This syndrome is thought to medicine in ancient egypt buy lotensin 10mg lowest price reect selective damage to treatment chronic bronchitis discount 5mg lotensin fast delivery the ventral (‘what’) stream of visual processing in the lateral occipital area medicine rheumatoid arthritis discount lotensin 5 mg mastercard, whilst the dorsal (‘where’) stream remains intact medications with acetaminophen order lotensin in united states online, yet the workings of the latter are not available to consciousness. It may be heard in: • Essential tremor; • Cerebellar disorders; • Spasmodic dysphonia/laryngeal dystonia; • Parkinson’s disease; • Motor neurone disease. The pathophysiology is uncertain but may relate to rhythmic contractions of the cricothyroid and rectus abdominis muscles. Cross References Dysphonia; Tremor Von Graefe’s Sign Von Graefe’s sign, or Graefe’s sign, is the retarded descent of the upper eyelid during movement of the eye from the primary position to downgaze; the lid ‘fol lows’ the eye. This may be termed ‘lid lag’, although some authorities reserve this term for a static situation in which the lid is higher than the globe on downgaze. Cross Reference Myopathy ‘Waiter’s Tip’ Posture Lesions of the upper trunk of the brachial plexus (Erb–Duchenne type) produce weakness and sensory loss in the C5 and C6 distribution, typically with the arm hanging at the side, internally rotated at the shoulder with the elbow extended and the forearm pronated: the ‘waiter’s tip’ posture, also sometimes known as the ‘porter’s tip’ or ‘policeman’s tip’. Cross References Myotonia; Paramyotonia Wartenberg’s Sign (1) In ulnar neuropathy, Wartenberg’s sign refers to the slightly greater abduction of the fth digit on the affected side, due to paralysis of the adducting pal mar interosseous muscle and unopposed action of the radial innervated extensor muscles (digiti minimi, digitorum communis). With the patient standing, the examiner holds the shoulders and gently shakes backwards and forwards, the two sides out of phase. Normally, the passive arm swing induced by this move ment will be out of phase with the trunk movements, but in rigidity the limbs and trunk tend to move en bloc. Passive swinging of the wrist or elbow joint may also be performed to assess rigidity. Cross References Parkinsonism; Rigidity; ‘Rolex’ sign; Spasticity Wasting Wasting refers to a thinning of the musculature, also known as atrophy or, if of neurogenic origin, amyotrophy. Wasting may be a consequence of disorders of: • muscle (myopathies, dystrophies); • peripheral nerve (more so in axonal than demyelinating peripheral neu ropathies); • anterior horn cells. Wasting may also be seen in general medical disorders associated with a profound catabolic state. However, this is not a linear scale; grade 4 often becomes subdivided into 4,4,and4+(oreven5) according to the increasing degree of resistance which the examiner must apply to overcome activity. It is also important to assess what effort the patient is making to comply with the testing; ‘apparent weakness’ or ‘pseudoparesis’ may be shorthand for lack of patient effort. Testing records only 370 Wernicke’s Aphasia W the best forced maximal contraction and should not develop into an unseemly trial of strength between patient and examiner. Accepting all these difcul ties, it should be acknowledged that the grading of weakness, like all clinical observations, is subject to some degree of observer bias. However, there is no evidence that pure lesions of the pyramidal tracts produce this picture: pyramidotomy in the monkey results in a decit in ne nger movements, but without weakness. Moreover, a similar pattern of weakness may be observed in lower motor neurone disorders such as Guillain–Barre syndrome. Coexistent wasting suggests that muscle weakness is of lower motor neurone origin, especially if acute, although wasting may occur in long standing upper motor neurone lesions. Weakness with minimal or no mus cle wasting may be non organic, but may be seen in conditions such as multifocal motor neuropathy with conduction block. Cross Reference Rinne’s test Wernicke’s Aphasia Wernicke’s aphasia is the classical ‘receptive aphasia’, in distinction to the ‘expressive aphasia’ of Broca, although this classication is problematic since there are concurrent ‘expressive’ problems in Wernicke’s aphasia. Other terms sometimes used for Wernicke type aphasia are sensory aphasia or posterior aphasia. Considering