By J. Reto. Gordon College. 2019.

External root sheath is lined with skin surface epidermis with a granular layer (hematoxylin and eosin stain buy 2.5 mg tadalafil fast delivery, 400x) purchase 5mg tadalafil with amex. Trichilemmal keratin lines the upper isthmus extending to the level of entry of the sebaceous duct at the base of the infundibulum (Fig cheap tadalafil 20 mg with amex. The bulge area is located in the inferior portion of the isthmus near the insertion of the arrector pili muscle purchase 5mg tadalafil with mastercard. The bulge contains stem cells that are slow cycling and when activated gives rise to transit amplifying cells that can differentiate into hair follicle (15). Hair Bulb The follicular root consists of the hair bulb, which is found in the deepest portion of the hair follicle and surrounds the dermal papilla (Figs. The bulb contains undifferentiated, actively dividing hair matrix cells that extend to the widest diameter of the hair bulb known as the critical line of Auber. Hair matrix cells around this central area produce elongated cortical cells, which stream upward to form the developing hair shaft. Higher up in the keratogenous zone, these cells become compacted into hard keratin. The outer fringe of matrix cells forms the hair cuticle and the surrounding inner root sheath. The hair cuticle invests the hair ber with six to ten overlapping layers of cuticle cells. The volume of the dermal papilla cells dictates the size of the hair shaft and induces formation of hair follicle (24). Next is the outer root sheath, followed by the inner root sheath comprising Henle s layer, Huxley s layer and the cuticle of the inner root sheath. The central developing hair shaft is largely comprised of hair cortex invested by its cuticle and surrounding the medulla. Outer Root Sheath The outer root sheath, or trichilemma, has no granular layer and is glycogen rich, accounting for the pale cytoplasm. It appears at the base of the bulb as a thin lining becoming thicker as it extends upward to the level of the isthmus where it shows trichilemmal keratinization (Figs. The outer root sheath is covered by the hyaline or vitreous membrane, which is continuous with epidermal basement membrane surrounding the dermal papilla. Folds or corrugations of the hyaline membrane are sometimes seen projecting into the underlying trichilemmal layer. The hyaline membrane is surrounded by the brous dermal sheath of the hair follicle, which is continuous with the dermal papilla at the base of the hair bulb. Inner Root Sheath The inner root sheath starts from mid-isthmus extending to the base of the bulb. It expands and thickens as it continues upward (left) and is replaced at the level of the isthmus where it shows trichilemmel keratinization (right). Henle s layer keratinizes rst with the appearance of trichohya- line granules near the hair bulb, forming a distinct pinkish keratinized band higher up from the bulb (Fig. The cuticle of the inner root sheath is the next to keratinize, synchronizing with keratinization of the cuticle of the hair shaft (Fig. Finally, trichohyaline granules appear in Huxley s layer, signaling impending keratinization (Fig. Keratinization of the inner root sheath is completed halfway up the lower follicle. The keratinized inner root sheath occupies the upper half of the lower follicle (Fig. The inner root sheath is surrounded by one or more layers of cells of the outer root sheath or trichilemma. The potential space between inner and outer root sheaths is named the companion layer and it allows the inner root sheath to slide upward over the outer root sheath during hair growth. Hair Shaft The hair shaft consists of the cuticle, cortex, and medulla (present in terminal hairs) (Fig. The hair ber cortex is cylindrical and consists of keratin laments embedded in a sulfur-rich matrix, enclosing the medulla and surrounded by the cuticle of the hair shaft. Henle s layer, the outermost of the three layers of the inner root sheath, is beginning to keratinize (hematoxylin and eosin stain, original magnication 200x). The hair shaft is generated by transit amplifying matrix cells in the hair bulb, which surround the dermal papilla. The hair ber diameter remains uniform during a single growth phase under normal conditions. Hair shaft and inner root sheath cuticles interlock to stabilize the growing hair and to ensure that the inner root sheath and hair shaft grow upward together. A comparative electron microscopic analysis of the cuticular structures of Asian and white hair revealed Asian hair has more cuticlar layers that are thicker and more densely packed than white hair. This may account for susceptibility of white hair to damage during daily grooming (23). Follicular Units Horizontal sections at the sebaceous duct level show follicular units. Follicular units are roughly hexagonal in shape and are surrounded by a loose network of collagen; they contain several termi- nal and vellus follicles with sebaceous ducts and glands and arector pili muscles (Figs. In adults, the mean area of a follicular unit is 1 mm2; thus 12 to 14 follicular units are usually found in a horizontal section of a 4 mm punch biopsy, which has an actual area of 12. Terminal Anagen Hair Anagen involves the complete regrowth or regeneration of the lower, cycling portion of the fol- licle. Anagen hair formation begins with the activation of a cluster of epithelial cells present at the outer root sheath keratinocytes of a telogen hair follicle called secondary hair germ (telogen germinal unit), which gives rise to the matrical cells. An exchange of molecular signals causes the secondary germ along with the dermal papilla to migrate downward into the dermis. These represent follicular grouping at the skin surface (hematoxylin and eosin stain, original magnication 40x). Hair Follicle Anatomy in Human Scalp Biopsies 55 dermal papilla signals the matrical cells to actively proliferate and grow in an upward direction differentiating into the internal root sheath and hair shaft. The terminal anagen hair follicle penetrates deep into the dermis extending into the subcutaneous tissue. Terminal Catagen Hair When anagen ends, hair goes into catagen, the intermediate transition stage between growth and rest, for 10 to 14 days. This process involves regression of the lower cycling portion of the hair follicle via apoptosis. The catagen stage begins with the lower hair follicle and the dermal papilla retracting upward, leav- ing behind a collapsed perifollicluar sheath which forms into an angiobrotic streamer or stela, linking the follicle to the site of the former anagen bulb. The hair shaft and inner root sheath slide upward together inside the outer root sheath, leaving an elongated mass of trichilemmal outer root sheath below. Apoptosis of trichilemmal cells produces a marked shrinkage of the outer root sheath. Thickening and wrinkling of the surrounding hyaline layer occurs with this shrinkage of trichilemma (Figs.

