Get college assignment help at uniessay writers 1. If a physician asked you to prepare a wet mount of a patient’s throat culture, how would you go about preparing the slide for microscopy? 2. If the culture is stained first, howis the condensor and light intensity dial adjusted for maximum light and contrast? If the culture is not stained, how is the condensor and light intensity dial adjusted to maximize contrast of the “white on white” cells? 3. Define oil immersion microscopy, and explain how oil immersion is used to increase magnification and resolution above 400X. What are the steps for using oil immersion starting with putting your specimen slide under the scope at 40X and finishing with clean up.
Check Your Understanding Using the following key, indicate which of the following make up each section of the respiratory tract. 3.1 LR-Lower respiratory tract UR Upper respiratory tract Nose and nasal cavity Larynx and trachea Alveolt and lungs Paranasal sinuses and pharynx Bronchi and bronchioles .(Circle the correct answer.k 3.2 The respiratory system a. supplies oxygen to the cells of the body b. is involved in vocalizations and sense of smell, and controls pH of the body c. supplies oxygen that enables cells to undergo aerobic respiration and remove carbon dioxide d. both a andc e. all of the above are the sites of gas exchange in the lungs. 3.3 The 3.4 Describe tracheal, bronchial, and vesicular lung sounds 15 736 Exploring Biology in the Laboratory DO ofe45620349b3c@ tooeroeer3390
Check Your Understanding. 2.1 Explain any differences between the four areas of the heart during auscultation. 2.2 Did you witness an extra heartbeat or extra sounds? 2.3 Blood pressure OPY a. is the measure of pressure exerted upon the surface of the vessels by the blood b. is the pressure when blood is circulated throughout the body . (Circle the correct answer 6390 de ole ceti C. is a combined measure of diastolic and systolic pressures; blood leaving the heart generates the diastolic pressure while the pressure generated when the heart relaxes is systolik pressure d. both a and b e. all of the above 2.4 Discuss and account for differences in blood pressure readings throughout this activity 35 732 Exploring Biology in the Laboratory tns:llereader.cheep.com/bookv9781617317569/cfi/757 4/ 4@0 00-190 N p 6
2. Glven genes A,E,D
P, K, S, E, F or G. ary structure? ii) Which of these proteins would have the lowest molecular weight? iv) Which of these proteins wou ld have the strongest tertiary attractions at all pH? v) Which of these proteins could have H-bonding in its tertiary structure at pH 2 but not at pH 13? I) Which of these proteins would nave the nlghest pl? vi) Which of these proteins would have the highest Agao? vii) Which of these proteins would be most insoluble in water? viii) Which of proteins would have the weakest quaternary attractions with other same proteins at pH 11? ix)* Which of these pairs of proteins would have the strongest quaternary interactions at pH 7? x) Which of these proteins would have the stronger quaternary attractions at pH 11 than at pH 37 (10) 4. Sketch the following five graphs and label them clearly!!. a) hemoglobin a subunit in the presence and absence of BPG at low pH b) hemoglobin in the presence of BPG at low and high pH. c) myoglobin and hemoglobin a subunit in the presence at low pH. d) myoglobin and hemoglobin in the presence at high PCO2. e) an enzyme with no inhibitor, in the presence of a competitive inhibitor, and in presence of a non-competitive in (10) 5. Consider five conditions of some enzyme(s) with the following Lineweaver-Burk equations A) y 1 x 0.25 B) y 0.25 x 0.25 C) y 1 x 1 D) y 1 x 4 E) y 0.25 x 1 i Which set of conditions demonstrates the enzyme that is least able to form the ES complex easily? ) Which set of conditions demonstrates the enzyme with the highest Vmax? ii) Which set of conditions demonstrates the enzyme with the greatest specificity constant? iv) Which et of conditions most likely represent the enzyme’s natural substrate? v)Which pair of sets of cond itions would represent an enzyme with and without a competitive inhibitor? vi) Which pair of sets of conditions would represent an enzyme with and without a noncompetitive inhibitor? vii) Which pair of sets of cond itions would represent an enzyme in the presence of an allosteric activator and in the presen viii) Which set of conditions demonstrates the enzvme with the lowest k? eWhichcet Functional group 8-amino (lys) a-amino (all) a-carboxyl (all) B-carboxyl (asp) y-carboxyl (glu) phenolic (tyr) sulfhydryl (cys) guanidino (arg) imidazolium (his) pK 10 ER 2 4 4 10 8 12 6
With other same proteins at pH 117 gest quaterary interactions at pH 7? se proteins would have the stronger quaternary attractions at pH 11 than at pH 37 (10) 4. Sketch the following five graphs and label them cleartyl!l a) hemoglobin a subunit in the presence and absence of BPG at low pH. b) hemoglobin in the presence of BPG at low and high pH c) myoglobin and hemoglobin a subunit in the presence at low pH d) myoglobin and hemoglobin in the presence at high pCO2 e) an enzyme with no inhibitor, in the presence of a competitive inhibitor, and in presence of a non-competitive inhibitor. (10) 5. Consider five conditions of some enzyme(s) with the following Lineweaver-Burk equations. A) y 1 x 0.25 B) y = 0.25 x 0.25 C) y 1 x 1 D) y 1 x 4 E) y 0.25 x 1 i) Which set of conditions demonstrates the enzyme that is least able to form