By R. Silvio. Washington & Jefferson College. 2018.

Concentration of substrate At fixed enzyme concentration pH and temperature the activity of enzymes is influenced by increase in substrate concentration anafranil 75 mg without a prescription. This condition shows that as concentration of substrate is increased discount anafranil 50 mg on line, the substrate molecule combine with all available enzyme molecules at their active site till not more active sites are available (The active Sites become saturated) buy anafranil 50mg visa. Relationship between [S] and Km Km shows the relationship between the substrate concentration and the velocity of the enzyme catalyzed reaction buy anafranil 25mg without a prescription. Take the point in which 50% of the active site of the enzyme will be saturated by substrate discount anafranil 75 mg mastercard, Assume that at ½ Vmax-50% of the active site of enzyme becomes saturated. Therefore: 11 Vo = ½ Vmax, at 50% saturation ½ Vmax = Vmax[S] Km + [S] 2[S] = Km + [S] Km= [S] Figure: Relationship between [S] and Km Characteristics of Km Km- can defined as the concentration of the substrate at which a given enzyme yields one-half its max. Small Km - A numerically small (Low) km reflects a high affinity of the enzyme for substrate because a low conc of substrate is needed to half saturate the enzyme- that is reach a velocity of ½ Vmax. High Km - A numerically large (high) Km reflects a low affinity of enzyme for substrate b/c a high conc of substrate is needed to half saturate the enzyme. Relationship of Velocity to Enzyme Concentration The rate of the reaction is directly proportional to enzyme concentration at all substrate concentration. For example, if the enzyme concentration halved, the initial rate of the reaction (Vo) is reduced to one half that of the original. Effect of Enzyme concentration on enzymatic reaction Order of Reaction When [S] is much less than Km, the velocity of the reaction is roughly proportional to the substrate concentration. The rate of reaction is then independent of substrate concentration and said to be zero order with respect to substrate concentration. Enzyme Inhibition Any substance that can diminish the velocity of an enzyme-catalyzed reaction is called an inhibitor and the process is known as inhibition. Example: Inhibition of triose phosphate dehydrogenate by iodo acetate which block the activity of the enzyme. In competitive inhibition the inhibitor and substrate compete for the same active site on the enzyme as a result of similarity in structure. A classical example is Malonate that competes with succinate and inhibits the action of succinate dehydrogenase to produce fumarate in the Krebs cycle. The enzyme can be also inhibited by oxalate and glutarate because of the similarity of this substance with succinate Eg. This competition blocks the conversion of these precursors, and of hypoxanthine and xanthine, to uric acid and result in lower serum urate levels. A Lineweaver-Burk Plot An alternative linear transformation of the Michaelis-Menten equation is the Eadie-Hofstee transformation: v/[S] = -v [1/Km] + [Vmax/Km] and when v/[S] is plotted on the y-axis versus v on the x-axis, the result is a linear plot with a slope of -1/Km and the value Vmax/Km as the intercept on the y- axis and Vmax as the intercept on the x-axis. Both the Lineweaver-Burk and Eadie-Hofstee transformation of the Michaelis-Menton equation are useful in the analysis of enzyme inhibition. Since most clinical drug therapy is based on inhibiting the activity of enzymes, analysis of enzyme reactions using the tools described above has been fundamental to the modern design of pharmaceuticals 15 Effect of Competitive inhibitors 1. This means that in the presence of a competitive inhibitor more substrate is needed to achieve ½ Vmax. Figure: Competitive inhibition Non-Competitive Inhibition In non-competitive inhibition the inhibitor binds at different site rather than the substrate-binding site. When the inhibitor binds at this site there will be a change in conformation of the enzyme molecules, which leads to the reversible inactivation of the catalytic site. Figure: Uncompetitive inhibition 17 Regulation of enzyme activity There are several means by which the activity of a particular enzyme is specifically regulated. Irreversible covalent Activation / Zymogen activation Some enzymes are secreted in an inactive form called Proenzymes or zymogens. Reversible Covalent Modification By addition of or removal of phosphate or adenylate, certain enzymes are reversibly activated and inactivated as per the requirement. Allosteric Modulation In addition to simple enzymes that interact only with substrates and inhibitors, there is a class of enzymes that bind small, physiologically important molecules and modulate activity in ways other than those described above. These are known as allosteric enzymes; the small regulatory molecules to which they bind are known as effectors. Allosteric effectors bring about catalytic modification by binding to the enzyme at distinct allosteric sites, well removed from the catalytic site, and causing conformational changes that are transmitted through the bulk of the protein to the catalytically active site(s). Feedback inhibition In allosteric regulation in which end products inhibit the activity of the enzyme is called” feedback inhibition”. Feedback regulation generally occurs at the earliest functionally irreversible step unique in the biosynthetic pathway. Enzymes those have function in plasma) For example: - the liver secretes zymogens of the enzymes involved in blood coagulation.