each of the features suggested for the clinical classication of aphasias (see Aphasia), Wernicke’s aphasia is characterized by: • Fluency: uent speech with phonemic and semantic paraphasias and para grammatism (inappropriate use of syntax); ‘empty speech’ with few verbs and nouns; prosody usually preserved; at worst, owing speech (logorrhoea) 371 W Wheelchair Sign devoid of semantic meaning (jargon aphasia, semantic aphasia); automatic speech is often better preserved than spontaneous. Broca’s aphasia); • Reading: usually impaired, with numerous paralexic errors and impaired reading comprehension (cf. There may be associated anxiety, with or without agitation and paranoia, and concurrent auditory agnosia. Because of a loss of self monitoring of out put, patients are often not aware of the impairment, and behavioural disturbance sometimes misdiagnosed as ‘acute confusional state’ and even referral or admis sion to psychiatric hospital may occur, particularly if there is no or minimal accompanying hemiparesis. The differential diagnosis of Wernicke’s aphasia includes delirium and schizophasia. Wernicke placed it in the posterior two thirds of the superior temporal gyrus and planum temporale (Brodmann area 22), but more recent neuroradio logical studies (structural and functional imaging) suggest that this area may be more associated with the generation of paraphasia, whereas more ventral areas of temporal lobe and angular gyrus (Brodmann areas 37, 39, and 40) may be asso ciated with disturbance of comprehension. A correlation exists between the size of the lesion and the extent of the aphasia. A similar clinical picture may occur with infarcts of the head of the left caudate nucleus and left thalamic nuclei. Cross References Agnosia; Agraphia; Alexia; Anomia; Aphasia; Broca’s aphasia; Jargon apha sia; Logorrhoea; Paraphasia; Pure word deafness; Schizophasia; Transcortical aphasias Wheelchair Sign the so called wheelchair sign describes patients with parkinsonism who start to use a wheelchair for mobility early in the course of their disease, usually because of repeated falls. Early falls are a typical feature of progressive supranuclear palsy (Steele–Richardson–Olszewski syndrome), but not idiopathic Parkinson’s disease or other parkinsonian syndromes. Cross References Parkinsonism; ‘Rocket sign’ 372 Woltman’s Sign W Wing Beating Tremor Wing beating tremor is absent at rest but develops when the arms are extended, hence this is a postural tremor. Cross Reference Tremor Winging of the Scapula Winging of the scapula, or scapula alata, is a failure to hold the medial border of the scapula against the rib cage when pushing forward with the hands. It is most easily observed by asking the patient to push or press against a wall or the examiner’s hand whilst observing the scapula which lifts away from the posterior chest wall. Winging of the scapula may be a consequence of weakness of the serratus anterior muscle, usually due to a neuropathy of the long thoracic nerve of Bell, but sometimes as a consequence of brachial plexus injury or cervical root (C7) injury. Weakness of trapezius, particularly the middle trapezius muscle, may also cause winging of the upper part of the scapula, more prominent on abduction of the arm, when the superior angle of the scapula moves farther from the midline. Witzelsucht Witzelsucht, or the joking malady, refers to excessive and inappropriate face tiousness or jocularity, a term coined in the 1890s for one of the personality changes observed following frontal (especially orbitofrontal) lobe injury. Cross References Emotionalism, Emotional lability; Frontal lobe syndromes; Moria Woltman’s Sign Woltman’s sign denotes slow relaxing, or ‘hung up’, tendon reexes. These are most commonly seen in the context of untreated hypothyroidism, but have also been recorded in other situations, including treatment with blockers, diabetes mellitus, and complete heart block. The phenomenon is sometimes labelled ‘pseudomyotonia’ because of its supercial resemblance to the slow muscle relax ation of myotonia, but electrophysiological testing does not show myotonic discharges. Chorea may result in apparently ‘hung up’ reexes, perhaps due to a choreiform jerk after muscle relaxation. The mechanisms underlying Woltman’s sign are uncertain: changes in basal metabolic rate and in muscle bre types (selective loss of fast twitch bres) have been suggested. Normalisation of slow relaxing tendon reexes (Woltman’s