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So generic sildigra 50mg overnight delivery impotence 101, drugs that block β1-receptors lower the heart rate and blood pressure and hence are used in conditions when the heart itself is deprived of oxygen best order sildigra erectile dysfunction uptodate. In addition, β-blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. Drugs that block β2-receptors generally have a calming effect and are prescribed for anxiety, migraine, esophageal varices, and alcohol withdrawal syndrome, among others. Propranolol is a cardiac depressant that acts on the mechanic and electrophysio- logical properties of the myocardium. It can block atrioventricular conductivity and poten- tial automatism of sinus nodes as well as adrenergic stimulation caused by catecholamines; nevertheless, it lowers myocardial contractility, heart rate, blood pressure, and the myocar- dial requirement of oxygen. All of these properties make propranolol and other β-adrenoblockers useful antiar- rhythmic and antianginal drugs. Propranolol lowers blood pressure in the majority of patients with essential hypertension. These effects can be caused by a number of possible mechanisms, including lowering car- diac output, inhibiting the release of renin, lowering sympathetic release from the central nervous system, inhibiting the release of norepinephrine from sympathetic postganglionic nerves, and others. However, not one of the suggested mechanisms adequately describes the antihyperten- sive activity of propranolol and other β-blockers. Propranolol is used in treating arterial hypertonicity, angina, extrasystole, superventric- ular arrhythmia, ventricular tachycardia, migraines, hypertrophic subaortic stenosis, and pheochromocytoma. Universally accepted synonyms of this drug are anaprilin, inderal, and many others. Metoprolol is used in moderate hypertension, serious conditions of myocardial infarc- tion, for preventing death of cardiovascular tissue, in angina, tachycardia, extrasystole, and for secondary prophylaxis after a heart attack. Other β-adrenoblockers whose syntheses differ slightly from those above also are used widely in medicine. Therefore, only their names, structural formulas, pharmacological properties, and synonyms are listed below. It is used for arterial hypertension, preventing attacks of angina, and cardiac rhythm disturbances. Like acebutol, atenolol possesses antianginal, antihypotensive, and antiarrhythmic action. It is used for arte- rial hypotension, preventing attacks of angina, sinus tachycardia, and preventing supraven- tricular tachyarrhythmia. Like the other β-adrenoblockers above, it possesses antianginal, antihypotensive, and antiarrhythmic action. It is used for arterial hypertension, for preventing attacks of angina, and for sinus tachycardia. It is used for arterial hypertension, angina stress (pre- venting attacks), supraventricular tachycardia, tachsystolic form of atrial fibrillation, and superventricular extrasystole. Synonyms of this drug are mod- ucrine, thiamicor, timoptol, blocadren, timolide, and others. At the same time, the aromatic part of the molecule, unlike the typical structures of β-adrenoblockers described above, is sufficiently functionalized and constitute a substituted salicylamide. Pharmacologically, it is a selective, competitive α1-blocker and a nonselective blocker of β-adrenergic receptors, which leads to a decrease in blood pressure in hypertensive patients. The main synonyms of this drug are trandate, avetol, aimpress, pressalol, and others. The distinctive feature of α-adrenoblockers is their ability to reduce the pressor effect of pharmacological doses of epinephrine (adrenaline). Blood vessels with α1-receptors are pres- ent in the skin and the gastrointestinal system, and during the flight-or-fight response there is decreased blood flow to these organs. In particular, postsynaptic α1-blockers act on the α-receptive regions located on the smooth muscle of blood vessels and counteract the pressor, vasoconstricting effect of epi- nephrine and