Packed Red Cells: Most anemic should be transfused with packed red cells buy anafranil 50mg low price, after removing 80% of the plasma anafranil 25 mg discount, so that the volume of the component is about 150 ml buy 50 mg anafranil. Washed Red Cells Such preparations are needed for individuals who are IgA deficient and have had a life- threatening reaction to plasma containing IgA purchase anafranil 25mg on line. The washed red cells must be used within 24 hours to avoid growth of contaminating bacteria safe anafranil 25mg. Membrane and metabolic changes occur to 0 0 the red cells during this storage 1 - 6 C. Freezing requires the addition of glycerol, a cryoprotectant that enters the cells and limits the formation of intracellular crystals. Platelets 0 Platelets are concentrated by centrifugation and stored at 20-24 C since refrigeration destroys their ability to aggregate. Granulocytes must be transfused as soon as collected, since it is not possible to preserve their function by storage at any temperature. Granulocyte transfusions are frequently accompanied by fever and respiratory symptoms in the recipient; these reactions can often be fatal. Immunity means the body’s ability to resist or eliminate harmful foreign materials or abnormal cells. The leukocytes and their derivatives defend against invasion by disease-causing microorganisms by phagocytizing the invaders or causing their destruction by more complex means; identify and destroy cancer cells that arise within the body phagocytize cellular debris resulting from dead or injured cells; it is essential for wound healing and tissue repair. They can be rapidly transferred from their site of production or storage to where ever they are needed There are five different types of leukocytes Leukocytes vary in number, function, and structure. Five different cells - neutrophils, eosinophils, basophiles, monocytes and lymphocytes - each have different characteristic morphology and function. Neutrophils, eosionphils, and basophiles are classed as polymorphonuclear granulocytes. They are classified on the basis of varying affinity of their granules to the red dye eosin and basic dye methylene blue. Monocytes and lymphocytes are mononuclear agranulocytes Leukocytes are produced at varying rates depending on the changing needs for defense of the body All leukocytes originate from the same undifferentiated pluripotential stem cells in the red bone marrow that also produce erythrocytes and platelets The bone marrow produces all circulating blood cells except lymphocytes, which are produced by lymphocyte colonies in lymphoid tissues. The myeloblast is the earliest recognizable precursor in the granulocyte series that is present in the red bone marrow. A series of four to five divisions are associated and the mature neutrophil, cytoplasmic granules develop. On entering the peripheral blood, neutrophils are almost equally divided into circulating and marginal pools, which are in a dynamic equilibrium. Thus, a large reserve capacity of phagocytes is available in the bone marrow, and a large fraction of the neutrophils present in the peripheral blood; they are ready for egress into the tissues in response to infection or inflammation. The average time from the start of granulopoiesis to the entry of the mature neutrophil into circulation is 10 to 13 days. The mature neutophil remain in the blood for only about 10 to 14 hours before entering the tissues, where it soon dies after performing phagocytic function. Monocytes spend a short time in the circulating blood before entering the tissues. However, they survive in tissues for variably long period; they become transformed into macrophages, long-lived phagocytic cells that retain some capacity for continuing cell division. There are other growth factors that promote the growth and differentiation of eosinophils and lymphoid cells. Prostaglandin E produced by macrophages inhibit the production of monocytes, and to some extent of neutrophils. In addition, lymphokines and interleukin-5 can cause accumulation of eosinophils in tissues. Eosinophils release several granule derived cationic proteins, including major basic proteins that cause local tissue damage in diseases such as asthma and the hypereosinophilic syndrome. These cationic proteins are beneficial when released as part of eosinophil count is found during most bacterial and viral infections. Stress, endogenous secretion of corticosteroids and exogenous glucocorticoids suppress the number of blood eosinphils Eosinophils cannot engulf a much larger parasitic worm, but they do attach to the worm and secrete substances that kill it. Basophil granules have a high content of histamine and play a role in acute, allergic reactions.

