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Some examples of the role of sequencing in the personalized management of bacterial infections are given here order 100 mg prometrium fast delivery. The most ubiquitous and predominant organisms include various anaerobes order prometrium 100 mg with visa, Staphylococcus buy prometrium 200mg without prescription, Corynebacterium, and Serratia. Metagenomics provide a preliminary indication that there may be proto- zoa, fungi and possibly an undescribed virus associated with these wounds. Sequencing for Study of Antibiotic Resistance in Bacteria Antibiotic resistance can gradually evolve through the sequential accumulation of multiple mutations. To study this evolution, scientists at Harvard Medical School have developed a selection device, the ‘morbidostat’, which continuously monitors bacterial growth and dynamically regulates drug concentrations to constantly chal- lenge the evolving population. Over a period of∼20 days, resistance levels increased dramatically, with parallel populations showing similar phenotypic trajectories. Chloramphenicol and doxycycline resistance evolved smoothly through diverse combinations of mutations in genes involved in translation, transcription and transport. Toxicity, the ability to destroy host cell membranes, and adhesion, the ability to adhere to human tissues, are the major viru- lence factors of many bacterial pathogens, including S. Role of Rapid Molecular Diagnosis at Point of Care In medicine, quantitative measurement of specific strains of infectious organisms is very important in emergency situations because the physician must start therapy immediately if the patient is in critical condition. At the same time, better testing will quickly identify the organism’s strain and drug susceptibility, reducing the delay in finding the right antibiotic. Traditional diagnostic testing often requires several days to isolate and grow the infectious organism, and to test its sensitivity to specific antibiotics. Widespread use of these antibiotics leads to the emergence of drug resistance, which then narrows the num- ber of drugs available to treat serious infections. Detection, identification, and characterization of pathogens is being revolution- ized by the combination of the seemingly disparate fields of nucleic acid analysis, bioinformatics, data storage and retrieval, nanotechnology, physics, microelectron- ics, and polymer, solid state, and combinatorial chemistry. It will be possible to miniaturize test kits, which can be swallowed or added to body fluids and coupled with data transmitters so that results can be sent to remote site for analysis. Rapid molecular diagnosis will improve the initial management of the patient, determine the need for isolation and help the selection of optimal antimicro- bials if they are needed. Nanotechnology-based tests for detection of microorgan- isms are also in development. These refinements in diagnostic technologies will not only enable personalized management of infections but will also be an important factor in the control of emergence of microbial resistance and epidemics. Natural microbiota in the gastrointestinal tract appear to contribute to nearly every aspect of physiology of the host. It may be responsible for diverse vaccine efficacy observed in humans from developing Universal Free E-Book Store 386 11 Personalized Management of Infectious Diseases Manipulation of the microbiota by probiotics and/or prebiotics is a therapeutic as well as prophylactic strategy for many infectious and inflammatory diseases within the gut, but it may be also used for improving vaccine efficacy (Długońska and Grzybowski 2011 ). Personalized Management of Sepsis Severe sepsis and septic shock are among the leading causes of death with mortality ranging between 35 % and 50 %. Adequate management of sepsis depends on early detection (earlier than conventional blood cultures) and early administration of appropriate antimicrobials. Assessment of the immune status of the host should also be done faster than that possible by conventional biomarkers. Other molecular diagnostics for sepsis are described in a special report (Jain 2015c). There is more individual variability among septic patients than previously recog- nized. Pathophysiology of sepsis is a complex and dynamic process that originates from the host immune response to infection and varies according to the genetic predisposition, immune status and co-morbid conditions of the host, the type of pathogen and the site and extent of infection. Until now, efforts to stratify septic patients according to their immune profile were hampered by the lack of specific biomarkers. Advances in molecular medicine have enabled development of tools that will facilitate a faster and more precise diagnosis of infections. Individual vari- ability between each patient’s responses to infection can assist in tailoring therapeu- tic interventions to the individual’s disease profile and monitoring treatment response. Gene profiling of the host is a promising approach because of the indi- vidualized nature of sepsis to enable personalized management (Kotsaki and Giamarellos-Bourboulis 2012). Despite the availability of adequate effective treatment, many patients default on Universal Free E-Book Store Personalized Management of Viral Infections 387 treatment, experience adverse side effects from antibiotics or fail to respond rapidly and recover. Isoniazid, one of the most important first-line tuberculosis drugs, is acetylated in the liver to a variable degree in different individuals giving rise to fast, intermediate and slow acetylator phenotypes. Acetylation status of individuals plays an important contributory role in the tuberculosis pandemic. It is important to study the acetyla- tion alleles, and to understand isoniazid metabolism and the manner in which it could affect patient compliance, isoniazid-toxicity and the emergence of drug- resistant strains of mycobacteria. The standard drug dose currently administered to patients, regardless of their acetylator status, may not be appropriate for certain people. Individualization of isoniazid therapy may help to prevent adverse drug reactions experienced by a small percentage of patients thought to be ‘slow-acetylators’ of the drug. Personalized Management of Viral Infections Antiviral therapeutics is dealt with in detail in a special report on this topic (Jain 2015a). Most of these are specific for each infection whereas others such as protease inhibitors can be used in more than one type of infection. Ligand-binding epitopes of proteins can mutate rapidly, as shown by viral muta- tions that lead to escape from neutralizing antibodies.