norepinephrine. In addition, they exhibit a direct relaxant effect on smooth muscle, which leads to peripheral dilation of blood vessels, which in turn raises blood pressure. However, they also exhibit a cardiostimulatory effect, which is frequently a cause of tachycardia. Presynaptic α2-receptive regions are located on sympathetic nerve endings, and their blockage, evidently by a mechanism of reversible binding, increases output of epinephrine 168 12. Such pharmacological action has extremely limited clinical use; how- ever, it is a valuable laboratory instrument. Long-acting, noncompetitive antagonists (phenoxybenzamine), which form strong chemical bonds with α-receptor regions, can block α-receptors for days and even weeks. Reversible competitive antagonists, nonselective (phentolamine, tolazoline), and α1-selectively acting (prazosin, terazosin) that reversibly and competitively block α-receptive regions; terazosin can last a few hours. At the same time, blockage of α-receptors can be interrupted and stopped by large doses of an agonist such as nor- epinephrine. Ergot alkaloids (ergotamine, ergonovine) also exhibit certain nonselective α-adrenoblocking activity; however, they primarily exhibit spasmogenic action on smooth muscle, causing a constriction of blood vessels. Selective α2-adrenoblockers such as the alkaloid yohimbin have limited clinical use. Reacting this with 2-aminoethanol leads to formation of 1-phenoxy-2-(2-hydroxyethyl)aminopropane (12. Alkylation of the secondary amino group gives N-(2-hydroxyethyl)-N-(1-methyl-2-phenoxyethyl)benzylamine (12. The mechanism of its long-lasting blockage of α-adrenoreceptors can evidently be explained by its irreversible alkylation. The irreversible blockage most likely occurs after briefly affecting α1- and α2-adrenoreceptors. It is possible that the β-chlorethylamine region in tissue of the organism forms a highly reactive ethylenimo- nium intermediate, which then alkylates the receptor. Phenoxybenzamine is used in treating pheochromocytoma, swelling of the medullary layer of the adrenal glands, during which a large quantity of epinephrine is produced, which leads to a significant elevation of blood pressure. The structure of tolazoline is strikingly simi- lar to α-adrenergic agonists, which are antiedema sympathomimetics. However, it also exhibits β-adrenomimetic activity, which consists of the stimulation of cardiac work and is manifest as tachycardia, cholin- ergic activity, which consists of stimulation of the gastrointestinal tract, and histamine-like activity, which consists of stimulation of gastric secretion. It is used for treating stable forms of pulmonary hypertension in newborns, and in cases where systemic arterial oxygenation cannot be achieved in the usual manner under careful observation of professionals. Adrenoblocking Drugs Phentolamine is also a derivative of imidazoline that exhibits a direct α-adrenoblocking, muscle-relaxant effect on smooth muscle as well as cholinomimetic, histamine, and sympa- thomimetic effects. The chemical variation of its structure permits a few of its properties to be more expressed. For example, the aforementioned tolazoline, 2-benzyl-2-imidazoline, a structural analog of phentolamine, has more of an expressed muscle-relaxant effect on smooth muscle than an α-adrenoblocking effect. Phentolamine’s action is exhibited by competing with catecholamines for binding with α-adrenoreceptors—for which reason it is called a competitive blocker—that has high affinity, yet minimal activity with these receptive regions. This type of substrate–receptor blocker lowers the ability of α-adrenoreceptors to react with sympathomimetic amines, and consequently lowers the significance of the response brought about by endogenic or exogenic amines. The duration of the blockage of α-adrenoreceptors by phentolamine is significantly less than that of phenoxybenzamine. Phentolamine is used for peripheral blood circulation disorders, in particular in the beginning stages of gangrene, for treatment of trophic ulcers of the extremities, bedsores, and frostbite.

