By O. Nemrok. University of San Francisco.

Different probes have been used for detection cheap 5mg frumil fast delivery, such as the TaqMan probe order frumil 5 mg visa, Fluorescence Resonance Energy Transfer probes 5 mg frumil with mastercard, molecular beacons and biprobes (Shamputa 2004) buy frumil 5 mg free shipping. The main disadvantages would be the requirement for expensive equipment and reagents, and the need for skilled technical personnel. For the time being, and due to the high cost involved, the use of microarrays for detecting drug resistance in M. Phage-based methods There are currently two formats of phage-based assays that have been described for the rapid detection of drug resistance in M. Phage-based methods that rely on the biological amplification of mycobacterio- phages have gained wider application in the last years. Methods for detection of drug resistance 651 Figure 19-3: In house phage amplification method The luciferase reporter phage method is based on the efficient production of a light signal by viable mycobacteria infected with specific reporter phages expressing the firefly luciferase gene. Luciferase reporter tests have now been evaluated against the four first-line antibiotics with an overall agreement of 98. Not enough evidence is available on the accuracy of these assays when performed directly on sputum samples. Colorimetric methods Several colorimetric methods have been proposed in the last few years for the rapid detection of drug resistance in M. The tests are based on the reduction of 652 Drug Resistance and Drug Resistance Detection the colored redox indicator added to the culture medium after M. Resistance is detected by a change in color of the indicator, which is directly proportional to the number of viable myco- bacteria in the medium (Palomino 2004). As a result of studies identifying resazurin as the main component of the Alamar blue reagent (O’Brien 2000), this redox indicator was also introduced in a rapid test to detect drug resistance in M. Furthermore, a recent systematic review and meta-analysis of colorimetric redox indicator methods to detect multi- drug resistance in M. Colorimetric methods represent a good alternative for the rapid detection of drug resistance in laboratories with limited resources. Resistant strains will reduce the nitrate, which is revealed by a pink-red color in the medium, while susceptible strains will lose this capacity as they are inhibited by the antibiotic (Ängeby 2002). The assay has been evaluated in several studies for first-line drugs and ofloxacin with good results (Montoro 2005, Martin 2005a). It has the added advantage of using the same format and culture medium as the standard proportion method. Further evaluation studies are expected in target populations to assess the perform- ance of this method in different settings. Rapid and inexpensive drug susceptibility testing of Mycobacterium tuberculosis with a nitrate reductase assay. Single-nucleotide polymorphism-based differentiation and drug resistance detection in Mycobacterium tu- berculosis from isolates or directly from sputum. Epidemiology of antituberculosis drug resistance (the Global Project on Anti-tuberculosis Drug Resistance Surveillance): an updated analysis. Advances in techniques of testing mycobacterial drug sensitivity, and the use of sensitivity tests in tuberculosis control programmes. Tetrazolium microplate assay as a rapid and inex- pensive colorimetric method for determination of antibiotic susceptibility of Mycobacte- rium tuberculosis. Rapid, efficient detection and drug susceptibility testing of Mycobacterium tuberculosis in sputum by microscopic observation of broth cultures. Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs worldwide, 2000-2004. Direct detection in clinical samples of multiple gene mutations causing resistance of Mycobacterium tuberculosis to isoniazid and rifampicin using fluorogenic probes. Rapid detection of resistance in Mycobacterium tuberculosis: a review discussing molecular approaches. Evaluation of mycobacteria growth indicator tube for direct and indirect drug susceptibility testing of Mycobacterium tuberculosis from respiratory specimens in a Siberian prison hospital. Evaluation of hybridisation on oligonucleo- tide microarrays for analysis of drug-resistant Mycobacterium tuberculosis. Recent advances in molecular methods for early diagnosis of tuberculosis and drug-resistant tuberculosis. Drug susceptibility testing of Mycobacterium tuberculosis: a neglected problem at the turn of the century. Rapid assessment of drug susceptibilities of Mycobacterium tuberculosis by means of luciferase reporter phages. Application of molecular genetic methods in macrolide, lincosamide and streptogramin resistance diagnostics and in detection of drug-resistant Mycobacte- rium tuberculosis. Rapid, auto- mated, nonradiometric susceptibility testing of Mycobacterium tuberculosis complex to four first-line antituberculous drugs used in standard short-course chemotherapy. Resazurin microtiter assay plate testing of Mycobacterium tuberculosis susceptibilities to second-line drugs: rapid, simple, and inexpensive method. Multicenter evaluation of the nitrate reductase assay for drug resistance detection of Mycobacterium tuberculosis. Rapid detection of ofloxacin resistance in Mycobac- terium tuberculosis by two low-cost colorimetric methods: resazurin and nitrate reduc- tase assays. Colorimetric redox-indicator methods for the rapid detection of multidrug resistance in Mycobacterium tuberculosis: a systematic review and meta-analysis. A new rapid and simple colorimetric method to detect pyrazinamide resistance in Mycobacterium tuber- culosis using nicotinamide. A microplate indi- cator-based method for determining the susceptibility of multidrug-resistant Mycobacte- rium tuberculosis to antimicrobial agents. A low cost, home-made, reverse-line blot hy- bridisation assay for rapid detection of rifampicin resistance in Mycobacterium tubercu- losis. A commercial line probe assay for the rapid detection of rifampicin resistance in Mycobacterium tuberculosis: a systematic review and meta-analysis. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Use of 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide for rapid detection of rifampin-resistant Mycobacterium tu- berculosis. Drug susceptibility testing of Mycobacte- rium tuberculosis by a nitrate reductase assay applied directly on microscopy-positive sputum samples. Susceptibility testing of Mycobacteria, Nocardia, and other aerobic actinomy- cetes; tentative standard – second edition. Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. Bacteriophage-based assays for the rapid detection of rifampicin resistance in Mycobacterium tuberculosis: a meta- analysis. Nonconventional and new methods in the diagnosis of tuberculosis: feasi- bility and applicability in the field. Resazurin micro- titer assay plate: simple and inexpensive method for detection of drug resistance in My- cobacterium tuberculosis. Simple procedure for drug susceptibility testing of Mycobacte- rium tuberculosis using a commercial colorimetic assay. Molecular characterization of rifampin- and isoniazid-resistant Mycobacterium tuberculosis strains isolated in Poland. In house re- verse line hybridization assay for rapid detection of susceptibility to rifampicin in isolates of Mycobacterium tuberculosis. Molecular genetic methods for diagnosis and anti- biotic resistance detection of mycobacteria from clinical specimens. In-house phage amplification assay is a sound alternative for detecting rifampin-resistant Mycobacterium tuberculosis in low-resource settings. Detection of rifampicin resistance in Mycobacterium tuberculosis isolates from diverse countries by a commer- cial line probe assay as an initial indicator of multidrug resistance. Evaluation of a new rapid bacteriophage-based method for the drug susceptibility testing of Mycobacterium tuberculosis. As repeatedly stated, one third of the world’s population is latently infected with Mycobacterium tuberculosis and 10 % of these people will develop active disease at some point in their life. Substantial scientific advances were made in knowledge about the agent and the disease in that decade. Other articles in the top list were related to vaccine candidates, virulence factors, genomics, new drugs, bacterial survival, and metabo- lism. Bacillus and disease under the light of molecular epidemiology 663 and answering unsolved epidemiological questions (Mathema 2006). A common conviction of previous times was that the genome of the tubercle ba- cillus was extremely stable and homogeneous.

