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Each chemical reaction has a characteristic rate constant; these in turn directly relate to the equilibrium constant for that reaction order 20 mg levitra oral jelly free shipping. At equilibrium discount 20 mg levitra oral jelly, the rate of the forward reaction is equal to the rate of the reverse reaction: K+1 [B] Keq = = K−1 [A] Therefore the equilibrium constant for a chemical reaction is not only equal to the equilibrium ratio of product and reactant concentrations buy generic levitra oral jelly 20mg, but is also equal to the ratio of the characteristic rate constants of the reaction. Catalysts speed up both the forward and reverse reactions proportionately; although the magnitude of the rate constants of the forward and reverse reactions is increased, the ratio of the rate constants remains the same in the presence or absence of enzyme. It is apparent therefore that enzymes and other catalysts have no effect on the equilibrium constant of the reactions they catalyse. The Michaelis–Menten equation is a quantitative description of the relationship between the rate of an enzyme-catalysed reaction [v1], the concentration of substrate [S], the maximum reaction rate (Vmax) and the Michaelis–Menten constant (Km). If the Michaelis–Menten plot is extrapolated to infinitely high substrate concentrations, the extrapolated rate is equal to Vmax. Plots of 1/v versus 1/[S] yield straight lines with a slope of Km/Vmax, and an intercept on the ordinate at 1/Vmax and on the abscissa of 1/Km (Figure 9. The Km of an enzyme is a measure of its affinity for the substrate; the higher the Km the lower the affinity. Turnover number, related to Vmax, is defined as the maximum number of moles of substrate that can be converted to product per mole of catalytic site per second. Enzyme activity is frequently expressed as the amount of substrate transformed (or product formed) per minute, under standard conditions. A unit (U) of enzyme activity is equivalent to the transformation of 1 µmol of the substrate per minute. Genetically determined differences in primary structure are the basis for the multiplicity in those groups classed as isoenzymes. Isoenzymes of one enzyme group are often expressed to differing extents in different tissues. These subunits come together in various combinations, leading to five distinct isoforms. The all-H isoform is characteristic of that from heart tissue, and the all-M isoform is typically found in skeletal muscle and liver. Isoenzymes all catalyse the same chemical reaction, but with different degrees of efficiency. Both enzymes convert glucose to glucose- 6-phosphate, the first reaction in glycolysis, but respond to quite different concentrations of glucose. Glucokinase has a high K (low affinity) for glucose, about 2 × 10−2 M, and operates m within the liver. On the other hand, hexokinase has a low K (high affinity) for glucose, about 5 × 10−5 M. It would be fully saturated at a blood glucose m concentration of 5 × 10−3 M (5 mM) and its activity would change little with changes in glucose concentration at this level. Hexokinase is located in muscle, where it is responsible for initiating glycolysis to provide energy for muscle contraction; muscle only imports and uses glucose, it does not export it (Figure 9. Inhibitors of the first class usually cause an inactivating, covalent modification of enzyme structure. The kinetic effect of irreversible inhibitors is to decrease the concentration of active enzyme. Irreversible inhibitors are usually considered to be poisons and are generally unsuitable for therapeutic purposes. Reversible enzyme inhibitors are usually either competitive or non-competitive; a third type, uncompetitive, is rarely encountered (Table 9. Most therapeutic drugs are reversible competitive inhibitors, which bind at the catalytic (active site) of the enzyme. Competitive inhibitors are especially attractive as clinical modulators of enzyme activity because they offer two routes for the reversal of enzyme inhibition, by decreasing the concentration of inhibitor or by raising the concentration of substrate. Since high concentrations of a substrate can displace its competitive inhibitor, it is apparent that Vmax should be unchanged by competitive inhibitors. This characteristic of competitive inhibitors is reflected in the identical vertical-axis intercepts of Lineweaver–Burk plots, with and without inhibitor (Figure 9. Competitive inhibitors often structurally resemble the substrate of the enzyme (structural analogues). The similarity between the structures of folic acid and methotrexate is shown in Figure 9. Most allosteric enzymes are oligomeric (consisting of multiple subunits); generally they are located at or near branch points in metabolic pathways, where they are influential in directing substrates along one or another of the available metabolic routes. Effectors may control enzyme activity by altering the Vmax or the Km of the enzyme; Km effectors work on K-type enzymes, Vmax effectors work on V-type enzymes. Numerous enzymes of intermediary metabolism are affected by phosphorylation, either positively or negatively. Covalent phosphorylations can be reversed by