By Q. Runak. Allegheny College.
Diabetic medicine : a journal of the British Diabetic Association 2008;25(9):1129-31 cheap tadapox 80 mg mastercard impotence pronunciation. A randomized generic 80 mg tadapox amex erectile dysfunction and diabetes type 2, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association Functional Class I or II Heart Failure 80mg tadapox sale impotence male. A 24-week discount tadapox 80mg without prescription erectile dysfunction without pills, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of the efficacy and tolerability of combination therapy with rosiglitazone and sulfonylurea in African American and Hispanic American patients with type 2 diabetes inadequately controlled with sulfonylurea monotherapy. Addition of pioglitazone to stable insulin therapy in patients with poorly controlled type 2 diabetes: results of a double-blind, multicentre, randomized study. Increased high-density lipoprotein cholesterol predicts the pioglitazone-mediated reduction of carotid intima-media thickness progression in patients with type 2 diabetes mellitus. Efficacy of inhaled insulin in patients with type 2 diabetes not controlled with diet and exercise: a 12-week, randomized, comparative trial. Effects of 1 year of treatment with pioglitazone or rosiglitazone added to glimepiride on lipoprotein (a) and homocysteine concentrations in patients with type 2 diabetes mellitus and metabolic syndrome: a multicenter, randomized, double-blind, controlled clinical trial. Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with glimepiride: a twelve-month, multicenter, double-blind, randomized, controlled, parallel-group trial. Modulation of adipokines and vascular remodelling markers during OGTT with acarbose or pioglitazone treatment. Blood pressure control and 2 Exclude Excluded References Code inflammatory markers in type 2 diabetic patients treated with pioglitazone or rosiglitazone and metformin. Hypertension research : official journal of the Japanese Society of Hypertension 2007;30(5):387-94. Pioglitazone metabolic effect in metformin-intolerant obese patients treated with sibutramine. Rosiglitazone therapy improves insulin resistance parameters in overweight and obese diabetic patients intolerant to metformin. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Current Medical Research and Opinion (England) 2009;25(4):1019-27. Effect of pioglitazone versus insulin glargine on cardiac size, function, and measures of fluid retention in patients with type 2 diabetes. Differences in effects of insulin glargine or pioglitazone added to oral anti-diabetic therapy in patients with type 2 diabetes: what to add--insulin glargine or pioglitazone? Rosiglitazone and myocardial infarction in patients previously prescribed metformin. The risk of fractures associated with thiazolidinediones: a self- controlled case-series study. Glucose control and vascular complications in veterans with type 2 diabetes. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08). The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. The effect of exenatide re-exposure on safety and efficacy. Angiographic and clinical outcomes of rosiglitazone in patients with type 2 diabetes mellitus after percutaneous coronary interventions: a single center experience. Intensification of oxidative stress and inflammation in type 2 diabetes despite antihyperglycemic treatment. Oral antidiabetic agents in pregnancy and lactation: a paradigm shift? Association between rosiglitazone use and decline in renal function in patients with type 2 diabetes mellitus. Addition of pioglitazone and ramipril to intensive insulin therapy in type 2 diabetic patients improves vascular dysfunction by different mechanisms. Predictive factors for in-stent late loss and coronary lesion progression in patients with type 2 diabetes mellitus randomized to rosiglitazone or placebo. Glitazone use associated with diabetic macular edema. Differential effect of beta-blocker 2 Exclude Excluded References Code therapy on insulin resistance as a function of insulin sensitizer use: results from GEMINI. Diabetic medicine : a journal of the British Diabetic Association 2007;24(7):759-63. Addition of nateglinide to rosiglitazone monotherapy suppresses mealtime hyperglycemia and improves overall glycemic control. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetes treatments have differential effects on nontraditional cardiovascular risk factors. A randomized trial of therapies for type 2 diabetes and coronary artery disease. GLP-1 receptor agonist, Treatment of type 2 diabetes, Treatment of obesity. Adding liraglutide to oral antidiabetic drug therapy: onset of treatment effects over time. International Journal of Clinical Practice 2010;64(Feb):267-76. Rosiglitazone: safety and efficacy in combination with insulin in poorly controlled type 2 diabetes mellitus patients treated with insulin alone. Journal of diabetes and its complications 2007;21(1):1-6. Decreased whole body lipolysis as a mechanism of the lipid-lowering effect of pioglitazone in type 2 diabetic patients. Thiazolidinediones improve beta- cell function in type 2 diabetic patients. A comparison of pioglitazone and rosiglitazone for hospitalization for acute myocardial infarction in type 2 diabetes. Effects of exenatide versus insulin analogues on weight change in subjects with type 2 diabetes: a pooled post-hoc analysis. Efficacy and safety of rosiglitazone plus metformin in Mexicans with type 2 diabetes. Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. Tolerability outcomes of a multicenter, observational, open-label, drug-surveillance study in patients with type 2 diabetes mellitus treated with pioglitazone for 2 years. Pioglitazone treatment in type 2 diabetes mellitus when combined with portion control diet modifies the metabolic syndrome. A randomized, controlled trial of the effects of rosiglitazone on adipokines, and inflammatory and fibrinolytic markers in diabetic patients: study design and protocol. A one-year study comparing the efficacy and safety of rosiglitazone and glibenclamide in the treatment of type 2 diabetes. Nutrition, metabolism, and cardiovascular diseases : NMCD 2007;17(1):13-23. Glycemic control and treatment failure with pioglitazone versus glibenclamide in type 2 diabetes mellitus: a 42-month, open-label, observational, primary care study.
