Stratification of foot ulcer risk in patients with diabetes: a population-based study.

This trial assessed whether a simple clinical tool can be used to stratify patients with diabetes, according to risk of developing foot ulceration. This was a prospective, observational follow-up study of 3526 patients with diabetes (91% type 2 diabetes) attending for routine diabetes care. Mean age was 64.7 (range 15-101) years and duration of diabetes was 8.8 (+/-1.5 SD) years. Patients were categorised into 'low' (64%), 'moderate' (23%) or 'high' (13%) risk of developing foot ulcers by trained staff using five clinical criteria during routine patient care. During follow-up (1.7 years), 166 (4.7%) patients developed an ulcer. Foot ulceration was 83 times more common in high risk and six times more in moderate risk, compared with low-risk patients. The negative predictive value of a 'low-risk score' was 99.6% (99.5-99.7%; 95% confidence interval). This clinical tool accurately predicted foot ulceration in routine practice and could be used direct scarce podiatry resources towards those at greatest need.

Contraindications to metformin therapy in patients with Type 2 diabetes--a population-based study of adherence to prescribing guidelines.

AIMS: To define the number of people in Tayside, Scotland (population 349 303) with Type 2 diabetes who use metformin, the incidence of contraindications to its continued use in these people and the proportion that discontinued metformin treatment following the development of a contraindication. METHODS: Retrospective cohort study of the incidence of contraindications to metformin in all patients with Type 2 diabetes using metformin from January 1993 to June 1995. The contraindications of acute myocardial infarction, cardiac failure, renal impairment and chronic liver disease were identified by: the regional diabetes information system, biochemistry database and hospital admissions database and a database of all encashed community prescriptions. RESULTS: One thousand eight hundred and forty seven subjects (26.3% of those with Type 2 diabetes) redeemed prescriptions for metformin. Of these, 3.5% were admitted with an acute myocardial infarction (71 episodes); 4.2% were admitted with cardiac failure (114 episodes); 21.0% received metformin and loop diuretics for cardiac failure concurrently; 4.8% developed renal impairment; and 2.8% developed chronic liver disease. The development of contraindications rarely resulted in discontinuation of metformin, for example only 17.5% and 25% stopped metformin after admission with acute myocardial infarction and development of renal impairment, respectively. In total, 24.5% of subjects receiving metformin, 6.4% of all people with Type 2 diabetes, had contraindications to its use. There was one episode of lactic acidosis in 4600 patient years. CONCLUSIONS: This population-based study shows that 24.5% of patients prescribed metformin have contraindications to its use. Development of contraindications rarely results in discontinuation of metformin therapy. Despite this, lactic acidosis remains rare. Diabet. Med. 18, 483-488 (2001)

Myasthenia, thymoma, presynaptic antibodies, and a continuum of neuromuscular hyperexcitability.

BACKGROUND: Autoantibodies specific for the nicotinic acetylcholine receptor (AChR) of skeletal muscle impair neuromuscular transmission in myasthenia gravis (MG). Autoantibodies specific for alpha3 neuronal AChRs or voltage-gated potassium channels have been reported in patients with Isaacs syndrome, an acquired disorder of continuous muscle fiber activity characterized by neuromyotonia. OBJECTIVE: To report the neuromuscular autoantibody profiles of three patients with a syndrome of MG and neuromuscular hyperexcitability. RESULTS: All three patients reported here had clinical and electrophysiologic evidence of MG and neuromuscular hyperexcitability. None had neuromyotonia. Thymoma was proven in two patients and suspected in the third. One had MG and thymoma and subsequently developed cramp-fasciculation syndrome; MG and rippling muscle syndrome appeared simultaneously in the other two. All patients had muscle and neuronal AChR binding antibodies and striational antibodies. Only one had antibodies reactive with alpha-dendrotoxin-complexed potassium channels. CONCLUSIONS: The coexistence of cramp-fasciculation syndrome and acquired rippling muscle syndrome with MG, thymoma, and neuronal AChR autoantibodies suggests that there is a continuum of autoimmune neuromuscular hyperexcitability disorders related pathogenically to Isaacs syndrome. Manifestations of neuromuscular hyperexcitability may be altered and less apparent in the context of MG because of the coexisting defect of neuromuscular transmission.

Myofibrillar myopathy with abnormal foci of desmin positivity. I. Light and electron microscopy analysis of 10 cases.