a separate subclass of enzymes known as phosphatases. The aberrant phosphorylation of growth factor and hormone receptors, as well as of proteins that regulate cell division, often leads to unregulated cell growth or cancer. The usual sites for phosphate addition to proteins are the serine, threonine and tyrosine R-group hydroxyl residues. Post-translation Phosphorylation or glycosylation may be used to activate Rapid modification or deactivate an enzyme. In the response to insulin, the phosphorylation of multiple enzymes, including glycogen synthase, helps control the synthesis or degradation of glycogen and allows the cell to respond to changes in blood sugar. Another example of post-translational modification is the cleavage of the polypeptide chain. Chymotrypsin is produced in the inactive form, the proenzyme, as chymotrypsinogen. Bacteria may Slow become resistant to penicillin because enzymes called β-lactamases are induced which hydrolyse the crucial β-lactam ring within the penicillin molecule. Compartmental- Fatty acids are synthesised by one set of enzymes in the isation cytosol, and used by a different set of enzymes as a source of energy in the mitochondrion. For example, haemaglutinin, in the influenza virus, is activated by a conformational change caused by the acidic conditions which occur when it is taken up inside its host cell and enters the lysosome. Many of the proteins that bind calmodulin are themselves unable to bind calcium, and so use calmodulin as a calcium sensor and signal transducer. Calmodulin undergoes a conformational change upon binding of calcium, which enables it to bind to specific proteins for a specific response. For example: • allosteric changes in enzyme activity occur in milliseconds or less • transmembrane ion channels open or close in milliseconds or less • G-protein transmembrane signalling operates over a few milliseconds • protein kinases and phosphatases operate over a few seconds • a protein switches compartments in a minute or so • changes in gene expression are evident over about 24 hours • growth/differentiation occurs over a few days. Today, commercially purified and sometimes immobilised enzymes are used by industry and medicine. A natural event; the gene for lactase (ß-galactosidase) is ‘switched on’ at birth and ‘switched off’ after weaning. As a result, lactose is unabsorbed by the body, ferments in the lower gut and produces intestinal gases (methane), leading to pain and flatulence. In most Europeans, however, the infant condition persists, and the lactase gene remains active (possibly linked with the domestication of cattle and goats in the Near East some 10 000 years ago; the ability to digest lactose throughout life could have conferred some nutritional advantage).

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Paradoxical removal Parkinsons Cardiovascular disease Hypoglycaemia Diabetic Ketoacidosis of clothing is seen in cases of severe hypothermia which correlates Hypothyroidism Thyrotoxicosis with the ‘umbles’ of hypothermia (stumbles buy cheap levitra oral jelly 20mg on-line, mumbles buy levitra oral jelly 20 mg amex, grumbles buy discount levitra oral jelly on line, Hypoadrenalism Febrile illness jumbles). The clinical signs and symptoms of hypothermia are Sepsis Neuroleptic malignant described in Table 24. There is progressive ‘slowing’ of function Malnutrition syndrome as initial efforts to keep warm cease and the patient becomes ‘one Patient Alcohol Alcohol with the surrounding environment’. Malignant hyperpyrexia (suxamethonium + Localized injury is a clinical spectrum from frostnip through the halothane) degrees of frostbite, from reversible to irreversible tissue damage Allergic drug reactions (Table 24. Non-freezing cold injuries such as Trauma Major trauma – chilblain, pernio and trench foot are also a spectrum from reversible entrapment, to irreversible and result from having cold wet extremities for an resuscitation, head injury, extended period and can cause extreme pain and disability. Patients who are hypothermic and/or cold injured need to Transport factors Open transport platform Enclosed transport platform Lack of heating Lack of air conditioning or be treated in a medical facility while following the steps listed in ventilation Table 24. The adage that ‘you are not dead until you are warm and dead’ needs to be interpreted with caution. There needs to be an awareness of periods of exposure be considered as part of the differential diagnosis. Elderly patients and ambient temperatures and should be realistic so as not to with pre-existing medical conditions are at particular risk from put rescuers at risk. In tropical environments, cold and dead is falls, lying on cold floors or the ground for long periods, until usually dead. Management of local tissue cold injury is described in discovered hypothermic or deceased. Cold tolerance depends on the individual, their fitness and The key to cold injuries is prevention (Table 24. Unfortunate preparation for the environment as well as the temperature, wind- scenarios in which lives have been lost due to cold exposure may chill factor and whether they are wet. While wind chill is measured have been prevented simply by