By Q. Goran. University of Hawai`i, West O`ahu.

Combin- ing tests may allow a clinical diagnosis to be conmed Joint aspiration (see Table 8 careprost 3 ml for sale. Rheumatoid factor: These are antibodies of any class Unexplained joint swelling may require aspiration to directed against the Fc portion of immunoglobulins buy discount careprost 3 ml on-line. The aspiration itself may be of therapeu- The routine laboratory test detects only IgM antibodies order careprost 3ml with mastercard, tic value lowering the pressure and relieving pain. It is which agglutinate latex particles or red cells opsonised often coupled with intra-articular washout or instilla- with IgG. It is the presence of these IgM rheumatoid tion of steroid or antibiotic as appropriate. Examina- factor antibodies that is used to describe a patient as tion of the synovial uid may be of diagnostic value (see seropositive or seronegative. Local spread from a soft tissue infection atively birefringent, whereas the crystals of pseudogout may also occur. Previously Haemophilus inuenzae was seen in young children, Many modalities of joint imaging and direct visualisa- but it is now rare due to vaccination. Patients with tion are used to diagnose and follow the course of mus- sickle cell anaemia are prone to osteomyelitis due to culoskeletaldisordersandareoftenusedincombination. The ndings in individual conditions will be described r Direct spread from local infection may occur with later. Streptococcus, Staphylococcus, anaerobes and gram- r X-ray: Many musculoskeletal disorders have charac- negative organisms. Pathophysiology Comparison of X-ray changes over time is especially In children the long bones are most often involved; in useful in monitoring disorders that have a degenera- adults, vertebral, sternoclavicular and sacroiliac bones tive course. In- r Ulrasound is of value in examining the joint and sur- fections from a distant focus spread via the blood stream rounding soft tissue. In children the organisms usually diagnosing the cause of a painful hip not amenable to settle in the metaphysis because the growth disc (physis) palpation. Acute inammation occurs accompanied by a rise in It can demonstrate both bone and soft tissue disor- pressure leading to pain and disruption of blood ow. In children infectious conditions prior to X-ray changes, it is of the physis acts as a physical barrier to intra-articular great value in identifying malignant bone inltration spread. Bone and joint infections Clinical features Presentationrangesfromanacuteillnesswithpain,fever, swelling and acute tenderness over the affected bone, to Acute osteomyelitis an insidious onset of non-specic dull aching and vague Denition systemic illness. Complications Age r As thebonehealsandnewboneisformed,infectedtis- Normally seen in children and adults over 50 years. Aetiology Investigations Previously, chronic osteomyelitis resulted from poorly r The X-ray nding may take 2 3 weeks to develop. It now occurs more fre- raised periostium is an early sign that may be seen quentlyinpost-traumaticosteomyelitis. With healing there is sclerosis and seques- Pathophysiology trated bone fragments may be visible. Blood cultures are positive in the bone may remain dormant for years giving rise to 50%. Clinical features The clinical course is typically ongoing chronic pain Management r and low-grade fever following an episode of acute os- Surgical drainage should be used if there is a subpe- teomyelitis. There may be pus discharging through a si- riosteal abscess, if systemic upset is refractory to an- nus. However, if the pus is retained within the bone or tibiotic treatment or if there is suspected adjacent join the sinus becomes obstructed, rising pressure leads to an involvement. Par- enteral treatment is often required for a prolonged period (2 4 weeks) prior to a long course of oral an- Investigations tibiotics to ensure eradication. Theperiostiummayberaisedwithunderlying with a third-generation cephalosporin to cover for new bone formation. Management r Adequate analgesia is essential and may be improved Discharging sinuses require dressing, and if an abscess with splints to immobilise the limb (which also helps persists despite antibiotic therapy it should be incised to avoid contractures). Prolonged combined parenteral antibiotics to reduce associated muscle disuse atrophy and to are required. In early stages the joint space is preserved, but later there is narrowing and ir- Tuberculous bone infection regularity with bone erosion and calcication within adjacent soft tissue. Incidence Patients with tuberculosis have a 5% lifetime risk of Management developing bone disease. Chemotherapy with combination anti-tuberculous agents for 12 18 months (see page 105). Rest and trac- tion may be useful; if the articular surfaces are damaged, Age arthrodesis or joint replacement may be required. Geography Septic arthritis Major illness in developing countries, with increasing Denition incidence in the developed world. Aetiology Tuberculous osteomyelitis is usually due to haematoge- Aetiology nous spread from a primary focus in the lungs or gas- Joint infection arises most commonly from haematoge- trointestinal tract (see pages 105 and 154). Other mechanisms include local trauma or creased the incidence of tuberculosis and tuberculous an adjacent infective focus such as osteomyelitis. The patient complains of pain and later swelling due to Pathophysiology pus collection.

