion cells, amacrine cells, and photoreceptors all contained significant levels of bFGF-immunoreactive material. Corneal epithelium consistently contained high levels of immunoreactive material. In the corneal endothelium, increasing levels of immunoreactive material were seen as development proceeded. CONCLUSION: It was hypothesized that bFGF may be involved in regulating the proliferation and differentiation of ocular cells in either an autocrine or paracrine fashion during development and that it may play a role in tissue maintenance in the adult eye. These conclusions are consistent with the temporal and spatial expression of bFGF described here.

Animals↗
PubMed2000

On variability in the density of corticocortical and thalamocortical connections.

Variability is an important but neglected aspect of connectional neuroanatomy. The quantitative density of the 'same' corticocortical or thalamocortical connection may vary by over two orders of magnitude between different injections of the same tracer. At present, however, the frequency distribution of connection densities is unknown. Therefore, it is unclear what kind of sampling strategies or statistical methods are appropriate for quantitative studies of connectivity. Nor is it clear if the measured variability represents differences between subjects, or if it is simply a consequence of intra-individual differences resulting from experimental technique and the exact placement of tracers relative to local spatial and laminar variation in connectivity. We used quantitative measurements of the density of a large number of corticocortical and thalamocortical connections from our own laboratories and from the literature. Variability in the density of given corticocortical and thalamocortical connections is high, with the standard deviation of density proportional to the mean. The frequency distribution is close to exponential. Therefore, analysis methods relying on the normal distribution are not appropriate. We provide an appendix that gives simple statistical guidance for samples drawn from exponentially distributed data. For a given corticocortical or thalamocortical connection density, between-individual standard deviation is 0.85 to 1.25 times the within-individual standard deviation. Therefore, much of the variability reported in conventional neuroanatomical studies (with one tracer deposited per animal) is due to within-individual factors. We also find that strong, but not weak, corticocortical connections are substantially more variable than thalamocortical connections. We propose that the near exponential distribution of connection densities is a simple consequence of 'patchy' connectivity. We anticipate that connection data will be well described by the negative binomial, a class of distribution that applies to events occurring in clumped or patchy substrates. Local patchiness may be a feature of all corticocortical connections and could explain why strong corticocortical connections are more variable than strong thalamocortical connections. This idea is supported by the columnar patterns of many corticocortical but few thalamocortical connections in the literature.

Animals↗
PubMed1995

Relationships between translation of pro alpha1(I) and pro alpha2(I) mRNAs during synthesis of the type I procollagen heterotrimer.

Final assembly of the procollagen I heterotrimeric molecule is initiated by interactions between the carboxyl propeptide domains of completed, or nearly completed nascent pro alpha chains. These interactions register the chains for triple helix folding. Prior to these events, however, the appropriate nascent chains must be brought within the same compartments of the endoplasmic reticulum (ER). We hypothesize that the co-localization of the synthesis of the nascent pro alpha1(I) and pro alpha2(I) chains results from an interaction between their translational complexes during chain synthesis. This has been investigated by studying the polyribosomal loading of the pro alpha-chain messages during in vitro translation in the presence and absence of microsomal membranes, and in cells which have the ability to synthesize the pro alpha1 homotrimer or the normal heterotrimer. Recombinant human pro alpha1(I) and pro alpha2(I) cDNAs were inserted into plasmids and then transcribed in vitro. The resulting RNAs were translated separately and in mixture in a cell-free rabbit reticulocyte lysate +/- canine pancreatic microsomes. Cycloheximide (100 mu g/ml) was added and the polysomes were collected and fractionated on a 15-50% sucrose gradient. The RNA was extracted from each fraction and the level of each chain message was determined by RT-PCR. Polysomes from K16 (heterotrimer-producing), W8 (pro alpha1(I) homotrimer), and A2' (heterotrimer + homotrimer) cells were similarly analyzed. Translations of the pro alpha1(I) and pro alpha2(I) messages proceeded independently in the cell-free, membrane-free systems, but were coordinately altered in the presence of membrane. The cell-free + membrane translation systems mimicked the behavior of the comparable cell polysome mRNA loading distributions. These data all suggest that there is an interaction between the pro alpha chain translational complexes at the ER membrane surface which temporally and spatially localize the nascent chains for efficient heteromeric selection and folding.

