Quantitative distribution of parvalbumin, calretinin, and calbindin D-28k immunoreactive neurons in the visual cortex of normal and Alzheimer cases

The distribution of parvalbumin (PV), calretinin (CR), and calbindin (CB) immunoreactive neurons was studied with the help of an image analysis system (Vidas/Zeiss) in the primary visual area 17 and associative area 18 (Brodmann) of Alzheimer and control brains. In neither of these areas was there a significant difference between Alzheimer and control groups in the mean number of PV, CR, or CB immunoreactive neuronal profiles, counted in a cortical column going from pia to white matter. Significant differences in the mean densities (numbers per square millimeter of cortex) of PV, CR, and CB immunoreactive neuronal profiles were not observed either between groups or areas, but only between superficial, middle, and deep layers within areas 17 and 18. The optical density of the immunoreactive neuropil was also similar in Alzheimer and controls, correlating with the numerical density of immunoreactive profiles in superficial, middle, and deep layers. The frequency distribution of neuronal areas indicated significant differences between PV, CR, and CB immunoreactive neuronal profiles in both areas 17 and 18, with more large PV than CR and CB positive profiles. There were also significantly more small and less large PV and CR immunoreactive neuronal profiles in Alzheimer than in controls. Our data show that, although the brain pathology is moderate to severe, there is no prominent decrease of PV, CR and CB positive neurons in the visual cortex of Alzheimer brains, but only selective changes in neuronal perikarya.     

Urinary calcium excretion and renal calbindin-D28k

A severe form of toxemia of pregnancy with microangiopathic hemolytic anemia, elevated liver enzymes, and low platelets has been called the HELLP syndrome. A patient with the HELLP syndrome developed a severe, reversible encephalopathy. Brain computed tomography and magnetic resonance imaging showed abnormalities consistent with edema limited to the posterior circulation territory. The location of the lesions and their occurrence in the HELLP syndrome support suggestions that the vulnerability of posterior structures in eclamptic encephalopathy is due to a vascular susceptibility of the posterior circulation and that endothelial cell dysfunction plays an important role in the pathogenesis of eclamptic encephalopathy.     

Induction of enhanced postnatal expression of immunoreactive calbindin-D28k in rat forebrain by the calcium antagonist nimodipine

Male Copenhagen x Fisher F1 rats, transplanted with the androgen-sensitive Dunning R3327 PAP rat prostatic adenocarcinoma, were castrated when tumor volumes were approximately 1300 mm3. The rats were thereafter followed with measurements of tumor volume. Castration stopped tumor growth, but some of the tumors started to regrow after 7-36 weeks. These tumors relapsing from castration treatment were now considered to be androgen-insensitive. In this study, we defined relapse as the time when the tumor volume had increased to 200% of the volume at the time for castration. At this time, the rats were treated either with estradiol-17 beta (E2, 50 micrograms s.c. daily) or vehicle for 8 weeks. After this period, tumor morphology was examined. The tumors in the vehicle-treated group were heterogeneous, and both highly and more dedifferentiated parts were present. The tumor growth rate was correlated to the epithelial cell nuclear size and its variance, and to the mitotic index. In the E2-treated group, tumor growth rate was retarded throughout the treatment period, and dedifferentiated tumor areas were rare. Estrogen treatment resulted in a reduction of nuclear area and mitotic index, a changed nuclear shape, and an increased apoptotic index compared to that in vehicle-treated tumors. By castration, it is possible to induce an alteration of the androgen-sensitive Dunning R3327 PAP tumor phenotype to an androgen-insensitive tumor with an altered morphology. Estradiol-17 beta apparently inhibits not only the growth, but also postpones the castration-induced dedifferentiation of the tumor.     

