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Airgun cataract surgery might be needed and deeper pellets cause particularly severe eye injuries and penetration can result in the need for retinal the eye is often lost because of the extensive dis- detachment surgery generic 30caps npxl overnight delivery zordan herbals. Some intraoc- On admission or in the casualty department discount npxl 30 caps with mastercard herbalsagecom, ular foreign bodies buy npxl 30caps with mastercard herbals safe during pregnancy, such as glass particles or the patient is given tetanus prophylaxis and some alloys order npxl 30caps mastercard herbalsagecom, might be tolerated quite well and a both systemic and local antibiotics. If early decision could have to be made as to whether surgery under general anaesthesia is likely to be observation is preferable in the rst instance. When a foreign body is not to be clear that the injury is a serious one, it is better removed immediately, many ophthalmologists to warn the patient at an early stage about the would insert intravitreal antibiotics as a pro- possible risk of losing the sight of the eye or phylactic measure against endophthalmitis. When a foreign body is found lying deeply in the cornea, its removal can result in loss of aqueous and collapse of the anterior chamber. Intraocular Foreign Body It is prudent to arrange that removal should be Metallic foreign bodies tend to enter the eyes of done under full sterile conditions in the operat- those who operate high-speed grinders without ing theatre, where the corneal wound can be goggles or those using a hammer and chisel on sutured if necessary. These injuries might seem slight at rst and sometimes Sympathetic Ophthalmia patients do not attach much importance to them. Any such eye injury with this occupational This rare complication of perforation is more history warrants an X-ray of the eye. The injured eye remains ferrous metals remain in the eye they can cause markedly inamed and the wound might have immediate infection, or at a later date the depo- been cleaned inadequately or too late. Over a sition of ferrous salts, in a process known as period of two weeks to several months or even siderosis. This can eventually lead to blindness years a particular type of inammatory of the eye. Other metals also tend to give reac- response begins in the uvea and subsequently a tions,particularly copper and for this reason the similar reaction occurs in the other eye. The condition does, however, Ocular Trauma 133 respond well to steroid treatment and it is paid when the medial part of the eyelid has been extremely rare. They need to be examined carefully for theatre, the risk of a permanently watering eye signs of uveitis. Contusion of the eyelids, otherwise known as a black eye, is of course a common problem, Injuries to the Eyelids especially on Saturday nights in a general cas- ualty department. Usually, the presence of a Loss or destruction of eyelid tissue should black eye is an indication that the aficted was always be treated as a threat to vision. The upper smart enough to close his eye in time to avoid lid especially is important in this respect. It is unusual to nd damage immediate concern is to ensure that the cornea to the eyes after Saturday night st-ghts,unless is properly covered when the eyelids are closed. Broken beer glasses If more than one-third of the margin of the produce devastating injuries to the eyes as well upper lid is lost, this must be replaced by graft- as to the eyelids. When less than one-third is missing, the gaping wound can usually be closed directly. Up to one-third of the lower lid Injuries to the Orbit can also be closed by direct suturing. When more than this is lost or when it has been trans- Blows on the side of the cheek and across one ferred to the upper lid, a slide of tissue from the or other eye occur in ghts, industrial accidents lateral canthus can be effected, combined if nec- and road trafc accidents. Here the globe One of the most important features of the and contents of the orbit are forced backwards, repair of lid injuries is the method of suturing. An untidy repair can there is mechanical limitation of upward move- result in a permanently watering eye because of ment. This interferes with the the orbital oor, can also be injured, producing proper moistening of the cornea during blink- anaesthesia of the skin of the cheek. Special attention must be surrounding swelling has subsided, the post- erior displacement of the globe becomes obvious and the globe of the eye itself often shows evidence of contusion. A considerable improvement from the functional and cosmetic point of view can be obtained by positioning a plastic or Teon implant in the oor of the orbit after freeing the prolapsed tissue. Fractures of the skull that extend into the orbit can be accompanied by retro-orbital haemor- rhage and proptosis. Cranial nerve palsies affect- ing the ocular movements are also commonly seen in this type of injury and the vision can be affected by optic nerve damage. There is usually severe pain and photophobia so that The eyes might be exposed to a wide range of it might not be possible to open the eyes, electromagnetic radiation