It is far much higher incidence of anal more common in parous women sphincter injuries (Figure 2) in (50%) purchase frumil 5mg with visa, compared to nulliparous asymptomatic women buy cheap frumil 5 mg line, the so- women (2%) order frumil 5mg mastercard. During vaginal called occult injuries with as many delivery generic 5 mg frumil free shipping, the mechanism is most as 35% of primiparous and up to likely due to mechanical trauma of 44% of multiparous women having these supporting structures with evidence of sphincter disruption. Risk factors for both the overt and Spontaneous healing might also occult sphincter injuries include lead to weaker collagen and so forceps delivery, prolonged second predispose to incontinence and stage, large birth weight, midline prolapse. Figure 1: Levator avulsion injury on ultrasound, the vagina reaching the pelvic sidewall (arrow) with no intervening muscle, unlike the healthy contralateral side. The protective effect of and has been reported in up caesarean delivery and nulliparity to 85% of women. The use of forceps is been reported to strongly predict the single independent risk factor postpartum incontinence. The frst vaginal delivery the vaginal delivery that is the has been suggested to be the risk factor for developing urinary most signifcant event leading incontinence. Less pelvic foor damage may occur Pelvic organ prolapse after elective caesarean section, Pelvic support defects appear to but not necessarily with emergency occur before delivery. We unnecessary in at least 50% of await prospective studies on the parturients, but many women impact of vaginal delivery and desire the experience of vaginal intrapartum management, on the delivery. Ideally, women should be development and prevention of offered strategies to reduce pelvic defects in the connective tissue foor injury such as pelvic foor and levator muscles that lead to exercises. Mechanisms of injury include direct muscular trauma, disruption of connective tissues, and denervation injury. The frst vaginal delivery is the most signifcant event impacting of the development on subsequent pelvic foor dysfunction. Other risk factors include advanced maternal age at frst delivery, prolonged second 118 Chapter 15 Conservative management of pelvic organ prolapse Trudie Smith Pelvic organ prolapse is common be considered in conservative and is seen in 50% of parous management consist of the women. One recent community following: survey by Slieker-ten et al found that 40% of the general female • Lifestyle interventions population aged 45 to 85 years had • Physiotherapy evidence of pelvic organ prolapse • Pessaries of at least stage two. Life Style life-threatening, but may have a Interventions signifcant impact on a woman’s quality of life. Choice of treatment Several studies have addressed for prolapse depends on the the association of heavy lifting severity of prolapse, its symptoms, and strenuous physical activity and the woman’s general health in the causation of pelvic organ and preference. Jorgensen and colleagues for treatment can be categorized compared the incidence of surgery as conservative, mechanical for prolapse in 28 619 Danish and surgical. Conservative or nursing assistance compared to mechanical treatment is generally a staggering 1652533 female considered for women with a mild population controls. The nursing degree of prolapse, those who assistants occupation constantly wish to have more children, the exposed them to repetitive heavy frail or those unwilling to undergo lifting. This study and did not allow any inference did not however adjust for parity about causal relationships. In another study by Spernol et al There is no conclusive evidence they found that 68% of women that lifestyle changes are going to with prolapse reported heavy to improve the degree of prolapse or medium work compared to 0% the symptoms associated with the of controls. Pelvic muscle training (Kegel Body weight was also considered exercises) is a simple, noninvasive a risk factor in the British Oxford intervention that may improve Family Planning Association Study. Whether Kegel All of these studies unfortunately exercises can resolve prolapse were cross -sectional studies and has not been adequately studied do not control for parity, degree in good randomized controlled of prolapse or other confounding trials since Kegel’s original articles. It is commonly prolapse has not been observed recommended as adjunct therapy in other studies that included for women with prolapse, often the condition as a potential risk with symptom directed therapy. Piya- and the use of a conscious Anant et al performed a cross contraction during an increase sectional study in 682 women in abdominal pressure in daily and an intervention study of activities. Women in the intervention Pessaries have been manufactured group were taught to contract from many materials including the pelvic foor muscles 30 times silicone, rubber, clear plastic, soft after a meal every day. Most pessaries not able to contract were asked to today are made of silicone and return to the clinic once a month as a result are non allergic ,do until they could perform corrected not absorb odours or secrete contractions. Silicone is resistant advised to eat more vegetables to breakdown with repeated and fruit and to drink at least two cleansing and autoclaving. They were followed- pregnant patients, the elderly and up every six months throughout in patients who do not want or the 2-year intervention period. The results indicated that the Pessaries may also be used to intervention was only effective in facilitate preoperative healing the group with severe prolapse. Another useful 121 advantage of these devices is that to ensure that the integrity of the they can be used to elicit occult silicone is intact. The vagina should stress