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Christian Luscher MD

• Departments of Basic and Clincial Neurosciences, Medical Faculty
• University Hospital of geneva, Geneva, Switzerland

http://www.addictionscience.unige.ch/team/christianluscher/

The diversity of life on earth has been an engine of biomedical discovery and sustained human Antibiotics rank among the most significant health for millennia impotence statistics best order for viagra capsules, contributing to countless breakthroughs that have considerably improved medical advances impotence mayo buy viagra capsules 100mg on line. With the arrival other sources explore these subjects in detail of penicillin and its descendants erectile dysfunction treatment thailand cheap viagra capsules 100mg, rates of death (see Chivian and Bernstein 2008) drugs for erectile dysfunction philippines buy discount viagra capsules 100mg, this chapter from pneumonia plummeted (see erectile dysfunction 20 buy viagra capsules overnight, for example erectile dysfunction treatment bangalore order 100mg viagra capsules overnight delivery, briefiy explores the substantial contribution of Podolsky 2006). The penicillins as well as nine of biodiversity to biomedical discovery, and discusses the thirteen other major classes of antibiotics in key health challenges posed by accelerating rates use derive from microorganisms. Why biodiversity matters to and Drug Administration can be traced back to natural product origins (Newman and Cragg medical discovery 2012). Percentages of antivirals and antiparasitics Many of the diseases that afiicted or killed most derived from natural products approved during people a century ago are to day largely curable that same period are similar or higher. Applying and misuse of antibiotics has cultivated a slew of scientific methods to medical research certainly highly resistant bacterial strains, which in some contributed to this development, as did the instances cannot be efiectively treated with any engagement of many researchers and medical currently available antibiotic (Levy and Marshall professionals. A race to find rigour, researchers, or any other fac to r could new antibiotics to overcome so-called superbugs sufice on its own to reduce the human sufiering ensued. Most of these rely unique reproductive physiology was lost with upon a natural product predecessor (Pew Health them, which could have alleviated the sufiering Initiatives 2014). For as long as we know, humanity has relied upon compounds from nature designed to treat what Plants have been the single greatest source of ails us (see also the chapter on traditional medicine natural product drugs to date, and although an in this volume). Otzi, the oldest known natural estimated 400 000 plant species populate the mummy, who was found under a thawing glacier earth, only a fraction of these have been studied in the Italian Alps, died more than 5000 years for their pharmacological potential (Hostettmann ago and carried with him a pouch that contained et al. For example, one of the largest plant birch polypore fungus Pip to porus betulinus known specimen banks, the natural products reposi to ry to reduce infiammation and kill bacteria (see, at the National Cancer Institute, contains ~60 000 for example, Bortenschlager and Oeggl 2000). The success of drug development from natural Plant species as diverse as the Himalayan yew, products manifests the common molecular Taxus wallichiana (and other Taxus spp. The establishment and enforcement of are, communicate within themselves and other efiective management and trade of wild-collected creatures using common molecular currencies species, both by governments and corporations, (Chivian and Bernstein 2008). One of several diversity and the medicines already discovered examples is the two species of gastric brooding from them (Chivian and Bernstein 2008). Tese species employ perhaps the most unusual reproductive strategies in the animal kingdom, using their s to machs as wombs for their young (Chivian and Bernstein 2008; McNeely 2006). Having gone extinct in the 1980s, their fi For further discussion on marine bioprospecting see, for example, Hunt and Vincent (2006). Connecting Global Priorities: Biodiversity and Human Health 165 Case study: plQsia;aliforni;a and the human brain Drugs derived from natural products may perhaps be the most direct and concrete bond that many may find between biodiversity and medicine. In many arenas of biomedical inquiry, biodiversity has beenan invisible linchpin of discovery. For example, of the 104 Nobel prizes in Medicine awarded since Emil von Behring received the prizein 1901 for his research on guinea pigs to develop a treatment for diphtheria, 99 were given to scientists who either directly or indirectly made use of other species to do their research. In 2000, Eric Kandel shared the Nobel prize in Physiology or Medicine with Arvid Carlsson for his groundbreaking research on memory. Kandelrs research established, at a cellular and molecular level, how our brains learn and form memories. A human brain has about 86 billion neurons whereas Aplysia has, all to ld, around 20 000, and only about 100 of those neurons are involved in memory. This makes moni to ring the electrical messages that scurry across their membranes, and exploring how these messages may alter genes and other molecules that control a neuronrs inner workings, comparatively easy. With these advantages, Kandel found what was dificult, if not impossible, otherwise. This bacterium was first identified in the Mushroom Spring of ellows to ne National Park in 1966 as part of an expedition to find life in places where it was not supposed to exist. The late summer day that Thomas Brock and Hudson Freeze collected samples from Mushroom Spring, the water temperature measured 69 fiC. Using these machines in a labora to ry proved to o dificult, so scientists turned to another method, heat. Infections are attacked, or more often prevented, through the secretion of several and antimicrobial resistance compounds at once. Far greater than what individual species ofier to medicine through molecules they contain Antibiotic use, aside from its potential to cultivate or traits they possess, an understanding of resistance, also carries the potential to disrupt biodiversity yields irreplaceable insights in to how relationships between hosts and their symbiotic life works, which bear upon current epidemic microbes. Consider the multiple pandemics that more microorganisms than cells that comprise the have resulted from antimicrobial or antibiotic human body, and antibiotic use can dramatically resistance (see also the chapters on infectious alter its composition and function (Cho and Blaser disease and health care and pharmaceuticals in 2012). Human medicine tends to use a its relationship to its host remains unknown, it paradigm for treating infections unknown in is already apparent that changes to the variety nature, which is treating one pathogen with one and abundance of various microorganisms, antibiotic. In this sulphurous hot spring was discovered Therm us aquaticus, the source of Taq polymerase, which serves as the essential cog in the polymerase chain reaction, arguably the single most important method used in genetic research. About 2 million of an microbiome may also shape mood and behaviour estimated 10 million species on earth have been (see also the chapter on microbial biodiversity given scientific names (Wilson 2003). Even with this limited view of the life we share the planet with, we know that each year the variety of organisms on earth continues to decline 4. Such statistics are often In this time of technological advancement, dificult for many people to grasp, especially as when the precision of measurement comes at most loss of biodiversity goes unnoticed. While increasingly diminutive scales such as nanoseconds each of us may in our own lifetimes recognize that or nanometers, and we begin to explore the most one, or even a few, species that were once common minute forms of life on earth, we have at best a in a place we know have disappeared, far more first approximation of the numbers of organisms often species vanish without notice. Given our ignorance of biodiversity, we would be foolish to try to conserve only what 5. The dividends a public health imperative of biodiversity realized in our economies must Too often, biodiversity harnessed from one corner be widely shared to promote the conservation of of the earth has benefited another corner, with biodiversity where it is needed the most (Pimentel little payback to its origins. To stem the tide of biodiversity loss, innovative Happily, successes have already been had in India methods must be used to convince policy-makers and Viet Nam for plant bioprospecting and in and the citizens of the world that biodiversity Kenya, Kazakhstan, Bulgaria and Poland for must be saved. It is inevitable that with infectious diseases, noncommunicable these will sometimes be released in to the natural diseases, and trauma associated with natural and environment through their manufacture, use human-induced disasters. The contribution of or disposal, and