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By Q. Amul. University of Wisconsin-La Crosse.

Fluorine was chosen to replace hydrogen at the C5 position because it is of a similar size to hydrogen (atomic radii: F safe silvitra 120 mg, 0 purchase silvitra 120 mg with amex. It was thought that this similarity in size would give a drug that would cause little steric disturb- ance to the biosynthetic pathway buy cheap silvitra 120 mg online. Analogues containing larger halogen atoms do not have any appreciable activity because they are too large to bind effectively to the actve site of the enzyme discount 120mg silvitra fast delivery. Amsacrine is used to treat ovarian carcinomas, lymphomas and myelogenous leukaemias. Camptothecin is an antitumour agent A wide range of compounds also inhibit a number of the enzyme systems that are involved in the biosynthesis of purines and pyrimidines in bacteria. For example, sulphonamide bacteriostatics inhibit dihydropteroate synthetase, which prevents the formation of folic acid in both humans and bacteria. Although the mechanism of this inhibition is not known, inhibition of cell replication can lead to cell death and an improvement in the health of the patient. Intrastrand cross linking agents form a bridge between two parts of the same chain. In both cases the nucleophilic nature of nucleic acids means that alkylating agents are usually either electrophiles or in situ give rise to electrophiles. A wide range of different classes of compounds have been found to act as nucleic acid alkylating agents (Table 7. However, a large amount of information is available concern- ing their structure–action relationships. The idea underlying this approach is that the antisense compound contains the sequence of bases complementary to those found in a short section of the target nucleic acid. The antisense compound binds to the target nucleic acid by hydrogen bonding between its the bases and the comple- mentary bases of the target. This inhibits the normal function of the nucleic acid, which hopefully leads to the desired clinical response. These compounds were found to be unsuitable as drugs because of poor binding to the target site and short half lives due to enzyme catalysed hydrolysis. At present, development is still in its early stages, but the concept has aroused considerable interest in the pharmaceutical industry. Currently, the main cleaving agents are the bleomycins and their analogues (Figure 7. These are a group of naturally Plasma Concentration concentration in the excreted urine 0 0 Time Time (a) (b) 166 for natural logarithms: ln p ln 0 el (86) and for logarithms to base 10: el log10 p log10 0 (87) 2303 Both these equations give straight line plots (Figure 8. However, it is advisable to take an average of several measurements of 1/2 made from different initial values of p in order to obtain an accurate 1/2 value. Determination of the values of 1/2 and el from logarithmic plots of plasma concen- tration against time. The logarithm plot for logs to base ten is shown but the natural logarithmic plot would be similar except the slope would now be equal to el Half-life and el values may be used to put the comparison of the pharmaco- logical effect of a lead with its analogues on a numerical basis. This could provide an indication of the best course of action to take for the successful development of a useful drug. For example, if a lead has a short duration of action, analogues with larger 1/2 and smaller el values than those of the lead are more likely to give the required pharmacological effect. Similarly, if the lead is too toxic, analogues with smaller 1/2 and larger el values need to be developed. It is emphasized that 1/2 and el data are not infallible and should not be considered in isolation. It is the parameter that relates the rate of ¼À À ¼ ¼ ¼ First order First order absorption elimination ab el d þ Table 9. Produced in collaboration with the Ethiopia Public Health Training Initiative, The Carter Center, the Ethiopia Ministry of Health, and the Ethiopia Ministry of Education. Important Guidelines for Printing and Photocopying Limited permission is granted free of charge to print or photocopy all pages of this publication for educational, not-for-profit use by health care workers, students or faculty. All copies must retain all author credits and copyright notices included in the original document. Under no circumstances is it permissible to sell or distribute on a commercial basis, or to claim authorship of, copies of material reproduced from this publication. Except as expressly provided above, no part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without written permission of the author or authors. This material is intended for educational use only by practicing health care workers or students and faculty in a health care field. Since it comprises most of the contents of course outline on medical bacteriology to nursing, pharmacy and environmental science students, it can be used as a main learning material to these category of students. This lecture note gives emphasis on the knowledge and procedures of medical bacteriology to common pathogens in our country. At last but not least, the