Mark Corson

By Y. Hamid. Harris-Stowe State College. 2018.

She was noted at that time to have a large liver cyst consistent with Echinococ- cus buy sinemet 125 mg mastercard. Although she was asymptomatic sinemet 300 mg with mastercard, resection of the left lobe of the liver was performed that year cheap 125 mg sinemet fast delivery. Despite surgical resection, she experienced recurrent cysts and on three occasions underwent percutaneous aspiration followed by injection of hypertonic saline. One month before admission and 6 years after her last aspiration and injection procedure,she began coughing up blood. Her coughing then became productive of gelatinous,foul-smelling serosanguinous uid. Pulmonary exam revealed decreased breath sounds and dullness to percussion at the right base. A computed tomography scan with both breath sounds and E-to-A changes were noted in the oral and intravenous contrast shows multiple echinococ- right posterior mid-lung eld. Humans represent an inadvertent intermediate host, the infection being contracted by ingestion of food contaminated with viable parasite eggs. In the southwestern United States, most cases are the infection being detected incidentally on an imag- contracted from sheep dogs. Symptoms generally develop when the Echinococcus multilocularis is the fox, and domestic cats hydatid cyst reaches a size of 8 to 10 cm and begins and dogs become secondarily infected. Because eggs are compressing vital structures or eroding into the biliary partially resistant to drying and can remain viable for tract or a pulmonary bronchus (as occurred in case many weeks, food can become contaminated without 12. The cysts can also become superinfected, result- coming in direct contact with infected animals. Cyst leakage or rupture can Ingested eggs hatch in the intestine, forming result in an anaphylactic reaction, causing fever and oncospheres that penetrate the bowel wall, enter the hypotension. Asymptomatic disease commonly the liver and lungs, and less frequently the caused by Echinococcus granulosus rarely progresses; brain, heart, and bones where they encyst. The resulting however, 90% of cases of asymptomatic Echinococcus hydatid cysts consist of a germinal membrane that pro- multilocularis infection eventually progress to sympto- duces multiple tapeworm heads and that also undergoes matic disease. To reduce the risk of spread, aspiration of the cyst is recommended a procedure that involves removing a fraction of the contents and instilling a hypertonic Causes neurologic complications in a signicant saline solution (30% NaCl), iodophore, or 95% ethanol number of infected patients many years after the to kill the germinal layer and daughter cysts. In cases with biliary communica- tion, the foregoing cidal agents are not recommended because of the risk of inducing sclerosing cholangitis. Like Echinococcus, Taenia can be contracted by period is generally recommended to limit the risk of ingesting viable eggs or by eating raw or undercooked intraoperative dissemination. Once ingested, the is recommended for patients with inoperable hydatid eggs hatch or the encysted larvae are released into the cyst (see Table 12. Cysts may lodge in the cerebral ventricles (causing hydrocephalus), the spinal cord About Echinococcus (resulting in cord compression and paraplegia), the subarachnoid space (causing chronic meningitis), or 1. Spread primarily by domestic dogs,who excrete the cerebral cortex (causing seizures). Eggs survive in dust and remain asymptomatic for many years, becoming clin- contaminate food. Eggs hatch in the intestine and oncospheres associated with cyst swelling and increased inamma- enter the bloodstream, where they migrate to tion. Larvae also encyst in other tissues (skin and mus- the liver or lung,or (less commonly) to the brain, cle), but rarely cause symptoms. Hydatid cysts survive and grow over decades, causing symptoms when they reach 8 to 10 cm Diagnosis and Treatment in diameter. Diagnosis is made by computed tomography Computed tomography or nuclear magnetic resonance scan or ultrasonography. Treatment involves administration of albenda- ing discrete cysts that may enhance following the zole, combined with surgical resection pre- administration of contrast media depending on ceded by instillation of an agent cidal to the the degree of surrounding inflammation. Alternatively, percutaneous nee- infection, multiple lesions are generally detected. A recent randomized trial and a meta-analysis suggested that in symptomatic