the ES complex easily? i) Which set of conditions demonstrates the enzyme with the highest Vmax? il) Which set of conditions demonstrates the enzyme with the greatest specificity constant? iv) Which et of conditions most likely represent the enzyme’s natural substrate? v) Which pair of sets of conditions would represent an enzyme with and without a competitive inhibitor? vi) Which pair of sets of conditions would represent an enzyme with and without a noncompetitive inhibitor? vii) Which pair of sets of conditions would represent an enzyme in the presence of an allosteric activator and in the presence of an allosteric inhibitor? vili) Which set of conditions demonstrates the enzyme with the lowest Ki? ix) Which set of conditions shows an enzyme with equal values for Vmax and Ku? x) Which set of conditions shows an enzyme with a specific constant of 1? Functional group 8-amino (lys) a-amino (all) a-carboxyl (all) B-carboxyl (asp) y-carboxyl (glu) phenolic (tyr) sulfhydryl (cys) guanidino (arg) imidazolium (his) pK 10 ER 2 4 4 10 8 12 6
5. Use the following data to prepare a standard curve. Attach the curve to this assignment. Concentration of the standard solutions in ug/mL x Absorbance 0.32 1.0 ug/mL 0.56 2.0 ug/mL 0.79 5.0 ug/mL 1.33 6.0ug/mL 1.50 7.0 ug/mL 1.77 From the above graph: A. What would be the absorbance of a solution with a concentration of 4.0 ug/mL? What is the concentration of a solution with an absorbance of 0.752 B. Now, suppose you had an unknown sample that had been diluted as follows: I ml, of unknown 3 mL of solvent. This diluted sample was then tested and had an absorbance of 1.0. What is the concentration of the original solution? Show all of your work done to determine this What is the concentration of your diluted sample at abs 1.0? What is the concentration of the concentrated original solution: C.. Finally, suppose you had an unknown sample with a absorbance of 3.2. Could you determine its concentration directly from the standard curve? Why or why not? Microscopy homework Be sure to read the lab manual section on microscopy before working on this homework. 1. Identify the following cells and state one function for each cell:
17, Which of the following mahes frait ies a gdmde A Eany to mantain. 1. Exhin on Geniraion Time C relevance considerations are never taken lnte m era wh h ng y 19. During the By tab you end up with 30 red eved females, 20 red eyedmales 26 w and 24 w A white ed males, What are the most probable pher / female X red/male 20. During the ty lab you end up with 52 red-eyed females, ored eyed males, whiteed m w matters A True Generation T the ly ot Pase eyed males. What are the most prebable pheeotypes of the parents (or eye-cor m w d red/female X red/m of the parets r e A white/female X red/male red/male Xw B red/female X red/male End of Test 4 redt mal Cumulative Test (Label your second scantron as “test 5 in the subject box) 1. Which of the following cuts DNA at specific sequences A Restriction Enrymes B. Agaroses Y Y 2. In the RFLP analysis, which of the following is true A Sequences are exanmined at the sequence level and matches are determined B. Lengths of restriction fragments are compared to find matches C. DNA from fingers are compared to find matches C Electrophoresis D. Centrifugation 3. In the RFLP lab, which of the following was used to separate DNA fragments by slze? A Centrifugation B. Electrophoresis C. Restriction Enrymes. 4. In the examination of a DNA fingerprints between an individual suspect and the crime scene evidence, complete matches of fragments indicate that: A. The fragments are definitely from the same person C. The fragments could be from the same person B The fragments are not from the same person 5. If RFLP was used in a paternity case, which of the following is true? A. 50% of the fragments should come from the mother C. Both are true. B. 50% of the fragments should come from the father 6. Which of the following best describes genetic variability between people. A. DNA sequences are at least 10 % identical between two non-relatives B. DNA sequences are mostly identical between non-relatives except for in polymorphic regions which tend to differ between non-relatives. C. DNA sequences are mostly identical between non-relatives especially in polymorphic regions which are exactly the same between relatives. 7. In the RFLP lab, which unit was used to measure the volume of DNA samples? D. liters 00LIKL C. microliters. B. nanoliters A. milliliters 8. Convert 50,000 I to kl A 0,005 kl D. none of these C. 5,000,000kl B. 50 kl on m 9. Convert 50,000 m to cm A. 0.005 cm D. none of these C5,000,000cm B. 50cm 10. Convert 50,000 mg to g A. 0.005 g D. none of these C.5,000,000g B.50g 11. If there are 5280 feet in a mile then how many feet would be in 15 miles? A. 79,200 miles E. none of these When using a microscope in the lab, which of the following objectives have a safe working distance? D.Both B and C D. 79,200 feet C.0.003 feet B. 352 feet C. 10X 12. 