sign) after cardiac pacing for complete heart block. Cross References Chorea; Myotonia; Pseudomyotonia Wrestler’s Sign this name has been given to the excessive effort in irrelevant muscle groups accompanied by prominent non verbal signs of effort such as grunting in patients with apparent (‘functional’) weakness. It may coexist with intermittent voluntary effort, collapsing weakness, cocontraction of agonist and antagonist muscles, and inconsistency in clinical examination. Cross Reference Collapsing weakness Wrist Drop Wrist drop describes a hand hanging in exion due to weakness of wrist extension. This results from radial nerve palsy, either in the axilla or spiral groove of the humerus (‘Saturday night palsy’, although other nerves may also be compressed by hanging the arm over a chair. Distal lesions affecting branches of the posterior interosseous branch of the radial nerve may produce more circumscribed deformity, such as weak extension of metacarpophalangeal joints (‘nger drop’, ‘thumb drop’). Writer’s Cramp Writer’s cramp, also known as graphospasm, la crampe des ecrivains,or scrivener’s palsy, is a focal dystonia involving the hand and/or arm muscles, caus ing abnormal posturing of the hand when writing; it is the most common of the task specic dystonias (once known as ‘craft palsies’). When attempting to write, patients may nd they are involuntarily gripping the pen harder, and there may also be involuntary movement at the wrist or in the arm. A tremor may also develop, not to be confused with primary writing tremor in which there is no dystonia. Attempts to use the contralateral hand may be made, but this too may become affected with time (‘mirror dystonia’). The problem may be exclusive to writing (simple writer’s cramp) but some peo ple develop difculties with other activities as well. There is some neurophysiological evidence that the condition is due to abnor malities within the spinal cord segmental motor programmes and muscle spindle afferent input to them. Writer’s cramp may be amenable to local botulinum toxin injections into the hand or arm muscles responsible for the involuntary movement. Excessive or pathological yawning (chasm) is compulsive, repetitive yawning not triggered by physiological stimuli such as fatigue or boredom.
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The small bowel fecus sign has been described in the context of small bowel obstruction but has also been also in other metabolic or infectious diseases medicine garden discount 10mg lotensin visa. The most common site of stone impaction in gallstone ileus is ileum followed by jejunum and duodenum medications i can take while pregnant order lotensin amex. A small bowel enema reveals smooth thickened folds in a 20cm segment of the small bowel medicine to prevent cold buy lotensin 10 mg with mastercard. Answers: (a) Not correct (b) Correct (c) Not correct (d) Correct (e) Correct Explanation: Generalised thickening of small bowel usually occurs in hypoproteinaemia treatment pink eye discount lotensin american express, congestive heart failure and nephrotic syndrome. Long segment thickening may reflect intramural haemorrhage example ischaemia, anticoagulant therapy. F ocal thickening of small bowel should include lymphoma, mesenteric metastasis and early Crohn’s disease. Complications of liver transplantation: (a) Hepatic artery thrombosis occurs in less than 1% of transplant recipients (b) Portal vein thrombosis is the most common vascular complication. Answers: (a) Not correct (b) Not correct (c) Correct (d) Correct 89 (e) Correct Explanation: Most common vascular complication of liver transplant includes hepatic artery thrombosis which occurs in 60% of the cases of vascular complications. Which of the following are correct about Carcinoid of the appendix and small bowel: (a) 40 50 arise in the appendix. Octreotide is a somatostatin analogue that can also be useful for diagnosing carcinoid tumours. Answers: (a) Not correct (b) Correct (c) Not correct (d) Not correct (e) Correct Explanation: Fibrolamellar carcinoma shows calcification in 40% of the cases. In the imaging of acute testicular torsion, which of the following are correct: (a) On sonography, a reactive hydrocoele is seen after 6 hours. Answers: (a) Correct (b) Correct (c) Correct (d) Not correct (e) Not correct Explanation: Spontaneous detorsion of testis may occur leading to unilateral testicle hypoperfusion. In the acute phase, there is reduced