that they could subsequently these chapters to understanding how population afiect biodiversity. Of particular interest, due health and the delivery of primary health care are to their biological activity, are pharmaceuticals. Impacts can occur from potential impacts that drug entities and related a number of sources, including health care chemical compounds may have when they enter associated manufacturing, health-care and health the environment. Potential great deal of scientific attention since the 1990s, environmental concerns include energy demand; and numerous studies have now been performed emissions to the atmosphere, soil and water; aimed at assessing and understanding their water use; waste disposal, including potentially environmental occurrence. Box 1 fate (what happens to these compounds after below provides an overview of some of the major release), and efiects (particularly ecological and environmental considerations associated with the (eco) to xicological impacts). Overview of some of the major environmental considerations associated with the delivery of health care Examples of potential impacts of health-care activities on ecosystems Issue Example Potential impacts Energy use Energy demand for health-care facilities Energy demand is associated with can be significant, with 24-hour the consumption of fossil fuels, requirements for medical equipment, emission of greenhouse gases and lighting, heating and air-conditioning. Water use Hospitals and other health-care facilities this adds significantly to can use large quantities of water, community demand for water particularly for patient hygiene, surface resources, potentially impacting cleaning, food preparation and general on aquatic ecosystems or water sanitation. Waste production As well as large quantities of general Waste disposal poses challenges paper and plastic waste, health-care for environmental and public facilities can produce large quantities health authorities. Inappropriate of food waste and hazardous waste waste management and disposal materials, including biohazardous and infrastructure can impact the radioactive substances. Air quality Many hospitals have incinera to rs to deal this has potential for local impacts with hazardous and/or biological waste, on human or ecological health which may release contaminants in to . Emissions associated with health care-associated transport can also be significant. Medicinal species Much modern and traditional health care Unsustainable exploitation of harvesting, medical depends on medicines derived from biodiversity for medicinal use or research and drug nature, from modern drugs to herbal research can endanger species and discovery remedies and complementary therapies. As such, the issue of ecosystem services, unintentional though these pharmaceuticals in the environment illustrates an may be. Where these efiects on ecosystems could important opportunity for collaboration between lead to downstream efiects on public health, health and environmental scientists, regula to rs interventions initially intended to promote and the private sec to r to tackle a critical, cross public health. Approaches has come under the scrutiny of regula to ry bodies, for reducing these inputs and impacts are also including drug approval agencies such as the discussed. Following operations, with a risk of a build-up in sediments use, in areas with sewerage connectivity, human. In terrestrial to the sewerage system and transported to ecosystems, the use of pharmaceuticals in wastewater treatment plants. However, the use for treatment of products can be discharged to the environment domestic pets, wildlife and feral animals may also in the final efiuent (treated water) when it is be important. Of particular interest in this regard released to surface waters such as rivers and may be long-term, widespread programmes for streams. Recent as well as naturally occurring hormones that enter research has also indicated that environmentally sewage treatment works. Tese freshwater could lead to bioaccumulation in the efiects have been particularly noted in aquatic preda to ry European perch (Perca fiuviatilis), with ecosystems, where eggs can develop in the testes significant impacts on feeding behaviour. Labora to ry research environment, over periods ranging from a few days has shown that environmentally relevant to several months (see also Lumaret et al. These birds played a vital role in the ecosystem, cleaning up carcasses of dead animals, and thereby helping to reduce the risk of disease and contamination of soil and water resources. Their numbers were supported by the huge numbers of lives to ck; India alone has the largest cattle population in the world. It became evident that the decline in vulture numbers was having an impact on ecosystem functioning, as evidenced by the number of animal carcasses that were left to decay in fields across the Indian subcontinent. This has helped to boost numbers of feral dogs, rats and other scavengers, resulting in a greatly increased threat of rabies and other diseases in the human population. Diclofenac has been widely administered by veterinarians and famers in analgesic, antirheumatic and antimicrobial preparations, and its availability increased greatly in the early 1990s due to numerous market fac to rs. There have been reports of widespread abuse of the prescription laws that should restrict drug sales, with poor dose controls for humans and lives to ck. This drug has been shown to be highly to xic to vultures at the levels to which they are exposed from lives to ck carcasses. Diclofenac has been banned in India, Pakistan and Nepal since 2008; however, there is concern that the ban is being circumvented or ignored in some areas, and more widespread controls are required, as well as greater cooperation with the farming community, if vulture populations are to recover in the region. Studies have shown that African Gyps vultures are equally vulnerable to diclofenac poisoning, suggesting that the risk may extend to all Gyps species, and there are concerns that many other scavenging bird species are also susceptible. However, a is the link to the growing threat of antimicrobial number of important issues surrounding inputs to resistance. The risk and wildlife, and thereby potentially leading to of resistance is also increased by the routine demands for the increased use of certain drugs, disposal of drugs and drug residues. The release and development of new drug entities to address of antimicrobial drugs in to the environment increased or emerging health threats. In some developing countries, exposure, and the development and transfer of environmental inputs from manufacturing sites antimicrobial resistance genes in pathogens. Introduction large sections of the population across the globe, and the health and development goals of many The contribution of biodiversity and ecosystem communities remain unrealized (Kim et al. Consequently, health-seeking for the development of modern pharmaceuticals behaviour in both urban and rural contexts around (Chivian and Bernstein 2008; Newmann and the world is increasingly becoming pluralistic or Cragg 2007; see also chapter on contribution of a mix of difierent medical systems. In socioecological contexts such traditional health knowledge and conservation as these, several resources used for food, cultural strategies as a way to complement mainstream and spiritual purposes are also used as medicines health systems, and fulfil the basic human right (Unnikrishnan and Suneetha 2012). Biological resources have been used extensively Despite noteworthy advances in public health, for health care and healing practices throughout modern health-care systems worldwide still do his to ry and across cultures. Such knowledge is not adequately meet the health-care needs of often specific to particular groups living in distinct fi A community here is defined as a group of people sharing a common ecosystem/landscape and associated knowledge. Traditional knowledge in health care can range Combined, the drivers of change pose a dual threat from home-level understanding of nutrition, to wild species and to the livelihoods of collec to rs, management of simple ailments (see also who often belong to the poorest social groups. In the chapter on nutrition in this volume) or this chapter, we highlight the various dimensions reproductive health practices, to treating serious related to the conservation of biological resources chronic illnesses or addressing public health and promotion of traditional health-care practices, requirements. In local communities, health illustrating the relevance of significant areas with practitioners trained in traditional and non-formal case study examples. A complete have been institutionalized and integrated in to list of all plants used in traditional medicine does health systems in their respective regions or not exist, but at least 30 000 species of plants countries. A variety of animal body and combined impact of these drivers on the parts and secretions are included in traditional biological resources used for food and medicine medicine pharmacopoeia (Alves and Rosa 2005).

