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Structural changes of neurons in the brain during aging are complex and not well understood. Neurons have significant homeostatic control of essential brain functions, including synaptic excitability, gene expression, and metabolic regulation. Any deviations from the norm can have severe consequences as seen in aging and injury. In this review, we present some of the structural adaptations that neurons undergo throughout normal and pathological aging and discuss their effects on electrophysiological properties and cognition. During aging, it is evident that neurons undergo morphological changes such as a reduction in the complexity of dendrite arborization and dendritic length. Spine numbers are also decreased, and because spines are the major sites for excitatory synapses, changes in their numbers could reflect a change in synaptic densities. This idea has been supported by studies that demonstrate a decrease in the overall frequency of spontaneous glutamate receptor-mediated excitatory responses, as well as a decrease in the levels of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl-d-aspartate receptor expression. Other properties such as γ-aminobutyric acid A receptor-mediated inhibitory responses and action potential firing rates are both significantly increased with age. These findings suggest that age-related neuronal dysfunction, which must underlie observed decline in cognitive function, probably involves a host of other subtle changes within the cortex that could include alterations in receptors, loss of dendrites, and spines and myelin dystrophy, as well as the alterations in synaptic transmission. Together these multiple alterations in the brain may constitute the substrate for age-related loss of cognitive function.
Brain complexity is reflected in the intricacy of its structural makeup. The brain, however small, is not structurally simple. Cortical microcircuits have the ability to reorganize functionally in response to a variety of cues, both intrinsic and extrinsic. Although it is established that there is no overt loss of neurons during normal aging, other, more subtle, changes occur in individual neurons. These include shrinkage in soma size, loss or regression of dendrites and dendritic spines, alterations in neurotransmitter receptors, and changes in electrophysiological properties (Nakamura et al., 1985; Barnes, 1994; Jacobs et al., 2001; Hof et al., 2002; Duan et al., 2003; Chang et al., 2005). Whereas such morphological alterations have been well documented, little is known about the possible mechanisms underlying such changes. Dendrites, the primary substrate for neuronal information processing, are profusely branched and varied. The integrative characteristics of dendrites are determined by several factors, including their morphology, the spatiotemporal patterning of synaptic inputs, and the balance of inhibition and excitation. Thus, dendrites play a vital role in the functional properties of neuronal circuits and any structural changes can have profound and detrimental effects.
Neuronal dendrites are instrumental in the formation and maintenance of neural networks, the regulation of synaptic plasticity and the integration of electrical inputs. Therefore, it is not surprising that there are many refined molecular cascades that are involved in the control of dendritic development and growth (Nguyen et al., 2004). In the cortex, the extent of a neuron's dendritic arborization is an important determinant of the cell's synaptic properties and affects how incoming information is integrated and processed. Dendritic shape and branching patterns vary among both neuronal classes and individual cells in each class (Samsonovich & Ascoli, 2006). Dendritic spines are specialized membrane compartments that protrude from the dendritic shaft of a neuron. Spines typically have a volume ranging from less than 0.01–0.8 µm3 and an average length of 0.5–2 µm (reviewed in Harris & Kater, 1994; Harris, 1999) and contain excitatory synapses. The linear density of spines on a mature neuron ranges between 1 and 10 spines per micrometer of dendritic length; however, spine density is not homogeneous throughout the dendritic tree, but increases at each order (Sorra & Harris, 2000). There is also a variation across cortical areas. Spine densities on basal dendrites in the prefrontal pole and orbitofrontal cortex are generally higher than in neurons of the primary visual and somatosensory cortices (Elston, 2000; Jacobs et al., 2001). It is estimated that the human brain contains more than 1013 dendritic spines (Nimchinsky et al., 2002).
It is known that cognitive abilities are impaired during normal aging. Once hypothesized to result from neuronal loss, cognitive decline is now known to be accompanied by subtle changes in neuronal morphology (Morrison & Hof, 2002). Many stereological studies have demonstrated minimal neuronal loss in cortical and hippocampal regions during normal aging (West et al., 1994, 2004; Morrison & Hof, 1997, 2002) suggesting that the age-related impairments that occur during normal aging and Alzheimer's disease (AD) are due to distinct pathological processes. In the absence of neuronal degeneration, irregularities in dendritic arborization and in spine length or volume, distribution, number, or morphology can have detrimental effects. Many studies have demonstrated age-related regression in the dendritic arbors and the dendritic spines of pyramidal neurons located in the prefrontal, superior temporal and precentral cortices in humans (Scheibel et al., 1975; Nakamura et al., 1985; de Brabander et al., 1998) and in nonhuman primates (Peters et al., 1998). Dendritic shrinkage and spine loss have also been reported in aged dogs (Mervis, 1978). An early study by Cupp & Uemura (1980) examined Golgi-stained sections from the prefrontal region of young and old rhesus monkeys and concluded that entire branches or segments were lost from apical dendrites with aging. In addition, there was an approximate 25% loss of spines in that region in old animals (Cupp & Uemura, 1980; Uemura, 1980). Similar results have been obtained by Nakamura et al. (1985) who report a decline in the number of dendrites of pyramidal cells with age in the motor cortex. Results consistent with these have been demonstrated by many groups. Electron microscopic examination of areas 46 (Peters et al., 1998) and 17 (Peters et al., 2001) in rhesus monkeys showed a loss of branches from apical tufts of pyramidal cells accompanied by a loss of spines and a 40–55% reduction in the number of synapses. In a study by de Brabander et al. (1998), analysis of basal dendritic branching patterns of pyramidal cells in the human prefrontal cortex revealed a decrease in total dendritic length, total number of dendritic segments, and terminal dendritic length with age. Further analysis of total dendritic length, mean segment length, segment number, spine number, and spine density of pyramidal cells from areas 10 and 18 of human cortex found a 9–11% decrease in total dendritic length and a 50% decrease in spine density (Jacobs et al., 1997, 2001).
More recent investigations in nonhuman primates have also examined the state of neurons during aging. Retrograde tract tracing of cortical pyramidal neurons filled with the dye lucifer yellow revealed age-related changes in the complexity of the apical dendrites in old compared to young monkeys. A minor difference in the length of dendritic segments in old animals was observed; however, this outcome was not statistically significant. There was significant loss of dendritic spines along all levels of dendrites analyzed. The total number of spines decreased by 28–37% in the basal and apical dendrites of aged animals compared to young animals, while spine densities per micrometer of dendrite decreased by approximately 23% (Page et al., 2002). Duan et al. (2003) extended these findings and found regressive dendritic changes in apical dendrites in aged macaque monkeys compared to young animals. Sholl analysis of apical dendritic arbors revealed a reduction in the number of dendrites extending to 140 µm and 180 µm from the neuronal somata. Furthermore, significant age-related decreases in dendritic length and segment numbers were observed at the second branch order for apical dendrites. There was also an age-related decrease in spine number and density in both apical and basal arbors. Spine loss on apical dendrites was estimated at approximately 43% and occurred mainly on proximal dendrites, whereas basal dendritic loss was estimated at 27% and occurred primarily on distal branches. Overall, there was a 25% reduction in both apical and basal dendrites in aged animals compared to controls (Fig. 1) (Duan et al., 2003). Senescence-accelerated mice, which are established models of aging (Takeda et al., 1991), display a gradual retraction of apical dendrites with relative preservation of overall complexity (Shimada et al., 2006). There was a 45% decrease in total apical dendrite length and a decline in stem thickness. Furthermore, there was a 55% total reduction in spine density and synaptic loss in aged animals compared to young ones (Shimada et al., 2003, 2006). In contrast, no age-related changes were observed in basal dendrites. Immunohistochemical analysis of microtubule-associated protein 2, a dendritic marker, revealed a reduction in the immunoreactivity of microtubule-associated protein 2 in the anterior and posterior cortex of aged senescence-accelerated mouse prone 10 mice indicating that dendritic retraction was not limited to layers 2/3 pyramidal cells, but rather affects other layers as well (Shimada et al., 2006). The remarkable morphological alterations and loss of dendritic spines in cortical pyramidal cells, as evidenced by many detailed studies, may underlie the first signs of cognitive decline in learning and memory performance seen in normal aging.
There is a strong link between dendritic changes and the post-synaptic effects of neurotransmitters. Neuronal alterations that occur during aging have a profound effect on the distribution of neurofilament proteins and impact important parameters of the cholinergic, serotonergic, dopaminergic, and glutamatergic systems. Changes to these systems render neurons vulnerable to impaired transmission. The resulting inability of neurons to function effectively leads to disruptions in corticocortical signaling pathways, such as those connecting the superior temporal cortex and the prefrontal cortex (Vickers et al., 1994; Gazzaley et al., 1996; Morrison & Hof, 1997; Hof et al., 2002). Several studies have demonstrated an age-related shift in the expression of neurofilament protein (Hof et al., 1990; Vickers et al., 1993, 1994). The increase of neurofilament protein in neurons is thought to make these neurons more prone to the formation of neurofibrillary tangles (NFT), a pathological hallmark of AD, and ultimately leads to neuro-degeneration and dementia. The expression and distribution of neurotransmitter receptors are also affected during aging. In particular, it has been shown that the number of neurons expressing certain ionotropic glutamate receptors (Glu R) and N-methyl-d-aspartate receptor (NMDA R) subunits is significantly reduced during aging (Gazzaley et al., 1996; Mishizen et al., 2001; Hof et al., 2002). Quantitative analysis of the distributions of Glu R2 and NMDA R1 in long and short corticocortical connections in young and old macaque and patas monkeys revealed a down-regulation of the expression of both receptors with aging. Glu R2 expression was decreased to a greater extent in the prefrontal cortex compared to other areas, such as the temporal cortex, whereas significant reductions in NMDA R1 occurred primarily in the long cortico-cortical projections from the superior temporal cortex (Hof et al., 2002).