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Without such sustentacular cell secretion anafranil 10mg with mastercard, the Müllerian duct will develop effective 10mg anafranil; without testosterone generic anafranil 75mg online, the Wolffian duct will degrade discount anafranil 25 mg with amex. For more information and a figure of differentiation of the gonads order anafranil 50mg without prescription, seek additional content on fetal development. Further Sexual Development Occurs at Puberty Puberty is the stage of development at which individuals become sexually mature. Though the outcomes of puberty for boys and girls are very different, the hormonal control of the process is very similar. In addition, though the timing of these events varies between individuals, the sequence of changes that occur is predictable for male and female adolescents. In pre-pubertal children, the sensitivity of the negative feedback system in the hypothalamus and pituitary is very high. In addition to age, multiple factors can affect the age of onset of puberty, including genetics, environment, and psychological stress. One of the more important influences may be nutrition; historical data demonstrate the effect of better and more consistent nutrition on the age of menarche in girls in the United States, which decreased from an average age of approximately 17 years of age in 1860 to the current age of approximately 12. Body fat, corresponding with secretion of the hormone leptin by adipose cells, appears to have a strong role in determining menarche. In girls who are lean and highly active, such as gymnasts, there is often a delay in the onset of puberty. Signs of Puberty Different sex steroid hormone concentrations between the sexes also contribute to the development and function of secondary sexual characteristics. Development of the Secondary Sexual Characteristics Male Female Deposition of fat, predominantly in breasts and Increased larynx size and deepening of the voice hips Increased muscular development Breast development Growth of facial, axillary, and pubic hair, and increased Broadening of the pelvis and growth of axillary growth of body hair and pubic hair Table 27. A growth spurt normally starts at approximately age 9 to 11, and may last two 1312 Chapter 27 | The Reproductive System years or more. In boys, the growth of the testes is typically the first physical sign of the beginning of puberty, which is followed by growth and pigmentation of the scrotum and growth of the penis. Testosterone stimulates the growth of the larynx and thickening and lengthening of the vocal folds, which causes the voice to drop in pitch. The first fertile ejaculations typically appear at approximately 15 years of age, but this age can vary widely across individual boys. Unlike the early growth spurt observed in females, the male growth spurt occurs toward the end of puberty, at approximately age 11 to 13, and a boy’s height can increase as much as 4 inches a year. Spermatogenesis, the production of sperm, occurs within the seminiferous tubules that make up most of the testis. Spermatogenesis begins with mitotic division of spermatogonia (stem cells) to produce primary spermatocytes that undergo the two divisions of meiosis to become secondary spermatocytes, then the haploid spermatids. Upon release from the seminiferous tubules, sperm are moved to the epididymis where they continue to mature. During ejaculation, sperm exit the epididymis through the ductus deferens, a duct in the spermatic cord that leaves the scrotum. The ampulla of the ductus deferens meets the seminal vesicle, a gland that contributes fructose and proteins, at the ejaculatory duct. The fluid continues through the prostatic urethra, where secretions from the prostate are added to form semen. Secretions from the bulbourethral glands protect sperm and cleanse and lubricate the penile (spongy) urethra. Columns of erectile tissue called the corpora cavernosa and corpus spongiosum fill with blood when sexual arousal activates vasodilatation in the blood vessels of the penis. Testosterone regulates and maintains the sex organs and sex drive, and induces the physical changes of puberty. Interplay between the testes and the endocrine system precisely control the production of testosterone with a negative feedback loop. The man’s penis is inserted into the vagina to deliver sperm, and the baby exits the uterus through the vagina during childbirth. As with spermatogenesis, meiosis produces the haploid gamete (in this case, an ovum); however, it is completed only in an oocyte that has been penetrated by a sperm. Supporting granulosa and theca cells in the growing follicles produce estrogens, until the level of estrogen in the bloodstream is high enough that it triggers negative feedback at the hypothalamus and pituitary. Following ovulation, the granulosa cells of the empty follicle luteinize and transform into the progesterone-producing corpus luteum. The ovulated oocyte with its surrounding granulosa cells is picked up by the infundibulum of the uterine tube, and beating cilia help to transport it through the tube toward the uterus.