correct clothing, adequate com- differently in the southern and northern hemispheres, the point is munications, weather checks, acclimatization and familiarization. As health professionals, ensuring that we Onceenergyisdepleted,theindividualissusceptibletohypother- listen to the history and look for signs of cold injury in susceptible mia even at relatively mild temperatures. The hypothermic patient populations to ensure early goal directed therapy is the key to good has impaired judgement that can lead to poor decision making and patient outcomes. All are characterized by hyperthermia, Cover and protect the head from further heat loss but with gradually worsening multi-organ impairment and eventu- Warm the patient, whether blankets, shelter, sleeping bag ally failure (Table 24. Mortality Check for airway and consider cervical spine precautions rates range from 10% to 70%, depending on background health, Check for breathing and administer high-flow oxygen (humidified if possible) age and length and severity of exposure. Heat waves kill more Fluid requirements are vastly underestimated working in cold climates and dehydration is common. Other Look at pupils and consider opioid antagonist if indicated Measure core temperature (oesophageal/rectal low reading thermometer) Table 24. Patient risk factors environment∗ Ice packs (axilla, groin, neck)∗ for environmental heat illness are described in Table 24. It is an easily measured heat stress Invasive Warm intravenous fluids∗ Cold intravenous fluids∗ index often used in guidelines for work in hot environments. Warm water pleural lavage Cardiac bypass Cardiac bypass ∗Able to be easily used in prehospital environment. Requires water as spray or Tg = black globe temperature (represents integrated effects of radi- application direct to skin, with vigorous air flow e. A useful approach to diagnosis of hyperthermia is to recognize risk factors and alternative diagnoses (Table 24. Heat illness is primarily caused by hyperthermia, with hydration status a secondary factor, and Most continents have venomous creatures, with many millions sufferers may present in either an overhydrated (hyponatraemic) suffering death and disability each year as a result of bites and or dehydrated state. The health burden of trolytes can occur concomitantly, but will not save the patient snakebite coupled with reduced production of snake antivenom has without cooling. The global distribution of envenomation is shown begin by any practical means with cooling methods described in in Figure 24. Evaporative cooling using water applied to skin while the world are vipers (mainly in Americas, Africa, Eurasia) and fanning is the most powerful cooling method. It is important to packs to neck, axilla and groin if available is partially useful. This immersion and ice packs can cause adverse shivering and limit explains the frequent reports of homeopathic first aid methods (e. The use of induced hypothermia aid revolves mainly around immobilizing the bitten body part after resuscitative efforts mandates prehospital clinicians have a and the patient and supportive care. Acclimatization cobra and death adder envenomings) have proved effective if no allows a gradual increased tolerance to heat stress. Problems with antivenom include cost, 7–60 days and is aided by routine exposure to ambient heat and need for refrigeration and a high rate of anaphylaxis. Heat adaptations include tification can also be difficult making use of specific antivenom increased sweat rates, lower temperature triggers for sweating, problematic. There is no specific first aid, other than symptomatic care, as the treatment of systemic symptoms requires antivenom. The Portuguese man of war (Physalia), Box jellyfish (Chironex fleckeri) and other chirodropids in southeast Asia and Irukandji jellyfish can cause significant sys- temic toxicity and in rare cases death. First aid mainly revolves around using vinegar to neutralize nematocysts, although promising work has been done using heat to reduce the pain of jellyfish stings. Stings by spiny fish usually result in severe local pain, and heat often provides effective first aid. Regional local anaesthesia blocks may be effective, and antivenom exists for stone fish stings. Barb injuries from stingrays usually cause local damage, while barbs have venom that can also cause tissue destruction. Most spiders are unlikely to cause systemic toxicity other than Preparation is essential, to ensure the ability to care for patients the Lactrodectus, (black widow, red back spider), funnel web and with envenoming injuries and for staff safety. Usual symptoms are local effects but systemic sonal knowledge of local wildlife, envenoming risks and clinical symptoms require medical attention and may require antivenom. Access to appropriate antivenoms should be secured pressure immobilization bandaging the required first aid. However, in North Africa, Central and Southern more reason to wear boots) and care should be taken with arrival America, and the Middle East stings can result in systemic toxicity at any scene or during patient movement that patients and staff are resembling a catecholamine surge with a significant number of not exposed to risks