Inhibitory Effects of Extracellular Matrix Modulator(s) on Lipopolysaccharide (LPS)- and Acidosis-Damaged Glia Containing Cerebellar Granule Cell Cultures

The inhibitory effects of a novel chondroitin sulfate compound on lipopolysaccharide (LPS)- and acidosis-induced neuronal dysfunctions were examined. Cell viabilities in cultured neurons and/or astrocyte-rich cerebellar granule cells were measured by the calcein-AM method. Ten and 20 microg, as a final dosage, of LPS damaged less than 20% cells during a-2 h incubation. More than 5000 ng/ml of chondroitin sulphate-dipalmitoylphosphatidylethanolamine (CS-PE), but not chondroitin sulfate (CS) treatment, significantly inhibited such damage. Twenty microg of LPS damaged more than 40% cells during 24 h incubation, and these cell damages were significantly inhibited by less than 1000 ng/ml of CS-PE. Moreover, treatments with between 5 and 500 ng/ml CS-PE, but not CS, significantly reduced the number of acidosis-damaged cells in a dose-dependent manner. The current results indicate that modulator(s) of ECM and its derivative containing covalently linked dipalmitoylphosphatidylethanolamine show neuroprotective effects under conditions of brain inflammation.     

Death of Cerebellar Granule Neurons Induced by Piperine Is Distinct from that Induced by Low Potassium Medium

We compared neurotoxicity of piperine and low K⁺on cultured cerebellar granule neurons. As considered from lactate dehydrogenase release and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide reduction, both piperine and shifting from high K⁺(25 mM) to low K⁺(5.4 mM) were cytotoxic to cerebellar granule neurons. Protein synthesis inhibitors, cycloheximide and anisomycin, and an endonuclease inhibitor, aurintricarboxylic acid, were protective against low K⁺-induced neuronal death whereas they were ineffective against that induced by piperine. D--tocopherol, trolox, and a spin trap 3,3,5,5-tetramethyl-l-pyrroline-l-oxide were protective against piperine neurotoxicity whereas they had no effect on that induced by low K⁺. These results suggest that piperine and low K⁺may exert neurotoxic effects on cerebellar granule neurons through different mechanisms. Death of cerebellar granule neurons induced by piperine may be mediated by non-apoptotic mechanisms and may involve membrane lipid peroxidation and/or free radical generation.     

The association between Harris lines and enamel hypoplasia in prehistoric California Indians

Hypoplastic defects of tooth enamel and Harris lines in the long bones have been heralded as potentially useful indicators of health conditions in prehistoric populations. Both result from temporary cessation of growth processes due to similar types of disease, malnutrition, or other metabolic insult. An association test for the first six years of life was conducted on a large series of prehistoric California Indians, using femora and canines from young adults. No significant association was found. This is ascribable to differences in etiology and stability.     

Effect of magnesium on calcium influx activated by glutamate and its agonists in cultured cerebellar granule cells

The effects of Mg²⁺ on the glutamate-, kainate-, N-methyl-d-aspartate- and quisqualate-induced influx of⁴⁵Ca²⁺ were studied in cultured cerebellar granule cells. The N-methyl-d-aspartate- and quisqualate-evoked influx was totally and the kainate- and glutamate-evoked influx partially blocked in 1.3 mM extracellular Mg²⁺. The increase in influx induced by kainate, quisqualate and glutamate was maximal at 0.1 mM Mg²⁺, whereas N-methyl-d-aspartate was most effective in totally Mg²⁺-free media.d-2-Amino-5-phosphonovalerate blocked partially and phencyclidine completely the enhancement of Ca²⁺ influx by 1 mM quisqualate in 0.1-mM Mg²⁺ medium. The effect of 10 M quisqualate was also significantly inhibited by antagonists specific for different glutamate receptor subtypes, including N-methyl-d-aspartate, (RS)-amino-3-hydroxy-5-methyl-4-isozazolepropionate and metabotropic recptors. This evidences a heterogeneous action of quisqualate, mediated by different glutamate receptor subtypes in 0.1 mM Mg²⁺ medium. The efficacy of quisqualate in inducing influx of Ca⁺ and the selectivity of antagonists for different receptors are also modified by extracellular Mg²⁺.     