Animals↗
PubMed1998

Functional maturation of the primate fetal adrenal in vivo: 3. Specific zonal localization and developmental regulation of CYP21A2 (P450c21) and CYP11B1/CYP11B2 (P450c11/aldosterone synthase) lead to integrated concept of zonal and temporal steroid biosynthesis.

Previous studies in the primate fetal adrenal gland have indicated that the gland is comprised of three functional zones: 1) the inner fetal zone (FZ), which has the enzymes necessary for dehydroepiandrosterone sulfate (DHEAS) production beginning early in gestation; 2) the transitional zone (TZ), which possesses enzymes necessary for cortisol production; and 3) the outer, definitive zone (DZ), which appears to function as a reservoir of progenitor cells that may populate the remainder of the gland and does not acquire a steroidogenic phenotype with the capacity to produce mineralocorticoids until near term. The enzymes CYP21A2 (P450 21 hydroxylase, or P450c21), CYP11B1 (11beta hydroxylase or P450c11) and CYP11B2 (aldosterone synthase) are necessary for glucocorticoid and mineralocorticoid synthesis but have not been localized previously in an ontogenic manner in the primate fetal adrenal gland. Therefore, we used immunocytochemistry (ICC) to assess specific zonal localization and developmental regulation of CYP21A2 and CYP11B1/CYP11B2 in the human (13-24 weeks' gestation) and rhesus monkey (109 d-term) fetal adrenal gland. In the fetal rhesus, ICC was performed with and without metyrapone administration to the fetus to assess the effects of endogenously increased fetal ACTH. In the human fetal adrenal, CYP21A2 immunoreactivity (IR) was present in only a few isolated cells in the DZ but was detectable in almost all cells in the TZ and FZ. In the fetal rhesus, CYP21A2-IR was present in cells throughout the DZ and TZ and, to a lesser degree, in the FZ. Staining intensity increased with advancing gestational age and was up-regulated in the DZ and TZ, but not the FZ, of the metyrapone-treated fetuses. In the human fetal adrenal gland, CYP11B1/CYP11B2-IR was absent in the DZ but present in the TZ and FZ. In the fetal rhesus monkey adrenal, CYP11B1/CYP11B2-IR was present in all cells of the TZ and FZ but was absent from the DZ until near term. After metyrapone, CYP11B1/CYP11B2-IR was induced in the DZ and was up-regulated in the TZ and FZ. Taken together, these data indicate that in the primate fetal adrenal gland, the FZ has the capacity to synthesize DHEA and DHEAS beginning early in development, the TZ has the capacity to synthesize cortisol after midgestation, and the DZ has the capacity to synthesize mineralocorticoids, but not until near term. The spatial localization of steroid metabolizing enzymes and steroid products in the human and rhesus monkey fetal adrenal suggests analogies of the three functional zones of the fetus (DZ, TZ, and FZ) to their adult counterparts (zona glomerulosa, zona fasciculata, and zona reticularis) and their steroid products (mineralocorticoids, glucocorticoids and androgens, respectively), although the reason for the presence of CYP11B1/CYP11B2- and CYP21A2-IR in the FZ remains to be elucidated.

Adrenal Glands↗
PubMed2025

Novel antibodies for identification, selection, and manipulation of T cells expressing Whitlow linker-containing CARs.

BACKGROUND: The translational study of chimeric antigen receptor (CAR) T-cell function, persistence, immunophenotype, and spatial localization after infusion is crucial for understanding factors that influence clinical outcomes. However, research has been limited by a lack of optimized tools to reliably detect CAR-engineered cells. To address this, we developed a novel platform to generate monoclonal antibodies (mAbs) targeting a linker peptide incorporated in single-chain variable fragments (scFvs) of most CAR constructs. METHODS: Using recombinant proteins and scFv linker peptides as immunogens, we generated murine mAbs against the Whitlow linker peptide, capable of binding cells expressing Whitlow linker-containing CARs in both fresh and formalin-fixed paraffin-embedded (FFPE) tissues. We evaluated these antibodies in multiple in vitro translational applications relevant to CAR T-cell research and manufacturing. RESULTS: We identified five unique mAbs reactive against the Whitlow linker and characterized their binding properties and three-dimensional structural conformation. One clone was evaluated in depth, demonstrating comparable capacity to identify CAR T cells in peripheral blood relative to other methods using anti-idiotype antibodies or recombinant CAR-target proteins. In contrast to these reagents, the anti-Whitlow mAb detects cells expressing Whitlow linker-containing CARs with different antigen specificities, including those harboring the widely employed anti-CD19 FMC63-derived scFv as well as other scFvs, such as those targeting B-cell maturation antigen (BCMA) or CD33. Importantly, the anti-Whitlow mAb identified CAR T cells in situ in archival FFPE tissues, and a DNA-barcoded format enabled their spatial characterization and immunophenotyping in highly multiplexed immunohistochemistry. We also assessed the functional consequences of antibody binding on CAR T cells in vitro and demonstrated the feasibility of anti-Whitlow mAb-mediated selective enrichment of CAR-expressing T cells for potential utility in manufacturing workflows. CONCLUSIONS: Anti-Whitlow mAb clones exhibited distinct structural and functional properties that can be leveraged for multiple applications, providing versatile tools for detection, selection and manipulation of a broad range of clinical and preclinical CAR T-cell products.