The structural changes that occur in neurons with age are likely to impact the electrophysiological properties of neurons. Indeed, Luebke et al. (2004) have demonstrated a significant decrease in excitatory synaptic transmission in the monkey prefrontal cortex, manifested as a significantly reduced frequency of spontaneous excitatory post-synaptic currents (PSC), which represent the post synaptic cells' response to both action potential-dependent and action potential-independent release of glutamate from pre synaptic nerve terminals (Fig. 2). Perhaps, the most plausible mechanism by which the frequency of spontaneous excitatory PSCs is significantly reduced is through a reduction of post-synaptic substrate. Such a reduction has been demonstrated by studies (described above) that have shown both a decrease in dendritic spines, the major post synaptic substrate for glutamatergic inputs (Jacobs et al., 1997; Page et al., 2002; Duan et al., 2003) and a decrease in glutamate receptors (Hof et al., 2002) in the primate neocortex with age. A second potential mechanism is an age-related decrease in the frequency of action potential firing in pre-synaptic glutamatergic neurons of the prefrontal cortex resulting in decreased glutamate release and hence decreased synaptic response frequency. This explanation is made less compelling by data that demonstrate no change in resting membrane potential and an increase in action potential firing rates in layer 2/3 neurons of the aged monkey prefrontal cortex (Chang et al., 2005). Nevertheless, a significant decrease in excitability and release of glutamate from neurons located in other layers or brain areas and forming synapses on layer 2/3 pyramidal cells cannot be ruled out.
While the overall level of excitatory input to pyramidal cells in the primate prefrontal cortex (PFC) is reduced with age, several lines of evidence indicate that the post-synaptic non-NMDA glutamate receptors, although reported to be present in lower numbers (Hof et al., 2002), may be functionally intact. This is indicated by observations that the amplitude distribution of miniature excitatory PSCs did not differ in cells from the two age groups (Luebke et al., 2004). In addition, the kinetics of the post synaptic currents reflect the distribution or composition of receptor subunits and significant alterations in the subunits might be expected to result in alterations in the kinetics of PSCs (Geiger et al., 1995; Angulo et al., 1997; Swanson et al., 1997). The finding that the rise and decay times of the currents did not differ also suggests that glutamatergic non-NMDA receptors are not significantly functionally altered in layer 2/3 pyramidal cells of the primate with age (Luebke et al., 2004).
In contrast to the findings on excitatory transmission, investigations in aged monkey prefrontal cortex revealed a significant increase in the level of inhibitory synaptic input to layer 2/3 pyramidal cells, which was manifested as a significant increase in the frequency of spontaneous inhibitory PSCs (Luebke et al., 2004). Perhaps, the most straightforward explanation for the increase in spontaneous inhibitory PSC frequency is an increase in the action potential-dependent release of γ-aminobutyric acid (GABA) from pre synaptic interneurons. Future studies of GABAergic interneurons are required to determine whether this is a plausible explanation for the finding of increased inhibition of layer 2/3 pyramidal cells. The amplitude and kinetics of inhibitory miniature PSCs did not differ in cells from the two age groups, indicating that GABAA receptor function per se is not likely significantly altered with age in layer 2/3 pyramidal cells of the monkey prefrontal cortex.
Single and multiple unit recordings of pyramidal cells in the prefrontal cortex of awake, behaving monkeys have shown that these cells dramatically increase (or decrease) firing frequencies during different epochs of a working memory task. Because the sustained firing pattern of prefrontal neurons represents a precise encoding of information during the execution of memory tasks, age-related alterations in these firing patterns could plausibly result in perturbed cognitive performance. Leventhal and co-workers have demonstrated that visual cortical neurons in the anesthetized aged monkey exhibit significantly increased spontaneous action potential (AP) firing rates in vivo, that are associated with degradation of stimulus selectivity (Schmolesky et al., 2000; Leventhal et al., 2003). Recently, Chang et al. (2005) have demonstrated a significant increase in AP firing rates in layers 2/3 prefrontal cortical pyramidal cells in aged compared to young monkeys. Interestingly, in the aged group of animals, firing rate correlated with performance on working memory tasks in a U-shaped manner, with monkeys exhibiting very low and very high firing rates performing poorly and those exhibiting intermediate firing rates (which were significantly higher than seen in young subjects) performing well. These findings are consistent with the idea that the optimal firing rate in aged monkeys is shifted to higher frequencies. Such a shift may plausibly be a compensatory response to increased AP conduction failure (Rosene et al., 2003) secondary to the extensive myelin dystrophy seen in the primate prefrontal cortex with aging (reviewed in Peters, 2002). Thus, in the aged prefrontal cortex, higher rates of firing may be required to maintain functions encoded by lower rates in the young prefrontal cortex.
The spatial complexity of branching patterns in neuronal dendritic arbors has traditionally been measured in two dimensions, using Sholl analysis (Sholl, 1953). Estimates of spatial complexity have also been derived from fractal analysis, both in two dimensions (Smith et al., 1989; Jelinek & Elston, 2001) and in three dimensions (Caserta et al., 1995; Henry et al., 2002). Rather than being a local property of individual branches, in these studies 'complexity' was quantified by a power law scaling exponent that described the global rate of increase or decrease of branch numbers with distance from the soma, over a large region of the tree. Recent theoretical work has extended these scaling analyses by separately measuring the contributions of branching and tapering to the three-dimensional dendritic mass distribution, and relating these measures to the electrotonic structure of the neuron (Rothnie et al., 2006). How dendritic mass is distributed with respect to any particular point on the tree is the major factor in determining electrotonic structure, and hence electrical function in neurons (Rall, 1959, 1964; Clements & Redman, 1989; Zador et al., 1995).
A recent theoretical study by Rothnie et al. (2006) measured spatial complexity in the dendritic trees of two distinct types of layers 2/3 neocortical pyramidal neurons from rhesus monkeys: long corticocortical projection neurons from superior temporal cortex to prefrontal area 46, and local projection neurons that contribute to local circuits within area 46. Global spatial complexity was quantified by three power law scaling exponents describing rates of change of dendritic mass (dM), branching (dN) and branch diameter, or taper (dT), with distance from the soma. Two distinct scaling subregions within which scaling behavior was constant, and could be described by a single value of dM, dN, or dT were found in both apical and basal trees. These scaling regions were robust, being present in both long and local projection neurons, and exhibited a remarkable homeostatic pattern of mass distribution such that branching and tapering rates were inversely related in a fine balance that maintained a constant spatial gradient of slowly decreasing mass with distance from the soma, over most of the tree. In proximal scaling regions (Region I, Fig. 3), where the branching rate (dN) was high, tapering (dT) was also high, effectively canceling out any mass increase due to branching. In medial regions (Region II, Fig. 3) where the branching rate was close to 0, tapering was also close to 0, maintaining the same uniform mass distribution across both scaling regions of the tree. This pattern was interpreted as a form of global mass homeostasis in which the conserved quantity was the spatial gradient of dendritic mass with distance from the soma (Rothnie et al., 2006).
The effect of aging on this homeostatic pattern of mass distribution was examined in a recent morphometric study of young and aged layer 2/3 long and local projection neurons (Kabaso et al., 2003, 2004, 2006). Despite significant age-related changes in specific indices of branching and tapering, these changes remained compensatory, such that the existences of two scaling regions, and the spatial gradient of mass distribution across them, were unchanged with age in either long or local projection neurons. In local projection neurons, aging did not alter specific indices of mass distribution (dM), branching (dN), or tapering (dT) rates in either proximal or medial scaling regions. Scaling exponents in long projection neurons, in contrast, were significantly altered with age. In apical trees, the mass scaling exponent dM was significantly larger in the proximal scaling region and tended to be larger in the medial region, indicating a consistently faster rate of mass accumulation with distance from the soma. Separate analysis of branching and tapering rates showed that this altered mass distribution was due not to increase branching rates, but to reduced tapering across both regions. In basal trees, scaling exponents were unchanged with age in the proximal region, but the branching exponent, dN, was significantly lower with age in the medial region, reflecting a significantly faster rate of branch die-off with age. The combined effects of these changes to dendritic diameters and lengths can alter the passive electrotonic structure of aged neurons sufficiently that, unless compensated by changes in densities of active conductances and synaptic input, the baseline excitability of these neurons will be altered with age (Kabaso, 2004, 2006; Chang et al., 2005). Interestingly, the more rapid branch die-off in the medial regions of basal trees with age tended to be compensated by a positive taper, or slight 'flaring' of individual branches in the aged neurons, such that the mass distribution again remained relatively uniform across proximal and medial scaling regions. An analogous form of mass homeostasis in which the conserved quantity was total dendritic size, was reportedly recently by Samsonovich and Ascoli in a morphometric meta-analysis of cortical pyramidal neurons (Samsonovich & Ascoli, 2006). These authors demonstrated that fluctuations in dendritic size in one portion of a neuron are systematically counterbalanced by the remaining dendrites in the same cell, in a pattern of mass homeostasis that was robust among different brain regions, cell types, and experimental conditions. Maintenance of a form of homeostasis related to spatial gradients of mass with age, despite changes in overall dendritic size and branching patterns, might reflect an intrinsic cellular control mechanism that is conserved with aging.