perfusion in the testis with decreased activity. In the subacute phase, there is a peritesticular reactive hyperaemia with a hilar or increased tracer activity. Answers: (a) Not correct (b) Correct (c) Not correct (d) Correct (e) Not correct Explanation: Chronic liver disease is present in 25% of adults with cystic fibrosis and the severity increases with age. In patients with cystic fibrosis, the gallbladder is typically small, trabeculated, contracted and poorly functioning. Portal vein stenosis or thrombosis developsslowly, presenting with varices, splenomegaly and ascites. Portal vein stenosis may be treated by balloon dilatation, but once the thrombus is extensive and reaches the periphery of the intrahepatic portal vein branches, then a repeat liver transplant is only option. Answers: (a) Correct (b) Correct (c) Correct (d) Not correct (e) Correct Explanation: Solid and papillary pancreatic neoplasms are large tumours that are better demarcated, thick walled and have solid and cystic areas. Imaging shows enhancement of the thick wall and lobular projections from the inner wall margins. Typhlitis is seen in neutropenia patients and usually presents as non specific thickening of caecum and ascending colon due to necrosis. Answers: (a) Not correct (b) Correct 93 (c) Not correct (d) Not correct (e) Correct Explanation: Males are commonly affected (9:1 = M:F). There is absence of bowel dilatation, no ulceration and thickening of duodenum and jejunum folds due infiltration by macrophages. Answers: (a) Correct (b) Not correct (c) Correct (d) Not correct (e) Not correct Explanation: the paracervical, parametrial, obturator and iliac nodes are involved first. Later there is spread to the common iliac and para aortic nodes with worse prognosis. The recurrent tumour commonly involve the rectum and recto vaginal fistula may develop. Answers: (a) Correct (b) Correct (c) Not correct (d) Correct (e) Correct Explanation: In the ovary cancer, lymph node spread is typically along the path of the gonadal vessels to the para aortic nodes and along the parameterial channels to the external iliac and hypogastric group. Answers: (a) Correct (b) Not correct (c) Correct (d) Not correct (e) Not correct Explanation: Cholangiocarcinoma have varied appearance on T2 weighted imaging, from very high signal to mildly increased signal relative to liver. The tumour spreads by local invasion and may involve the portal vein and hepatic artery. Answers: (a) Not correct (b) Correct (c) Not correct (d) Not correct (e) Correct Explanation: About 90% of the bladder cancers are transitional cell tumour. Transitional cell tumour may extend to the perivesicle fat, seminal vesicles and prostate in Males but extension to the uterus and cervix is uncommon in females the seminal vesicles are high signal on T2 weighted images. Milwaukee shoulder is calcium phosphate crystal deposition in elderly woman causing destruction of rotator cuff. With superior subluxation of humerus, forming pseudoarthrosis with clavicle or acromion with glenohumeral degeneration. Retropulsion of post fragment Diffuse low signal on T1 Normal signal on all High on T2 Band like low signal adjacent to fracture Pedicle involvement ‘Return to normal’ signal after contrast. Central nidus shows intense uptake surrounded by less uptake (double density sign). Malignant transformation of osteochondroma occurs due to: • New lucency • Increased activity • Growth after skeletal maturation • Pain after puberty • Cortical destruction • Cartilagenous cap > 1cm. Staging of osteosarcoma: T1 – Single lesion less than 8cm T2 – >8 cm T3 – Skip lesions of any size. They are perpendicular & do not point away from joint with absence of cartilaginous cap & have a wide base. Subchondral irregularity, erosions, fragmentation with joint space widening is seen. Jefferson fracture is unstable fracture & are not usually associated with neurological deficit however there is vertebral artery injury & retropulsion of fragments with displacement of lateral masses of C1 due to transverse ligament rupture. Disruption of either of these results in communication of radiocorpal compartment with mid carpal compartment. Contrast material seen in distal radioulnar joint is suggestive of ligament disruption. Le Fort fractures: I – Inferior Portion of both medial & lateral maxillary buttress > maxillary arch floating free from face. It comprises costoclavicular ligament ossification, sternoclavicular joint arthropathy, osteitis & hyperostosis of medial clavicle, sternum & upper ribs. There is thickened coracohumeral ligament, joint capsule & axillary recess is significantly reduced in volume. Paget’s disease results is unilateral cortical thickening with bowing & shows intense uptake with raised serum Alkaline phosphatase levels. It can be monostotic or polyostotic (calvarium, pelvis & long bones can be simultaneously affected). False 110 positives are due to anistropy, acoustic shadowing, poor transducer positioning. Prostate Ca with urinary tract obstruction can have increased renal activity (false negative scan). In marfan syndrome, there is reduced upper to lower segment ratio, dissection of ascending aorta, spontaneous pneumothorax, scoliosis, pectus carinatum & excavatum, protrusion acetabuli & pes planus. Which of the following are correct regarding intra articular osteoid osteoma: (a) Most commonly affects the hip. Answer: (a) Correct (b) Not correct (c) Not correct (d) Not correct (e) Not correct Explanation: Nocturnal pain is a feature of long bone osteoid osteoma and not of intra articular lesions. Extensivereactive sclerosis surrounding the nidusis a feature of long bone lesion and not of intra articular lesion. Which of the following are correct regarding ankylosing spondylitis: (a) the hip joints are involved in more than 20% of patients. Answer: (a) Correct (b) Correct (c) Not correct (d) Correct (e) Not correct Explanation: Romanus lesions are seen in early stages of disease and consist of inflammation at the site of anterior longitudinal ligament attachment to vertebrae and discs giving rise to erosions at discovertebral junction. Extraspinal manifestations include enthesopathy and peripheral arthropathy favouring the lower limbs. Iritis, aortic insufficiency and pulmonary fibrosis are extraskeletal manifestations of Ankylosing spondylitis. Which of the following are correct regarding popliteal (Baker’s) cysts: (a) Are commonly associated with meniscal pathology in adults.
Increasing incidence of testicular cancer in the United States and Europe between 1992 and 2009 medicine qhs lotensin 10 mg visa. Recent trends in the incidence of testicular germ cell tumors in the United States medicine administration discount lotensin 10mg without prescription. Innovations in health care and mortality trends from five cancers in seven European countries between 1970 and 2005 anima sound medicine generic lotensin 10mg otc. German second opinion network for testicular cancer: sealing the leaky pipe between evidence and clinical practice treatment 1st degree burn discount lotensin 10 mg line. Is surveillance for stage 1 germ cell tumours of the testis appropriate outside a specialist centre Impact of the treating institution on survival of patients with “poor prognosis” metastatic nonseminoma. European Organization for Research and Treatment of Cancer Genito Urinary Tract Cancer Collaborative Group and the Medical Research Council Testicular Cancer Working Party. Population based study of perioperative mortality after retroperitoneal lymphadenectomy for nonseminomatous testicular germ cell tumors. Long term oncological outcome after post chemotherapy retroperitoneal lymph node dissection in men with metastatic nonseminomatous germ cell tumour. Testicular dysgenesis syndrome comprises some but not all cases of hypospadias and impaired spermatogenesis. A meta analysis of the risk of boys with isolated cryptorchidism developing testicular cancer in later life. The association risk of male subfertility and testicular cancer: a systematic review. Familial testicular germ cell tumors in adults: 2010 summary of genetic risk factors and clinical phenotype. Tallness is associated with risk of testicular cancer: evidence for the nutrition hypothesis. Is increased body mass index associated with the incidence of testicular germ cell cancer Early predicted time to normalization of tumor markers predicts outcome in poor prognosis nonseminomatous germ cell tumors. Improved accuracy of computerized tomography based clinical staging in low stage nonseminomatous germ cell cancer using size criteria of retroperitoneal lymph nodes. Metastases to retroperitoneal and pelvic lymph nodes: computed tomography and lymphangiography. Chest staging in testis cancer patients: imaging modality selection based upon risk assessment as determined by abdominal computerized tomography scan results. The role of positron emission tomography in the evaluation