quality of this lecture note is kept updated by continous comments made by users of this lecture note. Dennis Carlson for his invaluable technical and moral support for the completion of this work. We also extend our appreciation to those individuals who reviewed this lecture note in different teaching institutions for the materialization of this lecture note. Identify the chemical meanses of sterilization and disinfection, and their effect on bacterial cell 6. It considers the microscopic forms of life and deals about their reproduction, physiology, and participation in the process of nature, helpful and harmful relationship with other living things, and significance in science and industry. Hippocratus, father of medicine, observed that ill health resulted due to changes in air, winds, water, climate, food, nature of soil and habits of people. Although Leeuwenhoek was not concerned about the origin of micro-organism; many other scientists were searching for an explanation for spontaneous appearance of living things from decaying meat, stagnating ponds, fermenting grains and infected wounds. Theory of Biogenesis 2 Theory of Abiogenesis deals with the theory of spontaneous generation; stating that living things originated from non-living things. He observed spontaneous existence of fishes from dried ponds, when the pond was filled with rain. Francesco Redi (1626-1697): He is the scientist who first tried to set an experiment to disprove spontaneous generation. He designed a large curved flask (Pasteur goose neck flask) and placed a sterile growth broth medium. Air freely moved through the tube; but dust particles were trapped in the curved portion of flask. Therefore Pasteur proved that micro-organisms entered to substrates through the air and micro-organisms did not evolve spontaneously. Discovery of streptococci The germ theory of disease The complete establishment of the germ theory of disease depended on the work of a German scientist, Robert Koch (1843- 1910). Koch’s postulates Koch’s postulates: proof of germ theory of disease A micro-organism can be accepted as a causative agent of an infectious disease only if the following conditions are satisfied. The micro-organism should be found in every case of the disease and under conditions which explain the pathological changes and clinical features. It should be possible to isolate the causative agent in pure culture from the lesion. When such pure culture is inoculated into appropriate laboratory animal, the lesion of the disease should be reproduced. It should be possible to reisolate the bacterium in pure culture from the lesion produced in the experimental animal. It has not been possible to fulfil every one of Koch’s postulates, but by adhering to them as closely as possible, serious errors have been prevented. Some microbes are very difficult or impossible to grow in vitro(in the laboratory) in artificial media. Certain diseases develop only when an opportunistic pathogen invades immunocompromised host. Classification is the assignment of organisms (species) into anorganised scheme of naming. The establishment of criteria for identifying organisms & assignment to groups (what belongs where) 5 2. At what level of diversity should a single species be split in to two or more species? Species) are more similar to each other than are members of higher level taxa (eg. Thus once you know that two individuals are member of the same taxon, you can inter certain similarities between the two organisms.

He called this process divergent thinking and by four-year-olds increased dramatically when novel de- its opposite—the tendency to narrow all options to a sin- signs were praised by adults; when this positive rein- gle solution—convergent thinking purchase line silvitra. Guilford identified forcement was stopped silvitra 120mg generic, the children reverted to produc- three components of divergent thinking: fluency (the ing unimaginative patterns cheap silvitra 120 mg without prescription. Other studies have used sim- ability to quickly find multiple solutions to a problem); ilar techniques to boost creativity scores of fifth graders purchase discount silvitra on line, flexibility (being able to simultaneously consider a vari- improve the originality of stories written by sixth ety of alternatives); and originality (referring to ideas graders, and increased the ability of college students to that differ from those of other people). One interesting finding signed to assess an individual’s aptitude for divergent in studies such as these is that positively reinforcing one thinking included the Torrance (1962) and Meeker kind of creative activity encourages original thinking in (1969) tests. See also Intelligence quotient Those that measure verbal ability include: Further Reading • Word fluency : writing words containing a given letter Briggs, John. Fire in the Crucible: The Alchemy of Creative • Ideational fluency: naming things that belong to a Genius. Understanding Creativity: The Interplay of Bi- ological, Psychological, and Social Factors. San Francis- • Associational fluency:writing synonyms for a specified co: Jossey-Bass, 1998. In addition, it may • Alternate uses: listing as many uses as possible