13. Which the following is used to adjust the amount of light? B. the course adjustment B.40 X D. the ocular A. 100X C the iris/diaphragm A the mirror 14, wh A Is oes whm 15. tyen are wang he be A 4000x wo oculars s he w w400x t yo are viwing M tha y a A 3 e e sie ot the obie s and the 17. dialysis tubing (ned with a sb ) ea ekwg 0.25mm t vw At was places a bhypotonle soluton 18, t dialysis r percent change (ned wah 10g g s wae A 1% ht is B-10% 19. Ifyou centrifuges C 10% supernatant you would d, er peas wolution and aher g y w A densee than the material in that it was den thn the mata te e D. 20% None o the the pettet 20. If you centrifuged homogenised, ter peas solution and sher testng yo n ha th stained positive with oaie you would concude that M m g eue A. contained starch B. contained the wacleas 21. If you adjust the pH of water with Nao, you wowhd expect that A would get more acidic D. Achieve a pH reading below 70 Ccon B would get more bas E Both B and C a C.bveage 22. When you boil leaves in alcobol w you are trying to A. moisten the leaf 23. Experinmentally, pyrogallate was used to A detect mitochondria B.remove C0 B. stain for starch Cremove lodine B remove chirlasL B dect the ade C remove O 24. Experimentally, calclum hydrowide was used to A. detect mitochondria B. remove CO D.detect the swl C. remove O 25. Experimentally, tetrozolium was used to A detect mitochondria B. detect the amyloplast D. detect the male Lre d Cremove 0. 26. Experimentally, acetocarmine was used to, A. detect mitochondria B, detect the amyloplast B.detect the tos C.remove O 27. In the geranium leaf experiment, why was the leaf covered with petroleum jelly A. To see how petroleum products aflected the diffusion of lodine B. To see how blocking gas exchange affected cellular respiration C. To measure the amount of photosynthesis using petroleum products as an indicator D. To remove chlorophyll (which is soluble in petroleum) before adding iodine to stain for photoythe E. To see how gas exchange influence photosynthetic activity. 28, You need to measure 100 ml of a liquid in the laboratory as precisely as you can. Therefore, you should A. use an appropriately-sized beaker and read from the top of the menisous at the 100 ml mark B. use an appropriately-sized graduated cylinder and read from the top of the meniscus at the 100 mi mark C. use an appropriately-sized beaker and read from the bottom of the meniscus at the 100 nl mark D. use an appropriately-sized graduated cylinder and read from the bottom of the meniscus at the 100 ml mark 29. You need to measure 10 pl of a liquid in the laboratory as precisely as you can. Therelore, you should A. use a small cylinder B. use a small flask 30. You need to separate pigments from a plant extract to view which individual pigments (coler-wise) are la extract. Therefore, you should perform A. centrifugation C. Dialysis with dialysis tubing D. paper chromatography with organic solvents D. use a small beaker C use a micropipette B. a test with acetocarmine and pH paper End of Cumulative Test
Questions 1. How do abnormally low GABA (y-aminobutryic acid) levels affect a person’s behavior? Why? tootC fiote Chemically speaking how does Dilantin help to control epileptic seizures?
Questions 15-18 pertain to the following setup: In Drosophila melanogaster, the genes crossveinless wings (cv) and vermillion eyes (ym) 20 map units apart on the X-chromosome. A wild type female who is the offspring of a double mutant male and a true-breeding wild type female is mated toa male with wild type wings and vermillion colored eyes. are 15. What proportion of the female offspring is expected to have wild-type wings but vermillion colored eyes? G. 80% F. 50% A. 0% E. 40% B. 5% C. 10% D. 20% 16. What proportion of the female offspring is expected to have crossveinless wings but wild type, red eyes? I G.80% E. 40% F. 50% C. 10% D. 20% A. 0%. B. 5% 17. What proportion of the male offspring is expected to have crossveinless wings but wild type, red eyes? E. 40% F. 50% G. 80% D. 20% C. 10% B. 5% A. 0%. 18. What proportion of the male offspring is expected to be a double mutant like his ‘Granddad’? D. 20% E. 40% G. 80% F. 50% C. 10% B. 5% A. 0%.
Get college assignment help at uniessay writers sickle-cell hemoglobin lowers the net negative charge of sickle-cell hemoglobin compared with normal hemoglobin Imagine that you have placed a sample of normal hemoglobin (Hb) into well # 1 and a sample of sickle cell Hb into well # 2 in the gel illustrated below. Draw two marks to show the location of each protein sample after electrophoresis. 6. In well #3 you have placed a sample of hemoglobin beta peptide from a person who is a carrier of the sickle-cell disease. Draw the banding pattern for the protein sample that will result from electrophoresis. 7. In lane 4 you place a sample of DNA from the same person. The DNA sample is the part of chromosome11 that encodes hemoglobin beta chain. Draw the banding pattern that will result from electrophoresis. 3 GEL for elelcrophoresis
Please take the job satisfaction assessment, which is found in this week’s lecture, to learn more about what’s important to you in an employer or career path. Then, follow this link to the CNN.com listing of the top 100 employers, paying special attention to Google. After you’ve take the assessment and spent some time reading about the top employers, write a 250 to 300 word paper about: What you have learned about yourself and what motivates you at work. What types of benefits you would offer your employees if you were an employer seeking to maximize your employee productivity and job satisfaction. Explain your answer. Submit your assignment AS A MICROSOFT WORD DOCUMENT CNN link: http://money.cnn.com/magazines/fortune/bestcompanies/2009/index.html
Although nationalism created political problems in many nineteenth-century European states, it may have been a postive force increasing a sense of naional identity in?