Obstruction may lead to dilated ureters and kid- to reduce the risk of clot retention until haematuria is ney(hydroureter quality 3ml careprost,andhydronephrosis) careprost 3 ml for sale. Investigations Antibiotic prophylaxis is usually given to prevent Itisimportanttoexcludeothercausesof bladderoutow urinary tract infection cheap 3 ml careprost. Between10and15mL/second,combined bladder neck contracture or urethral stricture requir- pressure/ow studies may be done to exclude those ing surgery or dilatation, incontinence. The disad- Other options (not widely available) include: vantage of the latter, is that urinary catheterisation is r Stent which is cost-effective in those with a short required. Denition r Finasteride is a 5 alpha reductase inhibitor which in- Urinary incontinence is the involuntary loss of urine hibits the conversion of testosterone to dihydrotestos- from the urethra. It is also useful, but generally less effective for and functional impact on the individual. This is mainly due to detrusor instability/over- 30% of women <65 years but only up to 5% of men <65 activity. Rates are much higher in certain settings such as care of r Overow incontinence is continual or unprecipitated the elderly institutions (up to 45%) and psychiatric care leakage without urge. Bladder outow obstruction may lead Age to overow incontinence due to bladder decompen- Increases with age. Rare causes include spinal cord compression affecting the sacral segments (S2, 3 and 4) or the conus medullaris. F > M Acomprehensive examination is important and can avoid the need for specialist tests. It is important to as- Aetiology sess uid balance, mobility, cognitive ability and relevant Incontinence has been associated with many conditions neurology. Toremaincontinentthere r Avoiding diary is useful to record the time, volume must be: and relevant events, e. This is due to poor sphincter func- Stress incontinence: Initially non-surgical options tion. Systemic or topical oestro- r Inspinalcordcompressionemergencydecompression gen therapy may be of benet. Ring tions intermittent self-catheterisation is the preferred pessaries are useful for those with uterine prolapse. For vaginal cys- Urinary tract infections toceles (where the bladder herniates into the vaginal canal), a transvaginal approach may be used to re- pair the cystocele but this is generally less effective. In females, vaginitis is another syndrome Urge incontinence: unlike stress incontinence, be- which commonly overlaps. Surgery (clam cystoplasty to increase the size of the blad- Age der using bowel) is rarely successful. In patients with cognitive awareness of bladder Sex lling and the ability to independently toilet, bladder F > M training is used to learn methods of deliberately sup- pressing the urge to pass urine. In patients without cognitive awareness or lack of motivation to remain Aetiology dry, scheduled or prompted voiding reduces the num- Most frequently due to bacteria, in particular E. These and Histoplasma capsulatum), parasites (the protozoan tend to cause a dry mouth and may cause constipa- Trichomonas vaginalis and the uke Schistosoma haema- tion and/or urinary retention. Pathophysiology Combined stress and urge incontinence may be treated r Bacterialvirulencefactors:Criticaltothepathogenesis with behavioural therapy with or without medical ther- of bacteria is adherence to the uroepithelium as infec- apy. Surgicaltreatmentappearstobelesseffectivethanin tions ascend from the urethral orice to the bladder pure stress incontinence. A culture is regarded as Urine itself is inhibitory to the growth of normal uri- 5 positive if >10 of a single organism per mL. Further investigations are required in children Clinical features (see page 268), males and females with recurrent infect- Acute cystitis typically presents with dysuria (a burning ions. Macroscopic haematuria is not uncommon, although this should Management prompt further investigation for any other underlying Empirical antibiotic therapy is used in symptomatic pa- disease such as urinary stones or a bladder malignancy. Both Intravenous antibiotics should be used in those who are pyelonephritis and prostatitis may be due to ascending systemically unwell or those who are vomiting. Quinolones such present nonspecically with fever, falls, vomiting, or as ciprooxacin are useful as resistant E. Macroscopy r Intravenoustherapyisoftenwithacephalosporinwith The urine is cloudy due to the pyuria (pus cells) and or without gentamicin. Over time, recurrences can cause chronic sistance, and some centres advise a cycling regime, e. If there is any evidence of obstruction this requires rapid drainage Aetiology (see page 256). Management Mild cases may respond to oral antibiotics as for urinary Pathophysiology tract infection, but many require intravenous therapy Predisposing factors to ascending infection include suchasgentamicinandciprooxacin. Antibiotics should be tailored to the sensitivity stasis due to obstruction, dilatation or neurological and specicity, and continued for 10 14 days (longer causes and reux.