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As in the text sildigra 100mg otc adderall xr impotence, assume that the force generated by the legs is twice the unloaded weight of the person and the gravitational constant on the moon is 1/6 that on Earth buy generic sildigra 50mg erectile dysfunction causes heart. What is the time period in the standing broad jump during which the jumper is in the air? Consider a person on the moon who launches herself into a standing broad jump at 45◦. The average force generated during launching is, as stated in the text, F 2W, and the distance over which this force acts is 60 cm. Compute (a) the range of the jump; (b) the maximum height of the jump; (c) the duration of the jump. Assume that the density of the bug is 1 g/cm3 and that the bug is spherical in shape with a diameter of 1 cm. Calculate the radius of a parachute that will slow a 70-kg parachutist to a terminal velocity of 14 m/sec. Calculate the terminal velocity of a (a) 1-cm diameter hailstone and (b) a 4-cm diameter hailstone. Using the approach discussed in the text, calculate the energy expended per second by a person running at 3 m/sec (9-min. In this chapter, we will analyze some aspects of angular motion contained in the movement of animals. The basic equa- tions and definitions of angular motion used in this chapter are reviewed in Appendix A. The usual problem here is to cal- culate the centrifugal forces and determine their effect on the motion of the object. A common problem solved in many basic physics texts requires deter- mination of the maximum speed at which an automobile can round a curve without skidding. Consider a car of weight W moving on a curved level road that has a radius of curvature R. The centrifugal force Fc exerted on the moving car (see Appendix A) is mv2 Wv2 Fc (4. The car begins to skid on the curve when the centrifugal force is greater than the frictional force. When the car is on the verge of skidding, the centrifugal force is just equal to the frictional force; that is, Wv2 μW (4. If the road is properly banked, skidding may be prevented without recourse to frictional forces. In the absence of friction, the reaction force Fn acting on the car must be perpendicular to the road surface. The reason for this position can be understood from an analysis of the forces acting on the runner. Her foot, as it makes contact with the ground, is subject to the two forces, shown in Fig. The resultant force Fr acts on the runner at an angle θ with respect to the vertical axis. If the runner were to round the curve remaining perpendicular to the sur- face, this resultant force would not pass through her center of gravity and an unbalancing torque would be applied on the runner (see Exercise 4-1). Many of the limb movements in walking and running can be analyzed in terms of the swinging movement of a pendulum. If the pendulum is displaced a distance A from the center position and then released, it will swing back and forth under the force of gravity. The number of times the pendulum swings back and forth per second is called frequency (f ). Although this expression for T is derived for a small-angle swing, it is a good approximation even for a relatively wide swing. For example, when the swing is through 120◦ (60◦ in each direction), the period is only 7% longer than predicted by Eq. As the pendulum swings, there is continuous interchange between poten- tial and kinetic energy. At this point, the pendulum, subject to acceleration due to the force of gravity, starts its return toward the center. The acceleration is tangential to the path of the swing and is at a maximum when the pendulum begins to return toward the center. The velocity of the pendulum is at its maximum when the pendulum passes the center position (0). At this point the energy is entirely in the form of kinetic energy, and the veloc- ity (vmax) here is given by 2πA vmax (4. The motion of one foot in each step can be considered as approximately a half-cycle of a simple harmonic motion (Fig. Assume that a person walks at a rate of 120 steps/min (2 steps/sec) and that each step is 90 cm long. A more real- istic model is the physical pendulum, which takes into account the distri- bution of weight along the swinging object (see Fig. If we assume that the 1 center of mass of the leg is at its middle (r ), the period of oscillation is 2 I (W/g)( 2/3) 2 T 2π 2π 2π (4. Because each step in the act of walking can be regarded as a half-swing of a simple harmonic motion, the number of steps per second is simply the inverse of the half period. In a most effortless walk, the legs swing at their natural frequency, and the time for one step is T/2. Walking faster or slower requires additional muscular exertion and is more tiring. In Exercise 4-6 we calculate that for a person with 90 cm long legs and 90 cm step length the most effortless walking speed is 1. The speed of walking is proportional to the product of the number of steps taken in a given time and the length of the step. The size of the step is in turn 1References to the bibliography are given in square brackets. The same considerations apply to all animals: The natural walk of a small animal is slower than that of a large animal. Whereas in a natural walk the swing torque is produced primarily by gravity, in a fast run the torque is produced mostly by the muscles. Using some reasonable assumptions, we can show that similarly built animals can run at the same maximum speed, regardless of differences in leg size. We assume that the length of the leg muscles is proportional to the length of the leg ( ) and that the area of the leg muscles is proportional to 2. In other words, if one animal has a leg twice as long as that of another animal, the area of its muscle is four times as large and the mass of its leg is eight times as large. The maximum force that a muscle can produce Fm is proportional to the area of the muscle. The maximum torque Lmax produced by the muscle is proportional to the product of the force and the length of the leg; that is, 3 Lmax Fm ∝ The expression in the equation for the period of oscillation is applicable for a pendulum swinging under the force of gravity. In general, the period of oscillation for a physical pendulum under the action of a torque with maxi- mum value of Lmax is given by I T 2π (4.