1. An exergonic reaction has the DG (a) >0 2. True or False: Enzymatic reactions have higher activation energy requirement. (b) < 0 (c) 0 3. The type of macromolecule that contain phosphodiester bonds is kinds of naturally occurring amino 4. There are acids found in proteins 5. Name two organelles that have two-layers of membrane: and
Extra Credit (5 pts) DUE June 7, 2019 MIDNIGHT Part A (2.5 pts) Petal coloration in foxgloves is determined by three genes. M codes for an enzyme that synthesizes anthocyanin, the purple pigment seen in these petals; m/m produces no pigment, resulting in the phenotype albino with yellow spots. D is an enhancer of anthocyanin, resulting in darker pigment; d/d does not enhance, giving light purple petals. At a third locus, w/w allows for pigment deposition in petals, but Wprevents pigment deposition except in the spots, so results in the white spotted phenotype. Consider the following two crosses: Cross Parents Progeny 1 Dark purple x white with yellowish spots /2 dark purple:V2light purple X : 2white with purple spots: 4 dark purple: 4 light purple 2 White with yellowish spots x light purple X A. In each case, give the genotypes of the parents and progeny with respect to the three genes. I MUST SEE YOUR WORK!!!!.don’t just give me the answer, but show me the explanation. В. Suppose you were to cross two individuals with the genotypes: Mm Dd ww x МM dd Ww. What phenotypic ratio would you expect in the offspring? In order to make sure your answer is clear, please provide the phenotype with the general genotype in parentheses e.g. 1 Purple, Tall (P-T-): 1 Purple, short (P-tt)
DD LL C If Mla C a S https://www./homework-help/1 -ml-sample-milk-diluted-1-10-sterile-water- 1-ml-milk-9-ml-w-chapter.. C E Study Textbook Solutions Search Expert Q
anythin d. If you have used imme e. Wrap the power cord around the base ot the f. Replace your microscope in the cabinet. REMEMBER to carry it with both hands. g. If you have broken a slide, throw it in the BROKEN GLASS container. Do not throw it in the regular trash-it is a hazard. Make sure you let your instructor know if you broke a slide. h. Throw your lens tissue and any other paper waste in the regular trash, NOT in the broken glass container. Part G: Application 1. A forensics lab technician is trying to solve an ATM robbery. They have a picture of the suspect from the bank camera but even when the photo is enlarged, the face is too blurry to use for identification. Explain why the image is blurry when enlarged. 2 lfa feld of view is 3.2 mm at 60X, what is the field of view ar 25×2 32×60 112 8H5mm 25 x 25 3. If you are using your microscope and a specimen takes up 4 of the field of view at 1 1000X, what is its diam 4. A student is viewing the letter “e” on a slide. The student can clearly see objectives, but when the 40X objective was the letter when using the 4X an used, the “e” was no longer visible. What happened? S rt H: Post-lab Questions Explain why the light microscope is also called a compound microscope. LAB 2 The
3. Individuals with type AB blood can theoretically receive blood from individuals with types A, B, AB, and O blood. Conversely, individuals with type O blood can theoretically give blood to individuals with type A, B, AB, and O blood. Explain why both situations are basis of the antigen-antibody response. Can you relate this response to hemolytic disease of the newborn? How is this condition treated? How can it be prevented? possible on the TIOW Can it be prevented? Which white blood cells would be elevated during 4 allergic reaction? A cancerous tumor? A an tissue injury? Leuko n tos
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9 Functional group PK 10 E-amino (lys) a-amino (all) a-carboxyl (all) B-carboxyl (asp) y-carboxyl (glu) phenolic (tyr) sulfhydryl (cys) guanidino (arg) imidazolium (his) 8 PAPER 2 4 10 8 12 6 4
447 447 Module 3: Discussion #3 – Transmission genetics Importance of sickle cell gene against malaria You have been studying genetic transmission and should be aware of law of dominance in gene expression pattern Studies have shown that sometimes being a carrier for a certain disease is advantageous over being affected or completely healthy for that gene. Sickle-cell anemia (SCA) is an example of this kind of ‘heterozygote advantage’ in certain populations. SCA is a genetic blood disorder when hemoglobin has abnormal sickle shape. Hemoglobin S (HbS) is a variant form of normal hemoglobin (HbA) gene and is very common in Africa. Interestingly, heterozygotes for that gene (HBAS) are in positive selection in those regions compared to homozygotes (HBSS) and are more protected from malaria morbidity/mortality (see image) Malaria transmision НЬАА HbAS HbSS Malaria infection Malaria mortality TRENDS in Parasitology Part I. Fill in the blanks (copy/paste the table in your reply) Part I. Fill in the blanks (copy/paste the table in your reply) Genetic make up of Outcome with no Outcome with Characteristic of individual malarial infection individual malarial infection Dies young HBAA Sickle cell trait Survives HBAS HBSS Part II. Respond with a minimum of 150 words. Please describe some ways in which being a SCA carrier can be advantageous and disadvantageous. What are some reasons why the SCA allele frequency is higher in Africa than in America? Part IlI. Respond to your peers (two replies are required) Replies should be substantive and reflect that the student read and thought about the assigned reading and additional sources posted by the person they are replying to. The reply post meets the word requirement of 100 to 150 words The reply moves the conversation forward or makes a reply to a question asked in response to their own posting. Replies are made over several days rather than all crammed into the due dates Sickle cell disease and malaria morbidity: a tale with tails two Thomas N. Williams.12,3,4,5 and Stephen K. Obaro6,7 KEMRI Centre for Geographic Medicine Research (Coast), Kilifi, Kenya Department of Paediatrics, University of Oxford, Oxford, UK Nuffield Department of Medicine, University of Oxford, Oxford, UK INDEPTH Network of Demographic Surveillance Sites, Accra, Ghana SEVIMalR Network, Glasgow, UK Division of Pediatric Infectious Diseases, Department of Pediatrics and Human Development, Michigan State University, Michigan, USA National Hospital, Abuja, Nigeria More than 230 000 children are born in Africa with sickle cell disease (SCD) each year: approximately 85% of all affected births worldwide. Although malaria is common ly viewed as a major problem for African patients with this condition, questions still remain about its relative importance as a cause of ill heath and death. In the absence of definitive studies investigating the contribu- tion of malaria to morbidity and