So most than in industrialized countries order tadapox 80 mg free shipping erectile dysfunction treatment in bangladesh, and that the cir- patients you’ll see for primary dysmenorrhea will cumstances for girls going to school are much more be of younger age buy tadapox 80mg with mastercard erectile dysfunction l-arginine. The onset of pain is usually a difficult in many parts of the world 80mg tadapox overnight delivery erectile dysfunction age statistics, you can imag- few hours before blood flow starts and will last ine how effective treatment for this common con- for the first one to two days of the period generic tadapox 80mg with amex impotence is a horrifying thing. Often dition can significantly influence socioeconomic primary dysmenorrhea becomes less with age or performance and social well-being. In addition, dysmenorrhea has a psychological aspect, as women and especially adolescents suffer- Secondary dysmenorrhea relates to pain during men- ing from it are often concerned that something strual periods with an underlying pathology (see might be wrong with their reproductive organs, below). As a matter of fact, symptoms will only hampering their fertility in later years. This can start after the underlying cause has developed. Patients with secondary dysmenorrhea will be In adolescent girls dysmenorrhea might cause mostly more mature women. Often, pain starts the first contact with a reproductive health service. In some, traction (adhesions, PID), or This is caused by an excessive production of pros- the production of prostaglandins or prostaglandin- taglandins in the body just before menstruation like factors (acute STI, endometriosis) might play a starts. Prostaglandin is a hor- mone which you might know from obstetrics as misoprostol. The additional symptoms of dysmen- HISTORY TAKING orrhea such as nausea and diarrhea are the same as the side-effects of misoprostol! Other strual changes of the endometrium and it is not symptoms: watch out for the above-mentioned known why some women produce more prosta- accompanying symptoms such as diarrhea and glandin than others, but this seems to be only poss- nausea. Endometriosis can grow in the bladder ible when menstrual cycles are ovulatory (with an and bowel and cause hematuria and bloody ovulation). Ask about pain during intercourse (dys- in a girl are anovulatory explains why primary pareunia) hinting at endometriosis, adenomyo- dysmenorrhea often only starts a few cycles after sis, fibroids or PID. Excess of prostaglandins leads to hyper- (pain during defecation) which is a sign for frequent, dysrhythmic uterine contractions and re- bowel endometriosis. Watch out: every newly congenital or acquired malformations of the female appearing dysmenorrhea can be a mistaken ec- reproductive tract, such as imperforated hymen, topic pregnancy! Spotting and irregular bleeding can be a sign for STI. Bleeding after or during Secondary dysmenorrhea intercourse can hint at STI but also at cervical cancer. Possible causes of secondary dysmenorrhea are: • Parity, pelvic operations: subfertility can be a sign • Endometriosis (endometrial cells growing out- for endometriosis, PID and fibroids; recurrent side the uterus, leading to cysts and adhesions) abortion can hint at the existence of uterine (see Chapter 6). Pelvic operations can cause adhesions • Adenomyosis (endometrial cells growing within or lead to infections which in turn can cause the uterine wall in the muscle layer called PID. D&Cs carried out under unsterile condi- myometrium). In most of these conditions, menstrual pain is re- • Stress or a family history of dysmenorrhea: primary lated to pressure of the impaired tissue (fibroids, dysmenorrhea can be psychosomatic. The way 80 Painful Menstrual Period: Dysmenorrhea older female relatives deal with their menstrual Speculum examination period can influence the perception of girls During a speculum examination you can find signs about womanhood and menstruation and the of cervical cancer (bleeding, ulcers, erosions, way they deal with painful periods. Stress in masses) or for STI (abnormal vaginal discharge, a school or around issues of adolescence and reddish cervical surface, discharge from the cervical growing up can lead to a change in pain percep- os) and for vaginal endometriosis (dark-red or tion and primary