Pathognomonic macular ripples are revealed by polarized infrared retinal imaging

A pathognomonic macular ripple sign has been reported with scanning laser ophthalmoscopy images in patients with foveal hypoplasia, though the optical basis of this sign is presently unknown. Here we present a case series of seven individuals with foveal hypoplasia (based on spectral domain optical coherence tomography). Each patient underwent infrared scanning laser ophthalmoscopy retinal imaging in both eyes, acquired with and without a polarization filter and assessment for a ripple-like effect in the fovea. On imaging, macular ripples were present in all eyes with foveal hypoplasia when using a polarization filter, but not when imaged without the filter. We conclude that the macular ripple sign is an imaging artifact attributable to the unique pattern of phase retardation of the Henle fiber layer in the setting of foveal hypoplasia. By utilizing a polarization filter with retinal photography, this feature can be exploited to promptly identify foveal hypoplasia in settings where OCT is not possible due to nystagmus.     

Smoothened and ARL13B are critical in mouse for superior cerebellar peduncle targeting

Patients with the ciliopathy Joubert syndrome present with physical anomalies, intellectual disability, and a hindbrain malformation described as the “molar tooth sign” due to its appearance on an MRI. This radiological abnormality results from a combination of hypoplasia of the cerebellar vermis and inappropriate targeting of the white matter tracts of the superior cerebellar peduncles. ARL13B is a cilia-enriched regulatory GTPase established to regulate cell fate, cell proliferation, and axon guidance through vertebrate Hedgehog signaling. In patients, mutations in ARL13B cause Joubert syndrome. To understand the etiology of the molar tooth sign, we used mouse models to investigate the role of ARL13B during cerebellar development. We found that ARL13B regulates superior cerebellar peduncle targeting and these fiber tracts require Hedgehog signaling for proper guidance. However, in mouse, the Joubert-causing R79Q mutation in ARL13B does not disrupt Hedgehog signaling nor does it impact tract targeting. We found a small cerebellar vermis in mice lacking ARL13B function but no cerebellar vermis hypoplasia in mice expressing the Joubert-causing R79Q mutation. In addition, mice expressing a cilia-excluded variant of ARL13B that transduces Hedgehog normally showed normal tract targeting and vermis width. Taken together, our data indicate that ARL13B is critical for the control of cerebellar vermis width as well as superior cerebellar peduncle axon guidance, likely via Hedgehog signaling. Thus, our work highlights the complexity of ARL13B in molar tooth sign etiology.     

Preferential expression of linear enamel hypoplasia on the sectorial premolars of rhesus monkeys (Macaca mulatta)

Three hundred and sixty rhesus macaque specimens at the Caribbean Primate Research Center were examined for evidence of linear enamel hypoplasia (LEH). A previously unreported intertooth pattern in LEH was observed. Defects occur preferentially on the sectorial premolar of both males and females. Relative to other teeth, the sectorial premolar exhibits more prominent defects and is more likely to exhibit multiple defects. This pattern is unlike the human intertooth LEH pattern and unlike patterns previously reported for monkeys and apes. These observations are discussed in the context of factors thought to influence the intertooth distribution of LEH in humans and in nonhuman primates. The authors reject crown height, the timing of crown development, and the duration of crown formation as factors contributing to the observed pattern and favor an explanation involving enamel thickness, perikymata spacing, and/or prism orientation. Am J Phys Anthropol 107:179–186, 1998. © 1998 Wiley-Liss, Inc.     

Neural recordings and behavioral observations in the monkey vestibulo-ocular reflex constrain the cellular mechanisms for cerebellum-dependent behavioral learning

Recordings from the cerebellum under behavioral conditions that cause learning in the vestibulo-ocular reflex (VOR) constrain the cellular mechanisms that could mediate learning. Analysis of the complex-spike responses of Purkinje cells demonstrates a mismatch between the properties of cerebellar long-term depression (LTD) in vitro and the signals available to guide learning in vivo. To resolve this mismatch, it may be necessary to assume that there are multiple cellular mechanisms of VOR learning, including both depression and potentiation.