mortality in African children with SCD, policy makers will continue to lack the evidence on which to base appropriate management guidelines. ized. Although malaria is widely cited as a major cause for these deaths (6-81 the evidence is somewhat scanty. Here we review the available data and suggest that definitive studies are long overdue. Sickle cell disease and malaria The relation between SCD and malaria is intriguing. When the protective effect of HbS was first suspected more than 60 years ago  the genetic basis for HbS had not yet been described and tests were not available that could reliably differentiate heterozygotes from homozygotes. Although the strong protective effect of heterozygosity has subse quently been confirmed in multiple studies conducted in various countries [10,11, far fewer have focused on homo zygotes. Virtually nothing is known about malaria in patients with other forms of SCD, hence this review is imited to a discussion of HbSS. Sickle cell disease is a common problem in Africa The gene for haemoglobin S (HbS), a structural variant of normal haemoglobin (HbA), is widely distributed in the developing world, having been selected to high frequencies by the protection afforded to carriers (HbAS; sickle cell trait) against malaria 1,2. HbS is the classic example of a balancing polymorphism, its frequency in populations reflecting the equilibrium between the historic degree of positive selection for heterozygotes (HbAS) and negative selection for homozygotes (HbSS), who suffer from a chron ic form of haemolytic anaemia known as sickle cell disease (SCD) 3. HbS results from an amino acid substitution at position 6 of the B-globin subunit . Under conditions of low oxygen tension, HbS polymerizes and results in the sickling (Figure 1) that underlies much of the pathology associated with the condition . Although HbSS is the most common genetic variant of SCD, accounting for around 70% of cases worldwide, the term SCD encapsu lates any condition in which pathological consequences result from HbS production  (Table 1) Globally, around 280 000 children are born with SCD every year 5]. Large family sizes coupled with the corre- lation between allele frequencies for HbS and the historic incidence of malaria 12, mean that 85 % ofaffected children (approximately 230 000 cases/year) are born in sub Saharan Africa. Nevertheless, the prognosis for these chil dren remains poor, the majority dying undiagnosed in early childhood from diseases that are poorly character- Theoretical considerations Although not completely understood, the mechanisms by which HbAS protects against malaria probably include reduced parasite growth and enhanced removal of para sitized cells through innate or acquired immunological processes 10. Moreover, it has been suggested that the degree of this protection might be correlated with the intracellular concentration of HbS [12 and, as such, it might be expected that subjects with SCD, whose erythro- cytes contain the highest concentrations of HbS, might be even more protected than carriers. Equally, however, there are numerous theoretical reasons why malaria might be more dangerous in patients with SCD than normal subjects. First, the chronic haemolysis experi enced by patients with SCD is associated with a marked reticulocytosis, commonly exceeding 10%. As a conse quence, it is possible that increased efficiency of infection by both Plasmodium falciparum, which appears to show some preference for the youngest, most metabolically active red blood cells 13, and Plasmodium vivax, which only invades reticulocytes, might render patients with SCD more susceptible to malaria attacks. Second, another central feature of SCD is early deterioration in splenic function through auto-infarction, and because the spleen Corresponding author: Williams., T.N. (twilliamkilif. kemei-wellenmte.org) 1471-4522s-e fromt matter 2011 Elseviar Lid. All rights resarved. doi: 10.1016,pe. 2011.02.004 Trends in Parasinology, July 2011, Vol. 27, No. 7 315 when patients do get infected. Although malaria did not feature strongly in early descriptions ofthe natural history of SCD 23,24], the infection has been implicated as a significant problem in several later reports. The descrip- tion of a SCD patient admitted to the hospital with severe malaria infection in Ibadan [251 prompted a flurry of letters stating the clinical impression that malaria is a frequent and significant cause of il health and death among patients with SCD (26-28). This impression is supported by many subsequent reports describing the experience of clinicians in a range of situations [21,29,30]. Nevertheless, in regions where a large proportion of children carry malaria parasites throughout their early life, it is difficult to interpret the relevance of a positive blood film in the absence of data regarding parasite carriage in either con trols or in children with SCD at steady state, data that are missing from virtually all such studies. TRENDS in Parasitology Figure 1. Peripheral blood smear showing sickled red blood cells The figure shows a peripheral blood film from a patient with sickle cell disease. The arrows mark red blood cells that have become misshapen in the classical sickled shape because of the polymerzation of the abnoemal haemoglobin S molecules at low ambient oxygen concentrations. Natural history studies Although cohort studies offer one approach to addressing the causal relation between malaria infections, morbidity and mortality in patients with SCD, surprisingly few plays such an important role in malaria immunity, this could well be associated with a reduction in the ability of patients to clear infected red cells. Third, subjects with SCD are chronically anacmic with haemoglobin concen- trations roughly half of normal, at only 6-8 g/dl. A rapid. fall from sucha low base line level because of the haemo- lysis or ineffective erythropoeisis that normally accompa- ny malaria infections [14 could easily be catastrophic Finally, it is also probable that the tissue hypoxia and inflammatory processes that typically accompany malaria infection are potent triggers of ‘sequestration crises, in which red cells sequester in the spleen, lungs and other deep organs, resulting in sudden declines in peripheral haemoglobin concentrations. In theory, therefore, the bal ance of probabilities is that subjects with SCD are at increased risk from malaria infections. But what clinical reports have been published that have used this study design. A major problem of this approach relates to ethical considerations: given the wide-spread perception that ma laria can be dangerous in patients with SCD it would generally be considered unethical to withhold prophylaxis from malaria-exposed patients once a diagnosis of SCD has been