for a be impossible for any test to measure certain personal given object traits that are necessary for success in creative endeav- ors, such as initiative, self-confidence, tolerance of ambi- • Plot titles: writing titles for short-story plots guity, motivation, and perseverance. Tests also tend to • Consequences: listing consequences for a hypothetical create an anxiety-producing situation that may distort the event (“What if no one needed to sleep? Growing Up Creative: Nurturing a Lifetime of Cre- sketches of recognizable items ativity. Divergent thinking tests are generally evaluated based on the number and variety of answers provided; the originality of the answers; and the amount of detail they contain (a characteristic referred to as elaboration). Crisis intervention A number of creativity tests currently in use include sec- tions that measure divergent thinking. Rather than ways of thinking, some creativity tests evaluate attitudes, behavior, creative perception,orcre- The term crisis intervention can refer to several dif- ative activity. Some creativity tests specifically address ferent therapeutic approaches, which are applied in a va- the problem of assessing creativity in minority popula- riety of situations. The common denominator among tions, who are at a disadvantage in tests that place a these interventions, however, is their brief duration and strong emphasis on verbal and semantic ability. The Eby their focus on improving acute psychological distur- Gifted Behavior Index reflects the growing view of cre- bances rather than curing long-standing mental disor- ativity as specific to different domains. Some common examples of crisis intervention in- six talent fields: verbal, social/leadership, visual/spatial, clude suicide prevention telephone hotlines, hospital- math/science problem-solving, mechanical/technical, based crisis intervention, and community-based disaster and musical. Two psy- chiatrists in particular heavily influenced our approach to Creativity tests have been found reliable in the sense crisis intervention with their crisis theory. Erich Linde- that one person’s scores tend to remain similar across a mann and Gerald Caplan believed that, when people are variety of tests. However, their validity has been ques- in a state of crisis, they are anxious, open to help, and tioned in terms of their ability to predict the true creative motivated to change. In one study, there was programs is therefore the belief that providing support little correlation between the scores of both elementary and guidance to people in crisis will avert prolonged and secondary students on divergent thinking tests and mental health problems. Creativity tests have Crisis or suicide hotlines offer immediate support to also been criticized for unclear instructions, lack of suit- individuals in acute distress. Further, some centers rope indicates that this type of counseling often has no will arrange referrals to clinicians. If a volunteer feels a It is possible that having people focus on the upsetting caller is at immediate risk, however, confidentiality will event emphasizes the victimization that has already be broken and a mental health worker will be called taken place, rather than people’s innate abilities to over- upon to intervene. Some researchers fear that the people who call that a particular psychological intervention may be intu- may not be those at highest risk. A further problem is that there appears to be significant discrepancies in the Further Reading training of telephone operators at these hotlines. When treatment is administered, however, it is usually in Critical period the form of psychotropic drugs with follow-up outpatient A specified time span, also referred to as the opti- therapy scheduled upon release. Although this term is used in a variety of contexts, The professionals who arrive on the scene attempt to ad- the term is most closely associated with ethology, the minister preventative procedures to avert mental disor- study of animal behavior in its natural environment ders such as post-traumatic stress disorder,which may from the perspective of evolutionary adaptation. For example, many issues of interest propriately maternal object during a critical period to psychologists are not addressed by anthropologists, would activate the “following” instinct of newborn who have their own concerns traditionally, including such goslings: he successfully had a group of goslings follow topics as kinship, land distribution, and ritual. However, there is no significant posed to humans in order to make good pets and the body of anthropological data on many of the more ab- early months in which birds must be exposed to the char- stract questions commonly addressed by psychologists, acteristic song of their species in order to learn it. In one of The specifically human phenomenon of language the best known studies, researchers found evidence that development also appears to be subject to a critical peri- human perceptual processes develop differently depend- od. So-called “wild” or “feral” children deprived of ing on what types of shapes and angles people are ex- human society for an extended period show that they posed to daily in their