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The most promising approaches are M-protein-based generic anafranil 25 mg line, including those using multivalent type-specific vaccines discount 75 mg anafranil free shipping, and those directed at non-type-specific order 75 mg anafranil otc, highly conserved portions of the molecule discount anafranil 10 mg mastercard. Success in developing vaccines may be achieved in the next 5–10 years buy discount anafranil 10 mg on line, but this success would have to contend with important questions about the safest, most economical and most efficacious way in which to employ them, as well as their cost-effectiveness in a variety of epidemilogic and socio-economic conditions. A review of past attempts and present concepts of producing streptococcal immunity in humans. Intravenous vaccination with hemolytic streptococci: its influence on the incidence of rheumatic fever in children. Persistence of type-specific antibodies in man following infection with group A streptococci. Epitopes of group A streptococcal M protein shared with antigens of articular cartilage and synovium. Rheumatic fever: a model for the pathological consequences of microbial-host mimicry. Streptococcal M protein: alpha-helical coiled-coil structure and arrangement on the cell surface. Alternate complement pathway activation by group A streptococci: role of M-protein. Inhibition of alternative complement pathway opsonization by group A streptococcal M protein. Streptococcal infections: clinical aspects, microbiology, and molecular pathogenesis. Type-specific immunogenicity of a chemically synthesized peptide fragment of type 5 streptococcal M protein. Multivalent group A streptococcal vaccine designed to optimize the immunogenicity of six tandem M protein fragments. Protection against streptococcal pharyngeal colonization with a vaccinia:M protein recombinant. Intranasal immunization with C5a peptidase prevents nasopharyngeal colonization of mice by the group A Streptococcus. Vaccination with streptococcal extracellular cysteine protease (interleukin-1 beta convertase) protects mice against challenge with heterologous group A streptococci. Acute rheumatic fever in Auckland, New Zealand: spectrum of associated group A streptococci different from expected. Adding to the burden on health systems of developing countries are the costs of outside referrals that are often required during the course of treatment. The socioeconomic costs were also borne by the parents of the patients, with 22% exhibiting absenteeism from work, and about 5% losing their jobs. As a programme design strategy, it is advisable to attempt small-scale pilot programmes before initiating large-scale national control programmes, as the lessons learnt from pilot schemes can, in addition to many other benefits, prevent the waste of scarce resources (2, 7). These studies emphasize that national prevention programmes based on secondary prophylaxis have the potential for considerable cost savings, which could be used to improve the spread and gains of a programme. Evidence has been presented from a simulation study suggested that the most cost-effective strat- egy was to treat all pharyngitis patients with penicillin (particularly those within an at-risk group), without a strict policy of waiting for the disease to be confirmed by bacterial culture (7, 11). However, this approach has not been confirmed and cannot be advocated until more thorough studies are carried out. In hospital settings where facilities are available, the “culture and treat” strategy has been shown to be cost-effective (12). Analysis of costs of acute rheumatic fever and rheumatic heart disease in Auckland. Analysis of the cost-effectiveness of pharyngitis management and acute rheumatic fever prevention. It is important to implement such programmes through the existing national infrastructure of the ministry of health and the ministry of education without building a new administrative mechanism. This would minimize additional costs and prevent unsus- tainable monolithic programmes (2, 3, 6, 11, 12). Based upon previous experience (1, 2, 11, 12), planning and implementation of national programmes should be based on the following principles: • There should be a strong commitment at policy level, particularly in the ministries of health and education. A central or a local referral or registration centre should be established in participating areas. Attention should be given to patients who have difficulties in adhering to long-term secondary prophylaxis regimes, or who drop out of the prevention regime (i. Primary prevention activities Primary prevention is based on the early detection, correct diagnosis and appropriate treatment of individual patients with Group A strep- tococcal pharyngitis.