The terminal hair follicle penetrates deep into the dermis extending into the subcu- taneous tissue purchase tadalafil 2.5mg. In the vertical plane of section the terminal hair follicle consists of a permanent upper segment of follicular infundibulum and isthmus discount tadalafil 5 mg, and an impermanent lower segment of the hair follicle consisting of the lower follicle and root (bulb) (Fig buy tadalafil 2.5 mg lowest price. Infundibulum The infundibulum opens from the epidermal surface and ends at the entry of the sebaceous duct into the hair follicle tadalafil 2.5mg sale. The infundibulum is lined with a keratinized skin surface epithelium that contains a granular layer and basket weave keratin (Fig. Hence proliferation of the infundibulum gives rise to the epidermoid inclusion cyst (folliculo-infundibular cyst). The hair shaft is contained within the infundibulum and has no attachment to the isthmus or the infun- dibulum, allowing freedom of movement. Isthmus The isthmus extends down from the opening of the sebaceous duct and ends at the bulge where the arrector pili muscle inserts into the follicle. It is lined by the trichilemmal keratin that is characterized by an eosinophilic compact keratin material, devoid of a granular layer. The inner root sheath crumbles and disappears in the mid-isthmus of the upper follicle (Fig. There it is replaced by trichilemmal keratin formed by the outer root sheath or trichilemma. The hair follicle consists of infundibulum that ends at the sebaceous duct, an isthmus ending at the insertion of the arrector pili muscle, and lower follicle and hair root (bulb). The dilating follicular opening is surrounded by external root sheath lined by skin surface epidermis with granular layer and basket weave keratin (hematoxylin and eosin stain, 200x). External root sheath is lined with skin surface epidermis with a granular layer (hematoxylin and eosin stain, 400x). Trichilemmal keratin lines the upper isthmus extending to the level of entry of the sebaceous duct at the base of the infundibulum (Fig. The bulge area is located in the inferior portion of the isthmus near the insertion of the arrector pili muscle. The bulge contains stem cells that are slow cycling and when activated gives rise to transit amplifying cells that can differentiate into hair follicle (15). Hair Bulb The follicular root consists of the hair bulb, which is found in the deepest portion of the hair follicle and surrounds the dermal papilla (Figs. The bulb contains undifferentiated, actively dividing hair matrix cells that extend to the widest diameter of the hair bulb known as the critical line of Auber. Hair matrix cells around this central area produce elongated cortical cells, which stream upward to form the developing hair shaft. Higher up in the keratogenous zone, these cells become compacted into hard keratin. The outer fringe of matrix cells forms the hair cuticle and the surrounding inner root sheath. The hair cuticle invests the hair ber with six to ten overlapping layers of cuticle cells. The volume of the dermal papilla cells dictates the size of the hair shaft and induces formation of hair follicle (24). Next is the outer root sheath, followed by the inner root sheath comprising Henle s layer, Huxley s layer and the cuticle of the inner root sheath. The central developing hair shaft is largely comprised of hair cortex invested by its cuticle and surrounding the medulla. Outer Root Sheath The outer root sheath, or trichilemma, has no granular layer and is glycogen rich, accounting for the pale cytoplasm. It appears at the base of the bulb as a thin lining becoming thicker as it extends upward to the level of the isthmus where it shows trichilemmal keratinization (Figs. The outer root sheath is covered by the hyaline or vitreous membrane, which is continuous with epidermal basement membrane surrounding the dermal papilla. Folds or corrugations of the hyaline membrane are sometimes seen projecting into the underlying trichilemmal layer. The hyaline membrane is surrounded by the brous dermal sheath of the hair follicle, which is continuous with the dermal papilla at the base of the hair bulb. Inner Root Sheath The inner root sheath starts from mid-isthmus extending to the base of the bulb. It expands and thickens as it continues upward (left) and is replaced at the level of the isthmus where it shows trichilemmel keratinization (right). Henle s layer keratinizes rst with the appearance of trichohya- line granules near the hair bulb, forming a distinct pinkish keratinized band higher up from the bulb (Fig. The cuticle of the inner root sheath is the next to keratinize, synchronizing with keratinization of the cuticle of the hair shaft (Fig. Finally, trichohyaline granules appear in Huxley s layer, signaling impending keratinization (Fig. Keratinization of the inner root sheath is completed halfway up the lower follicle. The keratinized inner root sheath occupies the upper half of the lower follicle (Fig. The inner root sheath is surrounded by one or more layers of cells of the outer root sheath or trichilemma. The potential space between inner and outer root sheaths is named the companion layer and it allows