Inhibitory synaptogenesis in the rat anteroventral cochlear nucleus

Spherical cells in the anteroventral division of the cochlear nucleus, which relay excitatory inputs from the auditory nerve, also receive both GABAergic and glycinergic inhibitory synapses. Inhibition mediated by GABA and glycine fulfils essential roles in the processing abilities of these and other auditory neurons. However, the developmental program leading to a mature complement of GABAergic and glycinergic synapses and microcircuits is largely unknown. Because of their relatively simple geometry, spherical cells provide an excellent model for unraveling basic developmental patterns of inhibitory synaptogenesis. Using a combination of high resolution immunocytochemical methods, we report that, in the rat, synapses containing GABA or glycine are deployed on spherical cell bodies over a time period extending well beyond hearing onset. Such postnatal developmental recruitment of inhibitory endings is progressive, although there are two distinct leaps in their numbers. The first occurs by the end of the first postnatal week, prior to hearing onset, and the second, during the third postnatal week, after hearing onset. This pattern suggests that adjustments in inhibition could be driven by acoustic experience. While GABAergic and glycinergic endings are maturing and growing in number and size, their neurotransmitter content also appears to be developmentally regulated. Quantitative ultrastructural immunocytochemistry with colloidal gold suggests that GABA and glycine accumulation in synaptic endings follows a staggered pattern, with labeling stabilizing at adult levels by postnatal day 21. This may account for adjustments in synaptic efficacy and strength.     

Evidence against a presynaptic mechanism for kainate neurotoxicity in the cochlear nucleus.

Kainic acid produces a selective pattern of degeneration in the cochlear nucleus of the guinea pig. This pattern is not altered by destruction of the putative glutamatergic primary afferent innervation, even with minimal doses of kainic acid. Thus, kainate neurotoxicity does not require intact presynaptic terminals in the cochlear nucleus.     

Depression in the early stages of Pick's disease

To better understand the nature of the symptoms of depression in the early stages of Pick's disease, we performed a retrospective study of the medical records of eight patients who were originally treated for major depressive disorders before being clinically diagnosed with Pick's disease. Six of the eight manifested psychomotor retardation and social withdrawal, seven of the eight were agitated and five of the eight showed hyperbulia too. However, only two of the eight showed melancholia or physical symptoms such as insomnia or loss of appetite. All patients were treated with antidepressants but these were not effective in relieving the symptoms of depression. The data we gathered in this study will be useful in the future for distinguishing between Pick's disease-related depression (in the early stages of the disease) and major depression.     

Preliminary and early stages of atherosclerosis in childhood

According to the unified theory of atherosclerosis, endothelial cell injury and lipid infiltration play an important role in atherogenesis. Newborn babies may suffer endothelial cell damage, as may be detected by electron microscopy. Connective tissue elements are occasionally abundant already in newborns. Chondroitin sulfate A and C increase with age. The children may exhibit continuous accumulation of cholesterol esters in the intima of coronary arteries. Cholesteryl ester fatty acid composition, along with age, tends to approach that of serum low-density lipoproteins. Fatty streaks appear in coronary arteries in puberty, and fibrous plaques are recordable beyond the age of 20 years. The topography of myo-intimal thickenings, fatty streaks, and fibrous plaques is similar to complicated atherosclerotic lesions. Even newborn babies have obstructive myo-intimal thickenings in their coronary arteries. One fifth of all infants under one week of age suffer 20% stenosis, with percentile manifestation of stenosis in the arterial cross-section being established as ratio of intimal area to luminal area of a dilated coronary artery multiplied by 100. Occasionally, the intima is very thick, in our series initiating up to 57% of all narrowing. There are probably noxious factors which temporarily damage the endothelial cells and initiate a rapid, partially reversible thickening reaction. Some of this response of the intima to exogenous stimuli might be genetically determined. A thickened intima is susceptible to lipid deposition and atherosclerosis.     

Chromosomal alterations in early stages of malignant mesotheliomas

In a case of a 67-year-old man with two different early stages of a predominantly epithelioid mesothelioma (“mesothelioma in situ”, “early-stage mesothelioma”), chromosomal imbalances were determined by comparative genomic hybridisation (CGH), a molecular cytogenetic technique to detect chromosomal gains and losses in tumour cells. In the case of the mesothelioma in situ cells, nine different chromosomal alterations could be detected (losses on 3p, 5q, 6q, 8p, 9p, 15q, 22q, Y; gain on 7q), whereas the early-stage mesothelioma showed the same defects except for the gain on 7q. The simultaneous losses of 6q, 9p and 22q, as well as other chromosomal regions, correlate well with the most common defects previously found in 90 cases of more-advanced-stage mesotheliomas using CGH. These data demonstrate that initial chromosomal defects in early stages of mesotheliomas can be detected by conventional CGH in combination with laser microdissection. The molecular cytogenetic findings support the histological diagnosis of a pleural mesothelioma. The surprisingly high number and extent of genomic alterations found in the examined case probably reflects the genomic instability in the tumour cells and indicates a “genetic chaos” even in earlier stages of malignant mesotheliomas.     