One function may be in epi the deepest cells of the urothelium have basal pro thelial cell volume regulation during changes accompa cesses which are closely adherent to the underlying nying distension [140] erectile dysfunction causes depression trusted 100mg viagra capsules. Another role may be to actively140 basal lamina erectile dysfunction world statistics order discount viagra capsules, with occasional hemidesmosomal attach maintain urine hyper to nicity erectile dysfunction medication reviews purchase viagra capsules online now. A subepithelial vascular ments there to erectile dysfunction doctor nyc order viagra capsules 100mg on line, and abut those of their neighbours but network could function as a countercurrent exchanger without showing any specialized points of contact erectile dysfunction caused by stroke buy viagra capsules paypal. In addition erectile dysfunction causes and remedies buy cheap viagra capsules online, the143 Their cell bodies are generally columnar, having nume microvasculature of the bladder can change with disea rous folds and villi on their lateral and apical surfaces, se. Following obstruction, luminal diameters of intra and are adherent one to another only by means of scat mural vessels increase and become more sensitive to tered small desmosomes; they are thus well adapted to alpha-adrenergic agonists [144]. Epithelial permeabili-144 adjust their shape to the degree of stretch applied to the ty could provide a mechanism for exposing smooth urothelium. Their nuclei are characteristically ellipsoid muscle to intravesical contents, thereby altering bladder and indented, and are distinguishable from those of the contractility [143]. Investiga to rs have demonstrated143 umbrella cells by possession of a prominent rim of that intravesical installations of anti-neoplastic drugs, heterochromatin; their cy to plasm is polarized in that the anticholinergic agents [145] and calcium channel anta-145 majority of the cell organelles, including mi to chondria, gonists, [146] influence detrusor function and access146 golgi complexes, rough endoplasmic reticulum and systemic circulation. The intermediate cells have similar It is well recognised that the composition of the urine cy to logical characteristics to the basal cells and can may have a marked effect on the volumes of urine voi only be identified by their lack of contact with the basal ded. This could come about through penetration of lamina, a feature that is difficult to establish with cer small molecules through the urothelium having a direct tainty in tissue sections through such an irregularly sensitising effect on the dense meshwork of subepithe convoluted structure. Although apical epithe lial cells in the bladder are impermeable to water they 5. Disruption of this polysaccharide layer the urinary bladder is profusely supplied with au to no increases permeability to urea and has been linked to mic nerve fibres, which form a dense plexus among the inflamma to ry or hypersensitivity disorders of the blad detrusor smooth muscle cells. X100 47 they occur in profusion throughout the muscle coat of in to the epithelium, particularly in the urethra. The majority of the au to project to the detrusor muscle in the human bladder [56,56 nomic nerves innervating the detrusor muscle are consi 159]. The3 56 been suggested that chemicals released by the bladder human detrusor possesses an exceedingly sparse supply as a result of stretch, such as prostaglandins [163],163 of sympathetic noradrenergic nerves [152-158]. In addi sory collaterals may influence ganglionic neurotrans tion, there is evidence for the occurrence of a nonadre mission [56]. Such transmission may become more pro-56 nergic noncholinergic transmission in the human lower minent when the bladder functions abnormally [165]. Since these nerves account159 precise function of these peptides as neurotransmitters for such a small proportion of the to tal bladder innerva and/or neuromodula to rs remains to be defined. It is likely that these nerves are sen-166 smaller group of sensory nerves extends to the striated sory, since the postganglionic parasympathetic and urethral sphincter muscle via the pudendal nerve. These specia-167 der contraction, indicating that tension, rather than lised sensory endings are extremely rare, and appear to stretch, is the effective stimulus. These fibres corpuscles act as rapidly adapting pressure recep to rs fi are typically unmyelinated and respond to stimuli asso it is therefore unlikely that such fibres can transmit ciated with tissue damage, such as inflamma to ry information related to slow bladder distension. The nocioep to rs also respond subserosal location of the recep to rs reinforces this argu to cold, but not to stretch within physiological parame ment. Collateral sprouting, and the for around blood vessels, and surrounding intramural gan mation of new and sometimes aberrant connections can glion cells [56, 159]. The fibres occasionally penetrate56 159 occur as a result of spinal injury, inflammation [169],169 48 Figure 45 A; the general nerve marker protein gene product 9. X200 49 nerve injury [170170] or bladder hypertrophy [171] in ani-171 d) Paraganglia mals. This may occur at both the level of the spinal cord In addition to au to nomic ganglia, numerous paragan and within the periphery [171]. This increase is relatively selective,159 during fetal and early postnatal life contain specialized and does not involve other populations of nerves. The functional181 182 tion, and the involvement of neuronal growth fac to rs significance of this developmental association remains [170, 174] in this process clearly needs further investi-170 174 obscure, as does the subsequent fate of these corpuscu gation. However, occasional isolated cor Although it has been assumed that the subepithelial puscles have been observed in the adventitia of the plexus of nerves in human bladder is composed of sen bladder in older children. Many nerves rich in catecholamines [183] and as a consequence183 in this region supply the rich vascular bed of the sube contain large amounts of dopamine b-hydroxylase pithelium, and need not, therefore, be afferent. The finding that capsaicin-senitive sensory nerves express a vanilloid recep to r [175] should aid in175 the future identification of sensory fibres in humans. The majority of muscle bundles in the female Small clusters of au to nomic ganglion cells occur throu bladder neck extend obliquely or longitudinally in to the ghout all regions of the human bladder wall, being urethral wall. There is no ana to mical smooth muscle especially numerous in the adventitia of the bladder sphincter at the bladder neck, and it remains to be deter base. These intramural ganglia to gether with those mined whether this region plays a significant part in the which populate the vesical plexus consist of different maintenance of female urinary continence. One type contains noradre-56 In contrast with the rich sympathetic innervation in the naline and corresponds to the short noradrenergic neu male, the smooth muscle of the female bladder neck pos ron described in association with the genital tract of sesses fewer noradrenergic nerves, but is well supplied other species [178]. The role152 nergic (excita to ry) preganglonic nerves, some ganglion played by this type of nerve in the functional control of cells receive noradrenergic (possibly inhibi to ry) input the bladder neck remains uncertain. Recent studies, however, have56 179 neck taken from female dogs stimulation invariably pro demonstrated that the types of neuron associated with duces a large relaxation this is blocked by nitric oxide the lower urinary tract are much more complex than inhibi to rs to reveal a small to nic contraction (Creed and was previously believed [56]. X400 Figure 47; A paraganglion in the adventitia of the bladder of an 8 month old infant which contains several sensory cor puscles. However the precise role of this type of nerve in the functional control of the bladder neck and urethra has yet to be established. Embedded in the anterior wall of the vagi na it inclines downwards and forwards through a gap in the pelvic floor and terminates in the vestibule at the external meatus between the cli to ris and the vaginal opening. The female urethra is comprised of different regions along its length and can be unders to od by dividing the length of the urethral