The neurotoxin MPTP increases calbindin-D28k levels in mouse midbrain dopaminergic neurons

Interleukin (IL)-2-induced microvascular lung injury is an experimental paradigm commonly used to investigate the pathogenesis of the adult respiratory distress syndrome. Since tumor necrosis factor-alpha (TNF-alpha) is known to induce such an injury in vivo and since TNF-alpha is involved in other models of lung injury, we postulated that it might also mediate pulmonary toxicity after IL-2 administration. The present study tested this hypothesis by evaluating the effect of TNF-alpha inhibition on IL-2-induced lung injury in the rat. Recombinant human IL-2 (10(6) U IV per rat, n = 6) elevated lung water, myeloperoxidase activity, and protein accumulation in bronchoalveolar lavage fluid and induced tissue hypoxia. Also, IL-2 enhanced lung tissue TNF-alpha mRNA and peptide (1543 +/- 496 pg/g lung wet weight) localized to alveolar macrophages by in situ hybridization. In marked contrast, IL-2 failed to affect serum TNF-alpha, which remained at undetectable levels. Pretreatment with anti-TNF-alpha monoclonal antibody (25 mg/kg IV, n = 7) or the TNF-alpha synthesis inhibitor rolipram (200 micrograms/kg IV, n = 7) attenuated lung injury and reverted tissue hypoxia. Furthermore, TNF-alpha inhibition prevented the upregulation of lung tissue IL-1 beta, IL-6, cytokine-induced neutrophil chemoattractant, and E-selectin (ELAM-1) but not intercellular adhesion molecule-1 mRNAs in response to IL-2. These data imply that locally produced TNF-alpha mediates IL-2-induced lung inflammation and tissue injury and point to the potential utilization of TNF-alpha inhibitors in treating the pulmonary toxicity of IL-2 immunotherapy.     

Inhibition of calcium-dependent NMDA receptor current rundown by calbindin-D28k

NMDA receptors are regulated by several different calcium-dependent processes. To determine if the presence of the intracellular calcium-binding protein calbindin-D28k can influence the calcium regulation of NMDA receptor activity, human embryonic kidney 293 cells were co-transfected with cDNAs for NMDA receptor subunits and calbindin. Recordings were made using the nystatin perforated patch technique to preserve intracellular contents. When compared with control cells (transfected with cDNA encoding beta-galactosidase in place of calbindin), the presence of calbindin had no effect on either calcium-dependent inactivation or the calcium-sensitive, time-dependent increase in glycine-independent desensitization of NMDA receptor-mediated currents. However, the development of calcium-dependent rundown of peak glutamate-evoked current was slowed significantly in calbindin versus beta-galactosidase co-transfected cells. This result was true for cells transfected with either NR1/NR2A or NR1/NR2B subunits, although calbindin was relatively less effective at inhibiting rundown in NR1/NR2B-expressing cells. NMDA peak current rundown has been attributed to calcium-induced depolymerization of the actin cytoskeleton. Therefore, our results indicate that although calbindin may not influence calcium-dependent regulatory processes occurring very near the NMDA receptor channel, it appears to be more effective at buffering local elevations in intracellular calcium at the actin cytoskeleton.     

Shell and core in monkey and human nucleus accumbens identified with antibodies to calbindin-D28k

The neurochemical division of the rodent nucleus accumbens into shell and core is now a widely accepted concept. However, such divisions in the primate nucleus accumbens have yet to be fully clarified and described. In the present study, the forebrains of three primates--marmoset, rhesus monkey, and human--and a Wistar rat, were immunoreacted with antibodies directed against calbindin-D28k. The patterns of immunoreactivity in the primates' ventral striatum were mapped and compared to that of rat. Calbindin staining was uneven in all species and there was no evidence of a bicompartmental organization, i.e., striosome/patch and matrix, in central parts of the nucleus. Nucleus accumbens in primates, as in rat, could be divided immunohistochemically into a crescent-shaped outer shell--medially, ventrally and laterally--and an inner core. In general, medial parts of the shell stained less intensely for calbindin than did lateral parts. However, interspecific variation in the intensity of the immunoreactive staining and the mediolateral extent of the shell was obvious. The core, which immunostained unevenly, was consistently more intensely immunoreactive than either medial or lateral shell in all species except the marmoset. These results suggest that the neurochemical subdivisions of shell and core established for nucleus accumbens of rodents are also present in primates. However, further work is needed to establish whether these territories are homologous and, if so, the full extent of that homology.     