of secondary envenomation. Accidental hypother- not yours mia: rewarming treatments, complications and outcomes from one univer- • Patients are not dead until they are warm and dead, unless they sity medical centre. These changes occur at different rates in different people and there are no predicting factors as to who may perform better at altitude other than previous personal experience. Introduction However,ifascenttoaltitudeoccursmorequicklythanthebodycan High-altitude environments occur on all the world’s continents. The highest mountain peaks are accessible to only a few well- Aids to acclimatization are shown in Table 25. It describes a non- The effects of altitude begin to become apparent over 2500 specific collection of symptoms that occur 6–12 hours following meters above sea level. Altitude over 7500 meters is known as the death zone – well- acclimatized climbers can only spend very short periods of time at this altitude.

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In both these quotes order cheap levitra oral jelly on line, there was an unacceptable degree of editorialising which does not fit the presentation of a scientific paper trusted 20 mg levitra oral jelly, especially when neither the diets of the Bristol attenders nor those of the control sample had been seriously evaluated in the study buy levitra oral jelly amex. For example, does radical adherence to a stringent diet shorten life in patients whose survival is already threatened by cancer? The precipitous publication of the results before adequate follow-up data had been obtained, and the resultant furore, meant that the study had to be aborted. The person who received notification of the press conference did not realise its significance and so did nothing about it for some time. At this meeting Professor McElwain asked the Bristol contingent if they would not now consider closing the Centre down. The proposed platform of speakers who would announce the results, listed in the same letter, did not indicate a co-operative venture. The rest of the platform was to consist of Clair Chilvers, Felicity Bagenal, Doug Easton and Tim McElwain. Perhaps Bristol should say something along these lines: We find it difficult to believe that diet is really the problem but, just in case it is, we are now including on diet sheets a warning that patients should go to their family doctors if they experience a weight loss of more than X in Y weeks, while following the diet. It faintly damns the regime at the Centre, even though there was no evidence to merit such conclusions. The scientists wanted the argument about diet to suit them, whichever way it was argued. At one point Wilkins threatened to deny Bristol the right to attend the press conference if it did not reply to one of her faxes by 6 pm that evening. The workers and administrators at the Bristol Centre felt harassed and threatened. Some time before the conference began, the room was packed, and by the time it started there were people standing at the back. A few days before the conference, Tessa Glynn, one of the staff at Bristol, had received the press list from Janice Wilkins. Tessa felt prompted to ask Wilkins why they had decided to arrange a press conference. Very few journalists from the British press were not invited to the conference; anyone who was anyone was there, from the Sun to The Times, from Reuters to the Press Association. The room was packed with journalists jotting, film crews filming, and radio reporters recording. Even as the conference began, the workers from Bristol still thought that as the results did not make sense the press would consider their case with reason. She thought that everyone would be puzzled about where the results had gone wrong. There was insistent questioning about the number of deaths in the control group, a figure which the authors of the paper refused to reveal. From then on it was evident to Glynn and everyone else from Bristol that the scientists were going for the jugular. The intimation was quite specific — the regime at Bristol damaged patients and could kill them. It was the first time that I realised that human beings did that sort of thing to each other. Sikora was from the start on the side of Bristol over the Chilvers Report but made few public statements for fear of losing his funding. The programme makers had managed to find someone who had been to Bristol and had felt guilty because she had not stuck to the diet. They had invited Ros Coward, relying on her to argue against alternative care at Bristol. I decided to try and break down their plan, and went and sat with Tim McElwain, but was immediately told to move. Penny Brohn tried hard to defend Bristol and its ideas, but she was so loudly and vehemently attacked that she left the studio feeling that she had helped in the public humiliation of the Centre. For the next few days, however, Penny Brohn and the Centre were flooded with sympathetic mail. Members of the public expressed shock and disgust at the treatment she and the Centre had received. Bizarre is perhaps the only word which really does justice to the sudden wave of press coverage which the Bristol survey provoked. Every newspaper in Britain, whatever its