Alzheimer's disease (AD) is a progressive neurodegenerative disease of the central nervous system and is present in approximately 80% of all dementia cases in the elderly (Terry, 2006). Pathologically, AD selectively damages brain regions and neural circuits and is distinguished by the presence of dystrophic neurites, amyloid beta (Aβ) plaques and NFTs. Recent stereologic studies have shown that neuronal death is limited in normal aging, whereas in AD, there is considerable neuronal loss. The neuronal degeneration observed in AD is reflected by significant neuron and synapse loss in specific brain regions (West et al., 1994, 2004; Morrison & Hof, 1997, 2002; Price et al., 2001; Hof et al., 2003; Hof & Morrison, 2004). The circuits that are most vulnerable to degeneration are the perforant path, which connects the entorhinal cortex with the hippocampus, and the long cortico-cortical projections that link association cortices such as inferior temporal cortex and prefrontal cortex (Morrison & Hof, 2002). During normal aging, plaques can be found in the neocortical, hippocampal, and entorhinal regions of cognitively normal elderly people. In addition, NFTs, although rare in the aging brain, are commonly found in the medial temporal areas after 50 years of age. The presence of these few plaques and NFTs does not seem to have a significant effect on cognition (Price et al., 1991; Arriagada et al., 1992; Kazee & Johnson, 1998; Goldman et al., 2001). In AD, however, the robust number of plaques and NFTs has significant detrimental effects on neuronal morphology and synapses. Unlike in normal aging when neurons become smaller, neuronal loss is extensive in the neocortical and entorhinal regions of the AD brain, reaching roughly 30% (Terry et al., 1981). This loss is accompanied by an approximate 45% decline in neocortical synapses (Terry et al., 1991). Neuronal loss in the hippocampus is also evident, with an average cell loss of 68% in the CA1 region of AD patients compared to aged–matched controls (West et al., 1994). Studies from our laboratory have demonstrated that neurons in AD undergo morphological alterations. Data from three control and three demented cases, with clinical dementia rating (CDR) scores of 0 and 3, respectively, showed a large reduction in spine density with only minor changes in spine length and volume. Electron microscopy studies investigating synaptic loss and its relation to the stage of AD found that there was significant synaptic loss in the brains of patients with early onset AD compared to mild cognitively impaired and nondemented individuals. The loss of synapses also correlated with the Mini-mental state score and other cognitive tests. While there was a reduction in synapse numbers in mild cognitively impaired subjects than in nondemented subjects, it was not significant (Scheff et al., 2006). Other groups have corroborated these data and found a significant reduction in spine density as well as a decrease in overall dendritic area in AD patients when compared to age-matched controls (Ferrer et al., 1990; Einstein et al., 1994; Moolman et al., 2004). Knowles et al. (1999) examined the effect of amyloid plaques on neuronal processes in humans by measuring mean curvature, length, and width distribution of dendritic projections. After examining over 5000 dendrites from ten AD cases and five controls, it was found that dendrites were extremely dysmorphic in AD, with an increased curvature and curvilinear length. This was true for dendrites that traversed plaques as well as those that were in close proximity to plaques (Knowles et al., 1999).
It has been suggested that the amyloid precursor protein (APP) and APP cleavage products play a crucial role in neuro-protection, interneuronal connections, and synaptic plasticity (Seabrook et al., 1999) and appear to be located in neuronal structures, including synaptic compartments (Schubert et al., 1991; Shigematsu et al., 1992). In AD, the accumulation of Aβ, in particular the oligomeric forms of Aβ, mediate neurotoxic effects including interrupting synaptic transmission, synaptic plasticity, and disrupting neuronal connectivity (Wang et al. 2002; Raymond et al., 2003). Alterations in neuronal morphology and trajectory may cause disruption in neuronal signaling and function and are thought to ultimately contribute to the neuronal loss observed in AD (Knowles et al., 1999). Many studies using transgenic mice containing varying forms of the mutant human APP have investigated the morphological effects of Aβ on neurons. While many of these transgenic mice do not exhibit neuronal loss, a few of them (APP23 and APP751/PS-1M146L) exhibit significant age-related neuronal loss in brain regions containing Aβ aggregates (Calhoun et al., 1998; Schmitz et al., 2004). Moreover, neuronal loss was evident in regions that were distant from plaques suggesting a putative role for intracellular Aβ or soluble Aβ in neurodegeneration (Schmitz et al., 2004). This phenomenon of neuronal degeneration in the absence of Aβ plaques has also been observed in the presenilin-1 mutant mice, PS1L286V, and PS1H163R, where accelerated neuronal loss was demonstrated in the frontal cortex and hippocampus. Interestingly, these animals showed signs of intracellular Aβ in the aforementioned brain regions (Chui et al., 1999). In the context of extracellular Aβ aggregates, neurons that are in close proximity to (10–20 µm) or passing through Aβ plaques undergo spine loss and shaft atrophy and develop axonal varicosities (Le et al., 2001; Tsai et al., 2004). There is also increased curvature of dendritic processes, a decrease in dendritic density and abruptly terminated dendrite endings. Segments farther than 20 µm from Aβ plaques appeared unaffected (Knowles et al., 1998, 1999; Tsai et al., 2004). In APP/PS1 and J20 mice, swollen bulbous, dystrophic neurites were seen along with a 36% reduction in the number of spines (Moolman et al., 2004). Other studies in Tg2576, PDAPP, PDGF-APP, and APPV717F mice also demonstrated a reduction in spine density in neurons in the CA1 region and dentate gyrus of the hippocampus and in the somatosensory cortex (Games et al., 1995; Hsia et al., 1999; Mucke & Masliah, 2000; Lanz et al., 2003; Wu et al., 2004; Jacobsen et al., 2006). Interestingly, while changes in spine density occurred in the presence of Aβ aggregates, in some cases, the reduction in spine density was independent of the presence of fibrillar Aβ plaques and increased with age and the incidence of pathology. A more extensive study by Rutten et al. (2005) in APP751/PS-1M146L mice supported previous studies indicating a reduction in synaptic boutons. They also reported that transgenic animals had larger pre-synaptic boutons while in close proximity to Aβ plaques as well as a decrease in volume compared to wild-type controls (Rutten et al., 2005).
A recent study, Alpar et al. (2006a) examined more global morphological changes in the Tg2576 mouse model. Pyramidal cells in layers 2/3 of the primary somatosensory cortex were analyzed in three dimensions. No changes were observed in basal dendritic arbors; however, many unambiguous changes were found in the apical dendrites. Total length, surface area, and volume of basal dendrites were the same between Tg2576 mice and controls. There were also no variations in the branching patterns of basal dendrites and no change in the number of dendritic endings or in dendritic density. In contrast, apical arbors were shorter in length and less branched than controls and exhibited an increase in diameter in the proximal dendritic segments and a reduction in the distal; however, the total surface area and total volume did not change significantly. Spine density was reduced in both apical and basal arbors along the entire course of the dendrite (Alpar et al., 2006a). It is unclear if the actions of mutated human APP (hAPP) or the elevated Aβ levels contribute to the morphological aberrations observed. Studies in APP null mice showed a reduction in dendritic length and branching (Perez et al., 1997; Seabrook et al., 1999). Studies in mice expressing nonmutated hAPP (Lamb et al., 1993) found no overall difference in dendritic length. However, there was a significant increase in the total surface area and volume of basal dendrites in transgenic mice compared to controls (Alpar et al., 2006b). Whereas there was a shortening of third and fourth order branching, the average diameter of second, third, and fourth order segments was larger in hAPP mice than controls.
The mechanism of tau-mediated neuronal death in AD remains elusive. The abnormal phosphorylation of tau is considered one of the earliest signs of neuronal degeneration and precedes NFT formation and plaque aggregation. Few studies have investigated the effect of NFTs and tau on dendrites and dendritic spines. In a recent report where organotypic hippocampal slice cultures infected with Sindbis virus containing an EGFP-tau construct were assessed, it was found that while there was a loss of individual neurons over time, spine density and spine morphology were essentially the same as controls (Shahani et al., 2006). Preliminary studies in our laboratory have examined the effect of tau in a transgenic mouse model that expresses all six isoforms of human tau, but not mutant tau (Andorfer et al., 2003). These mice exhibit tau pathology in neurons of the neocortex and hippocampus in patterns similar to that occurring in NFTs of human brain and exhibited overt neuronal loss (Andorfer et al., 2003, 2005). Examination of dendritic arbors demonstrated a reduction in the total number of spines (~35%), as well as a decrease in spine density that became more severe with age. In humans, it has been demonstrated that dendrites that are immunopositive for Alz50, an antibody that recognizes NFTs and neuropil threads, are highly altered, with less than 5% of these dendrites being straight (Knowles et al., 1999). Le et al. (2001) found that there was a significant disruption in neuronal microarchitecture in cells that were positive for phosphorylated tau, and reported similar findings of an increase in the curvature of the dendrite, as well as an increase in length. Taken together, the changes that neuronal projections undergo in AD may account for the cognitive decline observed. Exposure to APP or proteolytic cleavage products and hyperphosphorylation of tau causes distinct remodeling of pyramidal neurons, which may severely impact synapse propagation ultimately resulting in neuronal death.