dysmenorrhea as well. The cervix can be distorted Please bear in mind that a menstrual period is to one side by fibroids, tubo-ovarian masses or the inevitable sign that a pregnancy did not endometriosis, or shortened by cervical or intra- work out. So, for women with difficulties in cavitary fibroid growth. Wet mount The wet mount can show signs of vaginal or cervi- cal infections including STI (pus cells, clue cells, PHYSICAL EXAMINATION Trichomonas). Most of the time you can make the diagnosis with- out many investigations in your facility. Primary Vaginal examination dysmenorrhea is a diagnosis of exclusion, but your During bimanual palpation you can find signs of history with onset of symptoms and menarche can adenomyosis (enlarged, soft, often tender uterus) or already help you to establish the diagnosis. In pri- fibroids (enlarged, firm uterus, bulky uterus with mary dysmenorrhea your examination outside humps, mobile or immobile) and ovarian masses menstruation will be normal as there is no under- such as benign or malignant ovarian tumors and lying cause for it. Most women come when they tubo-ovarian abscesses as a sign of PID (masses are having pain, so it might be wise to re-examine right, left or behind the uterus, mobile or im- them once their period is over to see the difference. Cervical tenderness can be a sign of acute Be aware of possible congenital malformations like or chronic infection (STI, PID) but also for endo- a rudimentary uterine horn that can cause the pain. A painful palpation Keep in mind: a woman can start with primary of the posterior fornix can be a sign of endometrio- dysmenorrhea and with time experience additional sis of Douglas’ space or infiltration of the tissue secondary symptoms due to new underlying causes. So ask every woman if the pain changed with time, especially concerning onset and duration. You Rectal examination must do a full gynecological examination on all patients with dysmenorrhea to establish or rule A rectal examination can reveal blood or anal pain out underlying causes. Special considerations for which can be signs of endometriosis and sometimes examination of young girls or virgins are given in endometriosis in recto-vaginal septum can be pal- Chapter 1 on gynecological examination and pated by recto-vaginal examination. You can find a description on each examination method or Further investigations investigation in Chapter 1. Vaginal/abdominal ultrasound Abdominal palpation If your clinical diagnosis is secondary dysmenor- rhea look for the following pathology: By doing an abdominal examination you can assess abdominal masses (fibroids, cancer) or points of Uterine fibroids Their echogenicity in ultrasound is a pain-related resistance (PID, adhesions). They usually should look for scars and assess their healing. An have well-defined borders to the myometrium and ugly broad scar might be a sign of secondary heal- a capsule. Don’t forget to do abdominal ultrasound ing with the likelihood of infection or adhesions. This is due to Adenomyosis Adenomyosis is difficult to see with their mode of action: NSAIDs stop prosta- ultrasound and the diagnosis is often one of exclu- glandin production, something which paraceta- sion. The posterior wall of the uterus might be mol or Buscopan cannot do. They do not reduce the effect of pros- ten enlarged. Patients with adenomyosis often taglandin on the uterus. Once prostaglandins are suffer from menstrual disorders together with in the circulation they will cause pain and dysmenorrhea. Endometrioma Endometrioma often appear as tumors Usually women with primary dysmenorrhea know in the ovaries. If they are big enough you may see when pain starts and how long it usually stays and them on ultrasound. They are usually cystic with there are only few cycles where they won’t experi- decreased or absent echogenicity and can resemble ence pain. Thus, for a successful treatment and ovarian cysts or hydrosalpinx. See • Always have your NSAIDs in stock and in reach Chapter 17 on STI for description of ultrasound when you are near your period. Don’t wait until the pain is Urine pregnancy test/urinalysis very strong because this is too late. Every patient with new pelvic pain should have a • Always take your NSAIDs as long as the pain urine pregnancy test (UPT) to exclude ectopic usually stays.