patients with cortical lesions, albendazole combined with oral dexamethasone (2 mg three times daily) or oral prednisone (40 mg daily) enhances resolu- tion of the lesions and reduces the incidence of seizures. Surgical resection of cysts may be required depending on the symptoms and on size and location of the offend- ing cyst. In late disease,how does egg deposition cause clini- reveals lymphocytes or eosinophils accompanied by cal symptoms? Serologic tests detecting antibody directed against Taenia solium may be positive, particularly in patients with multiple cysts. Albendazole and praziquantel may kill living Usually a chronic disorder resulting in debilitating complications. Contracted by ingesting eggs in fecally contam- inated food or encysted larvae in undercooked pork. Symptoms develop after many years when the are estimated to infect between 200 and 300 million peo- larvae die, causing increased inammation. Can cause seizures, hydrocephalus, paraplegia, United States because the critical intermediate host a and meningitis. Diagnosis is made by computed tomography approximately 400,000 imported cases occur in immi- scan, magnetic resonance imaging, or serology. Treatment involves administration of albenda- Brazil), the Middle East, and the Philippines. The parasite is contracted by exposure to fresh water A 32-year-old man was evaluated for a lesion of the containing infectious cercariae. He had been well until 16 months are able to swim to and penetrate the skin of people earlier. Soon after returning from a 1-week vacation wading in stagnant infested freshwater pools or rice pad- dies.

Some of the Plasmodium species have diverged tens of millions of years ago order sinemet 110mg line, so it is not surprising that they have dierent strategies for attach- ment sinemet 110 mg on-line, immune evasion cheap sinemet 300 mg with mastercard, and antigenic variation. The parasite expresses only a small subset of these genes in an infected erythrocyte. Sera from twenty-ve previously infected hosts provided a panel of antibodies to test for prior exposure to the vir gene products. One of the expressed proteins reacted with the serum from only one host, the other proteinreacted with sera from two hosts. Thus, vir gene products are immunogenic, but each variant appears to be expressed rarely the hallmarks of antigenic variation from a large archival library. Thediversityofgene families in Plasmodium that play a role in antigenic variation provides an excellent opportunity for comparative, evolutionary studies. These vsp loci are silent, archival copies that can, by gene conversion, be copied into the single expression site. The genes dier by 30 40% in amino acid sequence, providing sucient diversity to reduce or elimi- nate antigenic cross-reactivity within the host. Those analysesfocuson attributes such as runs of similar nucleotides between loci that occur more often than would be likely if alleles di- verged only by accumulating mutations withineachlocus. The archival antigenic repertoire of Trypanosoma brucei evolves rap- idly (Pays and Nolan 1998). This species has a large archival library and multiple expression sites, but only one expression site is active at any time. New genes can be created within an active expression site when several donor sequences convert the site in a mosaic pattern (Pays 1989; Barbet and Kamper 1993). When an active expression site becomes inac- tivated, the gene within that site probably becomes protected from fur- ther gene conversion events (Pays et al. Perhaps new genes in silent expression sites can move into more per- manent archival locations by recombination, but this has not yet been observed. These examplesillustrate the scattered reports of recombination and the evolution of archived repertoires. These preliminary studiesshow the promise for understanding the interaction between mechanisms that create diversity and the strong forces of natural selectionimposed by immune recognition. Thecombination of generative mechanisms and selection shapes the archival antigenic repertoire. Reassortment of inuenza A s neuraminidase and hemagglutinin sur- face antigens provides the most famous example (Lamb and Krug 2001). When two or more viruses infect a single cell, the parental segments all replicate separately and then are packaged together into new viral particles. New neuraminidase-hemagglutinin combinations present novel anti- genic properties tothehost. Rare segregation events have introduced hemagglutinin from bird