environment. People living in have been unable to catch up on language due to lack of countries such as the United States with many buildings exposure early in life. For ex- studies have also discovered that the symptoms of most ample, the embryonic stage in humans is a critical period psychological disorders vary from one culture to another, for certain types of growth (such as the appearance of the and has led to a reconsideration of what constitutes nor- heart, eyes, ears, hands, and feet) which must occur for mal human sexuality. This observation A subfield of psychology concerned with observing posed a challenge to Freud’s oedipal theory by raising the human behavior in contrasting cultures. The ques- pass of psychological research beyond the few highly in- tions raised by Malinowski’s observation demonstrate a dustrialized nations on which it has traditionally focused. Psychological re- ly, most experts concur that “culture” involves patterns of search often confounds, or merges, two variables in a situ- behavior, symbols, and values. The prominent anthropol- ation in this case, the boy’s anger toward his father and ogist Clifford Geertz has described culture as “. A cross- torically transmitted pattern of meanings embodied in cultural perspective can untangle such confounded vari- symbols, a system of inherited conceptions expressed in ables when it finds them occurring separately in other cul- symbolic forms by means of which men communicate, tures—e. The cult leader governs most, if not all, aspects of those of the majority culture—may be constituted in dif- the lives of his or her followers, often insisting that they ferent ways. Often, it is an ethnic, racial, or religious break all ties with the world outside of the cult. Any group that develops its own customs, norms, groups are usually thought of in terms of religion, al- and jargon may be considered a subculture, however, in- though other types of cults can and do exist. The proliferation of religious cults in the United A prominent area of intersection between psychological States is considered by many experts as symptomatic of inquiry and subcultures within the United States has been the general social discordance that has plagued postwar the issue of cultural bias in testing. Cults offer the allure of an ordered assert that there is no evidence for bias across race or so- world that is easily understood. Clear rules of behavior cial class in “standardized” intelligence and achievement are enforced and nagging questions about meaning and tests. However, children whose primary language is not purpose are dispelled by the leader, who defines mem- English should be tested in their primary language. It is probably most useful to examine the phenomenon of cults without Further Reading dwelling on the sensationalistic practices of the flamboy- Barnouw, Victor. Rethinking Psychological Anthropology: Con- examines a cult and its dynamics, what is actually ob- tinuity and Change in the Study of Human Action. To understand this process, consider that many so- Cross-sectional study cial organizations other than what we traditionally think of as cults require strict adherence to a set of beliefs and, Research that collects data simultaneously from people of different ages, in contrast to a longitudi- in turn, provide a sense of meaning and purpose to their nal study, which follows one group of subjects over followers. The rigid social contract of the A cross-sectional study is a research method where military, for instance, is considered by many psycholo- data are collected at the same time from people in differ- gists as being cult-like. It contrasts with the method, known have had a profound impact on the lives of its followers as longitudinal study, where the same group of subjects include self-help groups, such as Alcoholics Anony- is studied over time. One weakness, or confounding vari- mous, where selflessness and devotion to the group are able, of the cross-sectional study is that its subjects, in highly valued and rewarded. Certain types of political addition to being different ages, are also born in different groups and terrorist organizations are still other exam- years, and their behavior may thus be influenced by dif- ples of “cults” that defy the common definition of the ferences in education, cultural influences, and medical term. In the longitudinal study, data can be obtained try at the University of California at San Francisco, is from subjects of different ages born within the same pe- one of many psychologists who has observed cultic be- riod of time. However, a confounding variable in longi- havior in many areas of society other than in extremist tudinal studies is the degree to which each person’s envi- religious groups. In the introduction to his 1990 book, ronmental influences will vary from those of others over The Wrong Way Home: Uncovering the Patterns of Cult the period of time covered by the experiment. Behavior in American Society, Deikman asserted that “behavior similar to that which takes place in extreme cults takes place in all of us,” and suggested that “the longing for parents persists into adulthood and results in cult behavior that pervades normal society.