from the shorter hence the term snow blindness. The use of wavelength ultraviolet rays through the wave- locally applied steroid and antibiotic drops lengths of visible light to the longer infrared hastens recovery. X-rays pass Unlike ultraviolet light, infrared rays pene- straight through the eye without being focused trate the eye and can cause cataract. A specic by the optical media and, in large enough doses, kind of thermal cataract has been well des- can cause generalised damage. It is important to cribed in glass-blowers and furnace workers realise that therapeutic but not diagnostic doses but this is now rarely seen because of the use of of X-rays tend to cause cataracts and the eye protective goggles. As one might expect, visible often expressed in the press or elsewhere about light does not normally damage the eyes, the possibility of radiation damage to the eyes although an intense light source can be absorbed from visual display units. Such damage has by the pigment epithelium behind the retina and never been demonstrated any more than it has converted to heat, producing a macular burn. Someone not After eclipses of the sun, there are usually a used to working with a visual display unit who number of patients who arrive in the casualty is suddenly made to spend several hours a day departments of eye hospitals with macular in front of one might experience eyestrain, esp- oedema and sometimes serious permanent ecially if incorrect spectacles are worn. The laser beam provides a source of intense light, which is used widely in ophthalmology as Chemical Injuries a deliberate means of producing gentle burns in the retina or making holes in the lens capsule These are quite common but usually not severe after cataract surgery. In indus- use of lasers can cause blinding foveal burns as trial premises there is now nearly always a rst- the subject tends to look directly at the beam aid post with facilities to wash out the eyes. Ultra- Plain water or a salt solution is the best uid to violet rays, which are shorter than visible light, use and valuable time may be lost if washing is do not normally penetrate the eye but in large delayed in order to search for a specic antidote. On the skin this is seen as erythaema used in the manufacture of plastics or from and later pigmentation, and on the cornea a alkalis, such as caustic soda. Acid burns as from after exposure of the eyes to sunray lamps, and exploding car batteries are quite commonly after exposure to the sun under certain condi- seen in large casualty departments but are tions such as in snow on mountain tops. All usually less severe as acids tend to coagulate these types of ultraviolet injury show a delayed corneal proteins, thereby slowing penetration. It has already been shown that the The simplest way to measure visual acuity differential diagnosis of the red eye can be might be to determine the ability to distinguish simplied by noting the vision in the affected two points when placed close together (resolu- eye. Such a method was supposed to have been tant to note the vision in the uninjured eye as in used by the Arabs when choosing their horse- the injured eye. They chose only those who were able to acuity is of limited value without a knowledge resolve the two stars that form the second star of the spectacle correction or whether the in the tail of the Great Bear constellation. This corrected visual acuity can also be est- the optical media are not perfect and allow imated with a pinhole held in front of the eye. In practice,it is pos- The effect of the pinhole is to eliminate the sible for a person with normal vision to distin- effect of refraction by the cornea and the lens guish two points if they are separated by on the extremely thin beam of light produced by 1 mm when placed 10 m away. This Measuring the visual acuity means measuring might be surprising considering that a spot of the function of the macula, which is of course light casts a minimum size of image of 11 mm only a small part of the whole retina. A patient because of scatter, but such an image is not might have grossly impaired visual acuity and uniform, being brighter in the centre than at the yet have a normal visual eld, enabling him to periphery. In fact, the resolving power of the eye walk about and lead a normal life apart from is limited by the size of the cones, which have a being unable to read. This is elds but normal macular function, as is some- placed at a distance of 6 m from the eye. The times seen in retinitis pigmentosa or advanced single large letter at the top of this chart is primary open-angle glaucoma. Here, the patient designed to be just discernible to a normal- 137 138 Common Eye Diseases and their Management sighted person at a range of 60 m.