According to a retro- spective study from Kenya discount tadapox 80mg with visa erectile dysfunction at 55, even gemcitabine has promising activity in KS (Strother 2010) generic tadapox 80 mg with visa impotence hypertension. Immunotherapy: With interferons (IFN) acceptable remission rates are reached purchase 80 mg tadapox free shipping erectile dysfunction q and a. However cheap tadapox 80 mg with mastercard impotence cure food, CR rates seem to be lower than with pegylated liposomal doxorubicin (Kreuter 2005). The effect mechanism of IFN on KS is not fully clarified. Apart from an immune modulating effect, IFN probably induces the apoptosis in KS cells. It is important to note that the effectiveness depends on the immune status. In patients with more than 400 CD4 T cells/µl, remission rates during IFN are at least 45%, com- pared with only 7% in patients with less than 200 CD4 T cells/µl. There may be other factors to predict response to IFN such as endogenous IFN levels, which are increased in the advanced stages of HIV infection. Table 1: Specific therapies for KS when ART is not sufficient Therapy Dosage Comments Pegylated liposomal 20 mg/m2 IV Treatment of choice, beware of myelotoxicity, doxorubicine every 2 weeks cardiotoxicity, hand-foot syndrome (Caelyx™ or Doxil™) Liposomal 40 mg/m2 IV Slightly less effective than Caelyx™, daunorubicin every 2–3 weeks seldom used during the past decade. SC or IM Considerable side effects, less efficacy than (Roferon™) 3x/week with doxorubicin. Use only when CD4 T cells are >200/μl and limited disease Pegylated 50 μg SC weekly Tolerability improved compared to Interferon- 2b conventional IFN- (2a,b), but lack of data in (PegIntron™) AIDS KS, off-label use! Paclitaxel 100 mg/m2 IV Beware of neutropenia, peripheral (Taxol™) every 2 weeks or neuropathy, allergic reactions, alopecia 135 mg/m2 IV Off-label Use! Caution with ART interactions every 3 weeks There are currently no standardized IFN treatment regimens. Due to the consider- able side effects, a high-dose treatment (up to 30 million IU/day) is not commonly administered. Daily doses of 3-6 million IU subcutaneously are usually given. After remission (tumour growth stopped, tumours flattened, loss of purple color, change to brownish color), interferon dosing can be reduced to 3x/week. Remission can be expected after 6–8 weeks of treatment (often significantly later). There is not suffi- cient data on the use of the pegylated IFN for HIV-associated KS. It is not licensed for KS and optimal dosage is unknown. However, there are some promising case reports in AIDS patients (Rokx 2013) and in patients with classical KS (Di Lorenzo 2008). Many different methods are used depending on the size and location of tumors: cosmetic camouflage, cryosurgery, intralesional injections of Vinca alkaloids or interferons, soft x-ray radiation, elec- tron beam therapy, cobalt radiation (fractionated) or Imiquimod (Celestin Schartz 416 AIDS 2008). Compressive therapy with elastic stockings is an important strategy for the treatment of KS associated lymphoedema (Brambilla 2006). KS is a strikingly radiosensitive tumor (Becker 2006, Donato 2013). Superficial macular or plaque-like KS lesions respond well to daily doses of 4–5 Gy (total dose 20–30 Gy, fractionated 3x/week) of soft x-ray radiation. In the case of large KS lesions with edema, radiation with fast electron beams (5 x 2 Gy per week, total dose 40 Gy) is recommended. As KS is a multifocal systemic disease, surgical treatment is limited to excisional biop- sies for diagnosis and palliative removal of small tumors in cosmetically disturbing areas. Since tumors often extend further into the surroundings than is clinically visible and local trauma can lead to new tumors (Koebner phenomenon), local and regional recurrences can be expected. These can be prevented by radiation therapy: in order to reach the tumor cells spreading along the vascular channels, the field of radiation should be extended 0. New therapeutic approaches: With regards to the KS pathogenesis, several new therapies have been suggested such as virustatic agents, cytokines and inhibitors of angiogenesis. They are described here briefly: •Valganciclovir –a promising approach; this antiviral agent significantly reduces HHV-8 replication, shown in a randomized trial (Casper 2008). Antiviral efficacy is higher than with valacyclovir or famciclovir (Cattamanchi 2011). However, there are no data on clinical efficacy in AIDS-related KS published to date. As HHV-8 is involved in the early steps of KS pathogenesis, it is questionable if valganciclovir has any effect on manifest lesions. In patients with classical KS, the drug remained inefficient (Krown 2011). Good response