In summary, we have presented the physical medicine and rehabilitation medicine approaches for treating patients with fibromyalgia and the myofascial pain syndromes. The importance of approaching these patients from a holistic and multidisciplinary standpoint has been stressed, paying attention to the physical, emotional, spiritual and behavioural components of the presentation. Although fibromyalgia and the myofascial pain syndromes are two distinct conditions, they often overlap, and when they do the myofascial component should be treated first. However, the clinician should remember that pain, tissue dysfunction and disability from pain are all separate issues and should be treated as such. Treatment in all cases should be individualized and comprehensive. It is imperative to make the patient an active participant in his care and to establish mutually agreed upon goals at the outset of treatment. It is important to establish an adequate and appropriate home exercise programme to supplement formal treatment. A good home exercise programme should stress both stretching and strengthening. Formal treatment programmes should not be geared to pain relief alone but rather to restoration of function, and return to functioning lifestyles. The clinician has available a wide array of modalities and tools to control pain, but the major goal of all treatment programmes is to restore individuals to functional lifestyles and to promote both physical and emotional flexibility, balance and 'wellness'. It is often necessary to involve the family unit as an inherent and critical part of the treatment team, particularly with the patient who continues to be dysfunctional despite apparently appropriate treatment. Although treatment always starts at the tissue level, a good treatment programme must always be holistic in nature and treat the tissues, the patient as a whole, and his or her environmental stressors and contingencies as well.

MFP is a regional muscle pain disorder characterized by localized muscle tenderness and pain and is the most common cause of persistent regional pain. The affected muscles may also display an increased fatiguability, stiffness, subjective weakness, pain on movement and slightly restricted range of motion that is unrelated to joint restriction. MFP is frequently overlooked as a diagnosis because it is often accompanied by signs and symptoms in addition to pain, coincidental pathological conditions, and behavioural and psychosocial problems. Chronic pain characteristics often precede or follow the development of MFP. Evaluation of MFP includes locating the trigger points and muscles involved as well as recognition of the contributing factors. Management of the syndrome naturally follows with muscle exercises, therapy to the trigger points, and reduction of all the contributing factors. The short-term goal is to restore the muscle to normal length and posture and full joint range of motion with exercises and trigger point therapy. The long-term goals include reducing the symptoms and their negative effects while helping the patient return to normal function without the need for future health care. The difficulty in managing MFP lies in the critical need to match the level of complexity of the management programme with the complexity of the patient's situation. Failure to address the entire problem, through a team approach if needed, may lead to failure to resolve the pain and perpetuation of a chronic pain syndrome.

A review of the evidence from diurnal physiological, seasonal environmental and prospective studies of social-behavioural functions suggest that a chronobiological theoretical model provides a comprehensive basis for the dynamics of central nervous system mechanisms, the assessment and the management of patients with fibromyalgia. The chronobiological model stresses the importance of temporal variation and the factors that influence and govern recurrent patterns of biological functions and behaviour that determine health and illness. Finally, the theory allows for an integrated study of brain, behaviour and somatic functions over time and emphasizes that such a comprehensive approach is core to any therapeutic intervention.

Since the first comprehensive description of the symptoms of FMS by Yunus et al (1981), numerous investigations have confirmed that FMS is a clinical entity. However, the aetiology of the syndrome is still not fully elucidated. It seems, however, logical to place the origin of the disorder in the muscle. Muscle pain, especially at the muscle-tendon junctions, fatigue and stiffness are the first symptoms. A malfunction of energy metabolism has been detected in part of the muscle fibres. However, it has to be considered that the muscle is not an isolated entity. Its activity is controlled by segmentally arranged motor units of the ventral horn of the spinal cord in response to proprioceptive afferent signals arising in the muscle spindles or in other sensory elements including nociceptors. Together with supraspinal descending inputs, the spinal motor neurone pool is the common final pathway for segmental and suprasegmental inputs, making the motor system extremely powerful for adaptive adjustments but also vulnerable if deficits occur in either of these input levels. A second, recently discovered abnormality seen in FMS is a lowered serotonin level in peripheral and most likely also central structures. The underlying mechanism seems to be defective absorption of the precursor amino acid tryptophan from the gut. Serotonin is involved centrally in the regulation of the sleep pattern, and at the spinal level it acts as a 'gain setter' of motoneurone excitability and suppresses signal transmission of noxious stimuli in dorsal horn neurones. Either of these two disturbances, muscle energy depletion or serotonin deficiency, could by itself evoke many of the symptoms of FMS, and their combined appearance will perpetuate the disease. Depressed levels of somatomedin C, caused by a deficit of stage 4 sleep-dependent release of GH, might represent an additional factor in preventing proper development or repair of myoskeletal structures. Malabsorption of certain amino acids, possibly due to a genetic disorder of gut transport mechanisms, may constitute an additional deleterious factor. The abnormalities found in the HPA and HPT axis may be seen as an attempt of the organism to restore homeostasis. The stimulus eliciting this counter-regulatory reaction may be pain or other afferent signals which normally do not reach the central nervous system. It is doubtful whether the unspecific activation of the HPA axis in a non-inflammatory disease is beneficial.(ABSTRACT TRUNCATED AT 400 WORDS)