inuenza into the genome of human inuenza (Webster et al. The novel hemagglutinins cross-reacted very lit- tle with those circulating in humans, allowing the new combinations to sweep through human populations and cause pandemics. Intergenomic recombination occurs when chromosomes from dier- ent lineages exchange pieces of their nucleotide sequence. In protozoan parasites such as Plasmodium and Trypanosoma,recombination hap- pens as part of a typical Mendelian cycle of outcrossing sex (Jenni et al. Recombination can occur in viruses when two or more particles infect a singlecell. In all cases, even rare recombination can provide an important source for new antigenic variants. To what extent have molecular attributes of antigenic genes been shaped by the costs and benets of generat- ing variants? Do microbes under intense immune pressure have higher genome-wide mutation rates compared with similar organisms that do not face immune attack? To what extent have nucleotide sequences of antigens been shaped by the tendency of particular motifs to generate replication errors a form of local hypermutation? Idescribed various mechanisms bywhichgene expression shifts between archived variants. The rate at which switches occur prob- ably aects the parasite s ability to extend infection. If switches happen too quickly, then novel variants will not be expressed after the immune response develops against the many variants expressed early in infec- tion. If switches happen too slowly, then the parasite may be cleared before the variants are expressed. Thus, natural selection can strongly inuence the molecular details of the switch process in order to adjust the rate of change between variants. One could also test the evolution of the switch rate in vivo, comparing situations that imposed dierent immune pressures on rates of change and on particular orders in which variants are expressed. Such studies allow one to relate the molecular mechanisms of switching to the adap- tive signicance of switching. I described studies of Borrelia hermsii and Trypanosoma brucei in which intrage- nomic recombination between archival copies generated new variants. This calls attention to the rate at which new variants can be created and the rateofdiversication between members of archival gene families. If this estimate is correct, then the diverse var family of antigenic variants must have evolved very rapidly. However, this conclusion remains contentious Hughes and Verra (2001) argue that the P. It would be interesting to compare rates of diversication in these families of variants between the dierent Plasmodium species, Trypano- soma brucei, Borrelia hermsii,andother microbeswithsimilar families of variants.

This may seem a bizarre and unlikely prospect but one that is not beyond the bounds of possibility if a few more celebri- ties could be persuaded to aunt their hair loss rather than advertise ctitious remedies generic 300 mg sinemet with mastercard. Classication of the types of androgenetic alopecia (common baldness) occurring in the female sex buy discount sinemet 110mg on-line. Measuring reversal of hair miniaturization in androgenetic alopecia by follicular counts in horizontal sections of serial scalp biopsies: results of nasteride 1 mg treatment of men and postmenopausal women purchase sinemet 125mg free shipping. Follicular miniaturization in female pattern hair loss: clinicopathological correlations. Characterization of inammatory inltrates in male pattern alopecia: implications for pathogenesis. Characterization and chromosomal mapping of a human steroid 5 alpha-reductase gene and pseudogene and mapping of the mouse homologue. The effects of N,N-diethyl-4-methyl-3- oxo-4-aza-5androstane-17carboxamide, a 5reductase inhibitor and antiandrogen, on the development of baldness in the stumptail macaque. Hair growth effects of oral administration of nasteride, a steroid 5 alpha-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque. The prevalence of hyperandrogenism in 109 consecutive female patients with diffuse alopecia. Role of androgens in female-pattern androgenetic alopecia, either alone or associated with other symptoms of hyperandrogenism. Serum androgens and genetic linkage analysis in early onset androgenetic alopecia. Insulin gene polymorphism and premature male pattern baldness in the general population. Polymorphism of the androgen receptor gene is associated with male pattern baldness. Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia. The E211 G>A androgen receptor polymorphism is associated with a decreased risk of metastatic prostate cancer and androgenetic alopecia. The psychosocial consequences of androgenetic alopecia: a review of the research literature. Psychological effects of androgenetic alopecia on women: comparisons with balding men and with female control subjects. Psychological characteristics of women with androgenetic alopecia: a controlled study. The reliability of horizontally sectioned scalp biopsies in the diagnosis of chronic diffuse telogen hair loss in women. Changes in hair weight and hair count in men with androgenetic alopecia, after application of 5% and2% topical minoxidil, placebo or no treatment. A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. Five-year follow-up of men with androgenetic alopecia treated with topical minoxidil. The effects of nasteride on scalp skin and serum androgen levels in men with androgenetic alopecia. Use of nasteride in the treatment of men with androgenetic alopecia (male pattern hair loss). An open, randomized, comparative study of oral nasteride and 5% topical minoxidil in male androgenetic alopecia. The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus nasteride. Quantitative assessment of spironolactone treatment in women with diffuse androgen-dependent alopecia. The diagnosis and treatment of iron deciency and its potential relationship to hair loss. The importance of adequate serum ferritin levels during oral cyproterone acetate and ethinyl oestradiol treatment of diffuse androgen-dependent alopecia in women. A randomized, placebo-controlled trial of 1% topical minoxidil solution in the treatment of androgenetic alopecia in Japanese women. Patients present with a complaint of increased shedding over normal levels and associated diffuse alopecia. The excessive shedding is the result of alterations of the hair-growth cycle with premature conversion of anagen follicles to telogen follicles, which represents a shift of 7 25% of anagen follicles to telogen (Fig. It presents as acute (<4 months), chronic (>4 months), and chronic-repetitive (Fig. The primary insult is to the dermal papillae of the anagen fol- licle, which induces an early shunt to telogen. Regeneration of the follicle is determined by the bulge area, so any damage, stress, or inammation that involves the bulge will affect regenera- tion (Fig. The shedding results in a diffuse loss with a more prominent central and frontal scalp loss. The patient usually relates loss of body hair and a diminished rate of hair growth, espe- cially of leg hair. When a trigger is identied and removed or treated, the patient experiences diminished shedding and later regrowth of hair (Table 3). The differential diagnosis of diffuse alopecia includes androgenetic alopecia, diffuse alopecia areata, and an inammatory alopecia such as central centrifugal cicatricial alopecia and lichen planopilaris, especially when the primary loss involves the central scalp.

One could also test the evolution of the switch rate in vivo cheap 110 mg sinemet with mastercard, comparing situations that imposed dierent immune pressures on rates of change and on particular orders in which variants are expressed buy sinemet 125mg free shipping. Such studies allow one to relate the molecular mechanisms of switching to the adap- tive signicance of switching effective 300mg sinemet. I described studies of Borrelia hermsii and Trypanosoma brucei in which intrage- nomic recombination between archival copies generated new variants. This calls attention to the rate at which new variants can be created and the rateofdiversication between members of archival gene families. If this estimate is correct, then the diverse var family of antigenic variants must have evolved very rapidly. However, this conclusion remains contentious Hughes and Verra (2001) argue that the P. It would be interesting to compare rates of diversication in these families of variants between the dierent Plasmodium species, Trypano- soma brucei, Borrelia hermsii,andother microbeswithsimilar families of variants. The immune response focuses on only a few of the many po- tential epitopes, a process called immunodominance. Immunodominant focus determines which epitopes are favored to vary antigenically to es- cape immune pressure. In this chapter, I describe how immunodomi- nance develops by competition among B and T celllineageswith dier- ent specicities. The diverse, naive B cells secrete IgM antibodies that bind to nearly any epitope. On initial infection, B cells that bind