quality, took a sudden and uncritical interest in medical research and the complementary therapies of a small cancer charity. None of the journalists who reported the research findings over the days following the press conference thought to question them. It was followed, weeks later, by a derisory attempt by a few journalists to advertise the fact that the study had been discredited. Then towards the end of the year, the matter caught the eye of the media again with the suicide of Professor Tim McElwain and the resignation of the two staff doctors from Bristol. Early in 1991 there was a series of articles which attempted to reconcile the two conflicting views of the study. Even when Professor McElwain cut his throat, thereby hinting at the fact that this could be an issue imbued with enormous conflict, no one was willing to begin attributing blame. The tabloids, on the other hand, splashed thriller headlines across their pages like blood. Inevitably, where they were able, the tabloids drew the Royal Family into the furore. Some made it appear that it was because Prince Charles had backed the Centre, that attenders were more likely to die! The tabloids shared a similarity of literary vision with the medical press, and it was their headlines and articles which most closely resembled the message between the lines in the Lancet. One of the most alarming aspects of the post-press conference publicity was that so many of the papers discussed the results of the survey in relation to the diet at Bristol. This is not a direction in which most journalists would naturally have strayed and many reports give readers a clear impression that behind the scenes someone was orchestrating the stories. The study did not present any information about diet despite the fact that the postal questionnaire asked a couple of questions about food intake. For reasons best known to the journalists involved, none of them appear to have turned to sociologists or statisticians for an analysis of the survey results. It was the journalists, inside and outside the medical press, either members or fellow travellers of the Campaign Against Health Fraud, who really put the boot in. They were at the ideological sharp end of publicising the report, and many of them did nothing at all to make palatable the bitter pill which the report was intended to be. Some, like James Le Fanu, a member of the Campaign Against Health Fraud, actually revelled in the results, writing an 24 opening paragraph in The Times, of which any orthodox doctor could have been proud.

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This The frst year required core course modules includes electron microscopes purchase levitra oral jelly online, confocal are as follows: Macromolecular Structure microscopes order levitra oral jelly 20 mg without prescription, nuclear magnetic resonance and Analysis (100 buy levitra oral jelly online now. The All seven departments enjoy excellent work- required second year course is Method and ing relationships with other departments in Logic in Biology (800. Courses are the medical school and with departments at detailed under the course descriptions listed the Homewood campus and the Bloomberg in the entries of the Departments of Biologi- School of Public Health. Inquiries for costs, medical insurance, and tuition is avail- admission should be directed to: Chairper- able for accepted candidates. Research Education and Research, The Art and Sci- projects in the program investigate the bio- ence of a Research Proposal, and Scientifc medical, genetic, and molecular basis of Writing and Reviewing. At the cal mechanisms underlying a great variety of conclusion of these rotations the student will normal biological processes. Our interests commit to a particular laboratory for pursing a span neurobiology, immunology, cellular and research project leading to a Ph. An developmental biology, glycobiology, pro- oral qualifying examination will be adminis- tein structure and folding, signal transduc- tered after completion of the frst year course tion, proteomics, and metabolism. Two elective courses should be study pathologies arising from abnormalities taken subsequent to the frst year. Certain in these processes, such as cancer, neuro- courses that are particularly demanding degeneration, infectious disease, diabetes, could be substituted for two courses. Applicants should have an under- Plan of Study graduate degree in any area of biology, chem- istry, or biochemistry. The program con- the course, it is similar to a tutorial and pro- tacts are: Denise J. Biomedi- Molecular Biology and Genomics; Genetics; cal engineers apply modern approaches from Cell Structure and Dynamics; Organic Mech- the experimental life sciences in conjunction anisms in Biology; Computational Biology with theoretical and computational methods and Bioinformatics. The Biomedical Engineering istry; Neurobiology; Epigenetics; Transcrip- Graduate Program of the Johns Hopkins Uni- tion Mechanisms; Virology; Post Transcrip- versity is designed to train engineers to work tional Events in Gene Regulation; Structure at the cutting edge of this exciting discipline. We typically recruit students in fve the importance of in-depth