of residual masses after chemotherapy for advanced stage seminoma. Value of pre and post orchiectomy serum tumor marker information in prediction of retroperitoneal lymph node metastases. Contralateral testicular biopsy procedure in patients with unilateral testis cancer: is it indicated The International Germ Cell Consensus Classification: a new prognostic factor based staging classification for metastatic germ cell tumours. Ultrasonography as a diagnostic adjunct for the evaluation of masses in the scrotum. Clinicopathological study of regressed testicular tumors (apparent extragonadal germ cell neoplasms). Prevalence of contralateral testicular intraepithelial neoplasia in patients with testicular germ cell neoplasms. Carcinoma in situ of contralateral testis in patients with testicular germ cell cancer: study of 27 cases in 500 patients. Intratubular germ cell neoplasia of the contralateral testis in testicular cancer: defining a high risk group. Incidence of contralateral germ cell testicular tumors in South Europe: report of the experience at 2 Spanish university hospitals and review of the literature. Clinical course and histopathologic risk factor assessment in patients with bilateral testicular germ cell tumors. Prevalence of carcinoma in situ and other histopathological abnormalities in testes of men with a history of cryptorchidism. Radiotherapy with 16 Gy may fail to eradicate testicular intraepithelial neoplasia: preliminary communication of a dose reduction trial of the German Testicular Cancer Study Group. Effect of graded testicular doses of radiotherapy in patients treated for carcinoma in situ in the testis. Carcinoma in situ testis, the progenitor of testicular germ cell tumours: a clinical review. Treatment of testicular germ cell cancer: a cochrane evidence based systematic review. Risk adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study. Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial. Stage I non seminomatous germ cell tumours of the testis: identification of a subgroup of patients with a very low risk of relapse. Impact of cytotoxic treatment on long term fertility in patients with germ cell cancer. Gonadal function and fertility in patients with bilateral testicular germ cell malignancy. Pharmacology and clinical use of testosterone, in Testosterone Action, Deficiency, Substitution. Feelings of loss and uneasiness or shame after removal of a testicle by orchidectomy: a population based long term follow up of testicular cancer survivors. Multicenter study evaluating a dual policy of postorchiectomy surveillance and selective adjuvant single agent carboplatin for patients with clinical stage I seminoma. Management of seminomatous testicular cancer: a binational prospective population based study from the Swedish norwegian testicular cancer study group. Radiotherapy versus single dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Randomized trials in 2466 patients with stage I seminoma: patterns of relapse and follow up. Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Long term results and morbidity of paraaortic compared with paraaortic and iliac adjuvant radiation in clinical stage I seminoma. Seminoma of the testis: is scrotal shielding necessary when radiotherapy is limited to the para aortic nodes Treatment specific risks of second malignancies and cardiovascular disease in 5 year survivors of testicular cancer. Second cancer risk and mortality in men treated with radiotherapy for stage I seminoma. Risk adapted treatment in clinical stage I testicular seminoma: the third Spanish Germ Cell Cancer Group study. Histopathology in the prediction of relapse of patients with stage I testicular teratoma treated by orchidectomy alone. Medical Research Council prospective study of surveillance for stage I testicular teratoma. Prognostic factors in clinical stage I nonseminomatous germ cell tumors of the testis: multivariate analysis of a prospective multicenter study. Non risk adapted surveillance for patients with stage I nonseminomatous testicular germ cell tumors: diminishing treatment related morbidity while maintaining efficacy. Active surveillance is the preferred approach to clinical stage I testicular cancer. Short course adjuvant chemotherapy in high risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report. Adjuvant chemotherapy for high risk clinical stage I nonseminomatous testicular germ cell cancer: long term results of a prospective trial.