Humans↗
PubMed1996

Propagation of spindle waves in a thalamic slice model.

1. We study the propagation and dynamics of spindle waves in thalamic slices by developing and analyzing a model of reciprocally coupled populations of excitatory thalamocortical (TC) neurons and inhibitory thalamic reticular (RE) neurons. 2. Each TC neuron has three intrinsic ionic currents: a low-threshold T-type Ca+2 current (ICa-T), a hyperpolarization-activated cation ("sag") current (Ih) and a leak current. Each RE cell also has three currents: ICa-T, a leak current, and a calcium-activated potassium current (IAHP). Isolated TC cells are at rest, can burst when released or depolarized from a hyperpolarized level, and burst rhythmically under moderate constant hyperpolarizing current. Isolated RE cells are at a hyperpolarized resting membrane potential and can burst when depolarized. 3. TC cells excite RE cells with fast alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) synapses, and RE cells inhibit TC cells with fast gamma-aminobutyric acid-A (GABAA) and slow GABAB synapses and inhibit each other with GABAA synapses only. GABAB postsynaptic conductances operate far from saturation, and the slow inhibitory postsynaptic potentials (IPSPs) increase with the width of the presynaptic burst. The model network is a one-dimensional cellular array with localized coupling. The synaptic coupling strength decays with the distance between the pre- and postsynaptic cells, either exponentially or as a step function. 4. The "intact" network can oscillate with partial synchrony and a population frequency of approximately 10 Hz. RE cells emit bursts almost at every oscillation cycle, whereas TC cells do so almost at every other cycle. Block of GABAB receptors hardly changes the network behavior. Block of GABAA receptors leads the network to a slowed oscillatory state, where the population frequency is approximately 4 Hz and both RE and TC cells fire unusually long bursts at every cycle and in full synchrony. These results are consistent with the experimental observations of von Krosigk, Bal, and McCormick. We obtain such consistency only when the above assumptions regarding the synaptic dynamics, particularly nonsaturating GABAB synapses, are fulfilled. 5. The slice model has a stable rest state with no neural activity. By initially depolarizing a few neurons at one end of the slice while all the other cells are at rest, a recruitment process may be initiated, and a wavefront of oscillatory activity propagates across the slice. Ahead of the wavefront, neurons are quiescent; neurons behind it oscillate. We find that the wave progresses forward in a lurching manner. TC cells that have just become inhibited must be hyperpolarized for a long enough time before they can fire rebound bursts and recruit RE cells. This step limits the wavefront velocity and may involve a substantial part of the cycle when no cells at the front are depolarized. 6. The wavefront velocity increases linearly with the characteristic spatial length of the connectivity (the footprint length). It increases only gradually with the synaptic strength, logarithmically in the case of an exponential connection function and only slightly for a step connection function. It also decreases gradually with a potassium leak conductance that hyperpolarizes RE cells. 7. To reproduce the experimentally measured wavefront velocity of approximately 1 mm/s, together with other in vitro observations, both the RE-to-TC and the TC-to-RE projections in the model should be spatially localized. The sum of the RE-to-TC and the TC-to-RE synaptic footprint lengths should be on the order of 100 microns. (ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1986

Localization in human thalamus of units triggered during 'verbal commands,' voluntary movements and tremor.