Over the past several years, it has become evident that the anatomical and functional organization of the human brain is dynamic and changes in response to many stimuli. In humans, age-related synapse loss, neuronal loss, and cognitive decline, are commonly seen in neurodegenerative disorders such as AD. However, age-associated cognitive impairment without neuronal loss has also been reported in many species and is likely mediated by dendritic and synaptic alterations. Otherwise, intact circuits in the brain are vulnerable in normal aging as a result of ultrastructural morphologic modifications in dendrites and reduced spine densities and are reflected in compromised synaptic communication. Thus, unlike AD where cognitive decline can be attributed to neuronal loss, age-related cognitive deficits appear to evolve from cellular changes that lead to the disruption of cortical connections. Although many studies have begun to elucidate the mechanistic relationships between synaptic integrity and age-associated cognitive impairment, there is still much that remains unknown. Understanding these mechanisms will help determine when and how dendritic changes contribute to the brain's capacity for memory, perception, and action, and will aid in the development of new therapeutic avenues to prevent or cure cognitive impairment.
We thank W.G.M. Janssen, B. Wicinski, A. Rodriguez, and D.B. Ehlenberger, and other members of the Hof, Morrison, Wearne, and Luebke laboratories who have been involved in our studies of brain aging for their support. This work was supported by National Institutes of Health grants AG00001, AG02219, AG05138, MH71818, and DC05669.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Haringey Youth Space
What's Bubblin'?
23 October 2015
24 August 2015
We are offering Apprenticeships in Business Administration; Information Technology; Employment Support, and Youth Work.
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Wedding Menu List
Crafting Time:
- 1-2 Hours
Skill Level:
- Beginner
Project Courtesy of: Jo-Ann Fabric and Craft Stores
Additional Information
• Framed chalkboard (or purchase large photo frame and paint glass with chalkboard paint)
• White chalk marker
• 3-4 sheets of 12"x12" printed paper
• 2-3 sheets of 8½"x11" solid cardstock
• 24" of burlap ribbon
• Glue
• Scalloped paper punches: various sizes
• Paper scoring board and bone folder
• Paper trimmer
• Scissors
• Ruler
• Paper & pencil
1. Plan out menu on paper.
2. Create menu with chalk maker, combining script and print hand writing.
3. Create paper rosettes using scoring board and strips of printed paper 2", 1" and ½" wide.
4. Form strips rosettes.
5. Punch scalloped circles from cardstock.
6. Layer paper rosettes and scalloped circles, adhere together.
7. Glue layered rosettes to bottom corner of frame.
8. Create a bow with burlap ribbon and adhere under rosettes.
Items in This Collection
Bazzill Classics Cardstock Paper 8.5"x11" - Lily White
Item # prd42687
Online Only
$9.99 $6.99


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Water & Air
Channel: intredasting
All of the water on Earth would fit into a sphere 1,385 kilometers across.
The amount of freshwater is much smaller. Though 1,300 kilometers is well beyond the clouds and even beyond the Thermosphere and into the Exosphere. That is where the space shuttle and ISS orbit around the Earth, so that sphere is still pretty huge but probably much less than what you imagined before.
Bair/ o


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Free speech or hate speech? Pro-life or anti-the-living?
There are 93 comments on the latimesblogs.latimes.com story from Mar 26, 2010, titled Free speech or hate speech? Pro-life or anti-the-living? . In it, latimesblogs.latimes.com reports that:Listen here to those Stupak voicemails:
A coffin was placed on a Missouri Democrat Russ Carnahan a s lawn. Gas lines were cut at the home of Virginia Democrat Tom Perriello 's brother after a blogger posted the address online, thinking it to be the congressman's. And then there are the phone calls to Michigan's Bart Stupak , an anti-abortion Democrat who provided the margin of victory ...
Join the discussion below, or Read more at latimesblogs.latimes.com.
#1 Mar 26, 2010
Hmm. Sounds like some tax payers don't like to be ignored.
"Headed toward the cliff"
Since: Nov 07
Tawas City, Michigan
#2 Mar 26, 2010
Hmmmm, sounds like some tax payers are whiny little hypocrites who are "pro-life" only when it comes to a lump of fetal tissue.
#3 Mar 26, 2010
It is sad that a major news organization has no clue about free speech. Some LA nitwit should go back and look at the "Free Speech Movement" that began at Cal-Berkeley.
"Tell the Truth"
Since: Nov 07
Orlando, Florida
#4 Mar 26, 2010
And they call liberals nuts? There's nothing nuttier than a pro-life conservative.
A coffin was placed on a Missouri DEMOCRAT Russ Carnahans lawn.
Gas lines were cut at the home of Virginia DEMOCRAT Tom Perriello's brother after a blogger posted the address online, thinking it to be the congressman's.
New York DEMOCRAT Louise Slaughter got a message from a caller saying snipers were being deployed to kill children of those who voted for healthcare reform. In the nearby offices of the local DEMOCRAT Committee, a brick thrown through the front door held a note recalling Republican Barry Goldwater's 1964 infamous rallying cry: "Extremism in defense of liberty is no vice."
And then there are the phone calls to Michigan's Bart Stupak, an anti-abortion DEMOCRAT who provided the margin of victory for healthcare reform after President Obama agreed to an executive order explicitly banning federal funding of abortions. Take a listen.
The FBI is investigating the death threats. Local prosecutors, even conservative ones who opposed the healthcare legislation, are looking to bring charges. But as members of Congress prepare to go home to their districts for the Easter/Passover recess next week, with members rattled over the violence, the political questions are equally riveting.
Is this free speech or hate speech -- constitutionally protected or criminal behavior? Was it caused by the media megaphone -- those 24/7 cable-news shouting shows -- or by rabble-rousing politicians like former Alaska Gov. Sarah Palin, who after the vote posted this on Twitter: "Commonsense Conservatives and Lovers of America: Don't retreat. Instead RELOAD!" As New York DEMOCRAT Steve Israel wrote in his tweet back to her, "Reload? Is your choice of words inciteful or ignorant?" And don't forget House Republican Leader John Boehner, who said yes-vote Ohio DEMOCRAT Steve Driehaus "may be a dead man." A spokesman explained Boehner didn't mean that literally.
Obama wasn't kidding when he thanked members of Congress for their courage.
Finally, why do some who call themselves pro-life show such little regard for the living? One caller to Stupak's office said,Congressman Stupak, you baby-killing I hope you bleed out your ..., got cancer and die. Is this the language of someone who holds life dear?
For his part, Stupak is calling anti-abortion forces hypocrites for not embracing Obama's executive order. Noting that they applauded when President Bush signed an executive order limiting embryonic stem cell research, Stupak told the Catholic Daily Caller, "I question, did they want to protect the sanctity of life, or did they want to defeat healthcare?"
On the other side of the issue, women's groups are furious with Obama for giving Stupak and other anti-abortion Democrats explicit language outlawing federal funding of abortion. "He campaigned as a pro-choice president," said Terry O'Neill, president of the National Organization for Women. "It really pains me to conclude that ... health reform ... has been achieved on the backs of women and at the expense of women."
But so far the women's groups haven't threatened to kill anyone.
Since: Dec 08
#5 Mar 26, 2010
Bloggers should get their facts stright. This coffin thing has been proven a hoax. As for the others, where is the proof it even happened and how does it prove who did it. It sounds like a disinformation campaign trying to discredit the opposition to ObamaCare.
#6 Mar 26, 2010
In the US, political violence has always been one of two types, with Lincoln's assassination being the only exception:
When a democrat or democrat ally is murdered, it was done by a republican or republican ally for political reasons.
When a republican or republican ally is murdered, it was done by sociopath or psychopath for NON-political reasons.
The democrats don't go around murdering people or advocating it. The republicans do it all the time.
#7 Mar 26, 2010
You know you were a lump of fetal tissue at one time.
#8 Mar 26, 2010
Obama is now goading opponents to his radicalism to act out in ways he and the radical Democrats can use to discredit opposition by over-generalization. He and his loony supporters can threaten people at election polls, throw red paint at people, sit in trees naked to promote getting perverts in the news, mouth specific propaganda designed to encourage killing, or degrading our military, camp out and physically attack those they hate, make films about assassinating their opponents... but all that and more is reasonable demonstration to them. However, in their insane world, opposition by a majority of people in America to fundamentally altering the country and violating a Presidential Oath of Office is radical and unreasonable. Welcome to ObamaSpeak morphed with PelosiSpeak morphed with LeninSpeak.
#9 Mar 26, 2010
Leftists don't care if the facts prove them wrong.