Peripheral blood vessel disorder
Capillary leak syndrome with monoclonal gammopathy
Hirschsprung disease type d brachydactyly
Tsukahara Kajii syndrome
Chang Davidson Carlson syndrome
Acute high level silica exposures may be associated with natural and other disasters symptoms tonsillitis buy genuine lotensin on-line, such as earthquakes treatment kidney infection purchase lotensin 5mg overnight delivery, volcanic eruptions symptoms indigestion order discount lotensin online, and building collapse medications to avoid during pregnancy purchase lotensin. High level exposure to respirable silica dust (particles <5 m) can cause chronic inflammation and fibrosis in the lungs and other organs. Silica exposure in humans has also been associated with increased production of autoantibodies, serum immunoglobulins, and immune complexes. Studying the association of silica related autoimmune effects in occupational settings is complicated by the fact that most auto immune diseases are fairly rare outcomes, particularly in men, who are the dominant workforce in the dusty trades. Similarly, the role of silica in autoimmune diseases is also difficult to assess in a population based setting, given the female predominance seen in many autoimmune diseases. Occupational silica exposure may be difficult to assess in case–control studies because of the diversity of sources of exposure encountered in the general population. Studies in women may present an even greater challenge, since exposure assessment techniques for women’s occupations are not well developed (Greenberg & Dement, 1994). The association between occupational exposure to crystalline silica and rheumatoid arthritis, scleroderma, the small vessel vascu litides. Wegener granulomatosis), and systemic lupus erythema tosus has been examined in recent reviews (Parks et al. The cohort, nested case–control, and registry linkage studies of highly exposed occupational groups. Although higher risks are generally seen in silicosis patients, there are now several studies that have reported associations between silica exposure, in the absence of silicosis, and risk of rheumatoid arthritis, scleroderma, and other systemic autoimmune diseases (Klockars et al. Other cohort studies were conducted in South African gold miners in the 1980s (reviewed in Parks et al. With the exception of the nested case–control study among pottery workers (Turner & Cherry, 2000), all of the studies of silica exposure and rheumatoid arthritis have reported odds ratios of 2. The pottery worker study matched cases and controls by date of birth and date on which employment began, making it difficult to detect differences in cumulative silica exposure. As with rheumatoid arthritis, almost all of these studies have reported a 2 to 3 fold increased risk of these diseases with silica exposure. Until recently, the evidence relating silica exposure to lupus was limited to case reports, mostly of male lupus patients with silicosis and a history of exposure to very high levels of silica. Since 1995, three epidemiological studies in different populations (uranium miners in Germany, silicosis patients in Sweden, and a population 124 Chemical/Physical Agents and Autoimmunity based case–control study in the southeastern United States) have been reported (Table 10). Each of these studies supports the hypothesis that occupational silica dust exposure is associated with risk of this disease. Recent (1985–2005) epidemiological studies of occupational silica exposure and risk of autoimmune diseases Disease and Sex (n)a / Exposure classification References design Occupation and resultsb Rheumatoid arthritis Nested M (157, 157) Silicosis and definite or Sluis Cremer case–control Gold miners probable rheumatoid et al. Migration of silica containing macrophages to the lymph nodes and increased systemic immunoglobulin production have also been shown to occur (Huang et al. In murine models, silica has been shown to increase the levels of antigen specific antibodies in the lung following intranasal or intratracheal instil lation (Granum et al. In a genetically suscep tible murine model of lupus, silica exposure exacerbated develop ment of autoimmune disease. Autoantibodies from these mice recognized specific epi topes on apoptotic macrophages (Pfau et al. In a rat model for multiple sclerosis, administration of silica up to one month prior to or concurrent with spinal cord homogenates increased the incidence and severity and advanced the onset of disease (Levine & Sowinski, 1980). Increased cytokine production may also play a role in silica induced autoimmune vascular disease. In vitro studies also provide important evidence that silica’s properties as an adjuvant may be relevant in silica induced auto immunity. Incubation of silica and silicate with isolated human T cells caused polyclonal lymphocyte activation, which in vivo could lead to a breakdown of tolerance via nonspecific stimulation of autoreactive T cell clones (Ueki et al. Silica also reacts with water to form hydroxyl radicals that further react with cell membranes, resulting in lipid peroxidation and production of additional reactive oxygen species that can activate transcription factors and lead to increased cytokine production (Vallyathan et al. The skewing towards a Th1 response and release of reactive oxygen species promote the continued secretion of proinflammatory cytokines, resulting