incontinence before surgical also be examined for signs of repair of genital prolapse. She should be aware While pessary manufacturers that it may cause some discomfort provide suggestions for different to both partners in the beginning pessary shapes to manage different but this often settles as the types of prolapse, experience patient and her partner become suggests that trial and error is comfortable with it. Women who really the only way to determine are able to remove and reinsert the best ft for each patient. Other factors, such as the patient’s physical capacity and willingness to participate in the care of the pessary, together with the size of the introitus, the patient’s weight and her physical activity also play a role when choosing a pessary. Fritzinger et al stated that there is no scientifc data outlining the A simulated picture depicting the standards of care for users of position and placement of the vaginal pessaries. However, most pessary authors agree that routine follow up of women using pessaries is necessary to minimize the risk of complications associated with Contraindications to Pessary their use. At each visit the pessary Insertion should be removed and cleaned • Severe untreated vaginal using mild antibacterial soap and atrophy warm water. It should be examined • Vaginal bleeding of unknown 122 origin remain in place • Pelvic infammatory disease • Abnormal pap smear • Dementia without possibility of dependable follow-up care • Expected non-compliance with follow-up Types of Pessaries Often referred to as the “incontinence ring” since it has been designed for use in women with stress incontinence. Complications of pessaries All authors listed vaginal discharge and odor as the most common complication. Other complications which may occur are pelvic pain, Arch Heel Gehrung bleeding and development of • U-shaped device that provides urinary incontinence. The heel rests fat on the or failure of the pessary to vaginal foor hold the prolapse properly is • It avoids pressure on the rectum an obvious disadvantage. They state that early intervention using an estrogen-based cream or vaginal lubricant are essential to proper pessary care. Severe complications such as vesico-vaginal fstulae, hydronephrosis, sepsis, and even 124 small bowel incarceration were cited in the literature as the result of inadequate follow-up. Conclusion There is paucity of good randomized controlled trails that evaluate the use of conservative methods for the management of pelvic organ prolapse. Its treatment is one of the • Associated incontinence most common surgical indications symptoms in gynaecology, accounting for • Patient’s wishes 20% of elective major surgery with this fgure increasing to 59% in Important point the elderly population. Despite There is as yet no surgical numerous modifcations to the technique that can guarantee traditional surgical techniques and 100% success in treating prolapse the recent introduction of novel and some procedures such as procedures, the permanent cure of anterior colporrhaphy carry failure urogenital prolapse remains one of rates of up to 30%. Surgical Management General principles The following factors need to All women should receive be taken into account when prophylactic antibiotics to considering surgical intervention cover gram-negative and gram for prolapse: positive organisms, as well as 126 thromboembolic prophylaxis in fascial plication. Surgical options extensive dissection stretching for Anterior from the pubis anteriorly to the Compartment ischial spine posteriorly. The underlying Through a Pfannenstiel incision, pubocervical fascia is then reduced the retropubic space is opened using vicryl 3/0 sutures, known as and the bladder swept medially, 127 exposing the pelvic sidewall, very at the level of the hymenal similar to a burch colposuspension remnants, allowing the calibre procedure. The rectocele is mobilized pubis to just anterior to the ischial from the vaginal skin by blunt and spine. The rectovaginal fascia is then plicated using either an interrupted or continuous absorbable suture (Vicryl 3/0), to 2. Care Compartment should be taken not to create a Prolapse constriction ring in the vagina which will result in dyspareunia. Traditionally this compartment The redundant skin edges are is approached vaginally when then trimmed taking care not to operated on by the gynaecologist. The posterior that the colo-rectal surgeons vaginal wall is closed with a also operate on the posterior continuous Vicryl 2/0 suture. The patient should be specifc plication, place a number referred to a colorectal surgeon of interrupted lateral sutures for assessment if the following are that incorporate the Levator Ani present: concurrent anal or rectal muscles. This Levator plication has pathology such as hemorrhoids, been shown to be associated with rectal wall prolapse or rectal signifcant dyspareunia and is no mucosal redundancy. Finally a perineorrhaphy is performed by placing deeper absorbable sutures Posterior Colpoperineorrhaphy into the perineal muscles and Procedure fascia thus building up the perineal Two allis or littlewood forceps body to provide additional support are placed on the perineum 128 to the posterior vaginal wall and uterosacral ligament sutures are lengthening the vagina. Injury to therefore tied in the midline and the rectum is unusual but should brought through the posterior be identifed at the time of the part of the vault and tied after procedure so that the defect the vault has been closed. Middle the ureters at risk and therefore ureteric patency should be Compartment confrmed post-operatively by cystoscopy. This is a purse- string suture that goes through The cervix is circumscribed and the both corners of the vaginal vault, utero-vesical fold and pouch of through the uterosacral ligaments Douglas opened.