epitopes with relatively high equilib- rium anity divide rapidly and dominate the early phase of the immune response by outcompeting other B cells. However, antibodies that bind too strongly clear the matching antigens quickly and prevent feedback stimulation to their B cells. The later phases of B cell competition and maturation of IgG favor antibodies with increased on-rates of associa- tion to epitopes rather than increased equilibrium binding anity. Earlier stimulation of T cell lineages in response to infection rather than more rapid T cell division seems to determine the dominance of lineages. Dominant lineages may repress subdominant lineages bypushing the abundance of pathogens below the threshold needed to trigger weaker, subdominant responses. The third section describes original antigenic sin, in which the speci- city of the immune response depends on the sequence of exposure to antigenic variants. If a host rst encounters a variant A and then alatervariant A,thesecond variant will sometimes restimulate the initial response against A rather than a new, specic response against A. Inthiscase,A recalls the memory against an earlier cross-reacting epitope rather than generating a primary, specic response against it- self. The initial antibody response, detected one week after injection into a mouse, contained heterogeneous IgM against several epitopes that collectively spanned theentire 100-amino-acid sequence. By contrast, the IgG response four weeks after injection was highly specic for a single epitope. These ob- servations support the idea that the naive antibody repertoire can bind almost any epitope, but that only a subset of the initially binding anti- bodies stimulate their B cell clones to expand signicantly and make the transition to IgG production. Thus, B cell stimulation requires binding to an epitope of an antigen, processing the antigen, and nding a helper T cell that can bind an epitope of the same antigen. T cell stimulation causes B cells to divide more rapidly, to undergo somatic hypermutation, and to switch from IgM to IgG production. Immuno- dominance arises when some B cells receive relatively greater stimula- tion from helper T cells. The vertebrate host has specialized organs to facilitate interaction be- tween B and T cells. The initial interaction occurs when antigen-binding Bcells are trapped in a zone of lymphoid tissue that has a high density of T cells. Some of the stimulated B cells dierentiate into antibody fac- tories, whereas others migrate along with matching T cells to primary follicles of the lymphoid tissue. There, if the B cells receive sucient stimulation from T cells, they undergo rapid division to form germinal centers. The relative stimulation of dierent B cell clones by an antigen determines progression to the next steps in B cell response. Very strong epitope-paratope binding prevents stimulation; weakly binding Bcells are outcompeted for stimulatory signals. One of these epitopes stimulated the immunodominant IgG response; the other wasatthe opposite end of the peptide. They began by constructing a peptide that had on one side a known B cell antigen of hepatitis B virus and on the other side a known T cell epitope from the malaria parasite Plasmodium falciparum. The early IgM response had specicities that spanned the entire hepatitis B segment. Immunodominance depended on competition for antigen-specichelperTcells, which arelimiting during the initial stages of an immune response. In laterexperiments, Agarwal and Rao (1997) manipulated the size of the helper T cell pool. Reduced numbers of T cells allowed IgM response but prevented the switch from the IgMstagetothe IgG stage. This sup- ports the hypothesis that competition for T cell help is the rate-limiting step in the transition from the broad IgM response to the narrow IgG response. This led to the hypothesis that the Gibbs free-energy of binding between epitope and paratope determines antibody anity, and that the amino acid sequence of the epitope inuences the potential free-energy of the bond. They suggested that the relative ordering of anities for particular epitopes could be predicted by the amino acid sequence of the epitope. In particular, the amino acid side chains of an epitope sequence determine the potential free-energy of binding to an antibody paratope. Chemical determination of free-energy seems particularly important in the early phases of antibody response, when the antibodies have not yet been optimized for binding by anity maturation.