Calbindin-D28k fails to protect hippocampal neurons against ischemia in spite of its cytoplasmic calcium buffering properties: evidence from calbindin-D28k knockout mice

We report the sequences of seven new cytoplasmic intermediate filament (IF) proteins of the cephalochordate Branchiostoma. The eight sequences currently known describe four subfamilies (A, B, C and D). All eight IF proteins show the short-length version of the coil 1b subdomain found in vertebrates and lack the additional 42 residues present in all nuclear lamins and the protostomic IF proteins. Although the lancelet is considered to be the closest relative of the vertebrates, it is difficult to relate its IF subfamilies unambiguously to a particular type I-IV subfamily of vertebrates. C1 and C2 have tail domains with two 64 residue repeats of coiled coil-forming ability, a structural feature unknown for IF proteins from vertebrates or protostomia. The epidermal protein D1 shows only a slightly better identity score with vertebrate type II keratins than with type III proteins, but the D1 gene organization is that of type III proteins. The same holds for A1, A2, B1, B2 and C2 genes, although the latter has an additional and uniquely positioned intron. Antibodies (Ab) raised against recombinant C2 and D1 proteins reveal these proteins in epidermis, some internal epithelia and parts of the spinal cord. The results on exonic sequences, gene organization and expression suggest that Branchiostoma IF proteins may retain a largely archetypal condition, whereas the vertebrates have established the well-known type I-IV IF system.     

Postnatal development of calcium-binding proteins calbindin and parvalbumin in human visual cortex

In adult primate visual cortex, the calcium-binding proteins calbindin (CB) and parvalbumin (PV) are localized in different subsets of GABAergic neurons with a characteristic laminar distribution. However, the emergence and development of CB and PV in relation to the periods of functional maturation of the human visual cortex are not known. Therefore, we examined (i) postnatal changes in the distribution of immunoreactivity (ir) for CB and PV in the visual cortex; (ii) the pattern of changes in immunoreactivity in relation to the synaptic maturation; and (iii) differences in the maturation of CB and PV immunoreactivity between areas 17 and 18. We found a consistently high expression of CB in neonatal visual cortex, particularly in layer IV and infragranular layers. However, despite an early appearance of PV, its peak in development occurred only after 2 months of age, characterized by a transient overexpression in the thalamo-recipient layer IV and a continuous inside-out maturation in supragranular layers. The neonatal pattern of high CB-ir in layers IV-VI was transformed during infancy and childhood into an adult pattern of high CB-ir in layer II, but low CB-ir in layer IV and infragranular layers. There was no difference in pattern and tempo of maturation of calcium-binding proteins between area 17 and 18, indicating simultaneous development of cortical inhibitory circuits among cytoarchitectonically and functionally distinct cortical areas. In addition, the reorganization of CB/PV expression temporally and spatially coincides with the course of cortical synaptogenesis, and delineates the major stages of maturation of the human visual cortex.     

Colocalization of calretinin and calbindin-D28k with oxytocin and vasopressin in rat supraoptic nucleus neurons: a quantitative study

Leptin is a peptide hormone that appears critical in regulating Fat metabolism. Recently, circulating leptin levels were reported higher in patients with alcoholic cirrhosis. In health, hepatic stellate cells store retinoids, but following liver injury they transdifferentiate into myofibroblast-like cells with loss of the retinoid stores. Leptin expression was demonstrated by detection of leptin mRNA by RT-PCR analysis and by immunohistochemistry viewed with confocal microscopy in transdifferentiated stellate cells after 14 days, or more, of culture. Leptin expression was not found in freshly isolated quiescent stellate cells. Leptin expression was not demonstrated in freshly isolated or cultured Kupffer cells. Treatment of activated stellate cells with either 1 microM retionic acid or 10 microM retinol acetate resulted in the inhibition of leptin mRNA expression. The observation that activated stellate cells in culture can express leptin has implications for understanding adipocyte biology in liver disease and treatment of malnutrition in cirrhotics.     