Microelectrode recordings in the rostral (n. reticularis) and lateral (ventralis lateralis) human thalamus were carried out in locally anaesthetized diskinetic patients during stereotaxic operations. Their responses to voluntary motor tasks prompted by imperative verbal stimuli were tested. Spontaneous and evoked unit activities were studied using computer processing techniques. In the n. reticularis thalami and immediately adjacent thalamic zones, not only units reacting during the initiation of voluntary movements (100-200 msec before the movement), but also units responding to the verbal command itself ('triggered verbal command' units) were found. They proved to be concerned directly with the semantic meaning of the command. In the VL anterior area (Voa-Vop in German nomenclature) the majority of the units responded during the phases of initiation and/or realization of the voluntary motor act ('voluntary movement' units of Jasper and Bertrand 1966); when these units were not spontaneously rhythmic they were transiently transformed into rhythmic (5 +/- 1 Hz) ones. This transformation appeared during the preparation and realization of movement but also in some cells as a rebound phenomenon. In patients without tremor (akinetic and rigid forms of parkinsonism, torticollis), the transient rhythmogenic transformation was frequently provoked by the repetition of motor tasks. In the posterior part of VL (Vim), cells were driven by proprioceptive inflow coming from a specific peripheral region. They react also during the voluntary movement of the same region. The majority of these units were rhythmic at 5 +/- 1 Hz, and they presented a close correlation in phase and frequency with the tremor. The anatomical locations of the three main pools of neurons were determined. 'Triggered verbal command' units were placed more anteriorly and laterally. 'Voluntary movements' and 'rhythmic 5 +/- 1 Hz units' had identical spatial localizations. This fact supports the contributions of these two last types to the central mechanisms of both tremor and voluntary movement.

Electromyography↗
PubMed1999

Responses of contralateral SI and SII in cat to same-site cutaneous flutter versus vibration.

The methods of (14)C-2-deoxyglucose ((14)C-2DG) metabolic mapping and optical intrinsic signal (OIS) imaging were used to evaluate the response evoked in the contralateral primary somatosensory receiving areas (SI and SII) of anesthetized cats by either 25 Hz ("flutter") or 200 Hz ("vibration") sinusoidal vertical skin displacement stimulation of the central pad on the distal forepaw. Unilateral 25-Hz stimulation consistently evoked a localized region of elevated (14)C-2DG uptake in both SI and SII in the contralateral hemisphere. In contrast, 200-Hz stimulation did not evoke elevated (14)C-2DG uptake in the contralateral SI but evoked a prominent, localized region of increased (14)C-2DG uptake in the contralateral SII. Experiments in which the OIS was recorded yielded results that complemented and extended the findings obtained with the 2DG method. First, 25-Hz central-pad stimulation evoked an increase in absorbance in a region in the contralateral SI and SII that corresponded closely to the region in which a similar stimulus evoked increased (14)C-2DG uptake. Second, 200-Hz stimulation of the central pad consistently evoked a substantial increase in absorbance in the contralateral SII but very little or no increase in absorbance in the contralateral SI. And third, 200-Hz central-pad stimulation usually evoked a decrease in absorbance in the same contralateral SI region that underwent an increase in absorbance during same-site 25-Hz stimulation. Experiments in which the OIS responses of both SI and SII were recorded simultaneously demonstrated that continuous (>1 s) 25-Hz central-pad stimulation evokes a prominent increase in absorbance in both SI and SII in the contralateral hemisphere, whereas only SII undergoes a sustained prominent increase in absorbance in response to 200-Hz stimulation to the same central-pad site. SI exhibits an initial, transient increase in absorbance in response to 200-Hz stimulation and at durations of stimulation >1 s, undergoes a decrease in absorbance. It was found that the stimulus-evoked absorbance changes in the contralateral SI and SII are correlated significantly during vibrotactile stimulation of the central pad-positively with 25-Hz stimulation and negatively with 200-Hz stimulation. The findings are interpreted to indicate that 25-Hz central-pad stimulation of the central pad evokes spatially localized and vigorous neuronal activation within both SI and SII in the contralateral hemisphere and that although 200-Hz stimulation evokes vigorous and well maintained neuronal activation within the contralateral SII, the principal effect on the contralateral SI of a 200-Hz stimulus lasting >1 s is inhibitory.

Animals↗
PubMed2006

Density effects on life-history traits in a wild population of the great tit Parus major: analyses of long-term data with GIS techniques.