Likewise purchase prometrium 100 mg mastercard, if a chan- cre is in the mouth best prometrium 100 mg, merely kissing an infected cervical vertebrae The upper seven vertebrae in individual can spread syphilis purchase prometrium 200mg with amex. Charcot-Marie-Tooth disease A genetic dis- cervicitis Inflammation of the uterine cervix. The cervix The low, narrow part of the uterus, which foremost feature is marked wasting of the extremi- forms a canal that opens from the uterus into the ties, particularly in the calves, resulting in “stork vagina. The disease is opening of the cervix dilates during birth to permit one of the most common genetic diseases, and it is the newborn’s head to emerge. The disease can be inherited as an autoso- cervix, incompetent A cervix that has an abnor- mal dominant trait, an autosomal recessive trait, or mal tendency to dilate and so may not be able to an X-linked trait. There are also sporadic cases in keep a fetus from being spontaneously aborted which there is no family history due to a new domi- (miscarried). Also known as peroneal muscular atrophy and hereditary motor cesarean section See caesarean section. A Central and South America caused by the parasite charley horse can last anywhere from a few seconds Trypanosoma cruzi. It is not uncommon for through bites from bugs that carry it (known as one to recur before it finally resolves. Soon after chart, Snellen The familiar eye chart used to infection, there may be symptoms such as swelling measure how well a person sees at various dis- of the eye on one side of the face, usually at the bite tances. A Snellen chart is imprinted with block let- wound, but many people do not become ill until ters that decrease in size line by line, corresponding many years after being infected. Infants and persons to the distance at which that line of letters is nor- with immunodeficiency are at risk of severe infec- mally visible. Also known as American trypanosomi- chase the dragon A practice of heroin use that asis. Women’s menstrual periods may stop, cheek The side of the face, which forms the side and women may have hot flashes and vaginal dry- wall of the mouth. In some cases, poral bone of the skull, and it provides the promi- bone marrow transplantation and peripheral stem- nence of the cheek. The term cheek also refers to cell support are used to replace bone marrow tissue something that has the form of the human cheek, that has been destroyed by the effects of chemother- particularly with two laterally paired parts, such as apy. Cherubism is inherited as an auto- chemokine One of a large group of proteins that somal dominant condition. The chest contains the chemokine receptor A molecule that receives a lungs, the heart, and part of the aorta. The walls of chemokine and associated proteins (chemokine the chest are supported by the dorsal vertebrae, the docks). Chest pain is a warning to seek medical atten- injected into a vein, but some are given by mouth. Chemotherapy is gen- chest X-ray A type of X-ray commonly used to erally given in cycles: A treatment period is followed detect abnormalities in the lungs. A chest X-ray can by a recovery period, another treatment period, and also detect some abnormalities in the heart, aorta, so on. When white blood cells are affected by brain tissue protrudes into the spinal canal as a anticancer drugs, patients are more likely to result of a small or misshapen skull. When red blood cells are mation is usually present at birth (congenital), but affected, they may have decreased energy. Also known as line the digestive tract also divide rapidly, so Arnold Chiari malformation. Also known as vari- scribed to help with side effects, especially with nau- cella. Chickenpox has nothing to gradually go away during the recovery period or do with chicken; the name originated to distinguish after treatment stops. In some men and women, this mild pox from smallpox (chicken being used, chemotherapy drugs may result in temporary or as in chickenhearted, to mean weak or