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By U. Arokkh. Southwest Bible College and Seminary.

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 avalide 162.5 mg sale. 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 buy 162.5 mg avalide free shipping, 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. Cellular senescence has been reported to occur in the vascular endothelium in the periphery, suggesting that this same cell type may be vulnerable in the aging brain. This may be important not only in these disease states themselves, but in terms of the effective use of cellular transplantation as a therapy for these disorders (see below). Cellular transplantation to replace lost or damaged neurons in patients with the disease is a therapeutic option that mimics what occurs to a lesser degree during endogenous adult neurogenesis. This suggests that long-term cell survival may be diminished, particularly in the environment of on aging brain. It would be of interest to know whether cell survival is increased in brains made more youthful, for example following removal of senescent cells. Masliah and colleagues have reported that -synuclein can interact with the demethylase Dnmt1 in the cytoplasm, preventing 244 J. Alpha-synuclein has itself been reported to interact directly with his- tones and to inhibit histone H3 acetylation [180, 181]. Aging is also associated with extensive remodeling of gene expression proles in different tissues as a consequence of epigenetic alterations. These include a better understand- ing of the dual protective roles of autophagy in turnover of damaged proteins and organelles like the mitochondria, the precise sources of inammation (glial cell acti- vation, cellular senescence), and causes of lost neurogenesis in adult neural stem cells (e. More work needs to be devoted to linking ndings in cellular and animal models to humans. Intermittent fasting (every other day fasting) has been proposed to have an effect on brain function [199 ]. The diversity and make-up of the gut microbiome has been shown to change with age, coinciding with inammaging [204]. These alterations have been demonstrated to be involved in risk for chronic age-related diseases including cardiovascular dis- ease, inammatory bowel syndrome, metabolic disease, and cancer [205]. This is alterable for better or worse by lifestyle and diet, and as a consequence the gut microbiome has been identied as a target for improving overall health in the elderly population [206]. Scientic evidence for an involvement of the gut microbiome in brain function has recently begun to gain ground for disorders such as autism and depression [207]. The gut microbiome is responsible for the production and processing of micronutrients such as folate, thiamine, riboavin, and biotin. Pyroxidine is also produced via activity of gut microbes and is known to accelerate the rate of conversion of L-Dopa in the periphery, which can be slowed by inclusion of carbidopa [209]. Disruptions in circadian rhythms have recently been linked to alterations in the gut microbiome [210]. Mice with genetically altered circadian rhythms were found to have signicantly altered gut microbiota when fed a high-fat, high-sugar diet [212, 213]. Recent animal studies have also shown that gut microorganisms can activate the vagus nerve via immunomodulatory effects and that this plays a critical role in mediating brain function [215, 216]. The vagus nerve connects the enteric nervous system to the brain and is considered a possible pathway for transmission of -synuclein [217]. This enterprise will involve additional research in order to identify the most promising potential therapeutic directions. Pillon B et al (1989) Does cognitive impairment in Parkinson s disease result from non- dopaminergic lesions?