While the primary trial end point buy npxl 30caps otc top 10 herbs, an improvement in cardiac function (as assessed by changes in peak systolic radial strain) was not statistically signicant purchase npxl 30caps free shipping herbs montauk, a trend to improvement was noted 30 caps npxl visa herbs to help sleep. More encouragingly purchase npxl 30 caps on-line 18 herbals, signif- icant improvement in one of the secondary end points, peak expiratory ow, was recorded. From a skeletal muscle perspective, no signicant improve- ment in upper limb muscle strength was seen. Unsurprisingly, as with many other readily available natu- rally derived compounds, alternative uses have been explored. Febrifugine and its derivatives have been investigated in the treatment of a variety of other diseases, including oncology and inammatory diseases, although the parent compound itself was found to exhibit gastrointestinal toxicity, and so was considered to be unsuitable for further development. In an eort to mitigate this undesirable side eect a range of analogues were synthesised. The Israeli biotechnology company Collguard Phar- maceuticals pursued halofuginone for various brotic indications, although these never progressed beyond early clinical trials. Results from a Phase 1 trial have been published as part of an oncology drug development programme,44 with the intention of investigating phar- macokinetics and safety of the compound, as have various sets of animal pharmacokinetic data. Pharmacokinetic evaluation showed halofuginone to 1 have a long plasma half-life of $30 hours, with plasma levels of $0. Repeat-dose studies showed compound accumulation, a not unexpected consequence given the long half-life of the compound. Of rather more concern were a number of unexplained bleeding events recorded during the trial, some of which proved fatal. The underlying reason for these, and how (or if) they were connected with the drug treatment or the disease itself, were not established. The eect of halofuginone on brosis in animal models of muscular dystrophy has been studied in some detail, and therapeutically relevant levels of ecacy seen. Investigation of the nature of the dosing therapy was also carried out, and it was established that if dosing of halofuginone was discontinued, then collagen content of muscle was elevated relative to the corresponding muscle in animals where continued dosing was main- tained. This implies that chronic treatment using this type of antibrotic treatment would be required in patients in order to have continued thera- peutic benet. It is only in recent years that more specic details of the mode of action of halofuginone in disease have started to be unravelled, although it is important to note that the parent compound itself is known to exist in equilibrium with a cyclic hemi-acetal derivative,38 and it is possible that the compound has activity on multiple pharmacological targets and pathways. Given the relatively low molecular weight and multiple potential pharmacophores present within the compound though, it seems likely that other biological targets of hal- ofuginone will be discovered, which may contribute to its pharmacological eects. Furthermore, this knowledge will allow further possible toxicological eects to be anticipated and tested proactively. A critical consideration with any reproling approach is availability of adened target hypothesis and accompanying assay system to test the compounds. Alignment of both the optimal compound set with a suitable test system with disease relevance is therefore essential. Given the encouraging results seen using the mdx mouse, results in patients will be of great interest to the scientic community. Following completion of the study, there was no evidence of ecacy with either the cyclosporin as a monotherapy, nor in combination with prednisone in providing improvement in the muscle strength of trial participants. Following 15 months of once daily oral dosing to mdx mice, striking eects on both muscle structure and function were seen, although the mechanism through which it acted was not clear. Importantly, signicant improvements were also seen in both the diaphragm and cardiac muscles, which oen prove refractory to experi- mental therapeutics. Alternative therapeutic modalities other than small molecules have been the subject of much investigation. Results from the Phase 1 clinical evaluation of a dystrophin mini-gene have been published,68,69 and the prospects for the approach recently reviewed. Although not observed in all treated patients, this phenomenon appeared to be associated with the exons downstream from the missing sections of the patient s dystrophin gene. Aside from the fact that this agent required direct injection to the site of action, and issues therefore remain over delivery to the heart and diaphragm muscle, it high- lights an important additional advantage for small-molecule therapeutic approaches such as those described elsewhere in this section. Aside from some cases involving compounds that form covalent bonds with biological targets (i. Further compounding the hereditary aspects of the disease is the fact that dystrophin is the largest gene in the human genome, and therefore the chances of spontaneous mutations occurring is far more likely than in most other genes. It is also for this reason that genetic screening of adults is unlikely to completely eliminate occurrence of the disease. Morpholino, and other related compounds ( oligos ), are chemically more stable derivatives of oligonucleotides, and have been extensively investigated as agents for promoting exon skipping. Indeed, several have demonstrated ecacy using in vivo