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The space ball probe was fully described in the literature 15 years ago by Mouton et al. (2002). Since then, it has been used in a number of studies in the nervous system that focus on axon, dendrite, and capillary length. The length of structural parameters in tissues reflect functional aspects of the tissues. Here, some of the various applications of this methodology will be presented, along with a review of the salient features of the methodology that has resulted in new wave of quantitative morphological studies of length in the nervous system. The validity of the method is discussed in view of its widespread use along with insights into the problems associated with its application to histological tissue and future techniques for applying space balls.

The pathologic changes of Alzheimer disease (AD) evolve very gradually over decades before the disease becomes clinically manifest. Thus, it is not uncommon to find substantial numbers of Aβ plaques and neurofibrillary tangles in autopsy brains of older subjects with documented normal cognition, a state that we define as asymptomatic AD (ASYMAD). The goal of this study is to understand the morphometric substrate of ASYMAD subjects compared with mild cognitive impairment and definite AD cases. We used designed-based stereology to measure the volumes of neuronal cell bodies, nuclei, and nucleoli in 4 cerebral regionsanterior cingulate gyrus, posterior cingulate gyrus, primary visual cortex, and CA1 of hippocampus. We examined and compared autopsy brains from 4 groups (n = 15 each) of participants in the Baltimore Longitudinal Study of AgingASYMAD, mild cognitive impairment, AD, and age-matched controls. We found significant hypertrophy of the neuronal cell bodies, nuclei, and nucleoli of CA1 of hippocampus and anterior cingulate gyrus neurons in ASYMAD subjects compared with control and mild cognitive impairment cases. In the posterior cingulate gyrus and primary visual cortex, the hypertrophy was limited to the nuclei and nucleoli. The hypertrophy of cortical neurons and their nuclei and nucleoli in ASYMAD may represent an early reaction to the presence of neurotoxic Aβ or tau, or a compensatory mechanism that prevents the progression of the disease into dementia.

To investigate the relation between the loss of substantia nigra (SN) neurons in normal ageing and Parkinson’s disease (PD), we measured the total number and the cell body volume of pigmented (neuromelanin) neurons in the SN. We examined young ( n  = 7, mean age: 19.9), middle-aged ( n  = 9, mean age: 50.1), and older controls from the Baltimore Longitudinal Study of Aging ( n  = 7, mean age: 87.6), as well as PD cases ( n  = 8, mean age: 74.8). On random-systematically selected paraffin Nissl-stained sections, we used the Optical Fractionator to estimate the total number of neurons on one side of the SN. Using the Nucleator probe, we measured the volume of these neurons. In young and older controls, we also estimated the total number and volume of tyrosine hydroxylase (TH) positive (+) nigral neurons. We observed a significant loss of pigmented (-28.3%, P  < 0.01) and TH (+) (−36.2%, P  < 0.001) neurons in older controls compared with younger subjects. Analysis of the size distribution of pigmented and TH (+) neurons showed a significant hypertrophy in older controls compared to young controls ( P  < 0.01). In contrast, in PD we observed a significant atrophy of pigmented neurons compared to all control groups ( P  < 0.01). These data suggest that neuronal hypertrophy represents a compensatory mechanism within individual SN neurons that allows for normal motor function despite the loss of neurons in normal ageing. Presumably, this compensatory mechanism breaks down or is overwhelmed by the pathological events of PD leading to the onset of the characteristic motor disturbances.