lumen in to fifths, each 20 % of the to tal length [186]. In the first quintile, the lumen of the186 urethra is surrounded by the vesical neck (0 fi 20%). Next the sphincter urethrae and smooth muscle encircly Figure 48; Small diameter muscle bundles in the female bladder neck. The arch shaped compressor urethrae and urethrovaginal sphincter are found from 2. At the male bladder neck, the smooth muscle cells form the striated urogenital sphincter muscle [187] has two187 a complete circular collar which extends distally to sur components as this division implies (fig. Because of the location and orientation of its constituent fibres, the thral sphincter (rhabdosphincter) is circular in orienta terms internal, proximal or preprostatic urethral sphinc tion and forms the outermost layer of the muscular ter have been used as alternatives for this particular wall. It is often deficient in the portion adjacent to the component of urinary tract smooth muscle. Distally, vagina, but can form a complete circle, especially in the bladder neck muscle merges with, and become indistin young. The more distal portion that lies adjacent to the guishable from, the musculature in the stroma and cap perineal membrane is comprised of two arch shaped sule of the prostate gland. The compressor urethrae arises late rally near the ischiopubic rami while the urethrovaginal In the male, bladder neck smooth muscle is supplied sphincter closely follow the wall of the vagina. Interes with cholinergic (parasympathetic) nerves and also pos tingly these muscles seem to be preserved with advan sesses a rich noradrenergic (sympathetic) innervation cing age while the more proximal sphincter deterio [153]. A153 similar distribution of au to nomic nerves rates, indicating the separate nature of these two ele occurs in the smooth muscle of the prostate gland, ments. On stimulation the sympathetic nerves cause contraction of smooth the striated sphincter can be contracted to increase ure muscle in the wall of the genital tract resulting in semi thra closure during times of urgent need and micturition nal emission. Concomitant sympathetic stimulation of occurs when bladder pressure is higher than urethral bladder neck muscle causes sphincteric closure of the pressure and is typically produced by contraction of the region, thereby preventing reflux of ejaculate in to the detrusor muscle of the bladder wall accompanied by bladder [184]. The muscle coat consists of the previously the outer aspect of the smooth muscle layer and inter described outer sleeve of striated muscle (striated uro mingle with the striated muscle forming the inner part genital sphincter or rhabdosphincter) to gether with an of the striated sphincter. When tra ced distally, urethral smooth muscle bundles terminate the striated muscle cells are of the slow twitch (type I) in the subcutaneous tissue surrounding the external ure variety (fig. These fibres188 is associated with relatively few noradrenergic nerves exert to ne upon the urethral lumen over prolonged per but receives an extensive presumptive cholinergic para iods, especially in relation to the middle third of its sympathetic nerve supply [152] identical in appearance152 length. Periurethral striated muscle of the leva to r ani to that which supplies the detrusor. From a functional aids urethral closure during events which require rapid, point of view it seems unlikely that competence of the albeit short-lived, increases in urethral resistance. The innervation and longitudinal the majority of which are orientated obliquely or longi orientation of most of the muscle fibres suggest that tudinally and are associated with a considerable quanti urethral smooth muscle in the female is active during ty of connective tissue. Of these layers, circular and micturition, serving to shorten and widen the urethral longitudinal, the latter is by far the more prominent lumen. X150 Figure 51; Inner aspect of the male intramural uretheral striated muscle coat consisting of darkly stained slow twitch (type I) fibres. Within the wall of the membranous urethra is the intrin sic striated muscle which, as in the female, is often 1. Lateral to the sphincter are the medial borders of approximately 20cm long and is usually described in the leva to res ani. The the intramural muscle of the wall of the membranous prostatic and membranous parts pass downwards while urethra consists of a relatively thin inner layer of smoo the spongy part turns forwards in the bulb of the penis. Most of the striated Furthermore, although the spongy and prostatic parts muscle fibres on the inner aspect of the sphincter are can be readily dilated, the external meatus and the unusually small in cross-section with diameters of only membranous urethra are comparatively narrow. It is about 3cm long and proximal extension of the striated muscle surrounding extends through the prostate from base to apex (fig. If esta the prostatic urethra is divided in to proximal and distal blished, this hypothesis offers an explanation for the segments of approximately equal length by an abrupt apparent differences in intramural striated muscle fibre anterior angulation of its posterior wall at the midpoint size and type between females and males. The prostatic urethra lies nearer the ante length, commencing in the bulb of the penis and traver rior than the posterior surface of the prostate. It is sing the erectile tissue of the corpus spongiosum and widest in the middle and narrowest below, adjoining the glans (fig. In cross-section it appears crescentic recesses or lacunae and most of its lumen forms a trans in outline with the convex side facing ventrally. Within the bulb the urethra is wider, forming the characteristic crescentic shape is due to the presen the intrabulbar fossa. The lumen is also expanded within ce on the posterior wall of a narrow median longitudi the glans to form the navicular fossa which opens at the nal ridge formed by an elevation of the epithelial lining surface as a vertical slit, the external meatus. On a) Basic properties each side of, or just within, this orifice are the openings of the two ejacula to ry ducts. The prostatic utricle is a the smooth muscle cells in the urethra are small, richly blind-ending diverticulum about 6mm long which supplied with afferent and efferent nerve fibres, gathe extends upwards and backwards within the substance of red in to small bundles and linked to each other by many the prostate. It develops from the paramesonephric adherens type junctions but no gap junctions. The ducts or urogenital sinus and as a consequence is a rem smooth muscle bundles in the urethral wall are thinner nant of the system which forms the reproductive tract in than in the detrusor and arranged in obvious layers (fig. In humans and larger mammals there is a relative ly thick inner layer that is predominantly longitudinally arranged and outside this, a thinner circular muscle 3. In the lamina propria of the urethra scat Emerging from the anterior aspect of the apex of the tered small bundles of only a few cells are often found. Figure 54; Sagittal section showing the parts of the male Figure 55; the left pelvic wall and leva to r ani have been urethra. His to chemically evidence193 times higher in the longitudinal than in the circular demonstrates the presence of cholinesterase-positive smooth muscle. The authors conclude that the results putative cholinergic nerves, and immunohis to chemical are consistent with a to nic role for the circular smooth techniques show the presence of tyrosine hydroxylase muscle in contracting the urethra during bladder filling, containing putative adrenergic nerves [194]. The abi Acetylcholine and noradrenaline both mediate contrac tion in the urethra, [196, 197] and both appear to be196 197 lity of the circular elements to maintain continuous to ne make it likely that there may be significant differences involved in the excita to ry response to intramural stimu in their ability to develop latch bridges, or in the Ca2+ lation, although the noradrenergic component is the sensitivity of the contractile proteins. Both excita to ry a1 and b2 ponses are also sustained, in contrast to the detrusor, adrenocep to rs are present, and there are distinct sub and in tissues generating to ne, relaxations and contrac types of a1 adrenocep to r subtypes in the human pros tions can be evoked by the correct stimuli. Nitric oxide synthase198 