models such as the mdx mouse. Hence they can be viewed as a development from anti-sense gene silencing strategies. While progress has been encouraging, with activity of morpholinos seen in clinical trials, a number of challenging technological questions remain, and have hampered the wider applicability of the strategy. Foremost amongst them relates to how to achieve the most eective and systematically widespread delivery of drug to patients, because the compounds evaluated clinically to date are not orally available molecules and thus far have had to be injected directly to the site of the aected muscle in both pre-clinical experiments using animals,80 as well as in clinical studies. This also suggests that there will be limited opportunity to treat cardiac muscle using this strategy, although one can imagine combination therapy with other therapeutic paradigms being explored. Micro- encapsulated derivatives have shown encouraging data, but nonetheless wider systematic bioavailability is still a problem. Ultimately, exon-skipping strategies should allow production of functional dystrophin protein in individuals who carry the mutation in that particular exon, although importantly the dystrophin protein produced is shorter. In an extension of this strategy, a screening approach was employed by Miceli and co-workers to search for small molecules that could enhance exon skipping. View Online Drug Discovery Approaches for Rare Neuromuscular Diseases 279 Data from both in vitro assays (mdx and human muscle cells), and func- tional tests in mdx mice indicated the eects of anti-sense were augmented by dantrolene, and although the precise mechanisms in play are not clear at this time, the results were encouraging in their own right and provide precedent for the use of drug combinations. Encouraging increases in dystrophin levels were seen in patient biopsies, and no series safety issues were noted. Increases in dystrophin protein have been seen in preclinical87 and clinical studies. Results from Phase 1 and 2 clinical trials for this agent were published recently. The advantage of the class was that the drugs had already been evaluated in humans as antibiotics (which was in fact where the ground-breaking observation of their stop codon read-through ability was originally made),95 and therefore had a known toxicological prole. Thus, in a way they could also be seen as a very early example of the reproling approach paying therapeutic dividends. The net result is that the usual discrimination which takes place in reading of codons during translation is relaxed somewhat, and allows for incorporation of an amino acid, rather than termination of translation occurring. Specically, the expression of dystrophin in cultured mdx muscle cells as well as in vivo in the mdx mouse itself was initially demonstrated using genta- micin 11. Encouragingly, gentamicin appeared to be well toler- ated in patients, with no signs of toxicity. At the end of the study, muscle biopsies revealed that dystrophin levels in several of these patients increased signicantly, from <5% to over 15%. This is particularly striking, because protein levels have reached a point that is thought to be therapeu- tically relevant based on the ecacy results previously noted for other read- through agents. Of more concern was the observation that in one subject an immune system T-cell response was noted, although whether this was related to the expression of dystrophin was unclear. It does highlight, however, that careful monitoring of subjects for propensity of immunological adverse events is critical in this paediatric patient population (both pre- and post-trial), particularly due to the chronic dosing anticipated for the agents. View Online Drug Discovery Approaches for Rare Neuromuscular Diseases 283 premature stop codon, vide infra); both of these latter concerns would be circumvented by the use of orally available small-molecule drugs. Compounds that were able to promote read- through of this premature stop codon would therefore result in an increased amount of luciferase expression, and more luminescence.
Communicating veins Clinical features Medial Venous hypertension is heralded by a feeling of heavi- malleolus ness in the legs and by pitting oedema purchase 30 caps npxl otc herbals product models. Other signs include: 1 red or bluish discoloration; 2 loss of hair; 3 brown pigmentation (mainly haemosiderin from Fig discount npxl 30 caps on-line kan herbals relaxed wanderer. Cause Incompetent perforating branches (blowouts) between Satisfactory venous drainage of the leg requires the supercial and deep veins are best felt with the three sets of veins: deep veins surrounded by muscles; patient standing discount npxl 30caps online herbals a to z. Under favourable conditions the supercial veins; and the veins connecting these exudative phase gives way to a granulating and togetherathe perforating or communicating veins healing phase discount npxl 30caps line herbs chart, signalled by a blurring of the ulcer mar- (Fig. When the muscles relax, with the help of gravity, the leg the look of an inverted champagne bottle. If an ulcer has a hyper- plastic base or a rolled edge, biopsy may be needed to rule