the inner root sheath to slide upward over the outer root sheath during hair growth. Hair Shaft The hair shaft consists of the cuticle, cortex, and medulla (present in terminal hairs) (Fig. The hair ber cortex is cylindrical and consists of keratin laments embedded in a sulfur-rich matrix, enclosing the medulla and surrounded by the cuticle of the hair shaft. Henle s layer, the outermost of the three layers of the inner root sheath, is beginning to keratinize (hematoxylin and eosin stain, original magnication 200x). The hair shaft is generated by transit amplifying matrix cells in the hair bulb, which surround the dermal papilla. The hair ber diameter remains uniform during a single growth phase under normal conditions. Hair shaft and inner root sheath cuticles interlock to stabilize the growing hair and to ensure that the inner root sheath and hair shaft grow upward together. A comparative electron microscopic analysis of the cuticular structures of Asian and white hair revealed Asian hair has more cuticlar layers that are thicker and more densely packed than white hair. This may account for susceptibility of white hair to damage during daily grooming (23). Follicular Units Horizontal sections at the sebaceous duct level show follicular units. Follicular units are roughly hexagonal in shape and are surrounded by a loose network of collagen; they contain several termi- nal and vellus follicles with sebaceous ducts and glands and arector pili muscles (Figs. In adults, the mean area of a follicular unit is 1 mm2; thus 12 to 14 follicular units are usually found in a horizontal section of a 4 mm punch biopsy, which has an actual area of 12. Terminal Anagen Hair Anagen involves the complete regrowth or regeneration of the lower, cycling portion of the fol- licle. Anagen hair formation begins with the activation of a cluster of epithelial cells present at the outer root sheath keratinocytes of a telogen hair follicle called secondary hair germ (telogen germinal unit), which gives rise to the matrical cells.

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However buy 5 mg tadalafil overnight delivery, results from various clinical trials proved to be contradictory order 20mg tadalafil overnight delivery, perhaps due to differences in trial design discount tadalafil 5mg overnight delivery. Other confounding factors include hetero- geneity of the patient population and the difculties inherent in teasing out symp- tomatic versus drug-mediated effects buy tadalafil 5mg visa. As with gene therapy, several clinical trials using cellular transplantation have been undertaken, as early as the 1980 s. Study results have been variable, but more detailed placebo-controlled double-blind trials (versus open-labeled) gener- ally report lack of signicant overall improvement in motor function and the induc- tion of drug-related side effects such as dyskinesia. However, excitement has been somewhat tempered based on evidence suggesting that transplanted cells have limited success in clinical trials and may actually take on the same fate as affected endogenous neurons [28]. More studies are undoubtedly required before moving such studies towards new clinical trials, including how to deal with reduced transplant efciency in the older brain. In other words, not only do we need to consider the cells themselves, but also the envi- ronment into which they are placed. These vary from individual to individual, which may to some degree help explain disparate disease presentation. Advanced age is certainly directly linked to a more rapid disease progression and older indi- viduals are more refractory to medical treatments for the disorder, suggesting that there is an important interplay between the two [67 ]. Identication of these molecular targets has led to exploration of interven- tions designed to prevent or reverse their detrimental effects as a means of slowing or reversing the course of the disease. These have been helpful in the segmental dissection of different aspects of disease pathology, including the role of mitochondrial defects in neuropathological features associated with the disease [73 ]. However, use of agents that act to increase mitochondrial biogenesis will need to be balanced with those which increase lysosomal turnover of defective mitochondria so as to not increase the build-up of the latter. Enhancement of ssion-fusion events in early stages of the disease may also be effective in repairing damaged mitochondria. However, as levels of damaged mitochondria increase, these pro- cesses lose their effectiveness and are replaced by removal of dysfunctional mito- chondrial via lysosomal degradation. A recent clinical trial using mitochondrially targeted CoQ10 (MitoQ) also failed to demonstrate slowing of clinical progression of the disease [83]. Losses in mito- chondrial function can affect the ability of the organelle to sequester calcium and this in turn can result in the generation of mitochondrial-mediated oxidative stress and subsequent damage to the organelle that can further affect its function [85 ]. In addition, preclinical studies in various animal models strongly suggest the involvement of inflammatory processes