Dogs with Canine Cognitive Dysfunction (CCD) accumulate amyloid beta (Aβ) in the brain. As the cognitive decline and neuropathology of these old dogs share features with Alzheimer's disease (AD), the relation between Aβ and cognitive decline in animal models of cognitive decline is of interest to the understanding of AD. However, the sensitivity of the biomarker Pittsburgh Compound B (PiB) to the presence of Aβ in humans and in other mammalian species is in doubt. To test the sensitivity and assess the distribution of Aβ in dog brain, we mapped the brains of dogs with signs of CCD (n = 16) and a control group (n = 4) of healthy dogs with radioactively labeled PiB ([(11)C]PiB). Structural magnetic resonance imaging brain scans were obtained from each dog. Tracer washout analysis yielded parametric maps of PiB retention in brain. In the CCD group, dogs had significant retention of [(11)C]PiB in the cerebellum, compared to the cerebral cortex. Retention in the cerebellum is at variance with evidence from brains of humans with AD. To confirm the lack of sensitivity, we stained two dog brains with the immunohistochemical marker 6E10, which is sensitive to the presence of both Aβ and Aβ precursor protein (AβPP). The 6E10 stain revealed intracellular material positive for Aβ or AβPP, or both, in Purkinje cells. The brains of the two groups of dogs did not have significantly different patterns of [(11)C]PiB binding, suggesting that the material detected with 6E10 is AβPP rather than Aβ. As the comparison with the histological images revealed no correlation between the [(11)C]PiB and Aβ and AβPP deposits in post-mortem brain, the marked intracellular staining implies intracellular involvement of amyloid processing in the dog brain. We conclude that PET maps of [(11)C]PiB retention in brain of dogs with CCD fundamentally differ from the images obtained in most humans with AD.

This study provides a light-microscopic description of the organization, morphology and number of neurons in the subthalamic nucleus (STN) of the Göttingen minipig. It is based on histological material stained with Nissl, Golgi and autometallographic techniques, and employs design-based stereological estimation of the total neuron number. The organization of several neurotransmitters in the STN has been evaluated in histological preparations stained for acetylcholinesterase (AChE) and immunostained for choline acetyltransferase (ChAT), tyrosine hydroxylase (TH), glutamic acid decarboxylase (GAD) and glutamate. In all of the stained preparations the STN appeared as a distinct lens-shaped structure located in the caudal diencephalon, medial to the internal capsule and ventrolateral to the zona incerta. Rostrally, the STN approached the globus pallidus pars interna, whereas caudally the ventromedial part of the STN was adjacent to the rostral part of the substantia nigra pars compacta (SNc), where some of the neurons of the two nuclei merged. The neurons in the STN had medium-sized (25-40 microm) ovoid or fusiform cell bodies, from which three to six large dendrites emanated in a direction predominantly parallel to the long axis of the STN. Immunohistochemistry revealed that most of the subthalamic neurons were glutamatergic and differed significantly in appearance from the large stellate TH-positive cells of the adjacent SNc. Numerous TH-positive bouton-rich fibers traversed the STN. The GAD-staining revealed a large number of terminals within the boundaries of the STN. The STN was highly AChE-positive, reflecting a prominent innervation by ChAT-positive terminals. The total number of subthalamic neurons in one hemisphere was estimated to be approximately 56,000. We conclude that the neuroarchitecture of the porcine STN is similar to primates, including humans, and appears well-suited for further studies examining the role of the STN in movement disorders.

The goal of the present study has been to quantify the morphological changes in myelinated nerve roots and dorsal root ganglion (DRG) cells in rats exposed to bismuth subnitrate. Male Wistar rats (n =30) were divided into three groups of ten animals. The ten animals in each group were given intraperitoneal injections of one of the following: (1) 500 mg/kg bismuth subnitrate, (2) 1,000 mg/kg bismuth subnitrate, or (3) saline. The mean total cell number of B-cells in the DRG was significantly smaller in the two treated groups, 18% (2P <0.001) and 23% (2P <0.001), respectively, than it was in the control group. In addition, there was an 11% reduction in the number of A-cells (2P =0.039) in rats exposed to the highest concentration of bismuth. Bismuth did not affect the total number or mean cross sectional area of axons and myelin sheaths of the myelinated nerve fibers in the ventral or dorsal nerve root of the DRG. This is the first study to investigate pathological changes of the peripheral nervous system after bismuth intoxication.