out a squamous cell carcinoma (Fig. The most important differences between venous and other leg ulcers are the following. Their edges are often sharply dened, their outline may be polycyclic and the ulcers may be deep and gangrenous. Cryoglobulinaemia Neuropathy Diabetes mellitus Leprosy The involvement of larger vessels is heralded by painful Syphilis nodules that may ulcerate. The intractable deep Syringomyelia sharply demarcated ulcers of rheumatoid arthritis are Peripheral neuropathy caused by an underlying vasculitis (Fig. These may appear at odd sites, Treatment such as the thighs, buttocks or backs of the calves. The most common types of panniculitis that ulcerate Venous ulcers will not heal if the leg remains swollen are lupus panniculitis, pancreatic panniculitis and and the patient chair-bound. Those caused by a squamous cell A common error is to use local treatment that is too carcinoma (p. Furthermore, squamous cell carci- the ward for many months only to have their appar- noma can arise in any longstanding ulcer, whatever ently well-healed ulcers break down rapidly when its cause. These large and into the following categories: physical, local, oral and rapidly spreading ulcers may be circular or polycyclic, surgical. Pyoderma gangrenosum may complicate Physical measures rheumatoid arthritis, Crohn s disease, ulcerative co- litis or blood dyscrasias. Compression bandages and stockings Compression bandaging, with the compression gradu- Investigations ated so that it is greatest at the ankle and least at the Most chronic leg ulcers are venous, but other causes top of the bandage, is vital for most venous ulcers; should be considered if the signs are atypical. Secure Forte and Coban) are convenient Investigations should include the following. Bandages stay on for 2 7 days at a time and are left Full blood count to detect anaemia, which will delay on at night. Secure Forte and Coban): it requires changing measurement of ambulatory venous pressure help only once a week and is very effective. The combined to detect surgically remediable causes of venous four layers give a 40-mmHg compression at the ankle. Once an ulcer has healed, a graduated compression Doppler ultrasound may help to assess arterial cir- stocking (e. If the maximal systolic ankle pressure divided preferably at pressures of at least 35 mmHg. A foam by the systolic brachial pressure ( ankle brachial pres- or felt pad may be worn under the stockings to pro- sure index ) is greater than 0. Care must be taken with all forms of compression to ensure that the arterial supply is satisfactory and not compromised. Patients should rest with their bodies horizontal and their legs up for at least 2 h every afternoon. The foot of the bed should be raised by at least 15 cm ; it is not enough just to put a pillow under the feet. Walking Walking, in moderation, is benecial, but prolonged standing or sitting with dependent legs is not. Diet silver proteinate in compound calamine cream spread Many patients are obese and should lose weight. The area should be cleaned Local therapy gently with arachis oil, 5% hydrogen peroxide or Remember that many ulcers will heal with no treat- saline before the next dressing is applied. Sometimes ment at all but, if their blood ow is compromised, immersing the whole ulcer in a tub of warm water they will not heal despite meticulous care. The pro- Local therapy should be chosen to: longed use of antiseptics may be harmful. Ointments containing recombinant we have found most useful are listed in Formulary 1 human platelet growth factor may aid revascularization. Lassar s paste, zinc cream or paste bandages (see above) are suitable alternatives. Pressure bandaging is more important as the oedema associated with venous ulceration is largely mechanical. Hospital admission and frequent dressings biotics should be reserved for spreading infections needed to save leg. Bacteriological guidance the development of allergic contact dermatitis to a is needed and the drugs used include erythromycin component of the paste, most often parabens (a pre- and ucloxacillin (streptococcal or staphylococcal servative) or cetostearyl alcohols. These have to be cleaned and dressed more often than clean ones, sometimes even twice daily. May help to promote healing, espe- ganate (1 in 10 000 dilution) and 5% hydrogen per- cially if the plasma zinc level is low. Helpful Oxypentifylline (pentoxyfylline) is brinolytic, in- creams and lotions include 1. It may speed the healing of venous ulcers if function of dextran polymer beads, and starch poly- used with compression bandages. This anabolic steroid may not heal an and are well tolerated, they should not be used for existing ulcer more quickly, but may prevent ulcera- long periods as they can induce bacterial resistance tion in lipodermatosclerosis and may protect against and sensitize. The manufacturer s advice on contrain- povidone-iodine, and a readily applied non-adherent dications, e. These may help the oedema and symptoms of venous hypertension and are said to reduce leakage from capillaries by acting on the endothelial cells. Sheets of human epidermis grown in tissue culture can be purchased and placed on granulating wound beds. Venous