rates in uncon- trolled studies on HIV-negative renal transplant recipients with KS (Stallone 2005, Campistol 2007). It is postulated that these drugs inhibit tumour angiogenesis through impaired vascular endothelium growth factor production. A study of combination with liposomal doxorubicine is ongoing. In a Phase II study, treatment with imatinib mesylate yielded to partial regression in 33% of AIDS/KS cases (Koon 2013). MMP inhibitors such as COL-3 have shown activity in a Phase II study on patients with advanced KS (Dezube 2006). However, clinical response rates were at best moderate. The most common adverse events were photosensitivity and rash. Encouraging Phase II study with topical halofuginone (Koon 2011). Many studies on different formulations have been conducted (Duvic 2000, Bodsworth 2001, Bernstein 2002, Aboulafia 2003). Retinoids will probably face a difficult path in attaining approval for KS. Achenbach CJ, Harrington RD, Dhanireddy S, Crane HM, Casper C, Kitahata MM. Paradoxical immune recon- stitution inflammatory syndrome in HIV-infected patients treated with combination antiretroviral therapy after AIDS-defining opportunistic infection. Blood 2004; 104: 810-4 Ardavanis A, Doufexis D, Kountourakis P, Rigatos G. A Kaposi’s sarcoma complete clinical response after sorafenib administration. Docetaxel in anthracycline-pretreated AIDS-related Kaposi’s sarcoma: a retrospective study. Bernstein ZP, Chanan-Khan A, Miller KC, Northfelt DW, Lopez-Berestein G, Gill PS. A multicenter phase II study of the intravenous administration of liposomal tretinoin in patients with acquired immunodeficiency syndrome- associated Kaposi’s sarcoma. Phase III vehicle-controlled, multi-centered study of topical alitretinoin gel 0. Prospective stage-stratified approach to AIDS-related Kaposi’s sarcoma. Immune reconstitution inflammatory syndrome associated with Kaposi’s sarcoma. The effect of HAART in 254 consecutive patients with AIDS-related Kaposi’s sarcoma.
MARM21 diﬀers from C-S8c1 by a single change from serine to arginine at VP1 139 (ﬁg cheap tadapox 80 mg overnight delivery what causes erectile dysfunction. The second mutant buy generic tadapox 80 mg on-line erectile dysfunction doctor brisbane, S-3T1 discount tadapox 80 mg otc erectile dysfunction in your 20s,camefromablood sample of a pig one day after experimental inoculation with C-S8c1 order 80 mg tadapox with visa erectile dysfunction lifestyle changes. That isolate had a single change from threonine to alanine at VP1 135 (ﬁg. Only one of ﬁfty- eight monoclonal antibodies diﬀerentiated between the parental type and S-3T1,and the diﬀerence in aﬃnity was small. The third mutant, C-S15c1, derived from a ﬁeld variant of type C1 isolated from a pig. This mutant type had eight amino acid diﬀerences in VP1 compared with C-S8c1. One of the three mutants was coinoculated with the parental type into each experimental pig. Two replicate pigs were used for each of the three pairs of mutant and parental types. Fever rose one day after infection and peaked two or three days postinfection. All animals devel- oped vesicular lesions two to four days postinfection. For each animal, between two and seven samples were taken from lesions, and the rela- tive proportions of the competing viruses were assayed by reactivity to monoclonal antibodies. The small sample sizes donotallow strong conclusions to be drawn. Rather, the following two results hint at what might be learned from more extensivestudiesof this sort. First, the parental type strongly dominated MARM21 in all seven lesions sampled from the two experi- mental animals, comprising between 80 and 94% of the viruses in each lesion. The MARM21 mutation appears to confer lower ﬁtness in vivo, at least in the two animals tested. The lower ﬁtness may arise because the mutant was cleared more eﬀectively by antibodies, bound less eﬃ- ciently to host cells, or had reducedperformanceinsome other ﬁtness component. In the two lesions analyzed from one animal, the parental type comprised 67±3. In the other animal, the three lesions analyzed had parental-type percentages of 75 ± 4. Diﬀerences in domi- nance between lesions also occurred between C-S15c1 and the parental type. Variations in dominance may arise from stochastic sampling of viruses that form lesions, from diﬀerences in tissue tropism, or from some other cause. Further studies of this sort may provide a more reﬁned understanding of the multiple ﬁtness consequences that follow from particular amino acid changes, their interactions withthegenetic background of the virus, the roleofdiﬀerent host genotypes, and the eﬀect of prior exposure of hosts to diﬀerent antigenic variants. Both antibodies and cellular binding impose