By N. Samuel. University of Wisconsin-River Falls.

This leads to an optimized zolpidem 10mg without prescription, temporally efficient MRI neurologic examination that cap- Amyotrophic Lateral Sclerosis tures the salient features of the structural discount 10mg zolpidem with visa, metabolic order 10mg zolpidem free shipping, and In amyotrophic lateral sclerosis (ALS) 10mg zolpidem otc, as degeneration of functional states as they change over time. Monitoring these the upper motor neuron occurs, a progressive damage to the manifestations enables us to elucidate the neurobiological corticospinal tract has been documented in the caudorostral underpinnings of normal brain development and aging in direction (42–45). We used DTI in two patients (cases 1 addition to the endpoints of etiology, natural history, and and 2) to document pronounced bilateral reduction in the therapeutic intervention in disease states (47). The ALS case size of the corticospinal tract at the level of the medulla 1 is an example of this application. Case 1 illustrates an integrated MRI examination this technique to assess the changes in both motor cortical of structure, function, and metabolism. We successfully per- ventional MR images or in the T2-EP images at its ventral formed fMRI in this same patient (Fig. The data indicated larger areas of activa- niques do not allowan accurate definition of the borders tion in the left than in the right hemisphere and reflected of the tract. With the aid of tractographic DTI, the cortico- the motor asymmetry of this patient. The pattern of activa- spinal tract is readily visualized as it courses rostrocaudally. Frac- degenerative conditions, such as Parkinson disease (48,49) tional and lattice anisotropy indices were measured in a and stroke (50–52). In this case, in CONCLUSION addition to DTI, we collected single-voxel MRS measure- ments in medulla, and the data indicated metabolic An understanding of the human cerebral white matter, spe- changes—loss of NAA (N acetylaspartate) and possibly cifically its fiber pathways, is needed. Historically, this ob- elevated glutamate/glutamine (glx), shown in Fig. The advancement of neuroimaging technology with is that the observed metabolic pattern showed a slightly such techniques as DTI has made it possible to study human decreased NAA/Cr (creatine) ratio in the left motor cortex white matter fiber pathways in vivo, and therefore in clinical in comparison with the contralateral counterpart. The DTI method opens up a newapproach, fMRI was acquired while flexion was performed (frequency tractography, for studying the various white matter fiber of 1. An expanded pathways that are particularly involved in normal cognitive 366 Neuropsychopharmacology: The Fifth Generation of Progress Chapter 27: Diffusion Tensor Imaging 367 A B FIGURE 27. Three-dimensional (3D) reconstruction of fiber tracts within the three-dimen- sionally rendered brain of a normal young adult. A: A combined 3D representation of the cingulum bundle (green) and the corpus callosum (red). B: A composite 3D rendition of the corticospinal projection (blue) and the corpus callosum (red). Red indicates medial–lateral, blue superior–infe- rior, and green anterior–posterior orientation, respectively. In neurologic examination would allow us to monitor the evo- addition, this imaging technique may allow a better under- lution of a pathologic condition and thus elucidate the end- standing of the state of white matter pathways during devel- points of etiology, natural history, and therapeutic interven- opment, aging, and recovery following brain damage. Three-dimensional reconstruction of stems of individual pathways of a living nor- mal young adult human subject. Red indicates medial–lat- eral, blue indicates superior–inferior, and green indicates anterior–posterior orientation, respec- tively, as shown in the color-coded sphere in the center of the figure. For this caption, three representative fiber tracts were selected based on class of pathway provenience and orientation. The corpus callosum, a commissural tract with general mediolateral orientation, is shown in supe- rior and lateral views. Specifically, its genu, body, and splenium are colored in red because they run mediolaterally, whereas its anterior (forceps minor) and posterior (forceps major) forcipes are colored in green because they are oriented anteroposteriorly. The corticospinal tract, a projec- tional pathway with superior–inferior orientation, is depicted in blue in a frontal view. Finally, the cingulum bundle, a long, associational corticocortical fiber tract with anterior–posterior orien- tation, is colored green above the body of the corpus callosum for its major trajectory, whereas it is colored blue along its vertically oriented portions in front of the genu and behind the splenium of the corpus callosum. Comparison of diffusion tensor imaging in the brainstem (medulla oblongata) of a normal control (D,F) and two patients with amyotrophic lateral sclerosis, ALS case 1 (A–C) and ALS case 2 (E,G). A T2 echo-planar image (T2-EPI) and tensor orientation map (TOM) are included at each level. In this image, green voxels indicate anteroposteriorly, red indicate mediolaterally, and blue indicate superoinferiorly oriented diffusion directions. H: Four magnetic resonance spec- tra from an ALS patient (case 1). The spectra in the top row come from a point resolved spectros- copy sequence (PRESS) with TR (repetition time)/TE (echo time) 2,000/144 ms in either left motor cortex (hand area), right motor cortex (hand area), or occipital cortex. The occipital cortex serves as a control region that is essentially unaffected by ALS. A slight asymmetry in the NAA/Cr and glx/Cr values between left and right motor cortex perhaps reflects the large motor asymmetry in this patient.