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In the middle of the second week: • Tell your senior that you’d really like some feedback order frumil 5mg line, constructive criticism order frumil 5mg with amex, etc cheap 5mg frumil with amex. If they feel they haven’t seen you work for a long enough period of time frumil 5mg mastercard, ask them if they wouldn’t mind giving you some suggestions to “improve your learning experience/be a more efficient student/etc. Also, you will look quite smart if you can whip out some terms like “R wave progression,” “bifascicular block” and the like. Reading up on differentials for headache, fainting/loss of consciousness, shortness of breath, chest pain, chronic/acute cough, abdominal pain, altered mental status, knee and joint pain, and complaints of early pregnancy will be extremely high yield. That being said, your differential needn’t be entirely inclusive--but you should have 1 or 2 potential diagnoses, ideally from different systems (i. Your presentations to the attendings and the residents are probably where you will be graded the most. Presentations should incorporate relevant past medical history and be focused on the presenting complaint. Different people want to hear different presentations, either short and to the point or complete H&P’s—when in doubt, go for completeness. While an attending is interested in your detailed physical exam findings, in the back of his/her mind he/she is thinking about what needs to be done for the patient and is focused on things that could be life-threatening. Depending on your site, your shifts will vary but students generally work approximately 110 hours over the course of the rotation in addition to didactics. To qualify for honors students need to receive at least an 85% on the test and have an average of at least 6/7 on their evaluations. Anesthesiology The week-long pass/fail clinical rotation in anesthesiology is a great experience for 200 level students. Over the course of the week, you will help with all aspects of pre-operative, intra- operative and post-operative patient management. Your experience will depend greatly on the residents you work with, the types of cases involved, and your interest level and motivation. In general, all of the residents are very excited about teaching medical students and clearly love their field. You can expect to learn a good deal about the induction of anesthesia, general anesthesia, local anesthesia, and the monitoring of physiologic functioning and how to respond to changes in those functions. Clinical experience is supplemented by a highly regarded lecture series covering important topics including local anesthetics, anesthesia risks, pain management and conscious sedation. They come in all formats, and they will all try to convince you that they will give you the best preparation for the shelf exam. All of us learn differently from each other and from you, so you will see quite a bit of variation among recommendations. In general, you will want to spend a good deal of time reading and reviewing, and will also want to do at least one book of practice questions. First, a general overview of the major series of review books: • First Aid o This series generally provides a good overview, covering the basics of the important topics related to the clerkship. The books are dense and full of detailed information; however, they are much more complete than Blueprints. Questions are arranged via topic and 63 explanations to questions are generally fairly complete, so doing the questions and analyzing the answers helps you learn the material. The book contains a couple of 50 question tests for each discipline and more for core rotations like medicine and surgery, and you would be wise to purchase this book and do the relevant questions for each rotation. Questions tend to be difficult, and several people noted that they could be damaging to confidence if done too close to the shelf. Probably unnecessary, but if you’re nervous before starting clerkship year this might be a good thing to flip through at Barnes and Noble. Particularly if you are on an inpatient medicine service in the 8 weeks prior to the test, it’s hard to find time to study. Keep in mind that it is nearly impossible to read the entirety of any of the three general