Ultimately order sildigra with paypal impotence when trying to conceive, agonist drugs that directly activate monoamine receptors would appear to be a logical development in this field purchase sildigra visa erectile dysfunction treatment in pune. Unfortunately, the peripheral side-effects of such compounds could well limit their acceptability even if we were to discover what subset of receptors to target. Yet an outstanding problem in treating depression is that the therapeutic response is both slow and progressive: a significant improvement usually takes at least 2±3 weeks and sometimes much longer. Obviously, if we are to explain the therapeutic effects of antidepressants, we must search for long-term neurochemical changes that occur after their prolonged administration. They found that repeated, but not a single, administration to rats of any of the antidepressants which were available at that time (i. Shortly afterwards, it was found that this desensitisation was usually paralleled by downregulation of b1-(butnotb2-) adrenoceptors. This action is even shared by repeated electroconvulsive shock(Stanford and Nutt 1982) but not by drugs that are ineffective in relieving depression (e. A logical conclusion from this workwas that depression is caused by hyperresponsive b-adrenoceptors. However, proliferation of receptors is the normal response to a deficit in transmitter release and so the opposite change, downregulation of b-adrenoceptors by antidepressants, would follow an increase in the concentration of synaptic noradrenaline. This would be consistent with both their proposed mechanism of action and the monoamine theory for depression. Nonetheless, there are many reasons to be confident that b-adrenoceptor desensitisa- tion does not explain the therapeutic effects of antidepressants. First, with the development of more selective ligands for use in radioligand binding studies, it became evident that b-adrenoceptor downregulation can occur after only 2±3 days of drug treatment (Heal et al. Evidently, we must lookelsewhere to find an explanation for the neurobiology of depression and its treatment. Indeed, apart from developing compounds that help patients who currently do not respond to any existing treatment, the most pressing problem in this field is to reduce the delay in treatment response. Yet, despite the numerous investigations of the effects of antidepressants on a wide range of transmitter receptors, few consistent findings have emerged. Results tend to vary not only from laboratory to laboratory and between different brain regions but they also vary with the species and compound tested. So far, the neurochemical changes induced by long-term drug treatment have not been tested in combination with procedures such as learned helplessness, but it cannot be assumed that they will be the same as those in normal (non-depressed) subjects. Some studies find reduction in locus coeruleus, only b-adrenoceptor binding (cortex) 1-adrenoceptors, only. This suggests that depression is associated with a defect in the regulation of glucocorticoid secretion and the locus of this disorder could be glucocorticoid receptors in the hippocampus. Since this happens even in cultured fibroblasts it is thought to involve an action at the level of the genome. However, different antidepressants seem to achieve this through different mechanisms. Yet, all this effort has so far failed to identify disruption of any single transmitter or hormone system as the sole culprit. This points to disruption of the interactions between these different systems as the cause of the problem. Also, a2-adrenoceptors, which normally limit release of noradrenaline, are desensitised after chronic exposure to excess cortisol. From this perspective, any single neurochemical factor could have far-reaching effects on all these (and other) neurohumoral systems and could lead to the mood and behavioural changes that culminate in depression. In other words, whereas the expression of an abnormal neuro- chemical response would be linked with one transmitter system, the problem could lie in another. If this is so, the prospects for finding either a marker for, or a definitive cause of, depression are gloomy, if not misguided. However, experience proves that depression can be reversed by drugs that augment serotonergic and noradrenergic transmission (and reinstated