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To branch and elongate 10 mg zolpidem with visa, the ureteric bud must digest its way through its own basement membrane generic zolpidem 10mg amex, a highly complicated complex of extracellular matrix pro- teins generic 10mg zolpidem overnight delivery. It is believed that this is accomplished by cellular projections discount 10mg zolpidem with amex, “invadopodia,” which allow for localized sites of proteolytic activity at their tips [77-81]. S-shaped body The metanephric mesenchyme not only induces ureteric bud branching but is also induced by the C ureteric bud to epithelialize and differentiate into the proximal through distal tubule [74–76]. Flow chart indicates relevance of in vitro m odels of kidney epithelial cell branching Basic research Applied research tubulogenesis to basic and applied areas of kidney research. W hile results from such studies provide critical insight into kidney devel- opm ent, this m odel system m ight also contribute to the elucidation Renal development Renal diseases of m echanism s involved in kidney injury and repair for a num ber of diseases, including tubular epithelial cell regeneration secondary Renal injury and repair to acute renal failure. M oreover, these m odels of branching tubulo- genesis could lead to therapies that utilize tubular engineering as Renal cystic diseases artificial renal replacem ent therapy. Urogenital abnormalities Hypertension Artificial kidneys 16. Schem atic representation of Cell proliferation M itogenesis the pleiotrophic effects of growth factors, which share several properties and are believed to be im portant in the developm ent and m orphogenesis of organs and tissues, such as those of the kidney. Cell movement Am ong these properties are the ability to regulate or activate M otogenesis num erous cellular signaling responses, including proliferation (m itogenesis), m otility (m otogenesis), and differentiation (m orpho- Growth Cell organization genesis). These characteristics allow growth factors to play critical M orphogenesis roles in a num ber of com plex biological functions, including factor em bryogenesis, angiogenesis, tissue regeneration, and m alignant Cell survival transform ation. Antiapoptosis D D Remodeling of cell substratum A B C D FIGURE 16-17 M otogenic effect of growth factors— hepatocyte growth factor type of cultured renal epithelial cell with H GF induced the dissoci- (H GF) induces cell “scattering. This phenom enon is tion the recruitm ent of cells to areas of new growth is vital. H GF was originally identified as scatter Growth factors have the ability to induce cell m ovem ent. H ere, factor, based on its ability to induce the scattering of M DCK cells subconfluent m onolayers of either M adin-Darby canine kidney. N ow, it is known that H GF and its receptor, the transm em - (M DCK) C, D, or m urine inner m edullary collecting duct brane tyrosine kinase c-m et, play im portant roles in developm ent, (m IM CD) A, B, cells were grown for 24 hours in the absence, regeneration, and carcinogenesis. Analyzing Growth the role of single factors (ie, extracellular m atrix, growth factors, factors cell-signaling processes) involved in ureteric bud branching tubulo- genesis in the context of the developing em bryonic kidney is an extrem ely daunting task, but a num ber of m odel system s have been devised that allow for such investigation [77, 79, 85]. The sim plest m odel exploits the ability of isolated kidney epithelial cells sus- pended in gels com posed of extracellular m atrix proteins to form branching tubular structures in response to growth factors. For exam ple, M adin-Darby canine kidney (M DCK) cells suspended in gels of type I collagen undergo branching tubulogenesis rem iniscent of ureteric bud