medicine books because they are very long and you simply won’t have enough time. You are better off being selective about which topics require more coverage and using the textbook or online references only for these topics. Harrison’s Internal Medicine is available online through the Biomedical Library website at no cost, and is a fantastic reference when you need more information than you find in your review books. Doing at least one entire book and reading explanations thoroughly will take a good amount of time but is crucial for the medicine shelf. The questions are very similar to the shelf style, you can time yourself, and the explanations are very thorough. You can skim topics for the main points just before you know you’re going to be asked a question, and there is space for your own notes. Focus on medical problems requiring surgical intervention, anatomy, post-operative management/ complications in your reading. It is much more valuable to use your time making it through a review book than looking through a text book, but if you’re going into surgery you might eventually want one of these. Consider doing the medicine questions as well as the surgery questions as the content overlap between the two exams is quite high (60-80%). A few of the answers in the book are incorrect, so if you find a different answer elsewhere, don’t get stressed about it. Nelson’s is a huge book that is available online (from the biomed library page) and is useful for reading about specific patients/ topics. Baby Nelson is more readable; some people found it useful, most noted that it was not an efficient use of time. Whatever book you choose for review, make sure to supplement it with question books and/or Case Files. Ob-Gyn • Most of us recommended using one book for an overview in this course: o Blueprints: The Ob/Gyn part of this series is more detailed than most of the other Blueprints books are. The majority of people felt that this was sufficient for the shelf exam, with the addition of Case Files and a question book. Their relevance varies from test to test, but they are generally reflective of the exam and often extremely helpful. It is especially helpful for the shelf exam, since you only have three weeks to study, and it covers many of the basic topics that will be on the exam. Pruitt’s review questions (“yellow pages”) that she hands out in the beginning of the course, as well as her review session on high-yield topics. For the most part, knowing the class notes well is sufficient, but the exam does test the notes in detail. You are expected to do the online cases as practice for the exam, and review your notes from the lectures. Additionally, you will sometimes encounter situations where residents or attendings are not following universal precautions (e. Penn Med policy regarding potential exposures is as follows: Any medical student who sustains a needlestick or other wound resulting in exposure to blood or body fluids should follow the following protocol. Please keep in mind, that drug prophylaxis following a high-risk exposure is time sensitive, therefore you must immediately seek help from the appropriate hospital department. Immediately wash the affected area with soap and water and cover the area with a dressing if possible. If you are seen in the Emergency Room, an occupational medicine doctor is on-call 24 hours a day to provide immediate consultation on post-exposure drug treatment and counseling. Do not hesitate to ask the physician treating you to page the Occupational Medicine doctor carrying the needlestick pager. Students should bring their records to Student Health Service so that appropriate follow-up testing can be scheduled. Children’s Hospital of Philadelphia - Report to Occupational Health Service during weekdays or to the Nursing Supervisor on weekends and evenings. Pennsylvania Hospital - Report to Employee Health (Wood Clinic) or to the Emergency Room if they are closed. Englewood Hospital – Report to the Employee Health service between the hours of 8:00 am – 4:00 pm or to Emergency Room after those hours. Luke’s Hospital – Check with your attending physician as the protocol varies according to the service. Billing Procedures All expenses that a student incurs, associated with needlesticks, will be paid for by the School of Medicine.