by a deficit in the synthesis of these monoamines). This would explain why, despite numerous neurochemical options for the causes of depression, all antidepressants developed so far (and even those discovered by chance) target these neuronal systems. Whatever the cause of depression, therefore, its relief seems to rest on appropriate secretion of these monoamines. What remains to be seen is whether it will be possible to accelerate the neuro- chemical readjustments triggered by antidepressant drugs that target these systems, so as to reduce the latency in their therapeutic effects. Is this because existing antidepressants simply fail to initiate the appropriate combination of changes in monoaminergic transmission in these patients or do they have a disorder that affects neuronal systems that function in parallel with (or override) the monoamines? If the former is the case, then drugs with combinations of actions which modify monoaminergic transmission in ways that differ from those of established antidepressants might prove to be effective. In the latter case, a new approach to development of antidepressant drugs, targeting completely different transmitter systems, is needed. Obviously, there is a pressing need for future research that will distinguish between these possibilities. Chaput, Y, de Montigny, C and Blier, P (1991) Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments. Ferrer, A and Artigas, F (1994) Effects of single and chronic treatment with tranylcypromine on extracellular serotonin in rat brain. Richelson, E and Pfenning, M (1984) Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block noradrenaline uptake. This is of particular importance in consideration of a rational basis for the treatment of both inflammatory and neuropathic pain where the damage to tissue and nerve leads to alterations in both the peripheral and central mechanisms of pain signalling. For many years, the neurobiological basis for understanding the causes and improving the treatment of pain states remained somewhat unclear. Fortunately, the development of a number of animal models of inflammation and nerve injury, produced by mani- pulation of either peripheral tissue or nerves, has greatly aided our understanding of the mechanisms of pain and realised many examples of this plasticity. Over the past two decades our knowledge of the pharmacology of pain and analgesia has made enormous strides so that whereas 25 years ago we had a rudimentary idea that morphine worked somewhere in the nervous system we can now recite the complete amino-acid sequence of the four opioid receptors. In parallel with advances in the opioid pharmacology a bewildering list of interacting mediators, transmitters and receptors, some peripheral, some central and some located at both sites, has been established as parts of the initiation and conception of pain. In recent years, further progress has been made in our understanding of both acute and chronic pain mechanisms that can be largely attributed to advancements in molecular biology and genomic techniques, as well as the use of animals. This has fundamentally altered our understanding of the pathophysiology of pain mechanisms, allowed us to explore new targets for pain relief and has led to the hope of development of novel analgesics. Unfortunately, despite this progress, the management of pain remains a major clinical concern and is still inadequate in many cases and a significant problem even to this day. Not only does it bring undesirable sensations, it can often impair the quality of living for many if not effectively treated. In broad terms, pain can be divided into two categories, acute and chronic, which differ in their aetiology, mechanisms and pathophysiology. Acute pain and its associated responses are provoked by noxious stimulation and/or disease, or by abnormal function of muscle or viscerae which does not involve actual tissue damage. Although acute pain conditions may last for a length of time if not treated effectively, many cases of acute Neurotransmitters, Drugs and Brain Function. In contrast, chronic pain can persist for a long period of time (3 months is usually considered as the transition point from acute to chronic) and results from damage and/or pathology in peripheral tissues or viscerae, or from dysfunction or lesions to the nervous system, either peripheral or central.