The clinical phenomenon of the MTrP is accessible to any clinician who takes the time to learn to palpate skeletal muscle gently and carefully, and who is willing to learn the functional anatomy necessary to understand the regional spread of MTrPs through functional muscle units (Travell and Simons, 1992). Yet despite the years of clinical study of MPS, the pathophysiology of the central feature, the trigger point, has remained elusive. Many investigators have contributed to the general understanding of the mechanisms of pain perception, but we owe a particular debt of gratitude to Dr Seigfried Mense of Heidelberg for his pursuit of the study of pain originating in muscle lesions. However, Dr Mense would be the first to caution us against the direct transference of the results obtained with an inflammatory lesion produced in the experimental animal to the pain of MTrPs in the clinic patient. Notwithstanding that, researchers in the field of pain have given us an understanding of the basis for the hyperalgesia, allodynia and the previously difficult-to-understand finding of referred pain zones that we see daily in our patients. Finally, the interesting initial observations of Hubbard and Berkoff (1993), suggesting that the muscle spindle may be associated with the trigger point, open yet another door in our understanding of the nature of MPS.

It may be concluded that both peripheral and central mechanisms may operate in the pathophysiology of both impaired muscle function and pain in FM. These mechanisms may in part be attributable to physical deconditioning and disuse of muscle secondary to the characteristic pain and fatigue so often seen in FM. Most likely the initiation of this condition is multifactorial and the combination of peripheral and central factors that constitute a vicious circle may perpetuate the condition into a chronic state.

The conclusion is that no one single mechanism can explain FMS and is thus in that sense a compromise. FMS in some patients may start in the muscle, in other patients in the brain. The combination of peripheral and central factors is the key to the pathogenesis of FMS as long as FMS is defined as a pain syndrome.

Approach to the management of AA amyloidosis complicating RA. (A) In case of proteinuria or loss of renal function a rectal biopsy or a subcutaneous fat biopsy is a suitable screening method for the detection of amyloidosis. If in any doubt, try to ascertain the diagnosis by renal biopsy. Adequate staining with alkaline Congo red and preferably immunohistochemical staining with anti-AA antibodies should be performed. Beware of renal pathology other than amyloidosis even in the presence of a positive rectal biopsy. (B) A vigorous attempt to control disease activity of the RA should be made in order to eliminate the production of SAA, an acute phase protein. The response to treatment should be monitored by serial measurements of CRP and preferably SAA. (C) The function of some vital organs should be evaluated: (a) endogenous creatinine clearance and the extent of proteinuria; (b) electrocardiogram and optional echocardiography; (c) thyroid function and adrenocortical function; (d) intestinal absorption tests; (e) optional--SAP scintigraphy and turnover studies. (D) Attention should be given to adequate supportive treatment: (a) blood pressure control; (b) treatment of intercurrent infections; (c) corticosteroids during major surgical procedures; (d) pay attention to the possible effect of NSAID on proteinuria and renal function. (E) In case of total renal failure or uncontrollable proteinuria: (a) consider the possibility of primary renal transplantation; (b) otherwise regular haemodialysis is indicated.