surgery on younger patients with varicose veins may prevent recurrences, if the deep veins are competent. Patients with atherosclerotic ulcers should see a vascular surgeon for assessment. Purpura from vasodi- an abnormality of the vessel wall or the surrounding latation and gravity is seen in many diseases of the dermis. It may also cause pura, often palpable and painful, but not bleeding; cold urticaria (p. The bleeding time, and a Hess tourniquet test for cap- When purpura has no obvious cause, investigations illary fragility, help less often. Skin biopsy will conrm should include a platelet count, prothrombin time, a small vessel vasculitis, if the purpura is palpable. The Infected pompholyx primary forms are developmental defects, although Lymphatic obstruction Filariasis signs may only appear in early puberty or even in Granuloma inguinale adulthood. Tumour Lymphatic destruction Surgery Treatment Radiation therapy Tumour Elevation, graduated compression bandages and stockings (p. If erysipelas recurs, long-term penicillin tongue and lymphoedema of lip) should be given. Surgery occasionally helps to remove Yellow nail syndrome an obstruction or restore drainage.
Probabilistic projections suggest that the effect on transmission depends on initial conditions purchase npxl 30 caps on-line wicked herbals amped. Keywords Mixed infections Ticks Coinfection Transmission dynamics Introduction Ticks serve as vectors for numerous pathogens purchase 30caps npxl with visa herbals on wholesale, and individual ticks are often infected with more than one pathogenic organism discount npxl 30caps amex herbals and surgery. Multiple infections can have medical signicance discount npxl 30caps with visa godakanda herbals, because coinfection can increase severity of symptoms in humans and animals (Belongia 2002; Thomas et al. Mixed infections in ticks can also potentially inuence transmission dynamics, because of either interactions between the pathogens within the H. This applies both to vertebrate pathogens in ticks and to entompathogenic organisms. For example, Ross and Levin (2004) found that some strains of Anaplasma phagocytophilum, the etiologic agent of granulocytic anaplasmosis in humans, affect molting of Ixodes scapularis ticks. In cases of mixed infections, these pathogens could potentially inuence transmission of other pathogens in the tick by virtue of their effects on tick behavior and survival. Investigators have used two major approaches to studying the ecological features of mixed infections in ticks. One is to infect ticks with single or multiple pathogens in the laboratory, and to quantify differences in pathogen persistence and transmission to lab animals. This approach gives direct information about pathogen interactions, but these interactions might differ in the laboratory than under eld conditions. The second approach is to quantify infection with each pathogen in eld collected ticks, and to test whether the prevalence of mixed infections is higher or lower than would be expected on the basis of chance alone. This approach provides eld tests of the interactions of pathogens, but interpretation can be difcult because the number of mixed infections results from factors other than just interactions of pathogens. For example, if two pathogens occur in different vertebrate host species, then these pathogens will generally not be found together in nymphal ticks, even if they have no interaction within the tick. Even for ticks with broad host ranges, nymphs have generally fed only once (as larvae) and have therefore acquired pathogens from only one vertebrate host species. In this case, proportions of mixed infections in nymphs would be expected to be lower than in adult ticks, because the nymphs have only fed once while adults have fed twice, and the adults might have picked up infections from different host species. To fully assess the causes of observed levels of coinfection at a given site, it is necessary to conduct laboratory studies and in-depth local eld studies. However, it is also worth- while to ask whether broad patterns of coinfection from numerous eld sites t the hypotheses of antagonistic or of mutualistic interactions within ticks, or whether tick host associations are adequate to explain the observed patterns. Evidence of interactions between pathogens within tick hosts Negative relationships between pathogens A well-known example of negative interactions of rickettsiae within ticks is the transov- arial transmission interference of Rickettsia rickettsii (agent of Rocky Mountain Spotted Fever) in Dermacentor andersoni ticks coinfected with the nonpathogenic Spotted Fever Group rickettsia R. Ticks coinfected with both rickettsiae vertically transmit only the nonpathogenic species, which inuences the distribution of R. Similar negative interactions apparently occur among other arthropod-transmitted rickettsiae (Macaluso et al. When Dermacentor variabilis Diseases of Mites and Ticks 31 males fed sequentially on calves infected with different strains of A. Negative interactions in ticks have also been reported for pathogens other than rick- ettsia. How- ever, this phenomenon could have resulted from the host-nding behavior of the