This study revealed a statisti cally significant difference between the values of systolic and diastolic pressure in upper and lower quintiles of 14% (21 mm Hg) and 9% (8mmHg) respectively purchase avalide 162.5mg with visa. It appears that vita 474 Oxidative Stress and Chronic Degenerative Diseases - A Role for Antioxidants min C has a lowering effect on systolic rather than diastolic pressure order 162.5 mg avalide free shipping. Supplementation with vitamin C (1g/day) does not influence the diastolic pressure. Subjects with low vitamin C levels in serum have a high risk of developing stroke compared with those with high values in plasma of the vitamin. Hypertensive subjects, usually overweight, and low levels of se rum vitamin C have the same risk. The increase in the consumption of vitamin C during periods of fat restriction occurs on the one hand a reduction in blood pressure. Thus dietary antioxidants en hance the production of prostacyclin for the purification of free radicals and peroxides that inhibit prostacyclin synthase. Vitamin C and blood pressure then are related, because it has a lowering effect on blood pressure especially when fat intake is low. Ascorbic acid and cardiovascular disease Vitamin C acts as a regulator of the catabolism of cholesterol into bile acids in the guinea pig and is an important factor in the regulation of lipid in several animal species (rabbit, horse, and rat). Correlation studies in humans have shown an inverse relationship between vitamin C in take and mortality from cardiovascular disease. Experimental and observational studies in humans have been inconsistent but indicate that individuals with high cholesterol consumption, greater than or equal to 5. This effect is explained by the promotion or in hibition of degradation of prostacyclin and its implications for thrombosis and atherogene sis, in addition to its protective effect on lipid peroxidation. In patients with high cardiovascular risk, supplementation with antioxidant vitamins shows no reduction in over all mortality or incidence of any vascular disease, cancer or other adverse events. Recent findings indicate a relationship between the nutritional status of vitamin C (as meas ured by the concentration of ascorbate in serum), biological markers of infection and haemo static factors and support the hypothesis that vitamin C may protect against cardiovascular events through effects on the haemostatic factors in response to infection. This relationship is surprising given the uncertainty and potential error in the estimation of consumption of vitamin and vitamin C status assessment (determined mostly by food intake records of 24 h blood samples isolated). Add to this the wide variation between subjects is greater than within the same subject. Lower socioeconomic status and smoking are associated with low concentrations of ascor bate and high concentrations of homeostatic factors that may be confounding factors in cross-sectional studies. The inverse association between homeostatic factors and serum concentrations of ascorbate is strong and consistent, however only some markers of infection (e. C-reactive protein and 1-antichymotrypsin) are related inversely and significantly with serum ascorbate. It is possible that this low concentration of ascorbate may be the result rather than the cause, of a biological response to infection. The strong relationship between serum ascorbate and diet ary intake suggest however that their serum concentrations reflect the nutritional status of the vitamin. The various studies reported in the literature indicate that vitamin does not prevent respira tory infection but may modulate the biological response, leading to less severe disease, so it has a protective function in lung function. Effect of antioxidants in cardiovascular disease It has been suggested a protective effect of antioxidants such as vitamin C, A (-carotene) and E plus selenium in cardiovascular disease. Prospective studies so far have documented an inverse relationship between vitamin C intake and cardiovascular disease, and a strong protective effect of vitamin E supplementation on coronary patients. Finnish and Swiss studies showed that blood levels of ascorbate and therefore a diminished nutritional status of vitamin predicts myocardial infarction. Mediterranean studies showed a 70% reduction in mortality and risk of myocardial infarction independent of the effect on blood pressure and lipids. The infection may contribute to the inflammatory process observed in atherosclerosis. C-reactive protein and alpha-1 antichymotrypsin are acute phase proteins are synthesized in hepatocytes in large numbers in inflammatory processes. Elevated fibrinogen favors these mechanisms and therefore an increased cardiovascular risk. In this way a reduction in diet ary intake in winter for instance, would lead to lower serum ascorbate levels, an increase in susceptibility to infection and the factors haemostatic factors and therefore to an increase in cardiovascular mortality. Increased intake of vitamin C to 90-100 mg/day can increase in these subjects more than 60 umol/L, which has a significant effect on all risk factors. Ascorbic acid and immunity In stress situations the adrenal glands react liberating a large number of active and ready hormones. It has been suggested that 200 mg of vitamin C per day can reduce stress levels caused by these hormones. Megadoses of vita min C increases the body levels of antibodies in animal models (rats stressed and un stressed) having the highest values stressed rats. Healing is characterized by synthesis of connective tissue, whose main component is colla gen. Ascorbic acid supplementation is necessary for healing since this is oxi dized during the synthesis of collagen. The collect ed cells from the blood, peritoneal or alveolar fluid usually contain high concentrations of vitamin C (1-2 ug/mg protein).

In the vertical plane of section the terminal hair follicle consists of a permanent upper segment of follicular infundibulum and isthmus purchase avalide 162.5 mg fast delivery, and an impermanent lower segment of the hair follicle consisting of the lower follicle and root (bulb) (Fig purchase avalide 162.5 mg online. Infundibulum The infundibulum opens from the epidermal surface and ends at the entry of the sebaceous duct into the hair follicle. 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.