1. Population density often has strong effects on the population dynamics and reproductive processes of territorial animals. However, most estimates of density-dependent effects use the number of breeding pairs per unit area in a given season and look for correlations across seasons, a technique that assigns the same density score to each breeding pair, irrespective of local spatial variation. 2. In this study, we employed GIS techniques to estimate individual breeding densities for great tits breeding in Wytham Woods UK, between 1965 and 1996. We then used linear mixed modelling to analyse the effect of density on reproductive processes. 3. The areas of Thiessen polygons formed around occupied nestboxes were used to approximate territory size (necessarily inverse of breeding density). There were significant, independent and positive relationships between clutch size, fledging mass and the number of offspring recruited to the population, and territory size (all P < 0.001), but no effect of territory size on lay-date or egg mass. 4. Thiessen polygons are contiguous and cover all of the available area. Therefore, at low nest densities territory polygons were excessively oversized. Using a novel procedure to address this limitation, territory sizes were systematically capped through a range of maxima, with the greatest effect in the models when territories were capped at 0.9-2.3 ha. This figure approximates to the maximum effective territory size in our population and is in close agreement with several field-based studies. This capping refinement also revealed a significant negative relationship between lay-date and territory size capped at 0.9 ha (P < 0.001). 5. These density-dependent effects were also detected when analyses were restricted to changes within individual females, suggesting that density effects do not merely result from either increased proportions of low-quality individuals, or increased occupation of poor sites, when population density is high. 6. Overall, these results suggest that, in the current population, great tits with territories smaller than c. 2 ha independently lay smaller and later clutches, have lighter fledglings, and recruit fewer offspring to the breeding population. These analyses thus suggest a pervasive and causal role of local population density in explaining individual reproductive processes.

Animals↗
PubMed1999

Spatial and temporal summation of sensory and affective dimensions of deep somatic pain.

There is considerable evidence in support of differential information processing of the sensory-discriminative and motivational-affective meanings of pain. The purpose of this work was to examine whether temporal (acute, tonic, persistent) and spatial (local, regional, widespread) aspects of deep somatic pain influence the sensory and affective dimensions of pain. Acute pain consisted of a short bout of pain, lasting about 100 s. Tonic pain was the experience of experimentally maintained pain for 18 min. Both acute and tonic pain were induced by infusion of an algesic or control substance into muscle with the subject blinded with respect to the type of infusion and randomization of the application sequence. Comparing the response of experimental subjects to a group of matched cases with persistent masticatory myalgia alone or in combination with widespread musculoskeletal pain, we examine whether the experimental state is different from the matched clinical condition, and whether there is a difference between the condition being restricted to the face or not. The McGill pain questionnaire was used to assess the sensory and affective correlates of pain. The normalized sensory score for acute/unilateral face pain was different from that established for tonic/unilateral face pain (P = 0.055, borderline s.), and so was the normalized affective score (P = 0.009, s.). When comparing tonic/unilateral versus tonic/bilateral face pain, the affective scores increased with increased pain involvement (P = 0.009, s.) while the sensory sores were unaffected by the additional pain induced in the contralateral masseter muscle (P = 0.357, n.s). Notably, sensory and affective scores for tonic/bilateral and persistent/bilateral face pain were not statistically different (sensory: P = 0.169, n.s.; affective: P = 0.643, n.s). On the other hand, when contrasting persistent/bilateral face pain with persistent/ widespread musculoskeletal pain, both scores were significantly different (sensory: P < 0.001, s.; affective: P = 0.041, s.). Time in and spread of pain influenced the perceptual correlates of pain to a significant degree. The major increase in the sensory dimension occurred from 'no pain' to 'acute pain'. Affective scores showed the most significant increases from acute to tonic pain, particularly with greater spatial involvement. The significant increases in sensory scores observed when contrasting persistent facial pain alone and in combination with widespread musculoskeletal pain was attributed to the broader body experience. Because the perceptual correlates of tonic and matched persistent (chronic) pain states were similar, we concluded that it does not require months for the development of the sensory and affective meaning of persistent pain as assumed.

Acute Disease↗
PubMed2005

Estrogen modulation of hypothalamic neurons: activation of multiple signaling pathways and gene expression changes.