The ability to predict the sensitivity and maintain a remission or tumour response according to the of bacterial pathogens to antimicrobial substances in vitro pro- following general principles buy 120mg silvitra with amex. It often entails complex regi- duced a profound change in the efficacy of treatment of infec- mens of two to four drugs order silvitra 120 mg on line, including pulsed doses of a cyto- tious diseases buy silvitra 120 mg overnight delivery. The development of analogous predictive tests toxic agent with daily treatment with agents with different has long been a priority in cancer research buy cheap silvitra. Knowing the details of such regimens is not be desirable because, in contrast to antimicrobial drugs, anti- expected of undergraduate students and graduate trainees in cancer agents are administered in doses that produce toxic oncology will refer to advanced texts for this information. Unfortunately, currently, clinically useful predictive drug sensitivity assays against tumours do • Drugs are used in combination to increase efficacy, to inhibit not exist. Chemotherapeutic drugs vary in adverse effects and there is • Treatment may be prolonged (for six months or longer) considerable inter-patient variation in susceptibility. The most and subsequent cycles of consolidation or for relapsed frequent adverse effects of cytotoxic chemotherapy are sum- disease may be needed. The • Cancer chemotherapy slows progression through the mechanisms of chemotherapy-induced vomiting include cell cycle. Reduced intracellular drug Doxorubicin Lomustine, carmustine Bleomycin concentration Cyclophosphamide Mitomycin C Cytarabine (i) increased drug efflux Anthracyclines (e. Increased detoxification 6-Mercaptopurine, alkylating lored to the emetogenic potential of the chemotherapy to be administered. It may also be necessary to give the patient a of drug agents supply of as-needed medication for the days after chemother- 4. No prophylactic anti-emetic treatment is 100% effective, target enzyme especially for cisplatin-induced vomiting. Decreased number of Hormones, lar catheters for intravenous cytotoxic drug administration is receptors for drug glucocorticosteroids mandatory. Agent-specific organ toxicity products (red cells and platelet concentrates) and early antibi- 3. The peripheral neuropathy with availability and use of recombinant haematopoietic growth vinca alkaloids, taxanes) factors (erythropoietin (Epo), granulocyte colony-stimulating 4. Infertility/teratogenicity caused by various chemotherapeutic regimens is a clear-cut 6. Second malignancy advance in supportive care for patients undergoing cancer chemotherapy. It is often enhance the ability to minimize cytotoxic induced bone mar- routine to use two- or three-drug combinations as prophyl- row suppression. However, many resume normal menstru- ation when treatment is stopped and pregnancy is then pos- 1000 sible, especially in younger women who are treated with lower 500 Secondary fall total doses of cytotoxic drugs. Sperm storage before chemotherapy can be considered for 100 03 9 15 21 03 9 15 21 27 33 39 45 51 57 males who wish to have children in the future. Reproductively active men and women must be advised to use appropriate Therapy Therapy contraceptive measures during chemotherapy, as a reduction in Figure 48. This malignancy is also approxi- Infection is a common and life-threatening complication of mately 20 times more likely to develop in patients with chemotherapy. It is often acquired from the patient’s own gas- ovarian carcinoma treated with alkylating agents with or tro-intestinal tract flora. This delayed treatment complication is pose-built laminar-airflow units, but this does not solve the likely to increase in prevalence as the number of patients who problem of the patient’s own bacterial flora. Broad-spectrum antibiotic treatment must be started empirically in febrile neutropenic patients before the Adverse effects of cytotoxic chemotherapy results of blood and other cultures are available. Combination • Immediate effects: therapy with an aminoglycoside active against Pseudomonas – nausea and vomiting (e. Therapeutic decisions need to be guided by knowledge of – drug-specific organ toxicities (e. Pneumocystis carinii) can occur; • Late effects: details of the treatment for such infections are to be found in – gonadal failure/dysfunction; Chapters 43, 45 and 46. This may be ameliorated in the case of doxorubicin by cooling the scalp with, for example, ice-cooled 1. It is an inactive prodrug given Alkylating agents are particularly