The diagnosis of systemic amyloidosis is only occasionally suspected on clinical grounds alone and is more often considered when an associated condition, such as a chronic inflammatory disease or monoclonal gammopathy, is present. No blood test is diagnostic of amyloid although routine haematological and biochemical investigations have important roles in defining the underlying disease process in amyloidosis, and evaluating organ function. A number of non-invasive investigations including echocardiography, electrocardiography and soft tissue scintigraphy with bone-seeking tracers give characteristic results in some patients with amyloidosis, but are non-specific. The diagnosis can only be confirmed by demonstrating the presence of amyloid deposits in the tissues. Histology is the traditional method in routine clinical practice and is sensitive for revealing microscopic deposits and permits immunotyping of fibril proteins. Disadvantages are that biopsies are invasive, open to sampling error and can only give limited information on the distribution and extent of amyloid deposits in an individual. Scintigraphic and turnover studies with radioiodinated SAP are new specific methods for confirming the presence of amyloid in tissues, based on the affinity of SAP for all types of amyloid fibril. Labelled SAP scans survey the whole body macroscopically for the presence and anatomical distribution of amyloid in a quantitative manner, and SAP turnover studies provide information on the whole body amyloid load. Although the availability of SAP scintigraphy presently remains restricted, the technique has been used in over 400 patients with amyloid in prospective studies, and has already provided a number of new insights into the natural history of amyloidosis. These include the observation that there is a consistently poor correlation between the quantity of amyloid in an organ and the resulting degree of functional impairment. Amyloid deposits accumulate at rates which vary substantially between different organs in a single subject and between individuals with similar types of amyloidosis, even when the rates of amyloid fibril precursor protein supply are apparently similar. In some patients amyloid accumulation may plateau without any measurable alteration in the precursor supply. In patients with amyloidosis in whom the supply of fibril precursors is reduced, either as a result of therapy directed towards the underlying process or through a natural remission, substantial regression of amyloid frequently occurs. This has been observed in patients with AA, AL and variant TTR-associated amyloidosis, and is usually associated with clinical benefits. In some such cases, however, the function of affected organs may continue to deteriorate despite halting the accumulation of amyloid, presumably because irreversible structural damage has already occurred.(ABSTRACT TRUNCATED AT 400 WORDS)

The limited available epidemiological information on AL amyloidosis suggests that there may be differences between population-based studies and case series data with respect to variables such as age and racial patterns. Much more work in this area is required before specific aetiologic hypotheses can be tested. Most available data to approximate the epidemiology of AA amyloidosis are derived from autopsies. Most patients with AA amyloidosis die from causes other than amyloidosis, therefore mortality data based on death certificates is of limited value in AA amyloidosis. Case ascertainment in autopsy studies may be difficult due to the frequent lack of adequate histological controls. Establishment of registries for both AL and AA amyloidosis would facilitate epidemiological research in these disorders.