Calbindin-D 28 kD and parvalbumin in the horizontal cells of rat retina during development

Restless legs syndrome (RLS) and periodic limb movements in sleep (PLMS) are disorders that are common and disturbing to uremic patients. The treatment of these is problematic. Eight patients on chronic hemodialysis and continuous peritoneal dialysis completed a double-blind placebo-controlled crossover study using incremental doses of pergolide up to 0.25 mg at bedtime for treatment of RLS and sleep disruption. Five patients (62.5%) noted subjective improvement in restless legs symptoms and sleep quality. Objective results were improved only slightly by treatment. The percentage of the first hour in bed during which leg movements occurred decreased from 20.5 +/- 6.0 to 11.5 +/- 3.3, p < 0.05. However, findings during sleep were less positive. The following measures were not significant between placebo and treatment: leg movements per hour of sleep [53.7 +/- 22.3 vs 35.8 +/- 11.8 (p = 0.2)]; and percentage of sleep time spent with leg movements [5.5% +/- 3.2 vs 4.4% +/- 1.4 (p = 0.37)]. Patients continued to have very disrupted sleep, and we could not document an objective improvement in sleep architecture. Thus, although pergolide at the dose of 0.25 mg at bedtime provided subjective improvement in symptoms of restless legs and quality of sleep, and objectively decreased leg movements during the first hour in bed, objectively sleep continued to be disrupted. In this small patient group, the response to pergolide was not uniform, and further investigation is required to test effectiveness at higher doses.     

Representation of motion boundaries in retinotopic human visual cortical areas

Edges are important in the interpretation of the retinal image. Although luminance edges have been studied extensively, much less is known about how or where the primate visual system detects boundaries defined by differences in surface properties such as texture, motion or binocular disparity. Here we use functional magnetic resonance imaging (fMRI) to localize human visual cortical activity related to the processing of one such higher-order edge type: motion boundaries. We describe a robust fMRI signal that is selective for motion segmentation. This boundary-specific signal is present, and retinotopically organized, within early visual areas, beginning in the primary visual cortex (area V1). Surprisingly, it is largely absent from the motion-selective area MT/V5 and far extrastriate visual areas. Changes in the surface velocity defining the motion boundaries affect the strength of the fMRI signal. In parallel psychophysical experiments, the perceptual salience of the boundaries shows a similar dependence on surface velocity. These results demonstrate that information for segmenting scenes by relative motion is represented as early as V1.     

Attentional modulation of visual motion processing in cortical areas MT and MST

The visual system is constantly inundated with information received by the eyes, only a fraction of which seems to reach visual awareness. This selection process is one of the functions ascribed to visual attention. Although many studies have investigated the role of attention in shaping neuronal representations in the visual cortex, few have focused on attentional modulation of neuronal signals related to visual motion. Here we report that the responses of direction-selective neurons in monkey visual cortex are greatly influenced by attention, and that this modulation occurs as early in the cortical hierarchy as the level of the middle temporal visual area (MT). Our finding demonstrates a stronger and earlier influence of attention on motion processing along the dorsal visual pathway than previously recognized.     