containing nerves also innervate the smooth muscle, Less work has been carried out on the electrical proper and mediate a fast transient relaxation (fig. In the pig, a systematic study has demonstrated 201 smaller mammals action potentials have been recorded, that both the density of the nerves and the response to [191] but in the pig, which seems a better model for the191 the various transmitters may vary along the length of human urethra, records from isolated urethral myocytes the urethra [194]. They show Little information is available on the mechanisms cou spontaneous hyperpolarizations and possess large and pling the membrane to the contractile machinery in ure small Ca2+-activated K+ channels, and glibenclamide thral smooth muscle. There is currently no evidence37 192 calcium through these channels occurs in the resting about electrical coupling in urethral smooth muscle, but state [197]. Depolarisation of the membrane by increa-197 its in vivo ability to generate sustained myogenic to ne sing extracellular K+ concentrations has variable suggests that the myocytes are well coupled. It has been suggested the innervation of the urethral smooth muscle is more that sufficient depolarisation may result in voltage complicated than the detrusor, with both excita to ry and dependent inactivation of the L-type calcium channels inhibi to ry innervation. Relaxation can also be mediated48 composed of two to 30 neurones, are found in the blad through activation of guanylate cyclase and elevation of der neck and middle and distal regions of the urethra. From the outside in you can see striated muscle fibres, then a circular smoo th muscle coat in which some striated muscles are intermingled. Within this is a thicker layer of longitudinally oriented smooth muscle, then the lamina propria and the urothelium. Note the development of spontaneous myogenic to ne, the spontaneous transient relaxations and the contrac tile response to the alpha agonist, phenylephrine. Figure 59; Intramural ganglion in the proximal female human urethra showing neurones with positive fluorescence for nitric oxide synthase immunoreactivity (green) and tyrosine hydroxylase immunoreactivity (red). Most neurones are immunoreactive to both enzymes, but others for only one or other. Note reduced size of contractile response (c) in the presence of atropine and guanethidine (3. A B Figure 61; Demonstration of the presence of a1a, a1b but not 1d-adrenocep to rs in human prostatic urethra. The figures show the results of agarose gel electro phoresis and size fractionation of the products, with Southern hybridization.

It comprises of seven key steps that include the initial assessment erectile dysfunction exercise video cheap viagra capsules master card, detailed action planning based on set goals and objectives and moni to ring and evaluation erectile dysfunction doctor generic viagra capsules 100 mg. The figure below presents the seven stages of project planning with examples of key questions to be addressed during the planning process incidence of erectile dysfunction with age buy viagra capsules 100mg on line. Figure 10-1: the planning cycle Assess the situation the first response to a crisis is a rapid assessment that gathers basic information to increase understanding about the magnitude of problems low testosterone erectile dysfunction treatment buy discount viagra capsules 100mg on line. Because problems are often more complex than they appear on the surface erectile dysfunction in 60 year old buy viagra capsules with a visa, a more thorough additional assessment is necessary to identify root causes otherwise wrong assumptions can result in planning inappropriate interventions erectile dysfunction instrumental discount viagra capsules 100 mg otc. It is important to understand that assessment is an ongoing process that continues even after a project has been initiated. It becomes part of moni to ring and identifying new gaps and ways of improving performance and project outcomes. Equally important for the assessors is a clear view of that which they are to assess: the impact of the disaster itself. The dilemma is often that the affected country or area might be in poor shape before the disaster. One must have a clear view of what extent those fac to rs should Public health guide for emergencies I 493 10 be included. In any case, the preliminary goal is to fill the service gap and meet needs caused by the disaster. Prioritise the needs If identified problems and root causes are to o many, try to group all that are related to make them more manageable. Thereafter, use a ranking system to determine which group of problems are to p priorities and are likely to have the greatest impact compared to others. However, other less urgent needs should not be forgotten since they are no less important. They should be moni to red and reassessed and given more attention as the situation becomes stable. Set goals and objectives the overall goal and specific objectives through which the goal will be reached should be defined. Goals are general statements about what one wants eventually to achieve through the programme. They can be derived directly from the common health needs identified in the assessment. Objectives are the specific targets or positions that need to be reached in order to achieve the overall goal. They are the intended results for priority problems identified in the initial assessment. Plan the activities Specify the actions to be taken to achieve the objectives with the required inputs and the expected outputs. In addition to defining the target population and the project timeline, measurable indica to rs for tracking progress to wards objectives should be identified at this stage. If possible, select a few indica to rs of quality, although they might be difficult to measure. During the planning process, coordination and cooperation with other agencies, governments and the International Federation is absolutely vital to ensure that there are no service gaps and no duplication of programming. Implement the plan Carry out the activities specified in the detailed action plan as necessary to reach the set objectives. Implementation requires regular review of unforeseen challenges or obstacles that might arise and require preventive or corrective actions. Moni to ring provides information on any deviation from the project objectives and allows managers to make adjustments if needed. It is important to establish a simple, accurate and reliable moni to ring system that does not overburden the health workers, but helps them as well the overall responsible managers. Important indica to rs to measure are project impact, efficiency, effectiveness and sustainability. This definition is not appropriate because some emergencies continue over decades and food insecurity might occur later. This chapter will consider complex emergencies as situations where death rates among the affected population substantially increases above the population baseline either because of the direct effects of war or indirectly by the increased prevalence of malnutrition and/or transmission of communicable diseases, particularly if the latter result from deliberate political and military policies or strategies (national, sub-national or 19 international). Note: this definition does not include natural disasters, which are often short-term and require a different response, but might include situations where war does not play a major part (such as famine where government policies contribute to food insecurity) or situations in which food insecurity is not prominent (such as war and civil strife in developed countries). A context sensitive approach means developing an understanding of the environment in which an agency operates, the interaction between the planned interventions, the context as well as acting according to the understanding of the interaction in order to avoid negative impacts and maximise the positive outcomes. Because the situation after major disasters and conflicts is often unstable, using only the traditional project management approach might not capture the changing dynamics. A project that adopts a context-sensitive approach is likely to provide short and longer term assistance that is less affected by existing or potential conflict and produces more peaceful outcomes. Public health guide for emergencies I 495 10 Conflict sensitivity is defined as being aware of