The primary adverse reac- thromycin administration has 125 mg sinemet otc, on rare occasions cheap sinemet 300 mg visa, been tions are related to these agents ability to stimulate associated with ventricular tachycardia purchase sinemet 110mg fast delivery. In fact, erythromycin can be used to These agents are metabolized by the cytochrome treat gastric paresis. Gastrointestinal toxicity can be debil- itating, forcing the drug to be discontinued. Patients have also experienced diplopia following ing in peak concentrations within 1 hour. Talithromycin treatment has and azithromycin should be taken on an empty stom- also resulted in the sudden onset of severe and occasion- ach. Cidal activity increases when antibiotic concentra- tions are high and bacteria are growing rapidly. Complex 14- to 15-member lactone ring struc- Resistance is more likely in intermediately penicillin- ture. Transient hearing loss with high doses, mainly single mutation, macrolides are generally not recom- in elderly individuals. Metabolized by the cytochrome P450 3A4 sys- Macrolides are the primary antibiotics used to treat tem; increase serum concentrations of other the two major pathogens associated with atypical pneu- drugs metabolized by that system. In many instances the erythromycins can be used as an alternative to peni- absorption and lower incidence of gastrointestinal toxi- cillin in the penicillin-allergic patient. Azithromycin is not bination with other antibiotics is also recommended for metabolized, being excreted unchanged in the bile. Clarithromycin levels in cobacter pylori include azithromycin or clarithromycin middle ear uid have been shown to be nearly 10 times combined with bismuth salts and either amoxicillin, serum levels. Single high-dose exceed serum levels by a factor of 10 to 100, and its aver- azithromycin (1 g) effectively treats chancroid, as well as age half-life in tissues is 2 to 4 days. Single- azithromycin have been estimated to persist for 5 days dose therapy also cures male Ureaplasma urealyticum after the completion of a 5-day treatment course. In the penicillin-allergic patient, clindamycin is a reasonable alternative for 1. Increased use of macrolides selects for resistant Clindamycin distinguishes itself from the macrolides by strains of Streptococcus pyogenes and S. It is used effectively in combination with an aminogly- niae are often resistant to macrolides. Talithromycin is effective against multi-resistant treat fecal soilage of the peritoneum. Recommended for treatment of Legionella damycin in combination with a rst-generation pneumophilia. Clarithromycin is a primary drug for treatment mended as alternative therapy in the sulfa-allergic patient. It binds to the same 50S ribosomal bind- ing site used by the macrolides, blocking bacterial protein synthesis. Clindamycin penetrates most tissues, but it penicillin-resistant Streptococcus pneumoniae, does not enter the cerebrospinal uid. Used to treat anaerobic lung abscesses and Small percentages of clindamycin metabolites are also toxoplasmosis in the sulfa-allergic patient. This blockade primarily including doxycycline and tigecycline are cleared pri- inhibits protein synthesis in bacteria, but to a lesser marily by the liver. Therefore, tetracycline is The tetracyclines are able to inhibit the growth of a termed a bacteriostatic agent. High concentrations of tetra- Photosensitivity reactions consisting of a red rash over cycline are achieved in the urine, and this agent can be sun-exposed areas can develop (Table 1. Doxy- tivity reactions are less common than with the penicillins, cycline combined with gentamicin is the treatment of but they do occur. Tetracyclines are also recom- mation, and in children, teeth often become permanently mended for the treatment of Lyme disease (Borrelia discolored. Because the tetracyclines inhibit protein synthe- thritis, and endocervical infections). They are also often used in combina- tumor cerebri) is another rare neurologic side effect. Doxycycline is effectively inhibits the growth of many resistant nearly completely absorbed in the gastrointestinal gram-positive bacteria (Table 1. Organisms That May Be Susceptible to the Tetracyclines Tetra-,Doxy-,and Minocycline Tigecycline Vibrio spp. The reticulocyte count decreases, and ane- About the Tetracyclines mia develops in association with elevated serum iron. Toxicities include photosensitivity, interference patient receiving chloramphenicol requires twice- with dental enamel formation in children, gas- weekly monitoring of peripheral blood counts. Recommended, in combination with other oral preparations of chloramphenicol are no longer antibiotics, for pelvic inammatory disease. Oral absorption blocked by calcium- and absorbed, and therapeutic serum levels can be magnesium-containing antacids, milk, and achieved orally (Table 1. Tigecycline has improved gram-positive and and crosses the blood brain barrier in uninamed as gram-negative coverage, with the exception of well as inamed meninges. It is and serum levels should be monitored in patients with approved for complicated intra-abdominal and hepatic disease, maintaining the serum concentration soft-tissue infections.