In situ analysis of lung antigen-presenting cells during murine pulmonary infection with virulent Mycobacterium tuberculosis buy discount frumil 5mg. Chemokine secretion by human polymorphonuclear granulo- cytes after stimulation with Mycobacterium tuberculosis and lipoarabinomannan buy generic frumil 5 mg on-line. Macrophage and T lymphocyte apoptosis during experimental pulmonary tuberculosis: Their relationship to mycobacte- rial virulence discount frumil 5mg. Human -defensin 2 is ex- pressed and associated with Mycobacterium tuberculosis during infection of human al- veolar epithelial cells frumil 5mg on-line. Induction of nitric oxide release from the human alveolar epithelial cell line A549: an in vitro correlate of innate immune response to Mycobacterium tuberculosis. Humoral immunity through immunoglobulin M protects mice from an experimental actinomycetoma infection by Nocardia brasiliensis. Cytokine gene activation and modified responsive- ness to interleukin-2 in the blood of tuberculosis patients. Phagocytosis of Mycobacterium tuberculosis is mediated by human monocyte complement receptors and complement component C3. Macrophage phagocytosis of virulent but not attenuated strains of Mycobacterium tuberculosis is mediated by mannose receptors in addition to comple- ment receptors. Phosphate is essential for stimulation of V gamma 9V delta 2 T lymphocytes by mycobacterial low molecular weight ligand. Type 2 Cytokine gene activation and its relationship to extent of disease in patients with tuberculosis. Comparison of intranasal and transcutaneous immunization for induction of protective immunity against Chlamydia muridarum respi- ratory tract infection. The ability of heat-killed Myco- bacterium vaccae to stimulate a cytotoxic T-cell response to an unrelated protein is as- sociated with a 65 kilodalton heat-shock protein. Effect of pre-immunization by killed Mycobacterium bovis and vaccae on immunoglobulin E response in ovalbumin- sensitized newborn mice. Arrest of mycobacterial phagosome maturation is caused by a block in vesicle fusion between stages controlled by rab5 and rab7. Inhibition of an established allergic response to ovalbumin in Balb/c mice by killed Mycobacterium vaccae. Mucosal mast cells are functionally active during spontaneous expulsion of intestinal nematode infections in rat. Selective receptor blockade during phagocytosis does not alter the survival and growth of Mycobacterium tuberculosis in human macrophages. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Long-term protective and antigen-specific effect of heat-killed Mycobacterium vaccae in a murine model of allergic pulmonary in- flammation. Differential regulation of lipopolysacharide- induced interleukin 1 and tumor necrosis factor synthesis; effect of endogenous and ex- ogenous glucocorticoids and the role of the pituitary-adrenal axis. With the advent of effective antibiotic therapy in the ’50s, the prevalence of the disease, and research on it, declined pre- cipitously. Hippocrates thought it was inherited, while Aristotle and Galen believed it was contagious (Smith 2003). As the disease was more common in particular families and racial or ethnic groups, a heritable component to susceptibility was a plausible assumption, but one that has defied solid experimental proof, perhaps due to the difficulty in eliminating the confounding biases of environment and exposure. While there are several recent reviews of the subject (Bellamy 2005, Bellamy 2006, Fernando 2006, Hill 2006, Ottenhoff 2005, Remus 2003), it is hard to come to definitive conclusions on most of the genes, because the accumulated literature is often contradictory. This has led to the recent publication of meta-analyses attempting to examine the body of published work on particular genes to determine whether a convincing consensus emerges (Kettaneh 2006, Lewis 2005, Li 2006). In addition, it will review studies performed prior to the molecular era to illustrate the history of the field, which may help to clarify why finding genetic determinants has been elusive. The basic epidemiological designs employed in studies of genetic association, in approximate decreasing order of confidence that the results obtained are free of the complicating influences of environment and exposure are: • twin studies comparing disease concordance in monozygotic vs. While this tour is not exhaustive, it attempts to critically present most of the relevant published work. Stocks and Karn (Stocks 1928) devised a correlation coefficient based on sibling disease concurrence expected by chance. Although the attempt was interesting in its design, it could not assure comparability of environment and exposure, as a tuberculous relative could have had a con- founding effect, either as a source of exposure or as a marker for lower socioeco- nomic status. To address the obvious criticism that the spouses could have been exposed in childhood from the affected relative, Puffer stated that two thirds had no known household contact, although the contact may have been forgotten or missed. Overall, due to the near impossibility of controlling for household exposure, the family studies failed to convincingly demonstrate a genetic predisposition. Monozygotic twins are genetically identical, while dizygotic twins are only as genetically similar as other siblings. The concordance in monozygotic twins can also serve as a