Getting out the accusation in the first place is the goal, because they know the media will ignore or bury the correction.
#10 Mar 26, 2010
Obama supporters can threaten to educate young women in how to kill their babies with metal clothes hangers if they aren't allowed to Federally fund abortions targeting Black people, but someone opposed to their inhumane policies is the radical... Sure.
#11 Mar 26, 2010
You just made the case for abortions. The world would be much better off with dirtbags like Sheeple.
#12 Mar 26, 2010
IF your a brain washed Obama person, they won't
let anyone tell you, on HERE.. You will never
know what you are. shame
#13 Mar 26, 2010
Maybe the girls
should know they have the money to PAY for their abortions befor
they get themselves pragnant. I don't want to pay to kill a baby
just because they don't take birth control or can't say no. ITS
United States
#14 Mar 26, 2010
The left/progressives believe it's free speech when they say anything but hate speech when the opposition says anything.
They do this to try to shut the opposition up but most Americans have caught onto their game and are exposing them.
#16 Mar 26, 2010
How is physically threatening someone anything other than hate speech, ever?
"Here we go!"
Since: Feb 07
#17 Mar 26, 2010
Hmmm.... A bullet was fired through REP Eric Cantor's (R-VA) window, voice mails threating death were left for REP Jenny Brown-Waite (R-FL) and REP Jean Schmidt (R-OH).
I wonder where those instances were in the article- Oh right, they're republican lawmakers, so it doesn't matter.
#18 Mar 26, 2010
When it is directed at those of us who are not pansies. If you weren't a pansy, you wouldn't have to ask.
United States
#19 Mar 26, 2010
Oh you mean like how Carnahan supporters the SEIU beat Kenneth Gladney up at the Carnahan town hall meeting?
And what about when a Carnahan supporter hit Kelly Owens?
Yes Carnahan supporters have physically beat people up and attacked the opposition.......
It's all on tape and their is no denying it happened.
#20 Mar 26, 2010
Calling someone names isn't a threat. Wish someone "ill" isn't a threat.
This is an example of a threat.
Notice his announced intent to shoot people in the face with his 9 mil.
See the difference?
"It's a Brand New Day"
Since: Feb 06
New Rochelle
#21 Mar 26, 2010
Retract that Cantor has been proves a liar. It never happened.
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Here is the latest news:
Daily Oklahoman / March 22, 2001
Airline sees East Coast direct routes from state
By Rick Robinson
TULSA -- Great Plains Airline Holding Co. said Wednesday that it has completed its takeover of Ozark Air Lines. The move could result in nonstop service from Oklahoma City and Tulsa to the East Coast by the third quarter of this year, a Great Plains executive said.
Great Plains announced last week that it was buying a controlling interest in Ozark, based in Columbia, Mo. Ozark is now a Great Plains subsidiary, the company said. Transaction terms were not disclosed.
Jim Swartz, Great Plains' chief executive, said Ozark will shortly begin flying its two jets from Oklahoma City and Tulsa to other regional cities. Currently, Ozark flies daily from Columbia to Dallas/Fort Worth, and offers charter service.
"It's fair to say that service will become Oklahoma-oriented soon," he said.
Swartz said the airline will announce new destination cities within days. He said the chosen destinations will be nonairline-hub cities with no current nonstop service from Oklahoma City and Tulsa. All current and future flights will operate under the Ozark banner, he said.
Great Plains Airlines, led by Swartz, Executive Vice President Jack Knight and Chief Financial Officer Steve Berlin, is seeking to establish nonstop service between Oklahoma and both U.S. coasts. The company is the result of a three-year effort aided by the Tulsa-area chambers of commerce. About $30 million has been raised from public and private sources for the venture, which has been helped by a state tax credit incentive program.
"Direct jet service is so essential to economic development throughout our state," Swartz said.
He indicated the deal's greatest single advantage is that it sidesteps the need for Great Plains to seek a Federal Aviation Administration safety
Check out the website www.gpair.com


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EAST RUTHERFORD, N.J. -- Rookie Terrence Williams is finally figuring out how to play in the NBA, and so are the New Jersey Nets to be honest.
Williams had 14 points and a career-high 14 assists and the Nets posted their biggest win of the season with a 115-87 decision over the slumping New Orleans Hornets on Saturday night.
"Terrence was terrific," Nets interim coach Kiki Vandeweghe said.
Unstoppable might have been a better word because the Hornets had no answer for Williams, who was 7 of 13 from the field and was the undeniable catalyst as the Nets (11-65) won for the fourth time in six games.
"He's a guy who can run the point guard, a guy who can play the two and the three and he's athletic," Nets point guard Devin Harris said. "He can do a lot of things on the floor and open things up. He adds a different dimension to the bench."
Over the last month, Williams has averaged 14.1 points, 6.7 rebounds and 4.9 assists, not bad for a guy who was in Vandeweghe's doghouse earlier this season.
Williams says the bench time helped him see what he needed to do.
"It was time to grow up," Williams said. "I'm in the NBA now, I'm not in high school and I'm not in college. It was time for me to take responsibility for myself and my actions and why I was playing the way I was."
David West, who had 25 points, seven rebounds and six assists to lead New Orleans, noticed Williams in the game in which the Hornets allowed 40 fast-break points.
"They ran and they were too athletic on the wing, and out front we couldn't guard them," West said. "Williams, I think that's what his name is, was too much. When he came in he turned the course of the game. He was a bad matchup for us and we were never able to get them under control."
Chris Douglas-Roberts scored 17 points, and Kris Humphries added 10 points and season-high tying 12 rebounds as New Jersey (11-65) shot a season-high 58.2 percent in sending the Hornets to their third straight loss and 11th in 14 games.
The Nets had a season-high 34 assists and had eight players score in double figures and two others with at least seven points in winning for the fourth time in six games. It marked the first time New Jersey had eight players in double figures since November 2002.
The Nets never trailed after Brook Lopez (12 points) converted a three-point play with 4:30 left in the first quarter.
New Jersey led 30-24 after the opening period and pushed the lead to 17 points in a second quarter dominated by Williams. He had 12 points and five assists and was a one-man highlight shot.
Williams hit a variety of shots, driving the lane for an awesome dunk, tossing in an off-balance 20-footer that beat the shot clock and waking up the crowd with an electrifying dunk on alley-oop from Harris.
"We're playing well right now," Harris said. "I like the way the ball is moving. I don't know how many assists we had but we're moving the ball from side to side. When we can attack from side to side we can be very effective."
New Jersey shot almost 54 percent from the field in taking a 59-47 halftime lead, but it had to fight off one run by New Orleans in the third quarter.
Yi Jianlian hit three jumpers early in the quarter to help the Nets take a 69-53 lead.
The Hornets drew within seven points on several occasions, the last time at 78-71 on two free throws by West with 1:46 left in the quarter.
Keyon Dooling then beat the shot clock with a jumper, Josh Boone scored on a dunk off Williams' feed and Humphries nailed a jumper for an 84-71 lead.
When New Jersey opened the fourth quarter with a 7-2 run capped by a Williams slam, the game was over and so was the Hornets' five-game winning streak over New Jersey.
- Nets official scorer Herb Turetzky worked his 1,100th consecutive game.
- Harris had a monster block on a fast-break layup attempt by Darren Collison late in the third quarter, sending the ball into the first row of the fans on the sideline.
- New Orleans was 1 of 11 from 3-point range. The Nets were 4 of 9.
- The teams split two games this season, with New Orleans winning 103-99 at home on Jan. 8.
- The Hornets have lost 12 of 13 on the road.
- The 28-point margin of victory was the Nets' biggest over New Orleans.


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All hail the conquering hero
- 183 views
- 98 clicks
- 35 admirers
Aug 6, 2012
My ginger cat, Pumpkin, took on a giant wolf spider last night!
Pumpkin is quite the hunter! Lovely fall collection here!
Yipes!! Great treasury!
Happy early halloween
Good for her - though I like spiders too:)
Gorgeous Treasury!
Fun! I think I'd like pumpkin!! :) thanks for including me!
Fun Halloween finds!!!!
Way to go, Pumpkin!
Beautiful! Thanks for including my baby bib!
sooo Spooky Fab!! I love it!!
Thank you so much for including my Halloween secret envelopes in your creation.
Hooray for spider eating cats! A job well done. My rule is outside, I leave you alone, inside you're.........
Awesome theme!!! I love this! And yeah for Pumpkin! My lab Daisy will take on the occasional fly, but that's about it! :) Thanks so much!!! :)
Very cute!
LOL! Fun title and fun collection!
WOnderful! Thanks so much!
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Love! Thank you!
Such an extremely unique collection!
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Great fun!


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Emmy-nominated "Scandal" star Kerry Washington explains why the hit show represents the "full spectrum of humanity" and why race is not the only defining aspect of her character. Plus, the style icon gushes on the fun of dress-selecting for the awards show.
at 3:49 PM GMT on Sep 20, 2013 | at 3:23 AM GMT on Sep 21, 2013


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Feed aggregator
Highlights from the Photograph Collection – Radiology Department
Our extensive Historical Photograph Collection includes some really fascinating images. Check out these from the UCSF Radiology Department.