Localization of parvalbumin, calretinin, and calbindin D-28k in identified extraocular motoneurons and internuclear neurons of the cat

There are many anatomic and biomechanical factors that define the structure and function of the normal glenohumeral joint. These factors influence the design and function of the prosthetic shoulder. Our best efforts in shoulder design should reflect an attempt to reproduce the normal structure-function relationships of the natural glenohumeral joint. Prosthetic design must also take into account the variable anatomic abnormalities associated with the pathologic condition. Prosthetic designs should attempt to facilitate the surgical correction of this pathology, with the goal of reproducing normal anatomy. Optimal prosthetic reconstruction of the shoulder is dependent on prosthetic design, prosthetic soft tissues, postoperative healing and rehabilitation, and the long-term biologic response to the implant. The success of any prosthetic reconstruction is dependant on many factors, and in some cases, normal anatomy and function cannot be achieved entirely by prosthetic design.     

Precocious development of parvalbumin-like immunoreactive interneurons in the hippocampal formation and entorhinal cortex of the fetal cynomolgus monkey

The calcium-binding protein parvalbumin (PV), a reliable marker of the hippocampal basket and chandelier cells, is first expressed on embryonic day 83 (E83), corresponding to midgestation of the macaque monkey, in restricted hippocampal groups of immature neurons (Berger and Alvarez [1996] J. Comp. Neurol. 366:674-699). In the present study, PV-like immunoreactivity (LIR) was used to follow the further development of this subclass of interneurons. Asynchronous area-specific developmental sequences were observed, predominating initially in the caudal half of the hippocampal formation and the laterocaudal division of the entorhinal cortex and occurring relatively simultaneously in the interconnected hippocampal and entorhinal subfields. Dendritic elongation of PV-like immunoreactive interneurons and perisomatic distribution of PV-like immunoreactive terminal boutons on their cellular targets were first observed in the subiculum around E127; then from E127 to E142 in CA3/CA2 and layers III-V of the entorhinal cortex and, to a lesser extent in CA1, the dentate hilus and deep granule cell layer; and finally from E156 to postnatal day 12 in the rest of the dentate gyrus, the presubiculum and parasubiculum, and layers III-II-I of the entorhinal cortex. These data provide the first indication that a population of basket cells, a major gamma-aminobutyric acid (GABA)ergic component of the hippocampal intrinsic inhibitory circuitry, reaches its cellular targets several weeks before birth in primates in contrast to rodents. The role of the prenatal PV expression in the hippocampal formation of nonhuman primates and whether it coincides with the onset of postsynaptic inhibitory potentials or is accompanied or preceded by a period of gamma-aminobutyric acid-mediated excitatory effects as in rat pups, are crucial questions. They underline the need to pursue direct investigations on primates to be able to legitimately extrapolate the data obtained in rodents.     

Calbindin-D28k is regulated by adrenal steroids in hypothalamic tissue during prenatal development

We report the case of a 42 year-old woman with amyotrophic lateral sclerosis (ALS). Neurological examination showed spastic paraparesis and muscular atrophy of the upper extremities. Increased signal intensity areas were present in the lateral corticospinal tract of the brain and cervical spinal cord on a T2-weighted image. Decreased signal intensity of the motor cortex on the T2-weighted image appeared during the course of the illness. SPECT showed hypoperfusion confined to the motor cortex. The area of increased signal intensity in the cervical spinal cord on the T2-weighted MR images extended to the anterolateral columns of the spinal cord. The area of hypoperfusion in SPECT extended to the fronto-parietal area with the progression of the disease. These changes in the MRI and SPECT findings may reflect progressive degeneration of the upper motor neurons in ALS.     

The role of temporal cortical areas in perceptual organization

The visual areas of the temporal lobe of the primate are thought to be essential for the representation of visual objects. To examine the role of these areas in the visual awareness of a stimulus, we recorded the activity of single neurons in monkeys trained to report their percepts when viewing ambiguous stimuli. Visual ambiguity was induced by presenting incongruent images to the two eyes, a stimulation condition known to instigate binocular rivalry, during which one image is seen at a given time while the other is perceptually suppressed. Previous recordings in areas V1, V2, V4, and MT of monkeys experiencing binocular rivalry showed that only a small proportion of striate and early extrastriate neurons discharge exclusively when the driving stimulus is seen. In contrast, the activity of almost all neurons in the inferior temporal cortex and the visual areas of the cortex of superior temporal sulcus was found to be contingent upon the perceptual dominance of an effective visual stimulus. These areas thus appear to represent a stage of processing beyond the resolution of ambiguities--and thus beyond the processes of perceptual grouping and image segmentation--where neural activity reflects the brain's internal view of objects, rather than the effects of the retinal stimulus on cells encoding simple visual features or shape primitives.     