in chronic macrophage activation. In fact, one hallmark of silica induced lung injury is its self perpetuating nature. In alveolar macro phages, the intracellular release of proteolytic enzymes in response to phagocytosis of silica particles leads to cell death. Silica is released from the dying cells and is reingested by other macro phages, creating a cyclical process of inflammation and necrotic cell death. Silica has also been shown to induce apoptosis in human alveolar macrophages and peripheral blood lymphocytes in culture (Iyer et al. Soluble Fas is produced as an alternatively spliced product of the Fas gene and protects cells from apoptosis by blocking the binding the interaction between mem branous Fas and Fas ligand. In silicosis patients, soluble Fas mes sage was dominantly expressed compared with membranous Fas expression, although the relative expression levels of the Fas and Fas ligand genes were not significantly altered (Otsuki et al. The mechanisms of renal pathology appear to differ among the various autoimmune diseases that may be associated with silica exposure. Silica particles can accumulate in the kidney, leading to localized inflammatory responses and fibrotic lesions similar to those observed in pulmonary silicosis (Slavin et al. Alternatively, circulating autoantibodies may deposit in the kidney, resulting in immune complex glomerulonephritis. There is little information on the duration of exposure and dose required for silica related autoimmune effects, and it is not currently known whether peak or cumulative dose is more predictive of disease development. Silica exposure may often occur in the presence of other exposures that may interact mechanistically to modify the risk of developing autoimmune disease. For example, even trace contam ination of quartz dust with iron particles may augment inflammatory effects in the lung (Castranova et al. Smoking is another common exposure in many silica exposed workers and has been shown to modify the association of high and moderate level silica exposure for risk of systemic lupus erythematosus (Parks et al. Silica dust exposure may be associated with a wide range of autoimmune diseases and immune abnormalities. Although some studies have explicitly focused on only one disease, several indicate an increased occurrence of several different diseases within the same study population. In addition to exploring the possibility of shared mechanisms, risk analyses should consider the impact of silica dust exposure across multiple diseases. There is also a need to consider the potential for effect modification by genetic or sex differences in disease susceptibility, as well as the modifying effects of other environmental exposures. Polymorphisms in tumour necrosis factor and other cytokine genes may be related to severity of silicosis in humans (Corbett et al. As allelic variation in these genes has also been linked to other autoimmune diseases, it is plausible that differences in silica related autoimmunity might be modified by these factors as well. Given that women have higher rates of many autoimmune diseases compared with men, it will be important to learn if they are more or less vulnerable to the effects of silica. It would seem likely that these heavy metals have the same effects on humans, presumably by a similar mechanism. Autoimmune manifestations induced by heavy metals include lupus type nephritis, autoimmune haemolytic anae mia, and skin diseases, such as pemphigus and scleroderma like lesion. Some manifestations of immune mediated nephritis and elevation of circulating autoantibodies have been noted in case studies of persons exposed to gold and cadmium as well as mercury (Ohsawa, 1993; Bigazzi, 1994, 1999). The lack of a clear correlation between mechanistic research on mercury toxicity and sublethal non cytotoxic effects and lack of consideration of mercury induced immunotoxicity as an important health outcome have limited the application of science based risk assessment on this issue (Silbergeld & Devine, 2000). Occupational exposure to mercury, in spite of immunological changes described even in workers with relatively low urinary mercury concentrations (Queiroz et al. The suggestion that mercury may cause autoimmune response and disease in humans is based mainly on several cases of nephrotic syndrome associated with mercury containing drugs that were in use until the mid 20th century, in which renal histopathological lesions and the presence of autoantibodies bound to the renal membrane in kidney biopsies were reported. The use of mercury for the production of dental silver amalgam restorations and the subsequent release of mercury have been a matter of concern over the last 30 years (Clarkson et al. In a recent epidemio logical study of 20 000 people (84% males) with detailed exposure data, a consistent level of amalgam treatment across the cohort, and investigation of a wide range of possible health outcomes, an association was evidenced only with multiple sclerosis, and this association was relatively weak (adjusted hazard ratio of 1. Additional epidemiological studies are needed to fully address the question of autoimmune related health effects of dental amalgams (Weiner et al. The organic alkylmercury compound thimerosal (sodium ethyl mercury thiosalicylate) is another modern facet of mercury.
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