Smoke and Fumes: A Hidden History of Oil and Tobacco
The Washington-based Center for International Environmental Law (CIEL) recently debuted an amazing database of documents pulled from the files of Big Oil as well as our Truth Tobacco Industry Documents archive (TTID). The Smoke and Fumes website is a culmination of their investigation into climate misinformation campaigns which in turn led to a dive into our tobacco documents to look for industry intersections. And find them they did!
The Oil industry's efforts to mislead the public about climate science are well documented. Amidst the ongoing investigations and recent wave of climate litigation, comparisons to Big Tobacco have been obvious yet Exxon and its associates have rejected these parallels. CIEL's research into TTID reveals compelling evidence that the relationship between these two industries is "neither coincidental nor casual." The connections between oil and tobacco date back nearly a century and our tobacco documents show these industries have a long history of shared marketing and advertising strategies, research interests, PR firms, and scientists. For instance, in the 1970s, the Chair of BAT also served on the Board of Directors of Exxon and RJ Reynolds once owned and operated an oil company, American Independent Oil, which engaged in industry-wide projects. In the late 1950s the oil industry lent their expertise in mass spectrometry to tobacco companies looking to test cigarette smoke for toxins and both industries attempted to engage in joint research on filters.
These are just a few examples CIEL pulled from the tobacco documents. If you head over to our search box and type in "Shell Oil", "Exxon", or even "Esso", you'll be amazed at the thousands of documents that are retrieved.
Smoke and Fumes: A Hidden History of Oil and Tobacco from CIEL on Vimeo.
After all, "…the framers of the Constitution enjoyed the...
After all, "…the framers of the Constitution enjoyed the use of tobacco…how indignant they would have been at any attempt to infringe on that personal right through taxation, restrictions and prohibitions!" - the Tobacco Institute (1978)
In 1978, the Tobacco Institute, the now defunct lobbying arm of the US Tobacco Industry, published a paper entitled "The Smoking Controversy: A Perspective". This paper attempted to tell the "other side" of the story, namely that the smoking controversy is just that, a controversy, and that it must be resolved by more scientific research: "years of scientific research have failed to provide conclusive evidence that smoking causes disease…"
In this short tract, a number of scenarios discredit the anti-tobacco movement including a political maneuver to seize or maintain power through the denial of pleasure, citing "this was true of ancient dietary laws, sexual taboos, restrictions on the theater and Prohibition. Others would say it is true today of anti-tobacco programs". A section called "The making of hypochondriacs" notes, "I wonder how many people who just could not give up smoking might have continued to lead a perfectly normal life had they not been plagued by fears of being not only in great peril, but actually sinful." And finally, the industry concludes that smoking is pleasurable and therefore a personal right - a fading freedom that should not be infringed upon.
Read the entire paper:
Tobacco Institute (1978) The Smoking Controversy: A Perspective.
An Old-Fashioned Expedition into the Vault
This is a guest post by Kristin Daniel, UCSF Archives and Special Collections Intern.
Dear Reader, you may not be aware of the fact that most—if not all—archives must deal with the looming specter of unprocessed legacy collections haunting their vaults. Hark, what's that I hear? The sound of researchers gnashing their teeth at the thought of virgin cartons, brimming with knowledge, just beyond their reach? In the name of Science and History, what can be done?
I'll tell you good Reader! An expedition is being undertaken at this very moment to survey those hidden but not forgotten boxes of lore that reside in the vault of the UCSF Archives. Possessing the requisite skills and patience, archivist David Uhlich and myself (your plucky and adroit, intern) are making our way through shelf after shelf of material – opening boxes, checking contents, and conferring with the notes of archivists gone by.
Sometimes we find what's on the shelf matches what information we have, but sometimes we come across half-created records or material lacking adequate description. Despite these setbacks, we roll up our sleeves and soldier on, updating existing records with new information about content and location, or creating shiny new records of our own.
It's a long process, but it is important work. Fear not, gentle Reader, for although the task seems Sisyphean in magnitude, the brave souls of the Archives and Special Collections are determined to succeed!
Highlights from the State Medical Society Journals digitization project
We've become somewhat accustomed to seeing "smoking doctor" pictures, typically the product of tobacco advertising cynically appealing to authority. The above image comes from a naturalistic setting however, depicting pathologist Dr. Harrison Martland (see table of contents below) at work.
Dr. Martland is featured on the cover of the January 1984 edition of the Journal of the Medical Society of New Jersey (Vol. 81 no. 1), digitized by the Internet Archive as part of the NEH grant-funded project to digitize many of our state medical society journals.
The journal lacks any commentary on the smoking but does lead us to an article on the analysis of Dr. Martland's historical autopsy records performed at Newark City Hospital from 1908 to 1911.
The author draws some interesting conclusions about the safety and violence of Newark from Dr. Martland's records, but perhaps one of the most interesting details is his attempt to record all his findings in Latin! He gave up eventually, doubtless making the author's analysis that little bit easier.
Check out this and many other journals from our collection and four other libraries at the Internet Archive's State Medical Society Journals project page. Expect continued updates to the collection throughout the year.
2014 Counter-marketing Study in NYC used Tobacco Documents to Highlight Racism
"Racism Still Exists": A Public Health Intervention Using Racism 'Countermarketing' Outdoor Advertising in a Black Neighborhood – a project and paper by Naa Oyo A. Kwate at Rutgers University.
This study and supporting tumblr blog reports on RISE (Racism Still Exists), a high-risk, high-reward public health intervention that used outdoor advertising to disseminate a "counter-marketing" campaign in New York City (NYC).
One component of the campaign was to use internal tobacco industry documents to demonstrate ways the industry marketed cigarettes, targeted specific populations, and sought to deny the dangers of smoking. Big Tobacco's targeting of Black populations reveals much about how these companies perceived African Americans and the strategies they used to create and maintain Black smokers.
The RISE campaign generated significant public discourse, particularly in social media and the study results suggest that racism counter-marketing campaigns may have promise as a community-based intervention to address health inequalities.
Tobacco Documents used in a 2014 Countermarketing Study in...
Tobacco Documents used in a 2014 Countermarketing Study in NYC:
"Racism Still Exists": A Public Health Intervention Using Racism 'Countermarketing' Outdoor Advertising in a Black Neighborhood - a project and paper by Naa Oyo A. Kwate at Rutgers. Reported in the Journal of Urban Health: Bulletin of the New York Academy of Medicine.
http://racismstillexists.tumblr.com/tagged/smoke/ - This amazing study and supporting tumblr blog reports on RISE (Racism Still Exists), a high-risk, high-reward public health intervention that used outdoor advertising to disseminate a "countermarketing" campaign in New York City (NYC). The campaign generated significant public discourse, particularly in social media and the results suggest that racism countermarketing campaigns may have promise as a community-based intervention to address health inequalities.
One component of the campaign was to show, through the internal tobacco industry documents, the ways the industry marketed cigarettes, targeted specific populations, and sought to deny the dangers of smoking. Big Tobacco's targeting of Black populations reveals much about how these companies perceived African Americans and the strategies they used to create and maintain Black smokers.
New Tobacco Documents and New Website Features for July
52 new documents have been added to the Truth Tobacco Industry Documents today.
This includes:
You may also notice some changes to the Industry Documents Library and Truth Tobacco Industry Documents homepages. Each homepage now contains four big-button links to highlighted materials, such as Industry Videos, Industry Web Archives, and Popular Tobacco Documents. The TTID homepage includes a link to the UCSF Library's Tobacco Control Archives, located in Archives and Special Collections on the Library's 5th floor.
We've also added a "Featured" section in the bottom right-hand corner, which displays links to random documents in the database; choices change each time you re-visit the page. Try it out for a quick browsing break!
Baunscheidt's Lebenswecker: The 19th-Century "Life-Awakener"
Another installment in our blog series that explores artifacts related to health practices now considered inaccurate or fraudulent. Check out Carl Baunscheidt's Lebenswecker.
The Lebenswecker, translated as the "Life-Awakener" or the "Resuscitator," was developed by German inventor Carl Baunscheidt in the mid-19th century. The small instrument included over 30 thin, spring-loaded needles concentrated at the end of an ebony staff.
According to Baunscheidt, the Lebenswecker was designed to quickly puncture the skin, creating "artificial pores." The "pores," i.e. puncture wounds, were then covered with a proprietary irritating oil called "Oleum Baunscheidtii" that produced blisters. As another option, the practitioner could dip the needles in the oil before application, thus creating a more concentrated injection. As the blisters formed and drained, Baunscheidt claimed, the "health-destroying morbid matter" in the body naturally escaped.
Baunscheidt developed a health philosophy around the Lebenswecker known as Baunscheidtism. His inspiration, as detailed in his book Baunscheidtism, or a New Method of Cure, came from his experience watching mosquitoes bite his rheumatic hand. As he writes, "it seemed as if the pains he had suffered, had fled with the flies…the inflicted sting caused an opening in the epidermis just large enough for the fine, volatile, but pathogenic substances lodged in the skin to exude."