Hypothalamic target neurons of estrogen include neurosecretory neurons such as gonadotropin-releasing hormone (GnRH) and dopamine neurons, and local circuitry neurons such as proopiomelanocortin (POMC) and gamma-aminobutyric acid (GABA) neurons. These and other hypothalamic neurons are involved in regulating numerous homeostatic functions including reproduction, thermoregulation, stress responses, feeding and motivated behaviors. Using a combination of techniques to examine the molecular mechanisms leading to physiological changes induced by estrogen, we find that both rapid effects and transcriptional changes alter excitability of hypothalamic neurons. We have identified membrane-initiated, rapid signaling pathways through which 17beta-estradiol (E2) alters synaptic responses in these neurons using whole-cell patch recording in hypothalamic slices from ovariectomized female guinea pigs. E2 rapidly uncouples mu-opioid and GABA(B) receptors from G protein-gated inwardly rectifying K+ (GIRK) channels in POMC and dopamine neurons as manifested by a reduction in the potency of mu-opioid and GABA(B) receptor agonists to activate these channels. Inhibitors of phospholipase C, protein kinase C and protein kinase A block the actions of E2, indicative that the E2 receptor is G protein-coupled to activation of this cascade. Taking advantage of an animal model we developed to investigate estrogen's feedback actions on secretion of gonadotropin-releasing hormone (GnRH), we studied the transcriptional changes induced by estrogen using suppression subtractive hybridization (SSH) and microarray analysis. Many of the observed mRNA expression changes include transcripts encoding proteins critical for neurotransmitter release and receptor dynamics. Some of these include gec-1, PI3-kinase p55gamma, rab11a GTPase, synaptobrevin2, synaptogyrin, taxilin, Ca2+-dependent activator protein for secretion (CAPS) and a number of proteins containing pleckstrin homology domains-domains that are involved in plasma membrane targeting of their host protein. In situ hybridization and quantitative film autoradiography analysis on selected transcripts show differential distribution and expression in hypothalamic nuclei. Furthermore, single-cell PCR analysis reveals these genes to be expressed in neurons such as POMC (and GnRH). Whether these expression changes are mediated by the classical or membrane estrogen receptors has yet to be delineated. More detailed investigations of transcript spatial localization within neurons and their temporal expression, i.e., within minutes or hours, will provide more insight regarding how estrogen alters neuronal excitability and synaptic efficacy that ultimately lead to changes in complex behavior.

Animals↗
PubMed2002

Visual field defects and multifocal visual evoked potentials: evidence of a linear relationship.

OBJECTIVE: To determine the relationship between spatially localized multifocal visual evoked potentials (mfVEPs) and Humphrey visual fields (HVFs) in patients with unilateral field defects. METHODS: Humphrey visual fields and mfVEPs were obtained from 20 patients with unilateral field losses due to either ischemic optic neuropathy or glaucoma. Monocular mfVEPs were obtained for each eye. The amplitude of the mfVEP responses was calculated using root-mean-square and signal-noise ratio measures. Estimates of the HVF loss in the same regions of the field used for the mfVEP were obtained by interpolating the 24-2 HVF data. RESULTS: Monocular mfVEP amplitude decreased with HVF loss, although small mfVEP signals were not uniquely associated with poor fields. On average, the monocular mfVEP was indistinguishable from noise for field losses between -5 and -10 dB, and good monocular mfVEP amplitudes were never associated with extensive visual field loss. The interocular ratio of the mfVEP amplitudes correlated well with the difference between the HVF values of the 2 eyes, and this correlation improved with increased signal-noise ratio. CONCLUSIONS: The monocular and interocular results were consistent with a linear relationship between the amplitude of the signal portion of the mfVEP response and linear HVF loss. One way to produce this relationship would be if both the signal in the mfVEP and linear HVF loss were linearly related to the percentage of local ganglion cells lost. The clinical limitations of the mfVEP technique can be understood by taking the signal-noise ratio, and the linear model proposed herein, into consideration.

Adult↗
PubMed2001

Reductions in occipital cortex GABA levels in panic disorder detected with 1h-magnetic resonance spectroscopy.