past, actual or potential conflict, the likelihood of further conflict and its severity. It also includes the capacity to work with all parties to reduce conflict and/or minimise the risk of further conflict. Good managers of humanitarian aid, peace-building or development programmes must develop a clear understanding of the humanitarian context and existing tensions that might adversely affect the project implementation or its outcome. To maximise the use of limited resources, managers can incorporate the conflict sensitive approach as part of the project planning cycle as follows: fi While performing the initial project needs assessment, managers can also carry out a conflict analysis to identify the causes, forces, ac to rs, and changing profile and dynamics of existing conflict. Update the findings regularly; fi By linking the conflict sensitive approach with the traditional project planning cycle, managers will ensure more conflict-sensitive planning, implementation, moni to ring and evaluation. Training volunteers will also ensure that basic health care services are provided by the community themselves with only occasional support or delivery of humanitarian aid goods; fi By planning, implementing, moni to ring and evaluating planned project interventions in a conflict sensitive manner might sometimes involve re-designing strategies and activities to minimise tensions. The figure below shows how the context sensitive approach can be integrated with the project planning cycle. Figure 10-2: Context-sensitivity planning cycle Conflict analysis is a systematic study of the profile, causes, ac to rs and dynamics of the conflict. Humanitarian development and peace-building agencies perform conflict analysis to develop a better understanding of the context they work in, to measure the interaction and potential impact of their programme to that context and determine how capacity can be built among beneficiaries for them to help themselves. It helps reduce negative impacts from their intervention while maximising the positive. Conflict analysis can be performed at any level of the response while linking with other levels if needed. Like the needs assessment, ongoing conflict analysis of underlying causes of a complex emergency helps improve understanding of the likely impact of the 496 I the Johns Hopkins and the International Federation of Red Cross and Red Crescent Societies 10 humanitarian response on the context. Although there are no standard indica to rs for conflict analysis, moni to ring and evaluation, the table below offers some key questions that could be applicable to many emergency situations. Table 10-1: Key management questions for emergency situations Profile Dynamics What kind of conflict forces are we What are the current conflict trends (increasing or dealing withfi What scenarios can be developed from the analysis of the conflict profile, causes and ac to rs (best case and worst case scenarios)fi What are What are its root causes (ethnic, religious, their interests, positions, capacities and alliancesfi Does anyone reach them warring parties and ethnic groups, religious with assistancefi Some local and international aid workers might not appreciate the need for a context sensitive approach, particularly those managing post-conflict situations. They may be to o busy focusing on relief distribution to recognise that their limited assistance to a minority group might be worsening tensions within a larger context. It is important to conduct a conflict analysis and to enhance the response to the emergency context. This enables managers to detect early if what they are doing is actually doing more harm than good and adjust their plans accordingly. Sometimes long-serving staff might be less concerned because of the trust they have developed with the beneficiaries, while new staff might become over-sensitive. Nevertheless, it is better to empower all staff to perform conflict analysis and planning so they do not operate in ignorance. Public health guide for emergencies I 497 10 During contextual analysis, cross-check findings with other sources of information to broaden understanding and the interactions. Because of the highly political nature of the information gathered however, conflict analysis should be conducted with caution and its findings kept confidential to avoid exposing interviewers or respondents to risk. Required skills for good conflict analysis include technical know-how, un-derstanding the context and its his to ry, cultural sensitivity, a proficiency in the local language, competency in moni to ring and evaluation. When deciding which to ol to use, review the aim, methodology and resource implications to determine its appropriateness. At the level of intervention, it serves as a springboard for longer development activities. Some groups might oppose the settlement and recovery plan if they see former enemies also receiving aid and resources. The logical framework can also be a basis for a plan of action as well as a budget. This is mainly applicable in the stabilising phase, during recovery and rehabilitation/ development and, to a certain extent, during conflict situations. In other words, the logical framework is simply a to ol that provides a basis for planning and managing projects. It looks like a table (or framework) which presents information on key project components in a clear, concise, logical and systematic way. However, for a log frame to guide project implementation, it must contain more information about the inputs, outputs and activities without being to o detailed. The following information must be filled in a log frame in a standard format: fi What is the project going to achievefi Table 10-3: the logical framework Measurable Means of Objectives Assumptions indica to rs verification Goal: To improve survival for earthquake victims through high quality care Purpose Outputs Activities the log frame is appropriate for planning and managing emergency and post-conflict projects because it can be adjusted to changing situations. If the log frame is developed in a participa to ry manner by those who will be directly responsible for implementation, it might not require any major changes. To ensure the information is correct, project managers can seek answers to the following questions: fi What impact will the objectives and indica to rs have on current workfi Public health guide for emergencies I 499 10 the size of a log frame depends on the complexity of a project. For large humanitarian programmes, each purpose in the log frame represents individual sub-projects with their own expanded log frame matrix. Good log frames are developed through wide consultation with key stakeholders, including other organisations and the government to guarantee, coordinated efforts. It is important to involve staff that can actually implement the project so that they can confirm whether proposed objectives, activities and assumptions are realistic. Log frames are best developed from the time a project is being formulated so that required baseline data can be gathered at the same time. When the log frame has been completed, invite someone with experience in developing log frames to review and give feedback. Once it is approved by donors, use the log frame for project moni to ring and evaluation. Some assumptions and indica to rs in the log frame might have to be updated periodically. This should only be done after consulting with the donor and other key stakeholders. The systems model the systems model is a management framework that allows managers to focus on the process of providing public health services in order to produce better results. The model defines the relationship between what is needed and what should be invested, and between what is invested and what is actually achieved. The systems model helps managers to gather and analyse information on the key processes of health care delivery so that they can identify weak links and take appropriate action when things go wrong, for example: fi Poor outcomes of a programme. By linking all the components in a systems diagram (inputs-process-outputs-effects impacts), the systems model can be used for planning, moni to ring and evaluating programmes. Distinguish between needs present before the disaster and needs caused by the disaster. Ensure that inputs are processed as planned to bring about the planned effects and moni to r the impacts.