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Ferrous iron is octahedrally coordinated having six ligands or binding groups buy 10 mg anafranil with amex, attached to it purchase anafranil 25 mg on line, the nitrogen atoms account for only four ligands discount anafranil 50mg without prescription. The two remaining coordination sites which lie along the ring contain on the plane of the ring contains one histidine with imidazole 2+ nitrogen that is close enough to bond directly to the Fe called proximal histidine the other 2+ histidine which facilitates the alignment of heme to O2 and that of Fe called distal Histidine discount 10 mg anafranil overnight delivery. The coordinate nitrogen atoms mainly prevents conversion of the heme iron to the ferric state 3+ (Fe ) due to their electron donating character discount anafranil 10 mg amex. In free heme molecules, reaction of oxygen at one of the two “open” coordination bonds of iron which is perpendicular to the plane of the porphryin molecule above and below can result in 2+ 3+ irreversible conversion of Fe to Fe. In heme containing proteins this reaction is prevented by 134 sequestering the heme deep within a protein structure where access to the two open coordination bonds is restricted polar amino acids are located almost exclusively on the exterior surface of globin polypeptide and contribute to the high solubility of these proteins. Amino acids which are both polar and hydrophobic, such as Threonine, tyrosine and Tryptophan are oriented to the exterior. Hydrophobic amino acid residues are buried with in the interior where they stabilize the folding of the polypeptide and binding of iron porphyrin ring. The only exceptions to this general distribution of amino acids residues in globins are the two Histidines that play an indispensable role in the heme binding are oriented perpendicular to and on either side of the planor heme prosthetic group. In the quaternary stucture of human Hb there exists two α- globin and two – β- globin sub units (α2 β2). Experimental analysis of the quaternary structure indicates multiple non-convalent interactions between each pair of dissimilar subunits, that is, at the α - β - interfaces. In contrast there are few interactions between identical subunits at the α - α or β – β interface so hemoglobin is considered more as a heterodmer (α β)2. Myoglobin contains a single polypeptide chain folded about a prosthetic group, the heme, which contains the oxygen binding site. Note, for example that myoglobin and each subunit of hemoglobin consists of eight helical segments, which are labeled A through H. In all vertebrates the oxygen transport protein is hemoglobin, a protein that can pick up oxygen in lungs or gills and deliver it to tissues. Fetal Hb (HbF) Contains a different type of Hb just after conception fetuses synthesize zeta chain (quite like α - chain) The HbF variant barely detectable and ε- chains just like β - chain later zeta replaced by α - and ε- by γ. HbF contain 2 γ and 2 γ subunits in most adult often increases up to 15 - 20% in individuals with mutant adult Hbs, such as sickle cell disease. The direct benefit of this structural change in Hb isoform is a more efficient transfer of O2 from maternal HbA to fetal( HbF). Sickle Cell Hemoglobin (HbS) HbS, the variant most commonly associated with sickle cell disease, cannot tolerate high protein concentration when deoxygenated. At low oxygen concentrations, deoxy HbS polymerizes, forms fibers, and distorts erythrocytes in to sickle shapes. Sickle Cell Trait The heterozygote individuals (sickle cell trait) (HbA/HbS) is associated with increased resistance to malaria. Sickled erythrocyte exhibits little or less deformity, they no longer move freely through the micorvasculature and often block blood flow. Moreover this cells lose water, become fragile and have a considerably short life span leading to anemia. Sickle Cell Disease Sickle cell disease is caused by an inherited structural abnormality in the β –globin polypeptide. Clinically, an individual with sickle cell disease present with intermittent episode of haemolytic and painful vaso–occlusive crisis. There is also a likely to be impaired growth, increased susceptibility to infections and multiple organ damage. Digestion and Absorption of Proteins Proteins are larger polypeptide molecules coiled by weaker bonds in their tertiary structure the digestion of proteins involves the gradual breakdown of this polypeptide by enzymatic hydrolysis in to amino acid molecules which are absorbed in the blood stream. The protein load received by the gut is derived from two sources 70-100g dietary protein which is required daily and 35 - 200g endogenous protein (secreted enzymes and proteins in the gut or from intestinal epithelia cell turnover) Only 1-2g of nitrogen equivalent to 6-12g of proteins are lost in the feces on a daily basis. Gastric Digestion Entry of a protein in to stomach stimulates the gastric mucosa to secrete a hormone gastrin which in turn stimulates the secretion of Hcl by the parietal cells of the gastric glands and pepsinogen by the chief cells. The acid denatures the protein and the whole protein susceptible to hydrolysis by the action other proteolytic enzymes.

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