measure of penetrance − the proportion of gene carriers who express the trait (Cantor 1992). This study would appear to be solid evidence supporting hereditary influences, but it is weakened by several sources of potential bias specific to twin studies (Cantor 1992, Fine 1981) that are worth examining in detail because they again illustrate the difficulties in isolating genetic components from differences in exposure, and the importance of experimental design. Table 6-1: Twin studies Monozygotic Dizygotic Monozygotic Dizygotic Total Pairs Concordant pairs Reference N % N % N % N % Diehl 1936 80 39 125 61 52 65 31 25 Dehlinger 1938 12 26 34 74 7 58 2 6 Kallman 1943 78 25 230 75 52 66 53 23 Harvald 1956 37 26 106 74 14 38 20 19 Simonds 1963 55 27 150 73 18 32 21 14 The Prophit study set out to re-examine the conclusions of Kallman and Reisner’s study by trying to correct all its shortcomings (Simonds 1963). A conservative conclu- sion might be that some inheritable component exists, but it has a maximal pene- trance of only 65 %, and the most careful study ever performed found only 31. While the near fixation on this topic by authors such as Rich (Rich 1951) might be ascribed to the prevailing racism of the period, the as- sumption of greater susceptibility of Africans and African Americans continues to be cited in current literature, with investigators now using molecular findings to try to explain it (Liu 2006). While Rich gave equal credit to “the marked influence of environment… in different economic strata of individual communities within a given country” for Whites, he attributed the higher rates in Africans and African- Americans predominantly to the effects of genetic composition. James McCune Smith in de- bunking the notion that African Americans were genetically predisposed to rickets by showing that whites of the same low socioeconomic status were similarly pre- disposed (Krieger 1992). It’s interesting that these three commonly cited examples all involve foreign conscripts or internees on a colonizer’s military base, and rely on the dubious assumption that their physical and emotional environments were the same as those of the host soldiers. This theory, though still cited in current literature (Fernando 2006), is completely unproven and will likely remain so. Nonetheless, the abundance of literature describing increased susceptibility and a more progressive disease course in Africans and Native Americans suggests that some racial difference may, in fact, exist. Putting aside the theory for the origin of racial differences, are there any studies that have sufficiently controlled for environment and exposure, in order to credibly document a difference? The difficulty in proving a genetic component for human susceptibility 215 rates of 936 and 725 per 100,000 were much higher than rates seen in any other study, but there is no data on other risk factors. In the Alabama study, the overall racial difference was predominantly due to very high rates in young Black women. The best single study was among Navy recruits, because the environment and follow-up were usually equivalent, at least once they were in the Navy. In that study, African Americans had an annual rate only 17 % higher than whites (91/78), but the Asians (195) had a rate more than double that of African Americans. The difficulty in proving a genetic component for human susceptibility 217 residents with positive skin tests. Al- though the nursing home setting convincingly controls for sources of bias, includ- ing age and sex, there is no data on the residents’ weights, general health, or pat- terns of association and rooming. Even if African-Americans have a slightly increased rate of infection, the fact that there was no difference in the rate of progression to disease deflates the credibility of arguments that their immune system is less capable of controlling the infection. No racial differences were found, leading the authors to question the validity of the conclusions from the nursing home study (Hoge 1994). McKeown concluded that improved nutrition was responsible for the decline in mortality and the increase in population, while others later argued that more im- portant factors were the general improvements in living standards and such public health measures as improved housing, isolation of infectious individuals, clean drinking water, and improved sanitation (Szreter 2002). Nonetheless, it is generally accepted that this dramatic decrease was mainly the result of societal factors. There are over 100 different primary genetic immunodeficiencies that predispose to infections with a variety of viruses, bacteria, fungi and protozoa, but only a few have been associated with severe mycobacterial infections (Casanova 2002). A patient was recently described, who had been clinically diagnosed with hyper IgE syndrome and was unusually susceptible to various microorganisms including mycobacteria, as well as virus and fungi (Minegishi 2006). A mutation was found in the gene for tyrosine kinase 2 (Tyk2), a non-receptor tyrosine kinase of the Janus kinase family. This defect in neutrophil killing makes them susceptible to severe recurrent bacterial and fungal infections. Affected patients are predisposed to dis- seminated infections with atypical mycobacteria, septicemia from pyogenic bacte- ria, and viral infections.

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