Cortistatin is expressed in a distinct subset of cortical interneurons

Cortistatin is a presumptive neuropeptide that shares 11 of its 14 amino acids with somatostatin. In contrast to somatostatin, administration of cortistatin into the rat brain ventricles specifically enhances slow wave sleep, apparently by antagonizing the effects of acetylcholine on cortical excitability. Here we show that preprocortistatin mRNA is expressed in a subset of GABAergic cells in the cortex and hippocampus that partially overlap with those containing somatostatin. A significant percentage of cortistatin-positive neurons is also positive for parvalbumin. In contrast, no colocalization was found between cortistatin and calretinin, cholecystokinin, or vasoactive intestinal peptide. During development there is a transient increase in cortistatin-expressing cells in the second postnatal week in all cortical areas and in the dentate gyrus. A transient expression of preprocortistatin mRNA in the hilar region at P16 is paralleled by electrophysiological changes in dentate granule cells. Together, these observations suggest mechanisms by which cortistatin may regulate cortical activity.     

Development of orientation preference maps in area 18 of kitten visual cortex

We investigated the development of orientation preference maps in the visual cortex of kittens by repeated optical imaging from the same animal. Orientation maps became detectable for the first time around postnatal day (P) 17 and improved continuously in strength unitl P30, the time at which their appearance became adultlike. During this developmental period the overall geometry of the maps remained unchanged, suggesting that the layout of the orientation map is specified prior to P17. Hence, before the visual cortex becomes susceptible to experience-dependent modifications its functional architecture is largely specified. This suggests that the initial development and layout of orientation preference maps are determined by intrinsic processes that are independent of visual experience. This conclusion is further supported by the result that orientation maps were well expressed at P24 in binocularly deprived kittens. Because the appearance of the first orientation-selective neurons and the subsequent development of orientation preference maps correlated well with the time course of the expression and refinement of clustered horizontal connections, we propose that these connections might contribute to the specification of orientation preference maps.     

Calbindin D-28k and monoamine oxidase A immunoreactive neurons in the nucleus basalis of Meynert in senile dementia of the Alzheimer type and Parkinson''s disease

The lungs must be kept "dry" for efficient gas exchange. The mechanisms that contribute to clear alveoli from fetal lung fluid at birth are still present during adult life and allow recovery from alveolar flooding. It has recently been shown with the use of different approaches in vitro, as well as in vivo, that alveolar epithelium performs solute-coupled fluid transport. Fluid absorption from alveoli occurs chiefly as a result of active transepithelial Na+ transport. The mechanisms of Na+ transport have been partly elucidated; Na+ enters alveolar cells through apical Na+ channels and Na(+)-coupled solute transporters and is pumped out at the basolateral membrane by a Na(+)-K(+)-adenosinetriphosphatase (ATPase). Transepithelial Na+ transport and fluid absorption are stimulated by beta-adrenergic agonists, with adenosine 3',5'-cyclic monophosphate being the likely intracellular second messenger. K+ is probably secreted into alveoli because its concentration in the epithelial lining fluid is larger than expected for passive distribution. K+ channels have been described that, in conjunction with Na(+)-K(+)-ATP-ase, might provide pathways for active transport. Active proton secretion or bicarbonate absorption have been reported, which may explain the low pH of the alveolar epithelial lining fluid. It is probable that active solute transports are the main determinants of epithelial lining fluid depth and composition. A challenge for the future is to understand how this homeostasis is achieved.