Summary The distinction between the neurodegenerative changes that accompany normal ageing and those that characterise Alzheimer's disease is not clear. The resolution of this issue has important implications for the design of therapeutic and investigative strategies. To this end we have used modern stereological techniques to compare the regional pattern of neuronal cell loss in the hippocampus related to normal ageing to that associated with Alzheimer's disease. The loss related to normal ageing was evaluated from estimates of the total number of neurons in each of the major hippocampal subdivisions of 45 normal ageing subjects who ranged in age from 13 to 101 years. The Alzheimer's disease related losses were evaluated from similar data obtained from 7 cases of Alzheimer's disease and 14 age matched controls. Qualitative differences were observed in the regional patterns of neuronal loss related to normal ageing and Alzheimer's disease. The most distinctive Alzheimer's disease related neuron loss was seen in the CA1 region of the hippocampus. In the normal ageing group there was almost no neuron loss in this region (final neuron count in the CA1 region: 4·40 X 10 6 neurons for the Alzheimer's disease group vs 14·08 × 10 6 neurons in the normal ageing group). It is concluded that the neurodegenerative processes associated with normal ageing and with Alzheimer's disease are qualitatively different and that Alzheimer's disease is not accelerated by ageing but is a distinct pathological process.

c-myc is a member of the helix-loop-helix/leucine zipper family of proteins that modulate the transcriptional activity of specific target genes. Although aberrant c-myc expression has been reported to play a role in multistage carcinogenesis in astrocytic gliomas, little is known about the effects of the expression of c-myc on oligodendrocytes. Using transgenic animals expressing a human c-myc oncogene under transcriptional control of the myelin basic protein gene, we investigated the effect of overexpression of this oncogene in oligodendrocytes. The MBP/c-myc transgenic mice developed severe neurological disturbances characterized by action tremors and recurrent seizures, and premature death during postnatal weeks three to five. Affected transgenic mice of various strains had severely hypomyelinated central nervous systems and expressed low levels of c-myc, myelin basic protein (MBP) and proteolipid protein (PLP) mRNAs in the brain. These c-myc transgenic mice also exhibited an increased number of TUNEL positive nuclei, which in most cases were located in cells that expressed c-myc, as judged by double immunohistochemistry. There was no evidence of brain tumors in the c-myc transgenic mice, including heterozygous mice from two strains that had normal lifespans. These observations indicate that the myelin deficiency observed in the MBP/c-myc transgenic animals results from a cytotoxic effect of the c-myc transgene.

Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in February 2020. We identified patients from nine Seattle-area hospitals who were admitted to the intensive care unit (ICU) with confirmed infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Clinical data were obtained through review of medical records. The data reported here are those available through March 23, 2020. Each patient had at least 14 days of follow-up. We identified 24 patients with confirmed Covid-19. The mean (±SD) age of the patients was 64±18 years, 63% were men, and symptoms began 7±4 days before admission. The most common symptoms were cough and shortness of breath; 50% of patients had fever on admission, and 58% had diabetes mellitus. All the patients were admitted for hypoxemic respiratory failure; 75% (18 patients) needed mechanical ventilation. Most of the patients (17) also had hypotension and needed vasopressors. No patient tested positive for influenza A, influenza B, or other respiratory viruses. Half the patients (12) died between ICU day 1 and day 18, including 4 patients who had a do-not-resuscitate order on admission. Of the 12 surviving patients, 5 were discharged home, 4 were discharged from the ICU but remained in the hospital, and 3 continued to receive mechanical ventilation in the ICU. During the first 3 weeks of the Covid-19 outbreak in the Seattle area, the most common reasons for admission to the ICU were hypoxemic respiratory failure leading to mechanical ventilation, hypotension requiring vasopressor treatment, or both. Mortality among these critically ill patients was high. (Funded by the National Institutes of Health.).