made. However, this treatment bias has been mini mized in two published studies. First, in a birth cohort study conducted in Western Kenya, a retrospective ap- proach was used to test participants for SCD on completion of the study using archived samples collected at the time of recruitment 31]. Although all-cause mortality was signifi- cantly higher among SCD than control children, on the basis of data collected during monthly cross-sectional blood sampling surveys, significantly lower incidence rates were reported for both severe malaria anaemia and high density P. falciparum infections in those with SCD [31. Again, although this study suggests that children with SCD might enjoy a degree of resistance to P. falciparum infections, the possibility that malaria infections might have been a pre- cipitating event in some or all of those who died cannot be excluded. In a more recent study, a cohort of patients attending a SCD clinic at a major teaching hospital in Tanzania was followed (201. Although at the time of the study, guidelines recommended routine prophylaxis with chloroquine, the drug was not routinely available, effec tively meaning that study patients were receiving no pre- ventive treatment. Two potentially important findings evidence is there to support this hypothesis? Clinical studies of SCD and malaria A lower prevalence and/or a lower density of malaria parasitaemia among subjects with SCD compared to non-SCD controls has been reported in several studies [15-221, On the face of it, this appears to support the conclusion that SCD subjects enjoy an even greater degree of resistance to malaria infection than heterozygotes. Nev ertheless, whether or not patients with SCD are relatively resistant to malaria infections, it is clear from numerous reports that malaria can result in serious consequences. Table 1. The most common genetic causes of sickle cell disease found in Africa Genotype Comments Sickle cell anaemia: accounts for 70% of cases of SCD. Hb5/S Less severe form of SCD. Accounts for 25-30 % cases of SCD in Africa. Largely confined to West Africa. HbS/C HbS/B-thalassaemia Hb5/0 Arab Rare in Africa; most prevalent in the Eastern Mediterranean and India. A rare form of scD found in North Africa, the Middle East and the Balkans HbS/D Punjab Occurs throughout the world but is most commonly found in Northern India B-thalassemia- an inherited condition characterized by the reduced production of normal beta-globin chains becsuse of mutations at the beta-globin gene locus. aHaemoglonbins 0 Arab and O Punjab result from mutations of the beta globin gene locus that lesd to the production of structurally abnormal forms of haemoglobin. were reported. First the prevalence of P. falciparum para sites was significantly lower among patients with SCD than in those without SCD both at routine hospital visits and during episodes of hospitalization. However, second, the prevalence of parasites was considerably higher among hospitalized than non-hospitalized patients with SCD, an observation that was particularly marked for patients with severe anaemia, and malaria was strongly associated with a fatal inpatient outcome [20. This study suggests that although patients with SCD might be relatively resistant to malaria infection when compared to non-SCD subjects, when they do become infected the disease can have serious, and sometimes fatal, consequences. In another recent study, conducted on the coast of Kenya, a similar conclu sion was reached. A surveillance study of children admit ted to Kilifi District Hospital was used as a sampling framework for a case-control analysis investigating the odds of SCD among patients admitted with a range of specific diagnoses. Although SCD was a significant risk factor for admission to the hospital, both with non-malaria diagnoses in general and with invasive bacterial diseases in particular, it was not associated with admission to the hospital with malaria [32. Nevertheless, both severe anae- mia and mortality were considerably higher in SCD than non-SCD children who were hospitalized with malaria, suggesting that any resistance to malaria infections might be offset by the massively increased risk of death when such children do develop the disease robust to inform the recommendations of a recent Cochrane review [33. In the first, a range of health out comes were compared in two groups of SCD children attending a Ugandan outpatient clinic during the 1960 s a treatment group receiving chemoprophylaxis with both oral chloroquine and intramuscular long-acting penicillin, and a placebo group receiving intramuscular sterile water . Several important observations were made. First, the treatment group experienced a significantly lower inci dence of dactylitis (a common complication of SCD in younger children) and of falls in haemoglobin to less than 6.0 g/dl (normal 7.3 g/dl (standard deviation 1.3 g/dl) [191). Although, as in the Garki project [16, it is impossible to ascribe these benefits to one or other component of the prophylactic regime, the treated group experienced both a lower prevalence of slide-positive malaria and a higher mean haemoglobin concentration at routine clinic visits Moreover, it was noted that ‘almost every positive finding of malaria was either preceded or followed by a fall of up to 2g Hb/100 ml blood. [34 This study, therefore, provides compelling support for a causal link between malaria and anaemia in patients with SCD. A second small trial, in volving a total of 97 Nigerian patients, included three groups of children with SCD: two groups received active oral malaria prophylaxis with either proguanil or pyrimeth amine and the third received oral placebo (vitamin C) [35. Although no significant differences were found in the inci dence of malaria between the three groups, patients in the placebo group were admitted to the hospital more frequent- ly, received more blood transfusions and experienced lower steady-state haemoglobin concentrations 35. Proguanil appeared more effective than pyrimethamine, possibly be- cause of the prevalence of resistance to the latter. Subse quently, a third randomized controlled trial, conducted in Senegal, found that, compared to those receiving placebo, patients with SCD receiving monthly intermittent pre- sumptive treatment with suph ing the malaria transmission season experienced significant benefits in terms ofthe incidence of malaria, SCD crises and the need for blood transfusions [36) Evidence from intervention studies Although valuable data have been derived from observa tional studies such as those described above, in many ways, intervention studies comprise a more robust approach to investigating the role of malaria in the health of subjects with SCD.As discussed already, in light ofthe general belief that malaria