A process should be established by which such information is validated for incorporation into a New Taxonomy to be used by physicians generic careprost 3 ml line, patients careprost 3ml overnight delivery, regulators buy discount careprost 3 ml on line, and payers. The speed and complexity with which such validated information emerges will undoubtedly accelerate and will require novel decision support systems for use by all stakeholders. The Committee envisions that a New Taxonomy incorporating molecular data could become self-sustaining by accelerating delivery of better health through more accurate diagnosis and more effective and cost-efficient treatments. A major beneficiary of the proposed Knowledge Network of Disease and New Taxonomy would be what has been termed precision medicine. These data are also critical for the development of the Information Commons, the Knowledge Network of Disease, and the development and validation of the New Taxonomy. In general, however, there is a growing shortfall: without better integration of information both within and between research and medicine, an increasing wealth of information is left unused. Twenty five years ago, the patient s mother had breast cancer, when therapeutic options were few: hormonal suppression or broad-spectrum chemotherapy with significant side effects. Today, Patient 1 s physician can suggest a precise regimen of therapeutic options tailored to the molecular characteristics of her cancer, drawn from among multiple therapies that together focus on her particular tumor markers. Moreover, the patient s relatives can undergo testing to assess their individual breast cancer predisposition. The diagnosis gives little insight into the specific molecular pathophysiology of the disease and its complications; similarly there is little basis for tailoring treatment to a patient s pathophysiology. No concrete molecular information is available to customize Patient 2 s therapy to reduce his risk for kidney failure, blindness or other diabetes-related complications. Patient 2 and his family are not yet benefitting from today s explosion of information on the pathophysiology of disease (A. Medical Encyclopedia 2011, Gordon 2011, Kellett 2011) 1 These scenarios are illustrative examples describing typical patients. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 8 What elements of our research and medical enterprise contribute to making the Patient 1 scenario exceptional, and Patient 2 typical? Could it be that something as fundamental as our current system for classifying diseases is actually inhibiting progress? Today s classification system is based largely on measurable signs and symptoms, such as a breast mass or elevated blood sugar, together with descriptions of tissues or cells, and often fail to specify molecular 2 pathways that drive disease or represent targets of treatment. Consider a world where a diagnosis itself routinely provides insight into a specific pathogenic pathway. Consider a world where clinical information, including molecular features, becomes part of a vast Knowledge Network of Disease that would support precise diagnosis and individualized treatment. What if the potential of molecular features shared by seemingly disparate diseases to suggest radically new treatment regimens were fully realized? In such a world, a new, more accurate and precise taxonomy of disease could enable each patient to benefit from and contribute to what is known. The information and opinions conveyed at the workshop informed and influenced an intensive series of Committee deliberations (in person and by teleconference) over a 6 month period. The Committee emphasized that molecular biology was one important base of information for the New Taxonomy, but not a limitation or constraint. Moreover, the Committee did not view its charge as prescribing a specific new disease nomenclature. Rather, the Committee saw its challenge as crafting a framework for integrating the rapidly expanding range and detail of biological, behavioral and experiential information to facilitate basic discovery, and to drive the development of a more accurate and precise classification of disease (i. Preventative or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not. Those who favor the latter term do so in part because it is less likely to be misinterpreted as meaning that each patient will be treated differently from every other patient. The workshop participants will also consider the essential elements of the framework by addressing topics that include, but are not limited to: x piling the huge diversity of extant data from molecular studies of human disease to assess what is known, identify gaps, and recommend priorities to fill these gaps. The ad hoc Committee will use the workshop results in its deliberations as it develops recommendations for a framework in a consensus report. The report may form a basis for government and other research funding organizations regarding molecular studies of human disease. A Brief History of Disease Taxonomies One of the first attempts to establish a scientific classification of disease was undertaken by Carolus Linnaeus, who developed the taxonomic system that is still used to classify living organisms. His 1763 publication Genera Morborum (Linn 1763) classified diseases into such categories as exanthematic (feverish with skin eruptions), phlogistic (feverish with heavy pulse and topical pain), and dolorous (painful). The effort was largely a failure because of the lack of an adequate understanding of the biological basis of disease. For example, without a germ theory of disease, rabies was characterized as a psychiatric disorder because of the brain dysfunction that occurs in advanced cases. This illustrates how a classification system for disease that is divorced from the biological basis of disease can mislead and impede efforts to develop better treatments.