strong natural selection on the GH loop of VP1. This leads to ageneral question: How much does immune pressure impede natural selection of functional performance? Experimental evolution may providesomeinsight into this problem. Consider two experimental lineages, one passaged in immunodeﬁcient hosts and the other passaged in immunocompetent hosts. If immune pressure constrains functional performance by improved cellular bind- ing, then the immunodeﬁcient line should respondwithaminoacid sub- stitutions that improvebindingfunction. In this context, improved binding function means increased viral ﬁt- ness rather than increased aﬃnity ofthevirusforthehostreceptor. Changes in ﬁtness can be measured by competing the original genotype against the genotype created by selection in immunodeﬁcient hosts. It would be interesting to study how amino acid substitutions aﬀect the ki- netics of cellular binding and reproduction and how those kinetics arise from structural changesinshapeandcharge. Onecould also compete these same genotypes in the immunocompetent line to study how amino acid substitutions change response to antibodies. Serial passage experiments impose a com- plex set of selective pressures on diﬀerentcomponents of pathogen ﬁt- EXPERIMENTAL EVOLUTION: FMDV 203 ness. For example, collecting pathogens from hosts early after infection favors very rapid reproduction within the host, perhaps at the expense of survival over the entire course of infection. By contrast, collecting pathogens late after infection favors survival within the host rather than rapid growth. In a naive host without prior exposure to the pathogen, early sam- pling may pick pathogens before strong antibody pressure develops. This may favor amino acid substitutions that promote improved cellular binding over avoidance of immune pressure. By contrast, late sampling may favor more strongly avoidance of antibody pressure. Early and late sampling in both immunocompetentandimmunodeﬁcient hosts would allow comparison of amino acid substitutions under varying selective pressures. One could also examine evolutionary response in experiments to test the idea that heparan sulfate binding modulates the pathogen’s sticki- ness to diﬀerent tissues and consequently the dynamics of growth and clearance. The passage experiments in guinea pigs showed that small changes in FMDV genotype allow virulent infections to develop in novel hosts. Host adaptation forms the central problem in the study of emerging diseases. Experimental evolution provides a useful tool to identify the amino acid changes required to infect new hosts, to cause virulent infections in those hosts, to transmit between the new hosts, and to transmit back to the original host. Pathogen genotypes thatdiﬀerbymany amino acids can have signiﬁcantly altered protein shape and charge. It can be diﬃcult to assess how those structural diﬀerences aﬀect selection on particular amino acid sites. Experimental evolution studies could ana- lyze a replicated design inwhichinitial pathogen genotypes vary. This approach can identify how genetic background alters selective pressure at particular sites. Diﬀerent genotypes may be chosen from natural isolates to study the forces that shape particular variants in the ﬁeld. Or special genotypes may be constructed to test hypothesesabouthow structure aﬀects the ﬁtness of amino acid substitutions at particular sites. Most experimental evo- lution studies of pathogens have been conducted on RNA viruses. These 204 CHAPTER 12 viruses often grow easily in culture, grow to large population sizes, mu- tate frequently, and evolve quickly. RNA viruses also tend to have very small genomes, making it easy to identify and sequence evolving genes. Experimental evolution will becomeanimportant tool for studying other kinds of pathogens. The mechanistic issue concerned whether switch rates between dif- ferent archival variants within a single genome could be modulated by natural selection, and if so, by what changes in DNA sequence or regu- latory control. This highlights experimental evolution’s role as a tool to study biochemical mechanism. The evolutionary problem concernedtheextent to which switch rates adapt to enhance bacterial ﬁtness versus the extent to which mechanistic properties of switching constrain rates of switching between variants. This highlights experimental evolution’s role in studying the constraints that govern evolutionary adaptation. Experimental Evolution: Inﬂuenza 13 Experimental evolution of inﬂuenza has identiﬁed amino acid sites that mediate escape from antibody attack. Experimental studies have also located sites that inﬂuence binding to host receptors.
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