Baunscheidt claimed that the Lebenswecker could cure everything from sleeplessness to measles to epilepsy. Baunscheidtism practitioners, like John Linden, made similarly broad claims. As Linden noted in his work, Manual of the Exanthematic Method of Cure, the Lebenswecker could eliminate a tapeworm because, after repeated applications, "the unwelcome guest will soon become disgusted with his quarters, and be compelled to vacate."
Baunscheidt's philosophy, backed by personal testimonies included in his publications, achieved a measure of popularity in the 19th and early 20th century, especially in Germany and the United States. Today, his treatment is widely discredited.
We house two different "Life-Awakeners" in the UCSF Archives and Special Collections and a similar instrument developed by Baunscheidt called an artificial leech. Please contact us if you would like to come in and see the artifacts! We also have editions of John Linden and Carl Baunscheidt's writings or you can read Baunscheidtism, or a New Method of Cure online in our digital collection.
New Equipment for Loan!
The Library Tech Commons Team is very proud to offer a comprehensive collection of video and audio equipment for loan, free of charge, to UCSF students, staff and faculty. Our equipment is used ever day for a variety of projects, including interviews, medical demonstrations, and even student skits. We listened to your feedback, and have added new items to the collection!
Among the new additions are a state-of-the-art LED light kit, two new digital audio recorders, a dual wireless mic kit (yes, mic-up two subjects at the same time!), and high-quality handheld mics and a shotgun mic for advanced users. For each new item, there is also an accompanying online help document to get you up-and-running quickly:
- Westcott LED Lights
- Zoom H2n
- Zoom H5
- Azden Wireless Mics
- Sure Handheld Mics
- Azden Shotgun Mic
- Gitzo Boom Pole
The full list is available on our Support Center website, and includes video cameras, external hard drives for video projects, tripods and more.
Please help us maintain this service (which, at many other institutions, isn't free), by reviewing the help documentation before you arrive to pick up the equipment, and by treating our equipment with care.
If you have any questions, or suggestions for us to improve this service, please do not hesitate to contact us. We welcome your feedback!
PS: Also coming soon… a new reservation system that will allow you to view an availability calendar and make your own reservations. Stay tuned for another announcement this Fall!
Article Spotlight: Analysis of British American Tobacco's questionable use of privilege claims
Every month, we highlight a newly published article along with a few key industry documents used by the author(s):
LeGresley E, Lee K. Analysis of British American Tobacco's questionable use of privilege and protected document claims at the Guildford Depository. Tobacco Control 2016 Jun 27.
Tobacco companies have a documented history of attempting to hide information from public scrutiny, including inappropriate privilege claims. The authors conducted a search of the Truth Tobacco Industry Documents Library which identified inconsistent privilege claims, and duplicates of documents withheld by BAT from public visitors. "A review of the validity of these claims was conducted against recognized legal definitions of privilege. The authors found that BAT has asserted inappropriate privilege claims over 49% of the documents reviewed (n=63). The quantity of such claims and consistency of the stated rationale for the privilege claims suggest a concerted effort rather than human error."
Key Documents from the UCSF Truth Tobacco Industry Documents:
- Supplemental Table – containing documents reviewed for appropriateness of privilege claims.
Marking some documents as confidential, secret or privileged was intended to protect company interests. The authors retrieved the following documents describing what BAT staff should deem as sensitive information and how privilege should be claimed to protect it:
The authors note the blanket protection afforded some personal documents also creates an opportunity to hide sensitive material simply by placing correspondence on home letterhead. This practice is referenced in the following document by Phillip Morris executive Thomas Osdene in a handwritten note regarding the destruction of potentially sensitive documents relating to the industry-funded Institute for Biological Research (INBIFO): "If important letters or documents have to be sent, please send to home—I will act on them and destroy"
Celebs, a future President and even Atticus Finch rep...
Celebs, a future President and even Atticus Finch rep Chesterfield back in the day…
Actors and entertainers such as Ronald Reagan, Tyrone Power, Charles Coburn, Ann Todd, Ethel Barrymore, Louis Jourdan, and Gregory Peck routinely endorsed cigarettes in ads such as these from the "Always Buy Chesterfield" campaign of 1948. These particular marketing images came from Life Magazine and the Saturday Evening Post, two mainstream media outlets.
For more ads, see our
Pollay Ads Collection with over 10,000 tobacco print advertisements spanning 5 decades - Online at the UCSF Industry Documents Library.
Summer 2016 Interns
This summer the UCSF Archives & Special Collections is hosting two interns who are working on diverse projects.
Sophia Lahey is helping with the manuscript collections survey project, updating the metadata for historic photographs and documents that are posted on Calisphere, and assisting with quality control of volumes digitized for the State Medical Society Journals project.
Sophia is currently a student at Sonoma State University majoring in history and liberal arts. She lives with her parents in Marin county. In the fall she will be moving to Japan to study Japanese language and work towards a history major with concentration in Asian studies.
In her free time she pursues photography and spends time with her friends. She also enjoys video games as a hobby. She is excited to get experience working with historical documents and archives management systems to help her in the future with her history major.
For the first time we are working with the Children's Hospital Oakland Research Institute (CHORI) Summer Research Program. "This program is designed to provide an opportunity for High School and Undergraduate students to immerse themselves in the world of basic and/or clinical research for three months during the summer. The program pairs students with one or two CHORI principal investigators who serve as mentors, guiding the students through the design and testing of their own hypotheses and methodology development. At the end of the summer, students present their research to their peers just as any professional researcher would do." Our CHORI intern, Laura Schafer is co-mentored by Drs. Aimee Medeiros and Brian Dolan from the UCSF Department of Anthropology, History, and Social Medicine and Polina Ilieva, Head of Archives & Special Collections.
As an undergrad senior student of Psychology and more recently also Pedagogy at UC Berkeley, Laura Schafer is deeply interested in research fields related to pediatrics and healthcare associated to socioeconomic status (SES) factors. She believes that having grown up experiencing the consequences of Brazil's developing societal reality while having juvenile diabetes plays a significant influence on what has developed into the focus of her academic career by far. She is mostly concerned with the consequences of low socioeconomic status (SES) factors potentially interfering with treatment affordability and proper healthcare practices for chronically ill children's mental, emotional. and physical health.
Although Laura has had the chance to acquire some fundamental research-enabling skills through involvement as an RA at the UC Berkeley Emotion and Social Interaction Laboratory and also from participating in an honors' thesis developing program through her University's department of pedagogy, Laura seeks further training and mentoring in the principles underlying conducts of research through her internship at UCSF. She is very enthusiastic about the opportunity to work with the UCSF mentors. The project Laura is involved with during her internship this summer aims to assist with the digitization and creation of metadata for the historical patient data from the 1920's to 1960's which includes pediatric records.
Customize Your CLE Course With Course Formats
The CLE is used across UCSF for Medicine, Dentistry, Nursing, and Pharmacy education and much more. Each school and department has their own unique needs, and faculty can choose from a number of course formats to customize the layout of their CLE course to best meet these needs.
If you have used the CLE, you are likely familiar with the Topics course format, the default in CLE courses. While the Topics format and the other five course formats are awesome, we want to take this opportunity to highlight one of our favorites – the Collapsed Topics course format.
You may have read about the Collapsed Topics course format in the CLE Improvements for Fall 2015 blog post. We have been busy getting to know the new course formats and documenting use cases, best practices, and instructions for using each.
Let's take a closer look at the Collapsed Topics course format:Description
Streamline the look of your course! The Collapsed Topics course format helps organize your CLE course and eliminate the "scroll of death." With this course format, course content is tucked away within individual topics. Topics can be expanded and collapsed with a single click. Topics will remain expanded or collapsed on a per course, per student basis.
Use Case
The Collapsed Topics course format is great for any academic or collaboration CLE course with a large number of resources and activities.Instructions
To apply the Collapsed Topics course format to your CLE course:
- Navigate to the CLE course (you will need to have an editing role in the course to change course formats)
- From the Administration block, click Edit Settings
- Scroll down and expand the Course Format section
- From the Format drop-down menu, select Collapsed Topics
- Scroll to the bottom of the page and click the Save Changes button
The Collapsed Topics course format will now be used in your course. You can always change the course format by returning to the Edit Settings page in the course and selecting another format.Get Help
Take time to review your course and the newly applied course format. Return to the Edit Settings page to continue to customize course format settings to better meet your needs.
For detailed instructions on customizing the format, click the Collapsed Topics tab in the Course Formats document located in the Learning Tech Support Center.
Have questions about using the Collapsed Topics or any of the five other course formats in your CLE course? Attend a Tech Clinic at the UCSF Library, contact a Learning Tech Specialist, or leave a comment below!
43 Million off-label prescriptions of Neurontin due to...
43 Million off-label prescriptions of Neurontin due to Parke-Davis' promotional activities
Ever wonder if physicians' prescribing practices are swayed by pharmaceutical companies and their promotions? Read the 2008 'Declaration of Meredith Rosenthal', Associate Professor of Health Economics and Policy at Harvard School of Public Health, found in our UCSF Drug Industry Documents archive collection: Neurontin Marketing and Sales Practices Litigation
Rosenthal: "Using standard econometric methods, I establish that Parke-Davis' challenged promotional efforts had a significant impact on the prescribing of Neurontin for off-label uses and at dosages higher than those recommended in the FDA-approved label…In total, I find that there were 43 million off-label prescriptions…of Neurontin as a result of the…promotional activities related to the off-label uses at issue in this case that would not have occurred absent the challenged conduct.