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These observations have coincided with several pertinent phenomena: (1) the incredible growth of scientific knowl- edge in recent years; (2) people in western populations living longer and spending increased leisure time exposed to sun in outdoor activities; and (3) the rampant cosmetic claims for products that will ‘‘turn back the clock’’ to youth overnight purchase sildigra from india ayurvedic treatment erectile dysfunction kerala. One is the northern hemisphere cheap 25mg sildigra free shipping erectile dysfunction pumps cost, where life is rigid, cold scientific proof is difficult, and only the hardiest survive in the frozen tundras of pharmaceutical bureaucracy and governmental regulation. The southern hemisphere is friendly and warm and things that make you ‘‘feel’’ better are considered good, rather than inherently evil because they are not ‘‘natural’’ and may prevent us from looking our age. Advocacy of the term cosmeceutical, as an attempt to compromise and bridge the gap between cosmetic and pharmaceutical, greatly enlivened the de- bate. In fact, the debate has forced us to reevaluate what we truly believe, even made us iconoclasts, willing to listen to new ideas. It has taken place during an era of unprecedented discovery about the structure and functioning of the skin, and the discussion has begun to rise above the former shrill hysteria and is now on a higher plane of logic and scientific facts. On one hand, appearance of the facial skin makes this condition so obvious to the subject and observers, which in turn makes the use of cosmetic products so appealing. On the other hand, only a pharmaceutical product can truly and meaningfully effect change in the substantial pathology of the condition. The clear demonstration of the clinical efficacy of tretinoin, a pharmaceutically active retinoid topically ap- plied for a cosmetic condition, speaks to the utility of the term cosmeceutical. Cosmetic effect should be at least a partial result of structural or functional change, which can be reproducibly demonstrated by some reliable, accurate, and validated methodology—be it clini- cal or instrumental. Topical products presently predominate in the discussion, yet nontoxic, systemic substances such as vitamins and naturally occurring sub- stances should also be considered in the definition. Distinction between intrinsic aging of the skin and photoaging has been repeatedly emphasized, but in the context of this discussion it has little relevance; skin that is visible and cosmetically deteriorated is invariably sun exposed and usually highly sun damaged. In the vast majority of individuals, photoaging over- shadows intrinsic changes, especially in the skin of the face, neck, and dorsal forearms (1). The terms photoaging and photodamage have frequently been used inter- changeably, although we have previously preferred to define photoaging as a process and photodamage as a description of the clinical or histological condition at any point in time. Photoaging begins at a very early time point, even in infancy, as a result of repetitive, chronic exposure of the skin to ultraviolet radiation. Clinical changes recognizable as photodamage may appear in early childhood, especially where exposure is high. A study of teenagers’ skin in Australia demon- strated that 70% of Australians have detectable sun damage by the age of 14 Photoaging 15 years (2). As the process of photoaging continues, additional clinical signs of wrinkling, texture, and pigmentary change become progressively noticeable. Both from the clinical and chronological standpoints, the process is a continuum with change possible in either direction. A subject’s self-assessment of appear- ance, the marketing claim made for the product, and the physical attributes of the cosmetic product are frequently strong forces in the equation, yet to the prac- titioner, investigator, and regulator, a rigorous endpoint of cosmetic improvement or demonstration of pharmacological activity may be most central. Evaluation for cosmeceutical effect must account for the following specific and distinct needs. The customer’s perspective is more related to the individual’s perceptions of their skin appearance than to a meticulously quantitated numerical assessment of its condition. These perceptions are more global than specific, and mandate an evaluation that is weighted toward overall appearance but adequately accounts for specific concerns of dryness, texture, wrinkling, skin color, and pigmentary unevenness. Cosmetic or therapeutic effects produced by the product are important to the consumer, but so are physical aspects of the product itself. A product that is not cosmetically elegant or that is drying or irritating to the skin will be less acceptable to the consumer in spite of alleged pharmaceutical properties. These aspects and physical attributes of cosmetics can be well quantitated by both con- sumer panel testing of the product as well as by specific instrumentation. Table 1 The