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Syndromes

• Hallucinations
• Thyroid function
• Mononucleosis
• Placing a drain into the brain to help remove cerebrospinal fluid (CSF)
• Kidney infection
• Having other illnesses or using medicines that suppress your immune system
• Surgery for impingement syndrome: Damaged or inflamed tissue is cleaned out in the area above the shoulder joint itself. Your surgeon may also cut a specific ligament, called the coracoacromial ligament, and shave off the under part of a bone. This under part of the bone is called the acromion. The spur can be a cause of inflammation and pain in your shoulder.
• Presbyopia -- difficulty focusing on objects that are close. This problem often becomes noticeable in your early to mid 40s.

In children younger than 1 year of age (ie erectile dysfunction testosterone cheap 100mg viagra capsules mastercard, infants) long term erectile dysfunction treatment viagra capsules 100 mg without prescription, the anterolateral aspect of the thigh provides the larg est muscle and is the preferred site drugs for erectile dysfunction pills purchase viagra capsules 100 mg on line. Ordinarily erectile dysfunction medications causes symptoms cheap viagra capsules 100mg, the upper erectile dysfunction drugs generic names buy viagra capsules 100 mg online, outer aspect of the but to cks should not be used for active immunization erectile dysfunction risk factors order 100 mg viagra capsules fast delivery, because the gluteal region is covered by a signifcant layer of subcutaneous fat and because of the possibility of damaging the sciatic nerve. Because of diminished immunogenicity, hepatitis B and rabies vaccines should not be given in the but to cks at any age. People, especially adults, who were given hepatitis B vaccine in the but to cks should be tested for immunity and reimmunized if antibody concentrations are inadequate (see Hepatitis B, p 369). The site selected should be well 1 For a review on intramuscular injections, see Centers for Disease Control and Prevention. This site is the center of a triangle for which the boundaries are the anterior superior iliac spine, the tubercle of the iliac crest, and the upper border of the greater trochanter. These vaccines should not be administered subcutaneously or intracutaneously, because they can cause local irritation, infammation, granuloma formation, and tissue necrosis. Reported adverse events include broken needles, muscle contracture, nerve injury, bacterial (staphylococcal, strep to coccal, and clostridial) abscesses, sterile abscesses, skin pigmentation, hemorrhage, cellulitis, tissue necrosis, gangrene, local atrophy, periostitis, cyst or scar formation, and inadvertent injection in to a joint space. Because of the decreased antigenic mass administered with intradermal injections, attention to technique is essential to ensure that material is not injected subcutaneously. When neces sary, 2 or more vaccines can be given in the same limb at a single visit. The distance separating the injections is arbitrary but should be at least 1 inch, if possible, so that local reactions are unlikely to overlap. Multiple vaccines should not be mixed in a single syringe unless specifcally licensed and labeled for admin istration in 1 syringe. Aspiration before injection of vaccines or to xoids (ie, pulling back on the syringe plunger after needle insertion, before injection) is not recommended, because no large blood vessels are located at the preferred injection sites, and the process of aspiration has been demonstrated to increase pain. A brief period of bleeding at the injection site is common and usually can be controlled by applying gentle pressure. Managing Injection Pain A planned approach to managing the child before, during, and after immunization is helpful for children of any age. Parents should be educated about techniques for 1 reducing injection pain or distress. Parents should be advised not to threaten children with injections or use them as a punishment for inappropriate behavior. Techniques for minimizing pain can be divided in to physical, psychological, and pharmacologic. Pain reduction during pediatric immunizations: evidence-based review and recommendations. In addition, breastfeeding is a potent analgesic intervention in newborn infants during blood collection. Infants may exhibit less pain behavior when held on the lap of a parent or other caregiver. Stroking or rocking a child after an injection decreases crying and other pain behaviors. A rapid plunge of the needle through the skin without aspirating and rapid injection may decrease discomfort. If multiple injections are to be given, having different health care professionals administer them simultaneously at multiple sites (eg, right and left anterolateral thighs) may lessen anticipation of the next injection. It may be helpful to give older children a degree of control by allowing some choice in selecting the injection site. Humor and distraction techniques tend to decrease distress, whereas excessive parental reassurance, concern, or apology tends to increase distress. Topical anesthetics (eg, lido caine/pilocaine) have been evaluated in placebo-controlled, randomized clinical trials and have been demonstrated to provide pain relief. Because currently available to pical anesthetics require 30 to 60 minutes to provide adequate anesthesia, planning is necessary, such as applying the cream before an offce visit or immediately on arrival. Oral admin istration of a small volume of a 25% to 75% sucrose solution (eg, dissolving 1 packet of sugar in 10 mL water) or dipping a pacifer in to a sucrose solution just before the injection reduces crying time in infants younger than 6 months of age. However, optimal immunologic response for the person must be balanced against the need to achieve timely protection against disease. For this reason, in some developing countries, oral polio vaccine is given at birth, in accordance with recommendations of the World Health Organization. With parenterally administered live-virus vaccines, the inhibi to ry effect of residual specifc maternal antibody determines the optimal age of administration. For example, live-virus measles-containing vaccine in use in the United States provides suboptimal rates of seroconversion during the frst year of life, mainly because of interference by transplacentally acquired maternal antibody. If a measles-containing vaccine is admin istered before 12 months of age, the child should receive 2 additional doses of measles containing vaccine at the recommended ages and interval (see Fig 1. An additional fac to r in selecting an immunization schedule is the need to achieve a uniform and regular response. For example, live-virus rubella vaccine evokes a predictable response at high rates after a single dose. With many inactivated or component vaccines, a primary series of doses is necessary to achieve an optimal initial response in recipients. For example, some people respond only to 1 or 2 types of poliovirus after a single dose of poliovirus vaccine, so multiple doses are given to produce antibody against all 3 types, thereby ensuring complete protection for the person and maximum response rates for the population. For some vaccines, periodic booster doses (eg, with tetanus and diphtheria to xoids and acellular pertussis antigen) are administered to maintain protection. This information is particularly important for scheduling immunizations for children with lapsed or missed immunizations and for people preparing for international travel (see Simultaneous Administration of Multiple Vaccines, p 33). Data indicate possible impaired immune responses when 2 or more parenterally administered live-virus vaccines are not given simultaneously but within 28 days of each other; therefore, live-virus vaccines not admin istered on the same day should be given at least 28 days (4 weeks) apart whenever possi ble. No minimum interval is required between administration of different inactivated vaccines. The recommended childhood (0 through 6 years of age), adolescent (7 through 18 years of age), and catch-up immunization schedules in Fig 1. These schedules are