URL : https://www.industrydocumentslibrary.ucsf.edu/drug/docs/mpgw0217
Author : Rosenthal, Meredith
Document Date : 2008 August 11
Digitizing the UCSF Black Caucus Records
This is a guest post by Jessica Jones, former UCSF Archives & Special Collections Intern.
As an intern for the UCSF Library, Archives and Special Collections, I have worked on many different projects that utilize my skills as a professional administrative assistant, including the State Medical Journals Digitization Project, a collection survey, rehousing and inventorying the portrait photograph collection, and more. I also attended Library Updates meetings and listened to presentations about changes within libraries. Although this was a very new experience to me I adapted very quickly and I am proud to say I have learned so much and have enjoyed my time here with UCSF.
I would like to share a bit more about my most recent project working with the Black Caucus records. I really found this project to be interesting; I researched, digitized, and uploaded material from the collection to the digital asset management system and assisted in creating original metadata to facilitate discovery of these items. You can now access the UCSF Black Caucus Records digital collection on Calisphere.
The Black Caucus was first established on the UCSF campus in May 1968 in the wake of the assassination of Dr. Martin Luther King, Jr. This organization worked to provide more job opportunities for qualified minority applicants and lobbied for more minority students in all four professional schools. The organization engaged in many civil rights initiatives and social justice projects, like supporting custodial and technical staff in labor disputes and campaigning for more diverse hiring at all levels of the university. Beginning in the 1970s, the group shared personal stories, event updates, and project achievements in a newsletter named the Black Bulletin. There were many notable UCSF figures that helped found and lead the Black Caucus. For instance, UCSF Medal winner Joanne Lewis served as one of the organization's first chairpersons and organized the publication of the Black Bulletin.
The Black Caucus records help to demonstrate that African Americans have contributed remarkable achievements in the fields of science and medicine during the 20th century. To encourage future researchers and clinicians of color I think that it is essential for boys and girls to be given the academic tools to succeed in science and medicine, preferably long before college. There are several programs that help facilitate this, such as the White House initiative "My Brother's Keeper" that helps young people reach their full potential. Medical schools should also continue to sponsor pipeline programs to encourage minority students to consider careers in medicine.
I am very proud and excited to be a part of this amazing project. The Black Caucus has helped support and encourage people of color at UCSF through advocacy and community. The organization's message of equality shows how important it is to have a diverse population of practitioners to address healthcare needs and to eliminate racial and ethnic disparities in healthcare.
600+ New Tobacco Documents Posted
We have added 604 new documents to the Truth Tobacco Industry Documents today.
This brings our total document holdings to 88,281,975 pages in 14,618,860 documents!
Article Spotlight: Implications of Tobacco Industry Research on Packaging Colors for Designing Health Warning Labels
Every month, we highlight a newly published article along with a few key industry documents used by the author(s):
Lempert LK, Glantz SA. Implications of Tobacco Industry Research on Packaging Colors for Designing Health Warning Labels. Nicotine Tobacco Research. 2016 May 4.
Tobacco companies conducted research to understand how pack colors affect consumers' perceptions of the products and make packages and their labeling more visually prominent. The companies found that black is visually prominent and black text on a white background is more prominent than white text on a black background. Yellow most quickly and effectively seizes and holds consumers' attention and signals warning or danger, while white connotes health and safety. In essence, using black text on a bright contrasting background color, particularly yellow, attracts consumers' attention to the message.
Using the tobacco companies' own internal research on improving the prominence of pack elements, advocates designing HWLs could consider using black lettering on a contrasting yellow background as this would most effectively seize and hold consumers' attention and signal the danger of cigarettes and other tobacco products.
Key Documents from the UCSF Truth Tobacco Industry Documents:
A Description of a Computer Aided Graphics System for Pack Design (1985)
The cigarette pack itself becomes more important due to advertising restrictions – the pack is often "the only means of communicating with the consumer"
- Color Documentation for Doral Packaging Colors (2001)
Companies' research showed that some colors (red and black) are more visible and prominent than others (gray), make information more memorable, and appear to advance and make one pack look larger and more visible than neighboring packs. "Yellow is the fastest color your eye sees…and is the best color to use to draw attention"
- Principles of Measurement of Visual Standout in Pack Design: Report No RD 2039 (1986)
A 1986 BAT research and development report on pack design found that "white is generally held to convey a clean, healthy association"
Packaging (1987)
RJ Reynolds document notes color and other visual cues are selected for communication of consumer expections: i.e. Reds = Flavor/strength and "White communicates Lightness…"
Internet Archive Partners Lunch
Friday the 13th of May was the auspicious date of our visit to one of our partner organizations, the Internet Archive, just across Golden Gate Park in the Richmond District. The Internet Archive is a non-profit digital library of millions of freely accessible books, movies, software, music, websites and more. Internet Archive graciously hosts a bi-weekly Partners Lunch, inviting anyone working in partnership with IA to tour the facility (a gorgeous re-purposed Christian Science church), meet staff in person, and participate in a lunchtime roundtable where IA folks and visitors share their projects' progress, successes and failures. The whole UCSF Archives team, plus UCSF collections staff members Beatrice Mallek and David MacFarland, were in attendance.
We met with our IA liason Jesse Bell, who gave us a look into the progress of some of our projects ongoing at Internet Archive. Here Eliza Zhuang is using a specially designed scanning booth to digitize volumes of bound medical journals for the State Medical Journal project. The "scanner" actually uses two conventional DSLR cameras to simultaneously photograph the pages of the book, optimally positioned by the pedal-operated V-shaped glass plate shown here.
After photography, the images undergo QA and metadata association before being uploaded to the Internet Archive, where they look like this.
IA's lobby provides plenty of excitement. A prominently displayed monitor shows the digitization currently underway on a number of different systems. Below, David Uhlich watches as pages from the book scanner are photographed. Immediately behind the monitor is a film scanner that similarly feeds the live-view monitor. The lobby also houses a beautiful antique gramophone near a small listening station that includes an iPad loaded with digitized music and other recorded sound.
After lunch, we took a more in depth tour of IA's facility. We saw an example of IA's specially designed "portable" book scanner, which is basically a scaled-down version of the one used by IA staff. Approximately $10,000 will get you your own book scanning station, software, and support from IA for your own scanning projects. We also looked inside the refurbished church that, in addition to the pews, now houses some of IA's servers and digitization equipment.
Sculptures of miniature people inhabit the aisles. Long-term IA staff are thanked for their service with a sculpture of their likeness; many depicted holding an item that reflects their interests or passions.
It was great to meet the IA team in person. Our partnership with IA continues to provide new opportunities to preserve and make accessible our material. We look forward to exciting projects in the future!
Groups and Groupings: What's the difference?
The CLE makes it possible for you to develop online group work in your courses with Groups and Groupings features. Although they sound very similar, they have different functions. It can be a little confusing until you understand how they both work.
A Group is a collection of one or more individual users. Groups enable instructors to split the students into sub-sets to view resources or work on an activity together.
A Grouping is a collection of groups that can be used to break up the class in to different sets of groups of students. Groupings can be applied to restrict access to an activity, resource, or topic.
We recently updated information and created videos about Groups and Groupings to help you understand how to use them and how to apply these features to your course.
Are you interested in developing a collaborative student assignment? Would you like to make resources in your course visible to one group and hide them from another? Take a look at the videos below to learn about using and applying Groups and Groupings to your course.
Have additional questions? Visit the Learning Tech Support Center to view detailed instructions for using both Groups and Groupings or contact a Learning Tech Specialist today!


text:
Chapter 22. An Overview of Continuous Electric Kilns
- John B. Wachtman Jr.
Published Online: 26 MAR 2008
DOI: 10.1002/9780470313107.ch22
Copyright © 1990 The American Ceramic Society, Inc.
Book Title
Ceramic Manufacturing Council - Kilns and Firing: Ceramic Engineering and Science Proceedings, Volume 11, Issue 11/12
Additional Information
How to Cite
O'Brien, D. A. (1990) An Overview of Continuous Electric Kilns, in Ceramic Manufacturing Council - Kilns and Firing: Ceramic Engineering and Science Proceedings, Volume 11, Issue 11/12 (ed J. B. Wachtman), John Wiley & Sons, Inc., Hoboken, NJ, USA. doi: 10.1002/9780470313107.ch22
Publication History
- Published Online: 26 MAR 2008
- Published Print: 1 JAN 1990
Book Series:
ISBN Information
Print ISBN: 9780470374962
Online ISBN: 9780470313107
- Summary
- Chapter
- continuous electric kilns;
- materials characterization;
Selection of the proper electric kiln for a ceramic firing process entails more than just selecting the least expensive supplier. Understanding the process allows the user to select the correct kiln for the job at hand. Understanding kiln design and construction allows the user to select the best kiln for the process.
I have outlined critical areas of concern to the user and supplier if an intelligent kiln selection is to be made. A better perspective of various parameters associated with the ceramic firing process and their interaction with kiln design will assist any user. Many of these parameters affect not only continuous electric kiln selection, but any kiln selection.