effective when cells are orally or intravenously. If a tumour is sensitive to one alkylating agent, it is usually sensitive to another, but cross-resistance does not necessarily occur. For example, although most alkylating agents diffuse passively T A A T into cells, mustine is actively transported by some cells. Alopecia (10–20%) Chemical cystitis (reduced by mesna) Mucosal ulceration Impaired water excretion Interstitial pulmonary fibrosis Ifosfamide i. These include the following: Cyclophosphamide is highly effective in treating various lymphomas, leukaemias and myeloma, but also has some use • dose-related haematopoietic suppression, leukopenia and in other solid tumours. It is an effective immunosuppressant thrombocytopenia at 10–14 days after treatment; (Chapter 50). It is converted to active metabolites in Pharmacokinetics the liver (see above); these are excreted by the kidneys. Absorption son see disulfiram, Chapter 53) and consequently causes from the gastro-intestinal tract is excellent (essentially 100% flushing and tachycardia if ethanol is taken concomitantly. Cyclophosphamide and its metabolites are is also a weak monoamine oxidase inhibitor and may precipi- excreted in the urine. Renal excretion of one of its metabolites, tate a hypertensive crisis with tyramine-containing foods acrolein, causes the haemorrhagic cystitis that accompanies (Chapter 20). Cisplatin is is important that it is given at the initiation of treatment, and markedly effective for testicular malignancies and several that the dosing interval is no more than four hours. The mesna other solid tumours, including carcinoma of the ovary, lung, dose and schedule vary with the dose of cyclophosphamide or head and neck, and bladder may also respond well. Urine is monitored for volume, proteinuria and is given intravenously in combination with other cytotoxic haematuria. The compara- Mechanism of action tive pharmacology of carboplatin and oxaliplatin is summar- Mesna protects the uro-epithelium by reacting with acrolein ized in Table 48. The other agent in this • nephrotoxicity (especially cisplatin) which is dose-related class is dacarbazine. Low excreted in the urine in potential for ototoxicity first 24h and neuropathy Oxaliplatin i. Folinic acid circumvents multiphasic and traces of platinum are detectable in urine this biosynthetic block and thus non-competitively antagonizes months after treatment. Drug interactions Determinants of methotrexate toxicity Additive nephrotoxicity and ototoxicity occurs with amino- These consist of: glycosides or amphotericin. Antimetabolites are structural analogues of, and compete Both factors must be exceeded for toxicity to occur in these with, endogenous nucleic acid precursors. The severity of toxicity is proportional to the length of pathways blocked by antimetabolites are not specific to neo- time for which the critical concentration is exceeded and is plastic cells. Thus, their selectivity for malignant cells is only independent of the amount by which it is exceeded. Folinic acid rescue bypasses the dihydrofolate reductase blockade and minimizes methotrexate toxicity. Methotrexate is curative for choriocarcinoma, also induces Monitoring of the plasma methotrexate concentrations has remission in acute lymphocytic leukaemia and is often active in improved the safe use of this drug and allows identification of breast cancer, osteogenic sarcoma and head and neck tumours. If a patient develops severe tox- Methotrexate is also an immunosuppressant (Chapters 26 and icity with protracted elevation of methotrexate concentrations, 50) and is used to inhibit cellular proliferation in severe psoria- methotrexate metabolism can be rapidly increased by adminis- sis (Chapter 51). About 80–95% of a dose of methotrexate These include the following: is renally excreted (by filtration and active tubular secretion) • myelosuppression; as unchanged drug or metabolites. It is partly metabolized • nausea and vomiting; by the gut flora during enterohepatic circulation. Other weak acids including furosemide palsies and a chronic demyelinating encephalitis. Pharmacokinetics Methotrexate absorption from the gut occurs via a saturable Mechanism of action transport process, large doses being incompletely absorbed. It 5-Fluorouracil is a prodrug that is activated by anabolic phos- is also administered intravenously or intrathecally. Adverse effects antimetabolites that are used clinically include tioguanine, fludarabine and 2-chlorodeoxyadenosine [cladrabine] (see • Oral ulceration and diarrhoea is an adverse event in Table 48.