timid). Treatment, other than the use of calamine lotion or other topical solutions to diminish itching, is not child health The care and treatment of children. However, adults (and some- Child health is the purview of pediatrics, which times children) can have major problems from became a medical specialty in the mid-nineteenth chickenpox, including pneumonia and encephalitis century. Before that time the care and treatment of (inflammation of the brain) that can lead to diffi- childhood diseases were included within such areas culty with balance and coordination (cerebellar as general medicine, obstetrics, and midwifery. Other serious complications can include ear infections, damaged nerves (palsies), and childbed fever Fever due to an infection after Reye’s syndrome. In such cases, antiviral medica- childbirth, usually of the placental site within the tions may be tried. See also chickenpox developed world due to improved sanitary practices immunization; herpes zoster; neuralgia, posther- in midwifery and obstetrics. This can terized by apparently normal development for at worsen to an aching, prickly (“pins and needles”) least the first 2 years after birth, as manifested by the sensation, and then numbness. It can develop in only presence of age-appropriate verbal and nonverbal a few hours in skin exposed to extreme cold. The communication, social relationships, play, and treatment for chilblain is to stop exposure to cold, adaptive behavior. Children with this disorder dis- remove any wet or constrictive clothing, gently wash play significant loss of previously acquired skills and dry the injured area, elevate the injured area, (before age 10 years). This loss may affect expres- cover the injured area with layers of loose warm sive or receptive language, social skills or adaptive clothes, and allow the injured area to rewarm. Childhood disintegrative disorder also include child neglect and the physical, emotional, involves impairment in social interaction and com- and sexual abuse of children. Although most people munication, often with the development of repetitive think first of physical abuse when they hear the term stereotyped patterns of behavior, interests, and child abuse, physical abuse makes up only a small activities, including motor stereotypes and manner- percentage of reported cases.

Treatm ent is allow ed provided that it causes no sym ptom s likely to im pair perform ance buy 100mg prometrium. Private drivers need not inform the licencing authority after m yocardial infarction discount prometrium 200 mg free shipping, but should not drive for one m onth prometrium 200mg overnight delivery. If arrhythm ia causes sym ptom s likely to affect perform ance, or if angina occurs w hilst driving, the licencing authority m ust be inform ed, and driving m ust cease until sym ptom s are adequately controlled. How should such patients be m anaged to im prove outcom e and what are the results? Prithwish Banerjee and Michael S Norrell The advent of the throm bolytic era has not altered the incidence or m ortality rate for cardiogenic shock com plicating m yocardial infarction (M I). It still represents alm ost 10% of patients w ith M I, w ith alm ost 90% dying w ithin 30 days. Recently, a few random ised trials have attem pted to com pare such early (w ithin 48 hours) revascularisation w ith a strategy of initial m edical stabilisation. Thirty day m ortality w as reduced in the early intervention group (46% vs 56% ) w ith this benefit extending out to 6 m onths and particularly apparent in the younger (<75 years) age group. The low m ortality in the control group is striking, and explains the lack of a large difference betw een the tw o groups. Nevertheless, it suggests benefit even w ith a relatively aggressive conservative policy in these patients. Because of trial recruitm ent difficulties it is unlikely that further random ised data w ill em erge in the foreseeable future. M ean tim e to revascularisation w as under 1 hour in the trial, and quite how m uch