in associated neuronal cell death [95]. Neuroinflammatory processes may contribute to deleterious events lead- ing to neuronal degeneration. Possible factors involved in neuroprotection may include inhibition of cyclooxygenase 2 and reduced production of prostaglandins [100, 101]. Neuroinflammatory processes represent an attractive therapeutic target for slowing progression of the disorder. During aging, astrocyte numbers increase and a greater proportion become acti- vated (astrogliosis) [104, 105]. This is another potential target for therapy, but although prion-like disease spread is known to require endo- somal release and uptake, much more about the molecular mechanisms involved in this process still needs to be elucidated. There is however some concern that this may prevent potentially neuroprotective aggregation of the protein, and this may actually exac- erbate the condition. It is also conceivable that post-translational modications that drive aggregate formation may evade antibody binding and may increase neuroin- ammation (see above). Unfortunately, attempts to intervene have to date provided little to no benet in human clinical trials [51]. It may also reect lack of thoroughly vetted pre-clinical studies in order to better understand dose responses, treatment pharmacokinetics, and appropriate therapeutic windows. Identication of a disease-modifying neuroprotective intervention has remained elusive to date, likely due in part to these factors. It may however also imply that exploration of novel targets far aeld from those conventionally studied is needed. While this has yielded important information and enormous efforts have been expended to develop therapies based on these ndings, there have been few successful interventions as a consequence. This is likely due to an incomplete picture of the nature of complex chronic disease states. Studying the role of aging mechanisms across a wide variety of disease states will allow scientists to broaden the scope of research beyond tradi- tional disciplines, towards the central concept that these multiple human disease states likely arise from a common underlying cause: aging itself. The term gerosci- ence was coined by scientists at the Buck Institute for Research on Aging in 2007 as an acknowledgement and organizing principle of this scientic concept. This led to a leading- edge commentary in the journal Cell entitled Geroscience: Linking Aging to Chronic Disease [119]. Accumulation of -synuclein has been linked to alterations in mitochondrial ssion-fusion and function [131]. Sirtuins are a family of conserved enzymes whose modulation has been demonstrated to alter the course of aging in various model systems. Parkinson s Disease and Aging 241 Aging is correlated with loss in function of various molecular chaperones nor- mally involved in repair of conformational alterations in cellular proteins in response to stress events. Loss of the ability to respond to stress can result in accumulation of age- and disease-related misfolded proteins, protein aggregation, and disruption of cellular function. Interventions towards replacing levels of chaperone function have been proposed as a potential therapeutic for brain aging. Recent studies suggest that activation of the peripheral immune system can elicit a pro-inammatory response in the brain of aged subjects that does not occur in younger cohorts. It has been suggested that this may be due to age-related microglial priming resulting in enhanced activation following entrance of immune signals from the periphery, releasing elevated levels of pro-inammatory cytokines. Secretion of chemokines by activated microglia can attract neutrophils and monocytes from the bloodstream. In contrast, up-regulation of anti-inammatory factors in the periphery may act to reduce glial cell activation in the brain and therefore neuropathology. Conversely, damage within the brain may trigger inammatory effects in the periphery. For example, brain injury has been reported to result in increases in pro-inammatory cells in the liver, resulting in neutrophil translocation in the brain [156 ]. The senescence response arrests cell proliferation, stably and essentially irreversibly, in response to stresses that puts cells at risk for malig- nant transformation. A seminal publication showed that elimination of senescent cells that accumulate in a progeroid mouse model prevents the onset of three major aging phenotypes (cataracts, sarcopenia and loss of subcutaneous fat), providing the rst evidence that senescent cells play a causal role in at least some age-related patholo- gies in vivo [163]. While cell senescence has been causally linked to age-related pathologies in peripheral tissues, its potential role in brain aging and neurodegen- erative disease has just begun to be explored. Telomere shortening in rat microglia both in culture following repeated cell divisions and with advancing age in vivo has been reported to lead to cellular senescence that may impact cellular function [165, 166 ]. This may be what primes microglia for enhanced activa- tion in response to systemic inammatory stimuli.

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