branching m orphogenesis in vivo [77, 79]. Although the results obtained from such studies in vitro m ight not correlate directly with events in vivo, this sim ple, straightforward system allows one to easily m anipulate individual com ponents (eg, growth factors, extracellular m atrix com ponents) involved in the FIGURE 16-18 generation of branching epithelial tubules and has provided crucial Three-dim ensional extracellular m atrix gel tubulogenesis m odel. Em bryonic kidneys (EK) induced the form ation of branching tubular structures in both m IM CD and M DCK cells after 48 hours of incubation at 37oC. EKs produce a num ber of growth factors, including hepatocyte growth factor, transform ing growth factor-alpha, insulin-like growth factor, and transform ing growth factor– , which have been shown to effect tubulo- A B genic activity [86–93]. Interestingly, m any of these sam e growth factors have been FIGURE 16-19 shown to be effective in the recovery of An exam ple of the branching tubulogenesis of renal epithelial cells cultured in three- renal function after acute ischem ic insult dim ensional extracellular m atrix gels. Flow chart of the establishm ent of ureteric bud and m etanephric m es- enchym al cell lines from day 11. Although the results obtained from the analysis of kidney epithelial cells— Pregnant SV40–transgenic mouse M adin-Darby canine kidney (M DCK) or m urine inner m edullary collecting duct (m IM CD) seeded in three-dim ensional extracellular m atrix gels has been invaluable in furthering our understanding of Isolate embryos the m echanism s of epithelial cell branching tubulogenesis, ques- tions can be raised about the applicability to em bryonic develop- Dissect out embryonic kidney m ent of results using cells derived from term inally differentiated adult kidney epithelial cells. Therefore, kidney epithelial cell lines have been established that appear to be derived from the Isolate metanephric mesenchyme Isolate ureteric bud ureteric bud and m etanephric m esenchym e of the developing em bryonic kidney of SV-40 transgenic m ice [94, 95]. These m ice have been used to establish a variety of “im m ortal” cell lines. A, UB cells grown for 1 week in the presence of condi- ureteric bud (UB) and m etanephric m esenchym e from day 11. B, After three-dim ensional extracellular m atrix gels. C, Interestingly, “conditioned” m edia collected from the culture of m etanephric after 2 weeks of culture in a three-dim ensional gel com posed m esenchym al cells. During norm al kidney m orphogenesis, these entirely of growth factor–reduced M atrigel, ureteric bud cells have two em bryonic cell types undergo a m utually inductive process not form ed cords or tubules, only m ulticellular cysts. Thus, chang- that ultim ately leads to the form ation of functional nephrons ing the m atrix com position can alter the m orphology from tubules [74–76]. This m odel system illustrates this process, ureteric bud to cysts, indicating that this m odel m ight also be relevant to renal cells being induced by factors secreted from m etanephric m es- cystic disease, m uch of which is of developm ental origin. Thus, this system could represent the sim plest in Sakurai et al. Proposed m odel for the gener- FIGURE 16-22 alized response of epithelial cells to growth factors, which the Signalling pathway of hepatocyte growth factor action. Epithelial cells constantly m onitor the proposed intracellular signaling pathway involved in hepatocyte their surrounding environm ent via extracellular receptors (ie, inte- growth factor (HGF)–mediated tubulogenesis. Although HGF is per- grin receptors) and respond accordingly to growth factor stim ula- haps the best-characterized of the growth factors involved in epithe- tion.

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