wasp (rather than from pathogen interactions within ticks), because I. Positive relationships between pathogens Sutakova and Rehacek (1990) found increased spread of Coxiella burnetii into tissues of Dermacentor reticulatus in the presence of Rickettsia phytoseiuli. In a survey of 738 Ixodes persulcatus ticks in Russia for infection with Babesia microti (Alekseev et al. Rickettsia amblyommii and Borrelia lonestari also showed higher than random levels of association in this tick. Of course, these high levels of coinfection in eld-collected ticks might have resulted from ecological factors relating to pathogen infections in reservoir hosts and tick feeding preferences, rather than from mutualistic interactions of pathogens within the ticks. No interactions between pathogens Levin and Fish (2000) studied transmission of Borrelia burgdorferi and Anaplasma phagocytophilum by Ixodes scapularis to white-footed mice in the laboratory. They found no differences in transmission rates between singly infected and coinfected ticks. These examples provide evidence that some pathogens display antagonistic interactions in ticks, others display mutualisms, and many apparently do not interact within the ticks. However, they do not provide insight into the frequency of each type of interaction among pathogens within ticks. In the following sections I assess the frequencies of various types of interactions between pathogens within ticks by compiling data from several eld studies 32 J. I then consider the implications of coinfections for trans- mission dynamics of these pathogens. Methods The scientic literature was surveyed to nd studies that reported raw data on infection rates of pathogens in ticks, including mixed infections, with sample sizes large enough for statistical analysis. This survey was restricted to papers where the pathogen strains were identied (thus mostly to recent literature) and where the numbers of individuals infected singly with each pathogen, the number coinfected with both, and the number not infected with either, could be ascertained. Much of this work has been restricted to pathogens of public health importance, so mostly pathogens that have been at least tentatively impli- cated in human illness were included. To quantify the degree of departure of the number of mixed infections from independence, I developed an index of coinfection (Ic), dened as the difference of the number of coinfections from the number expected due to chance alone, as a percentage of the total number of infected ticks in the sample. The index of coinfection (Ic) is: Ic O E=N100 Note that Ic is positive when the number of coinfections is greater than expected, and negative when there are fewer coinfections than would be expected due to chance alone. To assess the potential implications of coinfection for pathogen transmission dynamics, I used a simple binomial model of the probability of exposure to a pathogen (Pe) when an animal is bitten by n ticks, and with a prevalence of infection in ticks of kv (Ginsberg 1993, 2001). Pe is the probability that at least one of the n ticks is infected: n Pe 1 1 kv Results Levels of coinfection of various pathogens in Ixodes ricinus and I. The number of mixed infections differed signcantly from the expectation due to chance alone in about half the cases. One major effect of positive or negative interactions among pathogens within a tick would be to raise or lower infection prevalence of the affected pathogen. When tick numbers are low, the effect on Pe of changes in the proportion of ticks infected is more or less linear. Both of these Borrelia species commonly infect rodents, suggesting that these ticks fed as larvae on rodents with mixed infections. In both cases, the positive associations suggest that there are no negative interactions between these Borrelia species within I. Higher than expected occurrence of pathogens in adult ticks could result from immature ticks feeding on fre- quently coinfected hosts or from positive interactions among the pathogen species (e. Negative associations presumably result from negative interactions between the pathogens. Some Borrelia species primarily infect mammals while others primarily infect birds, but this would only lead to a negative association within a tick species if individual ticks tended to feed on mammals as both larvae and nymphs, while other individuals of the same species tended to feed on birds as both larvae and nymphs. This seems unlikely, although it is plausible that when engorged larvae drop from their hosts, they might be left in microhabitats that would favor them biting the same type of host after molting to the nymphal stage. Most pairs of Borrelia species showed at least some examples of higher than expected coinfections. Thus positive associations could result from ticks feeding on coinfected hosts of both mammal-associated species such as B. The one pair of Borrelia genospecies that generally showed lower than expected levels of coinfection was B. Nevertheless, nymphal ticks can attach to different hosts than larvae, so this negative association might suggest a negative interaction between these pathogens within I.
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