For over 70 years animal experiments have been performed to elucidate the pathogenesis of reactive amyloidosis and to investigate the formation of the beta-pleated sheet-rich amyloid fibrils in general. In appropriate species, primarily rodents like mouse and hamster, amyloid is formed after stimulation with amyloid-inducing injections after a lag phase (secondary or reactive amyloid, AA amyloid). For the formation of this AA amyloid, elevated values in blood of its precursor protein, SAA, is the first prerequisite. SAA is an acute phase protein of hepatic origin, released after stimulation by cytokines, and is associated in serum with high-density lipoprotein (apoSAA). In mouse, hamster and mink amyloidogenic subtypes of SAA are found. In the rat SAA is absent, although its mRNA is transcribed. Evidence is increasing that SAA crystallizes to fibrils first, whilst loss of its C-terminal end can be a post-fibrillogenic phenomenon. Glycoproteins, proteoglycans, glycosaminoglycans and lipids are reintroduced in experimental amyloid research. Basement membrane heparan sulphate proteoglycans (perlecans) are attributed to have a primary role. The pentraxin serum amyloid P-component is a calcium-dependent secondary phenomenon. Membrane-bound, lipid-rich vesicles are found amongst the newly deposited pericellular amyloid fibrils. These vesicles probably have to be interpreted as indicators of primary membrane alteration during amyloid fibril crystallization. The vesicles will be formed after rupture of the membranes caused by the stiff intramembranously crystallized protein fibrils. Morphological evidence supporting this hypothesis has been found in immunoelectron microscopical studies. Accumulation of intramembranous SAA preceded amyloid fibril deposition. Fibril formation then might be related to conformational change of the intramembranous SAA. The lag phase for amyloid deposition is shortened after a single injection of a fraction of amyloid, the AEF. It is a low-molecular-weight glycoprotein that easily associates with other molecules. When isolated from amyloid fibrils, the (F)AEF contains a large proportion of beta-pleated sheet molecular structure. It is probable that this structure holds an explanation for its enhancing potency: forming a nidus for physical crystallization. The major substances and animal species used in animal experiments on amyloidosis, are mentioned. Overlooked by-effects of amyloidogenic stimuli are discussed. Polyarthritis after systemic endotoxin injections found in the hamster acts as a source of cytokines, further triggering the reactive amyloidosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Serum amyloid A is an acute phase protein complexed to HDL as an apoprotein. The molecular weight is 11.4-12.5 kDa in different species and the protein has from 104 to 112 amino acids, without or with an insertion of eight amino acids at position 72. The protein is very well conserved throughout evolution, indicating an important biological function. The N-terminal part of the molecule is hydrophobic and probably responsible for the lipid binding properties. The most conserved part is from position 38 to 52 and this part is therefore believed to be responsible for the until now unknown biological function. The protein is coded on chromosome 11p in man, and chromosome 7 in mice, and found in all mammals until now investigated, and also in the Peking duck. In the rat a truncated SAA mRNA has been demonstrated, but no equivalent serum protein has been reported. Acute phase SAA is first of all produced in hepatocytes after induction by cytokines, but extrahepatic expression of both acute phase and constitutive SAA proteins have been demonstrated. Several cytokines, first of all IL-1, IL-6 and TNF are involved in the induction of SAA synthesis, but the mutual importance of these cytokines seems to be cell-type specific and to vary in various experimental settings. The role of corticosteroids in SAA induction is somewhat confusing. In most in vitro studies corticosteroids show an enhancing or synergistic effect with cytokines on SAA production in cultured cell. However, in clinical studies and in vivo studies in animals an inhibitory effect of corticosteroids is evident, probably due to the all over anti-inflammatory effect of the drug. Until now no drug has been found that selectively inhibits SAA production by hepatocytes. Effective anti-inflammatory or antibacterial treatment is the only tool for reducing SAA concentration in serum and reducing the risk of developing secondary amyloidosis. The function of SAA is still unclear. Interesting theories, based on current knowledge of the lipid binding properties of the protein and the relation to macrophages, in the transportation of cholesterol from damaged tissues has been advanced. A putative role in cholesterol metabolism is supported by the findings of SAA as an inhibitor of LCAT. The potential that SAA is a modifying protein in inflammation influencing the function of neutrophils and platelets is interesting and more directly related to the inflammatory process itself.(ABSTRACT TRUNCATED AT 400 WORDS)

The acute phase reaction is in most circumstances a good indicator of (local) inflammatory activity and tissue damage. CRP is a direct and quantitative measure for the acute phase reaction and due to its fast kinetics provides adequate information of the actual situation. The ESR on the contrary is in fact an indirect measure of the acute phase reaction. It does react much slower to changes of inflammatory activity and is influenced by a number of other factors. From studies on the 'behaviour' of CRP it has become clear that diseases may differ with regard to the extent in which they induce an acute phase response. Incidental measurement of the CRP level may add to the diagnostic procedure in selected cases, e.g. in the differentiation between a bacterial and a viral infection or between a bacterial infection and an exacerbation of diseases like SLE. In case of an extremely elevated CRP level (> 100 mg/litre) the possibility of a bacterial infection should always be considered. In clinical practice CRP is particularly useful when serial measurements are performed. The course of the CRP level may be useful for the monitoring of the effect of treatment and for the early detection of postoperative complications or intercurrent infections. The relationship between CRP and the local production and effects of cytokines on the one hand, and the possible functional role of CRP in the inflammatory process on the other hand have surely added a dimension to the clinical use of CRP as a parameter of inflammatory activity.