BACKGROUND: There is preclinical evidence and indirect clinical evidence implicating gamma-aminobutyric acid (GABA) in the pathophysiology and treatment of human panic disorder. Specifically, deficits in GABA neuronal function have been associated with anxiogenesis, whereas enhancement of GABA function tends to be anxiolytic. Although reported peripheral GABA levels (eg, in cerebrospinal fluid and plasma) have been within reference limits in panic disorder, thus far there has been no direct assessment of brain GABA levels in this disorder. The purpose of the present work was to determine whether cortical GABA levels are abnormally low in patients with panic disorder. METHODS: Total occipital cortical GABA levels (GABA plus homocarnosine) were assessed in 14 unmedicated patients with panic disorder who did not have major depression and 14 retrospectively age- and sex-matched control subjects using spatially localized (1)H-magnetic resonance spectroscopy. All patients met DSM-IV criteria for a principal current diagnosis of panic disorder with or without agoraphobia. RESULTS: Patients with panic disorder had a 22% reduction in total occipital cortex GABA concentration (GABA plus homocarnosine) compared with controls. This finding was present in 12 of 14 patient-control pairs and was not solely accounted for by medication history. There were no significant correlations between occipital cortex GABA levels and measures of illness or state anxiety. CONCLUSIONS: Panic disorder is associated with reductions in total occipital cortex GABA levels. This abnormality might contribute to the pathophysiology of panic disorder.

Adult↗
PubMed1997

Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats.

The distribution of microglia, macrophages, T-lymphocytes, and astrocytes was characterized throughout a spinal contusion lesion in Sprague-Dawley and Lewis rats by using immunohistochemistry. The morphology, spatial localization, and activation state of these inflammatory cells were described both qualitatively and quantitatively at 12 hours, 3, 7, 14, and 28 days after injury. By use of OX42 and ED1 antibodies, peak microglial activation was observed within the lesion epicenter of both rat strains between three and seven days post-injury preceding the bulk of monocyte influx and macrophage activation (seven days). Rostral and caudal to the injury site, microglial activation plateaued between two and four weeks post-injury in the dorsal and lateral funiculi as indicated by morphological transformation and the de-novo expression of major histocompatibility class II (MHC II) molecules. Similar to the timing of microglial reactions, T-lymphocytes maximally infiltrated the lesion epicenter between three and seven days post-injury. Reactive astrocytes, while present in the acute lesion, were more prominent at later survival times (7-28 days). These cells were interspersed with activated microglia but appeared to surround and enclose tissue sites occupied by reactive microglia and phagocytic macrophages. Thus, trauma-induced central nervous system (CNS) inflammation, regardless of strain, occurs rapidly at the site of injury and involves the activation of resident and recruited immune cells. In regions rostral or caudal to the epicenter, prolonged activation of inflammatory cells occurs preferentially in white matter and primarily consists of activated microglia and astrocytes. Differences were observed in the magnitude and duration of macrophage activation between Sprague-Dawley (SD) and Lewis (LEW) rats throughout the lesion. Increased expression of complement type 3 receptors (OX42) and macrophage-activation antigens (ED1) persisted for longer times in LEW rats while expression of MHC class II molecules was attenuated in LEW compared to SD rats at all times examined. Variations in the onset and duration of T-lymphocyte infiltration also were observed between strains with twice as many T-cells present in the lesion epicenter of Lewis rats by 3 days post-injury. These strain-specific findings potentially represent differences in corticosteroid regulation of immunity and may help predict a range of functional neurologic consequences affected by neuroimmune interactions.

Animals↗
PubMed1997

Spatial distribution of kainate receptor subunit mRNA in the mouse basal ganglia and ventral mesencephalon.

In an attempt to gain knowledge of the possible functions of kainate receptors, we have used in situ hybridization to examine the regional and cellular expression patterns of glutamate receptor subunits GluR5-7, KA1 and KA2 in the adult mouse basal ganglia, known to play a pivotal role in the translation of motivation into actions. Kainate receptor subunits were found to be differentially expressed in the circuitry forming the basal ganglia. They differ from each other in expression levels and their spatial localization. GluR6 appeared as the key subunit for the descending gamma-aminobutyric acid (GABA)ergic-glutamatergic pathways, with highest message levels in the caudate putamen, globus pallidus and subthalamic nucleus as well as in the nucleus accumbens and olfactory tubercle. GluR7 exhibited highest expression in the ascending nigrostriatal and mesolimbic dopaminergic neurons. GluR5 had a restricted distribution pattern, with high expression in the ventral pallidum, the islands of Calleja and pars compacta of the substantia nigra. KA2 was usually coexpressed with GluR6, although with a generally lower level of expression. Finally, KA1 mRNA was barely detectable in these neuronal circuits. These data suggest that kainate receptors in general may be involved in the functions associated with the basal ganglia, with a key role in the control of the central dopaminergic transmission. Thus, they might be implicated in the neurodegenerative and psychic disorders associated with an impairment of the basal ganglia.