Cosmeceutical Perspective Subject’s self-perceptions Customer cosmetic expectations Product physical attributes Regulatory aspects Marketing claims Degree of pharmacological activity 16 Cunningham Cosmeceutical properties of a therapeutic intervention are central to the discussion and may require both well-conducted studies of consumer satisfaction as well as adequate documentation and substantiation of cosmetic or therapeutic claims (e. Pharmaceutical testing of pharmacological effect is, by definition, the most stringent, requiring not only adequate trial design and execution but substantially more documentation of statistically significant changes that are also clinically and consumer relevant. This is the area where proper application of biometrics to photoaging is most helpful and important (3). They note that their skin is rough, dry, wrinkled, and that their face and hands, in particular, have numbers of variously colored flat spots. Tanning no longer produces an even darkening of the skin and, especially on the legs, numerous white spots have appeared. Occasionally they are aware of a less resil- ient quality of their skin, which in some areas tends to sag and not bounce back when it is stretched. Raised unsightly growths of cosmetic or medical concern to the patient may have appeared. Clinical Presentations Photoaging is most frequently progressive, yet modified by both environmental exposure and genetics (Table 3). The clinical presentation of photodamage is there- fore highly polymorphic but with many characteristic signs and symptoms (4). Table 2 Photoaging Signs and Symptoms Overall appearance older than chronological age Wrinkles, fine and coarse Diverse pigmentary alterations Rough texture Dryness Sallow complexion Various neoplasms, benign and malignant Photoaging 17 Table 3 Functional Abnormalities of Photoaging Uneven tanning Skin easily distends Slow return to normal contour Thinned skin easily traumatized Sensory decrease Decrease in immune competence The most casual observation of the face or neck of an individual with photo- damaged skin, even by the untrained observer, consciously and subconsciously gives an overall impression of a person older than their chronological age. Visu- ally, wrinkles both fine and coarse are frequently the hallmark of sun-damaged skin in many individuals, although genetic differences may, in some, favor pig- mentary alterations or thinning of the skin as the most prominent presenting sign. An overall sallow, or yellowish hue, is common and presumably due to the complex interplay of light absorption and reflection in photodamaged skin that is characterized by uneven thickness of the stratum corneum and abnormalities of melanization. Additionally, circulatory alterations of endogenous origin or as a consequence of photodamage produce variable contributions of heme pigment to overall skin color. Discrete alterations consistent with actinic lentigos, especially promi- nent on the face and hands, may alternate with mottled hyperpigmentation con- sisting of patchy and alternating lighter and darker macules due to diffuse abnor- malities of melanogenesis and melanosome distribution in keratinocytes. Diffuse pigmentary change may also present as melasma on the face due to either epider- mal melanin abnormalities or dermal macrophages containing melanin or heme pigment. Hypomelanotic macules are vitiligenous and are frequently observed most prominently on the lower extremities. Dryness and surface roughness, best perceived by tactile rather than visual means, are among the most common complaints related to aged and photoaged skin, but are not specific for either. Scaling due to dryness or perturbation in epidermal turnover is also common, but not specific to photodamage. Benign seborrheic keratoses are mostly cosmetic growths that appear in sun- exposed body areas. Grossly observed thinning and histological stratum corneum irregularity, epidermal thinning, and abnormal collagen and elastin result in skin that is easily traumatized with abrasions, cuts, and tears. Blood vessels can be easily seen through the skin and, because of epidermal thinning and decreased dermal integrity, the skin bruises and bleeds more easily than normal. Sensory decrease, not usually clinically obvious, has been partially docu- mented in increasing age, though not specifically in photoaging. Utilizing skin compliance and a two-point discrimination testing on the pad of the index finger, increasing age was correlated with decreased tactile sensitivity and said to be likely related to change in the nervous system (tactile discrimination), rather than change in skin itself (skin compliance) (5). An actual increase in intraepidermal nerve fibers, correlated with severity of photodamage, was observed in a recent study of the ultrastructure of photodamaged skin and was theorized to be indica- tive of a neural involvement in the pathophysiology and/or repair of photodam- aged skin (6). This complicated interaction continues to be an extremely important area of research (7).