later such benefit m ight extend is unclear. Em ergency cardiac procedures in patients in cardiogenic shock due to com plications of coronary artery disease. Early revascularisation in acute m yocardial infarction com plicated by cardiogenic shock. The figures given should ideally be those currently being achieved by the team to w hom the patient is referred. In general term s, registry data are m ore representative than published series, w hich inevitably include bias tow ards m ore successful figures. The data should be adjusted up or dow n to m atch the circum stances of the individual patient, w ho is helped tow ards a rational decision based on the anticipated risks and benefits. It therefore applies to the typical patients – m ale, elective, aged 60–70, w ith an adequate left ventricle. Patients w ith one or m ore risk factors for perioperative death, w hich are older age, fem ale sex, obesity, w orse ventricular function, diabetes, very unstable or em ergency status, or significant co-m orbidity of any type, should have the stated risk appropriately increased. The United Kingdom Heart Valve Registry provides very reliable thirty day m ortality figures w hich for the three years 1994–1996 inclusive w ere 5% for aortic valve replacem ent and 6% for m itral valve replacem ent. Lethal brain damage and permanently disabling hemiplegia are rare w ith a com bined risk of about 0. If every focal deficit discovered on brain im aging, or every transient neurological 100 Questions in Cardiology 71 sign is included the incidence w ould probably be nearer 5%. Air, left atrial throm bus and calcific valve debris are additional risk in valve surgery. Som e difficulty w ith concentration and m em ory affects about a quarter of patients – but very few are troubled by it to any extent. In good hands it rarely com plicates valve operations w ithout coronary artery disease. In coronary surgery incidence depends on definition but m yocardial dysfunction, local or global, is the com m onest cause of death. The incidence of infarction is entirely dependant on definition and any figure from 2% to 10% could be given, depending on the criteria used. London and Philadelphia: Current Science, 1994: 161–9 72 100 Questions in Cardiology 34 W hich patients with post-infarct septal rupture should be treated surgically, and what are the success rates? Tom Treasure M yocardial rupture is a m ore com m on cause of death after infarction than is generally appreciated. The hospital m ortality for surgical repair is probably 40% (w ithout reporting bias – but there is surgical selection and natural selection – m ost have had to survive transfer to a surgical centre). Favourable features are younger age, anterior rather than inferior infarcts, m ore surviving left and right ventricular m yocardium , and functioning kidneys. There w as a vogue for holding these patients on a balloon pum p to operate on them w hen the infarcted tissue is better able to take stitches. It is a long w ait before there is any m aterial advantage, and any benefit in reported figures of percentage operative survival w as due to loss of patients along the w ay. If you are going to operate on these cases, it is probably a case of the sooner the better. Should coronary artery bypass grafting be perform ed at the sam e tim e as repair of a post-infarct ventricular septal defect? The Society of Thoracic Surgeons National Database m ortality figures1 for 80,881 patients under- going isolated bypass surgery betw een 1980 and 1990 w ere 4. Recognised factors affecting in-hospital m ortality include older age, fem ale sex, co-m orbid renal and cardiovascular disease, diabetes, cardiogenic shock, em ergency, salvage or redo operation, preoperative intra-aortic balloon pum p use and associated valve disease. Long term survival after surgery The late results of bypass surgery depend on the extent of cardiac disease, the effectiveness of the original operation, progression rate of atherosclerosis and the im pact of non-cardiac disease.