is dangerous in subjects with SCD, withholding prophylaxis from malaria-expc diagnosis is ethically contentious. Nevertheless, several intervention studies have been undertaken and have ed subjects with an existi xine-pyrimethamine dur- yielded important data. The Garki study, conducted in the Sudan savanna of Nigeria during the 1970s, is one example 16. During the course of initial cross-sectional surveys of the study population, the investigators noticed that although the prevalence of SCD among newborns was as expected on the basis of the Hardy Weinberg equilibrium there was a deficit of subjects with SCD among older age groups, suggesting a high mortality in early childhood. Although the improved survival of children with SCD that followed the random assignment ofmalaria control to halfof the study population has often been cited in support ofa role for malaria in these early deaths, these data are inconclusive for two reasons. First, the study was small; there were four children with SCD in the population at the beginning of the study and seven at its conclusion, and the observed increase did not reach statistical sigificance. Second, the chosen intervention, a combination of sufalene and pyyrimethamine could also have influenced the incidence of other parasitic and bacterial diseases Several placebo-controlled trials of antimalarial pro phylaxis have been conducted in patients with an existing diagnosis of SCD, including two considered sufficiently The balance of evidence From the literature reviewed above, it can be seen that the relation between malaria and SCD remains somewhat confusing. A summary of what we consider to be the most probable relation between these two conditions is illustrat ed in Figure 2. On the basis of evidence collected during cross-sectional studies in multiple countries [15-221, SCD appears to be associated with reductions in both the prev alence and density of asymptomatic parasitaemia. In many cases, this effect is considerably greater than that seen in heterozygotes with HbAS, suggesting a dose-dependent effect of the gene for HbS with regard to protection from infection with malaria parasites. Nevertheless, this pro- tection is certainly not complete, and there is plenty of evidence to show that when patients with SCD do become infected the consequences can be grave. The strongest evidence relates to anaemia, where sudden and cata strophic falls in haemoglobin concentration can follow the onset of malaria infection [20,32,33,36, but it is possi ble that malaria infections in patients with SCD might also Malaria transmision HbAA HbAS HbSS Malaria infection Malaria mortality TRENDS in Parastology Figure 2. Amodel of the relative risks of malaria infection and malaria-specific mortality in subjects of dilferent HbS genotype. The cartoon illustrates one imterpretation of the available epidemialogical data regarding the relation between HbS and malaria. The size of the circles represents the genotype-specific risk of each event under conditions of equivalent malaria exposure. Subjects with HbAS are at lower risk of malaria infection than subjects with HbAA and even if infected are at lower risk of progression to severe and fatal disesse. Subjects with HbSS (SCD) sre at lower risk still of malaris infection but if infected are at substantial risk of subsequent mortality …. meaning that overal, despite the reduced risk of infection, malaris-specific mortality is greater than in nomal subjects (HbAA Although available data suggest that malaria mortality s90 % lower in HbAS than in normal subjects [101, insufficient data are available from which to estimate the relative risks of infection and death in subjects with SCD. Without considerable further research it is impoasible to scale the illustration with any degree of accuracy. have other downstream effects. Moreover, it is possible that the risk from malaria in any individual patient might be influenced by their wider genetic makeup. For example, -thalassaemia, a condition affecting the production of the -globin subunits of haemoglobin, is well recognized as an ameliorating factor in patients with SCD 37 and can also influence malaria risk [12,38). On the basis ofthe available evidence it seems probable that malaria prevention would have a major impact on the survival of children living with SCD in areas of high malaria transmission. However, an increasing proportion of patients are now being born in areas where transmis sion is on the decline [42,43] or in cities where, in many cases, malaria transmission is relatively low. Should all malaria-exposed patients be prescribed prophylaxis throughout life, or is it possible that at lower levels of malaria transmission the risks of treatment might out weigh the risks of infection? An obvious issue in this context is the optimal anti-malarial regime. Although for many years chloroquine was considered standard, this drug is no longer effective in most of the continent and long-term prophylaxis is associated with a risk of ocular toxicity. Similarly, whereas Paludrine is recommended in some settings, it is expensive, almost certainly of limited efficacy, and is also associated with side effects in a pro portion of users. Might alternative approaches, such as impregnated bed-nets, intermittent presumptive-or early diagnosis and treatment of malaria infections, be more appropriate in areas oflower transmission? Furthermore, should the same recommendations apply to both children and adults? Policy implications and research priorities Although there are few firm data on which to estimate current survival rates, the balance of evidence suggests that between 50% and 90% of children born with SCD in Africa will die before their fifth birthday . There can be little doubt that, as in the developed world, the early diagnosis of SCD through screening, followed by the pro vision of a limited number of essential interventions (in cluding parental education 40,41 and vaccination or prophylaxis against common bacterial infections (34)) would have a major impact on the survival of children born with SCD in sub-Saharan Africa. Nevertheless, our formulation of the relation between SCD and malaria raises several questions regarding the relative contribu tion that malaria prevention might make to this improved survival Review Trends in Parasitalogy July 2011, Vol. 27, No. 7 Whereas definitive answers to some of these questions are long overdue, what studies are needed and how would they be funded? Regardless of the indisputable benefits of malaria prevention in normal children, given the existing evidence from previous studiess [331, placebo-controlled 7 Dinllo, D. and Tchernia, G. (2002) Sickle cell disense in Africa. Curr. Opin. Hematol. 