Growth cone and dendrite dynamics in zebrafish embryos: early events in synaptogenesis imaged in vivo

We used time-lapse fluorescence microscopy to observe the growth of Mauthner cell axons and their postsynaptic targets, the primary motor neurons, in spinal cords of developing zebrafish embryos. Upon reaching successive motor neurons, the Mauthner growth cone paused briefly before continuing along its path. Varicosities formed at regular intervals and were preferentially associated with the target regions of the primary motor neurons. In addition, the postsynaptic motor neurons showed highly dynamic filopodia, which transiently interacted with both the growth cone and the axon. Both Mauthner cell and motor neurons were highly active, each showing motility sufficient to initiate synaptogenesis.     

Morphogenesis of early pre-lipid stages of atherosclerosis

Investigation of early changes in the aortal wall (focal edema of the intima, rhythmic structures, and primary fibrous plaques) in children and young subjects showed the possibility of nonlipidogenic mode of the development of atherosclerotic plaques. The data suggest that an important role in the genesis of atherosclerotic changes in man is played by local alterations of the arterial wall not associated with disorders in the general lipid metabolism. The local damage of the endothelial lining of the arteries in these sites may be very important in their genesis.     

Joint contact mechanics in the early stages of osteoarthritis

Joint degeneration in the early stages of osteoarthritis (OA) may be reflected in changes in structural and material properties in articular cartilage. The aim of the present study was to simulate numerically the contact area and stress distribution in normal and "diseased" cartilage layers for dynamic loading. The initial stages of osteoarthritis were simulated based on an experimental model: the anterior cruciate ligament-transected cat knee. In this model, cartilage layers become thicker, softer, and more permeable than the corresponding healthy cartilage layers within weeks of intervention. In our numerical simulations, the diseased cartilage was modelled by changing the thickness, permeability, shear modulus, and Poisson's ratio of the cartilage in accordance with observations in this experimental model of osteoarthritis. The theoretical model of normal and diseased articular cartilage was based on a biphasic representation of cartilage, and the joint was assumed to be axi-symmetric. It was found that, for a given loading condition, the contact areas increase and peak stresses decrease in the diseased compared to the normal joint. According to our simulations, areas of normal joint contact become unloaded and areas of little or no contact become overloaded in the early stages of osteoarthritis compared to the situation in normal joints. Based on these results, we speculate that OA may be initiated following ACL transection because of an overloading of specific regions of the joint, either because of the altered contact mechanics or the disrupted joint stability, despite a general decrease in the contact pressure.     

Histopathological diagnosis of acral lentiginous melanoma in early stages

Acral lentiginous melanoma is a rare variant of melanoma that is associated with a relatively low survival rate. The latter is partly due to the advanced stage in which the tumor is usually diagnosed. The diagnostic delay is mainly due to difficulties in identifying the very early histopathological signs of acral melanoma. The current article is a review of diagnostic clues, concepts, and definitions from the literature, as well as illustrating examples from our own archives. We have sought to provide an article that can be easily consulted in difficult cases of acral lentiginous melanoma.     

Leucocyte rheology in the early stages of ischaemic stroke

Summary Within 5 hours of the onset of ischaemic stroke the filterability patterns and the counts of the granulocyte, monocyte and lymphocyte subfractions were monitored. The results were compared to those of a healthy matched control group and to those of a matched group with cardiovascular risk factors. The granulocyte filterability rate was significantly impaired in the group at risk and even more so in the stroke group suggesting alterations in it may be a sign of latent ischaemia.     

Measurement reproducibility in the early stages of biomarker development

Biomarker discovery and development requires measurement reproducibility studies in addition to case-control studies. Parallel pursuit of reproducibility studies is especially important for emerging technologies such as protein biomarkers based on time-of-flight mass spectrometry, the case considered in this paper. For parallel studies, a way to improve reproducibility prior to identification of protein species is necessary. One approach is use of functional principal components analysis (PCA) as the basis for assessing measurement reproducibility. Reproducibility studies involve repeated measurement of a reference material such as a human serum standard. Measurement in our example is by SELDI-TOF (surface-enhanced laser desorption and ionization time-of-flight) mass spectrometry. Reproducibility is defined in reference to a source of variation, which in our example is associated with a type of commercially available protein biochip. We obtained spectra for 8 spots on each 11 chips. Two spectra are generally more alike when obtained from the same chip rather than different chips. Thus, our experiment indicates potential improvements from reducing variation in chip manufacture and chip handling during measurement. Our analysis involves careful registration of the spectra and characterization of the spectral differences. As shown by our example, a metrological analysis may enhance case-control studies by guiding optimization of the measurements underlying the biomarker.