At longer times buy prometrium 200 mg, however purchase prometrium 100 mg with amex, a drug may undergo redistribution Chapter 1 General Principles of Drug Action 25 among various tissues generic 100mg prometrium with amex, e. The induction of the cytochrome P-450 following chronic administration will increase the conversion of the inactive pro-drug to the active form. Maintenance dose rate ¼ (clearance) 3 (desired plasma concentration), and the whole body clearance is the sum of all the individual organ clearances. In most patients the hepatic metabolism, renal filtration, and biliary excretion account for 25%, 50%, and 25% of the whole body clearance, respectively. Since the creatinine clearance in this patient indicates that the renal filtration is only half normal, the renal clearance of the drug will be decreased by 12. This means that the whole body clearance will be 75% of that of normal (25% hepatic, 25% renal, and 25% biliary). If the oral dosing rate is constant but bioavailability increases, the fraction of the administered dose that reaches the general circulation unaltered increases. Thus, a decrease in clearance will increase the plasma drug concentration, whereas an increase in any of the other three parameters will decrease the steady state plasma concentration. Inspection of the plasma concentration values indicates that the half-life of drug does not become constant until 1–9 hours after administration. The drug concentration decreases by 12 (from 50 to 25 mcg/L) between 1 and 5 hours (a 4-hour interval) and again decreases by 12 (from 25 to 12. The rapid decrease in plasma concentration between 0 and 1 hour, followed by a slower decrease thereafter (and the constant half-life there- after) indicates that this drug obeys a two-compartment model with an initial distribution phase followed by an elimination phase. Receptor affinity for the drug will determine the number of drug–receptor com- plexes formed. Efficacy is the ability of the drug to activate the receptor after binding has occurred. Half-life and secretion are prop- erties of elimination and do not influence formation of drug–receptor complexes. A noncompetitive antagonist decreases the magnitude of the response to an agonist but does not alter the agonist’s potency (i. Because 20% of the drug is bound to plasma proteins, 80% of it is free and available for filtration, which would be at a rate of 100 mL/ min (i. A clear- ance of 10 mL/min must indicate that most of the filtered drug is reabsorbed. Long preganglionic axons originate from neurons in the cranial and sacral areas of the spi- nal cord and, with few exceptions, synapse on neurons in ganglia located close to or within the innervated organ. Short postganglionic axons innervate cardiac muscle, bronchial smooth muscle, and exo- crine glands. Parasympathetic innervation predominates over sympathetic innervation of salivary glands, lacrimal glands, and erectile tissue. Short preganglionic axons originate from neurons in the thoracic and lumbar areas of the spinal cord and synapse on neurons in ganglia located outside of, but close to, the spinal cord. The adrenal medulla, anatomically considered a modified ganglion, is innervated by sympathetic preganglionic axons. Innervation of thermoregulatory sweat glands is anatomically sympathetic, but the post- ganglionic nerve fibers are cholinergic and release acetylcholine as the neurotransmitter 3. This system contains long axons that originate in the spinal cord and directly innervate skeletal striated muscle. Norepinephrine and epinephrine are catecholamines, possessing a catechol nucleus and an ethylamine side chain. In the periphery, epinephrine, along with some norepinephrine, is the major catecholamine released from adrenal medullary chromaffin cells into the general circu- lation, where they function as hormones. Termination (1) The action of norepinephrine is terminated primarily by active transport from the cyto- plasm into the nerve terminal (uptake 1), a process that is inhibited by cocaine and tri- cyclic antidepressant agents such as imipramine. Norepinephrine is then transported by a second carrier system into storage vesicles, as is dopamine and serotonin, a process also blocked by reserpine. Nicotinic receptors: Cholinoceptors that are activated by the alkaloid nicotine (Fig. The Na current pro- duces membrane depolarization and a propagated action potential through the trans- verse tubules of skeletal muscle, resulting in the release of Ca2+ from the sarcoplasmic reticulum and, through a further series of chemical and mechanical events, muscle con- traction. During phase I block, skeletal muscle is unresponsive to either neu- ronal stimulation or direct stimulation. Muscarinic receptors: Cholinoceptors that are activated by the alkaloid muscarine (Fig. Adrenoceptor-mediated changes in the activity of protein kinases (and also levels of intracellular Ca2+) bring about changes in the activity of specific enzymes and structural and regulatory pro- teins, resulting in modification of cell and organ activity. Direct-acting parasympathomimetic drugs act at muscarinic cholinoceptors to mimic many of the physiologic effects that result from stimulation of the parasympathetic division of the autonomic nervous system (see Fig. Bethanechol (Urecholine) and carbachol are choline esters with a quaternary ammonium group that are structurally similar to acetylcholine but more resistant to hydrolysis by ace- tylcholinesterase. The b-methyl group of bethanechol substantially reduces its activity at nicotinic receptors. Eye (1) Direct-acting muscarinic cholinoceptor agonists contract the circular smooth muscle fibers of the ciliary muscle and iris to produce, respectively, a spasm of accommodation and an increased outflow of aqueous humor into the canal of Schlemm, resulting in a reduction in intraocular pressure. Vascular smooth muscle has muscarinic receptors but no parasympathetic innervation.