reviewed regularly, and updated national schedules are issued annually in February; schedules are available at Special attention should be given to footnotes on the sched ule, which summarize major recommendations for routine childhood immunizations. The use of a combination vaccine generally is preferred over separate injec tions of its equivalent component vaccines. Considerations should include provider assess ment, patient preference, and the potential for adverse events. The provider assess ment should include the number of injections, vaccine availability, the likelihood of improved coverage, the likelihood of patient return, and s to rage and cost considerations. Web-based childhood immunization schedulers using the current vaccine recommendations are available for parents, care givers, and health care profes sionals to make instant immunization schedules for children, adolescents, and adults (see Immunization Schedulers, p 5, or For children in whom early or rapid immunization is urgent or for children not immu nized on schedule, simultaneous immunization with multiple products allows for more rapid protection. In addition, in some circumstances, immunization can be initiated ear lier than at the usually recommended time or schedule, or doses can be given at shorter intervals than are recommended routinely (for guidelines, see the disease-specifc chapters in Section 3). The fnal dose of the hepatitis B vac cine series should be administered at least 16 weeks after the frst dose and no earlier than 24 weeks of age. Infuenza vaccine should be administered before the start of infuenza season but provides beneft if administered at any time during the infuenza season (ie, usually through March) (see Infuenza, Timing of Vaccine Administration, p 450). In many instances, the guide lines will be applicable to children in other countries, but individual pediatricians and recommending committees in each country are responsible for determining the appro priateness of the recommendations for their setting. A vaccine series does not need to be restarted, regardless of the time that has elapsed between doses. Always use this table in conjunction with the accompanying childhood and adolescent immunization schedules (Figures 1 and 2) and their respective footnotes. Vaccination should not be years or older and at least 6 months after the previous dose. Suspected cases of vaccine-preventable diseases should be reported to the state or local health department. Modifcations may be made by the ministries of health in individual countries on the basis of local considerations. Recommendations for vaccine schedules in Europe are available at the European Center for Disease Prevention and Control ( Minimum Ages and Minimum Intervals Between Vaccine Doses Immunizations are recommended for members of the youngest age group at risk of experiencing the disease for whom effcacy, immunogenicity, and safety have been dem onstrated. Most vaccines in the childhood and adolescent immunization schedule require 2 or more doses for stimulation of an adequate and persisting antibody response. Studies have demonstrated that the recommended age and interval between doses of the same antigen(s) provide optimal protection. Administering doses of a multidose vaccine at intervals shorter than those in the childhood and adolescent immunization schedules might be necessary in circum stances in which an infant or child is behind schedule and needs to be brought up to date quickly or when international travel is pending. In these cases, an accelerated schedule using minimum age or interval criteria can be used. Vaccines should not be administered at intervals less than the recommended mini mum or at an earlier age than the recommended minimum (eg, accelerated schedules). The frst is for measles vaccine during a measles outbreak, in which case the vaccine may be administered as early as 6 months of age. However, if a measles-containing vaccine is administered before 12 months of age, the dose is not counted to ward the 2-dose measles vaccine series, and the child should be reimmunized at 12 through 15 months of age with a measles-containing vaccine. A third dose of a measles-containing vaccine is indicated at 4 through 6 years of age but can be administered as early as 4 weeks after the second dose (see Measles, p 489). The second consideration involves administering a dose a few days earlier than the minimum interval or age, which is unlikely to have a substantially negative effect on the immune response to that dose. Although immunizations should not be scheduled at an interval or age less than the minimums listed in Fig 1. In this situ ation, the clinician can consider administering the vaccine before the minimum interval or age. If the child is known to the clinician, rescheduling the child for immunization closer to the recommended interval is preferred. If the parent or child is not known to the clinician or follow-up cannot be ensured (eg, habitually misses appointments), admin istration of the vaccine at that visit rather than rescheduling the child for a later visit is preferable. Vaccine doses administered 4 days or fewer before the minimum interval or age can be counted as valid. This 4-day recommendation does not apply to rabies vac cine because of the unique schedule for this vaccine. Doses administered 5 days or more before the minimum interval or age should not be counted as valid doses and should be repeated as age appropriate. The repeat dose should be spaced after the invalid dose by at least 4 weeks (Fig 1. However, such vaccines have been considered interchangeable by most experts when administered according to their rec ommended indications, although data documenting the effects of interchangeability are limited. An example of similar vaccines used in different schedules that are not recommended as interchangeable is the 2-dose HepB vac cine option currently available for adolescents 11 through 15 years of age. Infants and children have suffcient immunologic capacity to respond to multiple vaccines. No contraindications to the simultaneous administration of multiple vaccines routinely 1 Centers for Disease Control and Prevention. Immune response to one vaccine generally does not interfere with responses to other vaccines. Because simultaneous administration of routinely recommended vaccines is not known to affect the effectiveness or safety of any of the recommended childhood vaccines, simul taneous administration of all vaccines that are appropriate for the age and immunization status of the recipient is recommended. When vaccines are administered simultaneously, 1 separate syringes and separate sites should be used, and injections in to the same extrem ity should be separated by at least 1 inch so that any local reactions can be differentiated. Simultaneous administration of multiple vaccines can increase immunization rates signif cantly. Some vaccines administered simultaneously may be more reac to genic than others (see disease-specifc chapters). Individual vaccines should never be mixed in the same syringe unless they are specifcally licensed and labeled for administration in one syringe. Combination Vaccines Combination vaccines represent one solution to the issue of increased numbers of injec tions during single clinic visits and generally are preferred over separate injections of equivalent component vaccines. Health care professionals who provide immunizations should s to ck combination and monovalent vaccines needed to immunize children against all diseases for which vaccines are recommended, but all available types or brand-name products do not need to be s to cked. It is recognized that the decision of health care pro fessionals to implement use of new combination vaccines involve complex economic and logistical considerations. Fac to rs that should be considered by the provider, in consulta tion with the parent, include the potential for improved vaccine coverage, the number of injections needed, vaccine safety, vaccine availability, interchangeability, s to rage and cost issues, and whether the patient is likely to return for follow-up.

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