9, 111-116 8 Serjesnt, G.R. (2005) Mortality from sickle cell disease in Africa. BMJ 330, 432-433 9 Beet, E.A. (1946) Sickle cell disease in the Balovale District of Northern Rhodesia E Afr. Med J. 23, 75-86 10 Williams, T.N. (2006) Red blood cell defects and malarin. Mal. Biochem. Parasital. 149, 121-127 11 Williams, T.N. et al. (2005) Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases. J. Infect. Dis 192 trials would be considered unethical in most endemic settings. Comparative trials of different approaches to antimalarial prophylaxis are probably the only ethically acceptable method of addressing this question but such studies come with different challenges. For example, the most appropriate target population would be very young children, and given the likelihood that most approaches to malaria prevention wil be reasonably effective, such trials would need to be large. Such comparative studies would be predicated on the existence oflarge-scale, early life screening programs, which remain uncommon throughout most of the continent. Nevertheless, recent years have seen promising developments. Successful pilot studies have been established in several centres [44-461 and with support from the government of Brazil, a nation al screening program is planned for Ghana, suggesting that with good advocacy and international will it is possi ble to raise the profile of sickle cell disease on national health agendas An improved understanding of both the role of malaria and of broader issues relating to the health of African children with SCD wil be helped by several factors Most importantly, African countries themselves must embrace the problem of SCD and develop a research agenda. Much could be gained by the strategic develop- ment of sustainable scientific partnerships with research centres in richer countries [47, an objective promoted by the recent establishment of a major collaborative net- work to advance this agenda  (http://globalscd.ning com/). Finally, however, progress will remain slow without increased commitment from donor and develop- ment agencies and from major international research funders. 178-186 12 Williams, TN. et al (2005) Negative epistasis between the malarin- protective effects of athalassemin and the sickle cell trait Nat. Genet 37, 1253-1257 13 Pasvel, G. et al. (1980) The increased susceptibility of young red cells to invasion by the malaria parasite Plasmodium falciparum. Br J Hoematol 45, 285-295 14 Lamikanra, A.A. et al (2007) Malarial anemia: of mice and men. Blood 110, 18-28 15 Raper, A.B. (1959) Further observations on sickling and malaria. Trans. R. Soc. Trop. Med Hyg 53, 110-117 16 Molinesux, L et al 1979) Abnermal haemoglobins in the Sudan savanna of Nigeria, II. Malaria, immunoglobulins and antimalarial antibodies in sickle cell disease. Ann. Trop. Med. Parasitol. 73,301-310 17 Aluoch, J.R. (1997) Higher resistance to Plaamodium falciparum infection in patients with homozygous sickle cell disease in western Kenya. Trap. Med Int. Health 2, 568-571 18 Awotua-Efebo, O et al. (2004) Malaria parasite density and splenic status by ultrasonography in stable sickle-cell anaemia (HbSS) children. Niger J. Med. 13, 40-43 19 Sadarangani, M. et al. (2009) An observational study of children with sickle cell disease in Kilifi, Kenya. Br. J. Haematol. 146, 675-682 20 Makani, J. et al. (2010) Malaria in patients with sickle cell anemia: burden, risk factors, and outcome at the outpatient clinic and during hoepitalization. Blood 115, 215-220 21 Okuenghae, H.O. et al, (1992) Malarial parasitaemia in febrile children with sickle cell anaemia. J. Trop. Pediatr. 38, 83-85 22 Danquah, I. et al (2010) Influence of haemoglobins S and C on predominantly asymptomatic Plasmodium infections in northern Ghann. Trana R. Soc. Trop. Med. yg. 104, 713-719 23 Trowell, HC. et ol. (1957) The natural history ofhomezygous ickle-cell anaemia in Central Africa. QJ. Med. 26, 401-422 24 Lambotte-Legrand, J. and Lambotte-Legrand, C. (1955) Le prognostic de lanemie drepanocytaire au Congo Belge (a propos de 300 case et de 150 deces Ann Soc. Belg. Med. Trop. 35, 53-57 25 Adeloye, A. et al. (1971) Severe malarinl infection in a patient with sickle-cell anaemin. Br. Med. J. 2, 445-446 26 Konotey-Ahuala, FI. (1971) Malaria and sickle-oell disease. Br. Med. J Acknowledgments TNW and SO conceived the paper. TNW wrote the first draft and both authors contributed to subsequent revisions. We thank our colleagues at both the Wellecome Trust Programme, Kenya and at the Michigan State University, USA, for belpful comments. TNW is funded by the Wellcome Trast (Grnnt #076934) and by the European Union Network 7 EVIMalR Consortium. SO is funded by a Faculty grant from Michigan State University, the United Nations Development Progrnm and the Centre for Disease Control and Prevention, Atlanta, USA. 2, 710-711 27 Seymour, A. (1971) Malaria and sickle cell disease. Br. Med J. 2, 711 28 Pichanick, AM. (1971) Severe malarial infection. Br. Med J. 3, 114 29 Ambe, J.P.et al. (2001) Associated morbidities in children with sickle- cell anaemin presenting with severe anaemia in a malarious area. Trop. Doct. 31, 26-27 30 Ibidape, MO. and Akinyanju, 0.O. (2000) Acute sickle cell syndromes in Nigerian adults. Clin. Lab. Haematol, 22, 151-155 31 Aidoo, M. et al. (2003) Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 359, 1311-1312 32 McAuley, C.F. et al (2010) Hgh mortality from Plasmodium References 1 Allison, A.C. (1954) Protection afforded by sickle cell trait against subtertian malarial infection. Br. Med . 1, 290-295 2 Piel, F.B. et al. (2010) Global distribution of the sickle cell gene and geographical conirmation of the malarin hypothesis. Nat. Commun. 1 104 falciparum manlarin in children living with sickle cell anemia on the coast of Kenva, Blood 116, 1663-1668 33 Oniyangi, O. and Omari, A.A. (2006) Malaria chemeprophylaxis in sickle cell disesse. Cochrane Database Syst. Rev. 2006, CDO03489 34 Warley, M.A. et al. (1965) Chemoprophyinxis of homozygous sicklers with antimalarinls and long-acting penicillin. Br. Med. J. 2, 86 88 35 Eke, FU. et al (2000) An apen comparative study of dispersible piroxicam versus soluble acetylsalicylie acid for the treatment of osteoarticular painful attack during sickle cell crisis. Trop. Med. Int Health 5, 81-84 36 Diop, S. et al. (2011) Sickle-cell disease and malarin: evnluation of seasonal intermittent preventive treatment with sulfadoxine 3 Herrick, JB. (1910) Peculiar elongated and sickle-shaped red blood copuscles in a case of severe anaemia. Arch. Intern. Med 6 517-521 4 Rees, D.C et al. (2010) Sickle-cell disease. Lancet 376, 2018-2031 5 Modell, B. and Darlison, M. (2008) Global epidemiology of hnemoglobin disorders and derived service indicators. Bull. World Heaith Organ. S6, 480-487
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