training of students areas: Computational Biology, Imaging, Tis- in both life sciences and modern engineering. That is, they learn human to combine engineering with cutting edge biology with the medical students. This is a research in medicine, this may be the pro- unique and intensive curriculum covering a gram for you. Students choosing this as the medical students, including human option typically devote their entire frst aca- anatomy, molecules and cells, and genes to demic year to these courses. In their second year, our students is an excellent way to build a broad and solid take advanced engineering courses. Alternatively, fore, students that apply to our program need students may elect alternative life sciences to not only have a strong background in engi- curricula. These curricula have been carefully neering and mathematics, but also suffcient designed to provide training in areas of the background in chemistry (including organic life sciences that are appropriate to each of chemistry) and biology (at least two introduc- the program’s research areas. In-depth training in engineer- are interested in, and write about the kind of ing, mathematics and computer science is research they are considering. The faculty in achieved through elective courses that are each area vote and rank the applicants. This covers tuition and provides a All accepted students receive a full fellow- ship. The fellowship covers tuition and pro- modest stipend for the duration of their PhD. In this way, the Because the students are fully funded, they students are free to choose from almost any can choose to perform their dissertation in research lab in the university. To facilitate this essentially any laboratory in the University process, students do two or more rotations (subject to the approval of the program direc- during their frst year and typically choose a tors). A short list of Students typically do research rotations these students is formed by committee and during the summer before start of the frst aca- the top candidates are interviewed by phone. They too have the freedom are expected to choose a research laboratory to choose from any lab. Applications should be complete when Emphasis is placed on original research submitted. The plete application we must have: research is usually experimental in nature, and students are expected to learn biologi- • A completed on line application form. Research from North America must come for an inter- experience, course grades, and recom- view to be considered for admission. Interviews are the electronic test is no longer offered are generally conducted in March. Acceptance: Applicants will be notifed by Applications will be considered regardless of end of March of the outcome of their appli- which form of the exam was taken. An offer of admission from the pro- • Three letters of recommendation – these gram will include a yearly stipend, full tuition letters should come directly from faculty and paid medical and dental insurance. This members who are acquainted with you and applies to every accepted applicant, regard- your academic work. Those be sealed and comment on your aptitude and offered admission will be asked to let us know promise for independent research. In any • Personal statement – a typewritten state- case, we must have the applicant’s decision ment (one page maximum) indicating the by April 15. Included should be Fellowships for tuition and support stipends a discussion of any research experience you (regardless of citizenship or national origin) have had. Only online applications for admis- If you are interested in applying and do not sion are accepted and must be received by have the prerequisite courses, you may want December 15. In the past, applicants have taken advanced courses in engineering science the prerequisites at their present schools, and in biomedical science. Courses taken mathematics, and other physical science at any accredited college or university are courses to be taken are arranged between acceptable. A Masters degree is not required for course work in engineering, mathematics admission to our program. In addi- respondence and supporting documents tion, students must complete eighteen credit should be sent directly to The Johns Hop- hours of course work in the life sciences. Phone: 410-614-3385; Fax: 410-614- in a course with strong engineering or math- 3386; grad_study@jhmi. For sion consideration if his/her application is not additional courses available to students, see accepted by the Medical School admissions the catalogue of the Schools of Arts and Sci- committee. Students must fulfll a modest teach- The master’s degree program is designed ing requirement during one year of their pro- for students who wish to pursue careers gram. The remaining time is spent in thesis in research and development, or as a step research. This is taken in the ect may be basic research in a laboratory or frst half of the third year. The student must practical engineering, related to patient moni- then conduct original research, describe it in toring or other clinical problems. Students with undergraduate degrees in There is a minimum residency requirement of engineering are eligible to apply.