Animals↗
PubMed1997

Model of spatio-temporal propagation of action potentials in the Schaffer collateral pathway of the CA1 area of the rat hippocampus.

There is a sharp contrast between the profuse in vivo axonal arborization of CA3 pyramidal cells in the CA1 area and the low probability of finding pairs of connected CA3-CA1 pyramidal cells in vitro. These anatomical differences contribute to a connectivity argument for discrepancies between electrophysiological data recorded in vitro and in vivo. In order to investigate this issue, we have developed a realistic computer model of the Schaffer collateral pathway of the hippocampus and analyzed the spatio-temporal distribution of action potentials along this pathway following three different types of electrical test stimulus. Direct activation of mossy fibers, CA3 pyramidal cells and focal stimulation of CA1 stratum radiatum were investigated. The parameters of the model were selected from available biological data. Spikes in Schaffer collaterals were followed from their onset in the CA3 pyramidal cell initial segment to the last order branches of their axonal tree in two types of configuration: the whole hippocampus and the slice configuration. The anatomical and electropysiological characteristics of the mossy fibre and Schaffer collateral pathways were found to impose strong constraints on the spatio-temporal distribution of action potentials in the CA1 area. Specific projection zones are determined by the spatial localization of the emitting CA3 pyramidal cells. Their position also defines precise time windows during which some CA1 projection zones receive a large number of correlated signals. Moreover, the variability of the delay at the mossy fibre/CA3 pyramidal cell synapse seems to provide the CA1 projection zones with a background level of excitation. Finally, we show how the patterns of activation obtained in the whole hippocampus are different from those obtained in the slice.

Action Potentials↗
PubMed1996

31P NMR studies of human skin using a modified zig-zag surface coil.

Results are presented from an in vivo study of human skin in which a zig-zag surface coil together with a three-pulse Fourier Series Window (FSW) protocol have been used to obtain minimally contaminated 31P skin spectra of the posterior calf. Phantom experiments indicate that while the fall-off in the B1 field profile of the zig-zag surface coil is superior to conventional surface coil designs, it is still not sufficient on its own to reduce muscle signal contamination to acceptable levels in human studies. The additional spatial localization required is provided by the FSW, which reduces signal contamination to less than 30% of the total signal collected. In a study of 18 normal controls the measured pH was found to be relatively high (7.39 +/- 0.08), while the ratios of skin PCr/ beta-ATP (1.04 +/- 0.35) and PCr/Pi (1.67 +/- 0.4) were found to be low compared with that of skeletal muscle. In addition, substantial signal from phosphomonoesters and phosphodiesters were also observed.

Adenosine Triphosphate↗
PubMed1998

Dual role for the zeste-white3/shaggy-encoded kinase in mesoderm and heart development of Drosophila.

A Drosophila homolog of the serine/threonine kinase GSK-3 beta, encoded by the zest-white3/shaggy gene (zw3), has been implicated as a maternally provided antagonist of zygotic signaling by the secreted segmentation gene wingless (wg). The wg signal apparently causes a spatially localized inhibition of the ubiquitous repressor function of zw3. This double negative mechanism of signal transduction has been shown to mediate the patterning function of Wg in a number of developmental processes. Although wg is absolutely required for specifying the heart progenitors within the mesoderm of Drosophila, the role of zw3 in this process has been unclear. Here, we present evidence that zw3 has a dual role in mesoderm development: (1) zw3 acts as an antagonist in cardiogenic wg signal transduction, and (2) zw3 also seems to be required to promote positively the formation of a larger mesodermal region, the tinman- and dpp-dependent "dorsal mesoderm," which is a prerequisite not only for cardiogenesis, but also for visceral mesoderm formation. We also demonstrate that a recently identified proximal component of the wg cascade, which is a transcription factor encoded by pangolin/dTCF (dTCF), also seems to mediate wg-dependent cardiogenesis. Further, we present evidence that Notch (N), which opposes wg signaling in other situations, is unlikely to be directly involved in the cardiogenic wg pathway, but seems to have multiple other myogenic functions, one of which is to inhibit mesoderm differentiation altogether, when overexpressed as a constitutively active form.

Animals↗