These findings show that she is developing shock with inadequate perfusion of vital organs generic careprost 3ml line. Possible causes for shock Types of shock Example Hypovolaemic shock Blood loss Cardiogenic shock Myocardial infarction Extracardiac obstructive shock Pulmonary embolism Vasodilatory (distributive) shock Sepsis All these causes are possible in this woman with abdominal problems and a history of ischaemic heart disease cheap 3 ml careprost with amex. The fact that the cardiac output is high makes blood loss and cardiogenic shock unlikely discount 3 ml careprost with visa. The most likely cause is septic shock where peripheral vasodi- latation would lead to a high cardiac output but a falling blood pressure and rising pulse rate. Vasoconstriction and reduced blood flow occurs in certain organs, such as the kid- neys, leading to the term distributive shock with maintained overall cardiac output but inappropriate distribution of blood flow. The rise in central temperature and the lack of a marked fall in peripheral temperature would fit with this cause of the shock. The patient was stabilized with fluid replacement and antibiotics before going to theatre where the diagnosis of ischaemic bowel from an embolus was confirmed. Arteriography can confirm the diagnosis but confirmation is often at laparotomy which is usually required to remove the necrotic bowel. She complains that her muscles feel stiff, and it is taking her longer than it did to walk to the local shops. She is anxious about these problems since she lives alone and has to do every- thing for herself. Her daughter has told her that it is becoming increasingly difficult to read the small writing in the letters she sends. She complains that she has been sleeping poorly and is, consequently, rather tired. She has generally increased muscle tone throughout the range of movement and equal in flexors and extensors. There is a slight tremor affecting mainly her right hand, which is suppressed when she tries to do something. When asked to walk she is a little slow to get started and has difficulty stopping and turning. Her writing shows micrographia secondary to the rigidity and slowness of movement. Beta-blockers can cause tiredness and slowness but not to the extent seen in this woman. This woman has Parkinson s disease presenting with the classic triad of tremor, rigidity and hypokinesia. There is difficulty starting to walk (freezing) and the patient uses small steps and has difficulty stopping (festination). The characteristic pathological abnormality is degeneration of dopamine-secreting neurones in the nigrostriatal pathway of the basal ganglia. Parkinsonian features (parkinsonism) may occur in a variety of diseases: Parkinson s disease postencephalitic parkinsonism neuroleptic drug-induced Parkinson s disease parkinsonism in association with Alzheimer s/multi-infarct dementia. Classification of tremor Rest tremor: the tremor is worse at rest and is typical of parkinsonism. Benign essential tremor is not present at rest, but appears on holding the arms outstretched but is not worse on movement (finger nose testing). There is usually a family history of tremor and the tremor is helped by alcohol and beta-blockers. It is usually caused by brainstem or cerebellar disease caused by such diseases as multiple sclerosis, localized tumours or spinocerebellar degeneration. Selegiline, an inhibitor of monoamine oxidase B may delay the need to start levodopa and may slow the rate of progression of the disease, but has significant side-effects. Levodopa is usually used in combination with a selective dopa decarboxylase inhibitor which does not cross the blood brain barrier and reduces peripheral adverse effects. The commonest side-effects are nausea, vomiting, dizziness, postural hypotension and neuropsychiatric problems. After many years of treatment the effects tend to diminish and the patient may develop rapid oscillations in control the on off effect. When these develop, a sustained release for- mulation of levodopa or a dopamine agonist, e. Because of the loss of effect with time, treatment should not be started too early. She should be assessed by a physiotherapist and occupational therapist and provided with advice and aids. This has progressed so that she is now short of breath on walking up one flight of stairs and walks more slowly on the flat than other people her age.