A number of myopathies whose common denominator is abnormal foci of desmin positivity have been described under the rubrics of spheroid body myopathy, cytoplasmic body myopathy, Mallory body myopathy, myopathy with granulofilamentous inclusions, desmin storage myopathy, and intermediate filament myopathy. In this study we reevaluate the light microscopic and ultrastructural features of the myopathy with abnormal foci of desmin positivity. In 10 cases of the disease, ultrastructural analysis reveals 2 major types of lesions: (a) foci of myofibrillar destruction and (b) hyaline structures that appear as spheroidal bodies on electron microscopy. The foci of myofibrillar destruction consist of fiber areas containing disrupted myofilaments, Z-disk-derived bodies, dappled dense structures of Z-disk origin, and streaming Z-disks that are sometimes adjacent to lakes of dense material. The spheroid bodies are composed of compacted and degraded myofibrillar elements. Membrane-bound vacuoles harboring degenerating membranous organelles are a less frequent and probably secondary abnormality. None of the lesions in muscle comprise 8 to 10 nm intermediate filaments. The findings imply that spheroid body myopathy, cytoplasmic body myopathy, Mallory body myopathy, and myopathy with granulofilamentous inclusions are consequences of a single or closely related pathologic processes. Because the common denominator appears to be focal dissolution of the myofibrils followed by accumulation of the products of the degradative process, we propose the term myofibrillar myopathy to cover the observed spectrum of pathologic changes.

1,1'-Ethylidenebis[tryptophan] induces pathologic alterations in muscle similar to those observed in the eosinophilia-myalgia syndrome.

1,1'-Ethylidenebis[tryptophan] (EBT), a derivative of L-tryptophan (LT), is a trace contaminant in batches of LT implicated by epidemiologic evidence in the pathogenesis of the eosinophilia-myalgia syndrome (EMS). We treated female Lewis rats with EBT or unimplicated LT (4 mg per 100 grams daily) by intraperitoneal injection. No rash or weakness occurred in either group. All three EBT rats had a few necrotic muscle fibers. In two rats, perimysium and fascia were abnormally thickened and infiltrated with lymphocytes, macrophages, and sparse eosinophils; two rats had sparse perineurial inflammatory cells. Rats treated with unimplicated LT showed no abnormality. These findings replicate an important feature of human EMS and support the epidemiologic evidence linking EBT to the pathogenesis of the human disease.

Necrotizing myopathy with pipestem capillaries, microvascular deposition of the complement membrane attack complex (MAC), and minimal cellular infiltration.

Three adult patients, two with undifferentiated connective tissue disease and one with carcinoma, had a distinctive pathologic reaction pattern consisting of necrotizing myopathy, minimal cellular infiltration, and a microangiopathy with thick "pipestem" vessels and microvascular deposits of complement membrane attack complex. Quantitative analysis revealed focal capillary depletion. This pattern represents an immune-mediated microangiopathy and is distinct from that observed in other inflammatory myopathies.

Eosinophilia myalgia syndrome: I. Immunocytochemical evidence for a T-cell-mediated immune effector response.

Specimens of muscle and fascia from 13 patients fulfilling the Centers for Disease Control criteria for the eosinophilia myalgia syndrome (EMS) were studied by quantitative immunocytochemical analysis. The immunolocalization of CD3, CD4, CD8, CD22, and CD56 markers, the gamma delta T-cell receptor, major histocompatibility complex (MHC) class I complex and class II antigens, and complement membrane attack complex (MAC) were examined. The distribution and relative proportions of T cells and T-cell subsets, B cells, macrophages, and eosinophils were determined at perivascular, perimysial, endomysial, and fascial sites of accumulation. At all sites, T cells were predominant, CD8+ cells outnumbered CD4+ cells 6- to 20-fold, and between 60 and 80% of T cells were activated. B cells and eosinophils each accounted for less than 3% of inflammatory cells. Very few cells expressed either the gamma delta T-cell receptor or natural killer cell markers. As in dermatomyositis (DM), MHC class I antigen complex expression was increased on many structurally normal muscle fibers, but in contrast to DM, microvascular MAC deposits were not a feature of EMS. The findings implicate a cellular immune response directed against a connective tissue component in EMS.

Microvascular changes in early and advanced dermatomyositis: a quantitative study.

In adult dermatomyositis 10 muscle specimens with no or minimal histological alterations were compared with 7 that showed typical alterations. Five specimens from patients with inclusion body myositis, 5 from patients with polymyositis, and 8 from normal subjects served as controls. Vascular endothelium, visualized with the lectin Ulex europaeus agglutinin I, and complement membrane attack complex were demonstrated in the same cryostat sections by paired immunofluorescence. Large randomly selected fields were analyzed to determine the number of capillaries per square millimeter of fiber area (capillary density), per 1,000-microns 2 area of each muscle fiber (capillary index), and in 100 x 100-microns grid squares. In dermatomyositis specimens with minimal structural alterations there was focal capillary depletion, the capillary density was significantly reduced, and the frequency distributions of the capillary index and grid count were shifted to the left. In advanced dermatomyositis specimens, the findings were similar but more severe. In both kinds of specimens, clusters of capillaries reacted for complement membrane attack complex. The 2 patients with the highest proportion of vessels positive for membrane attack complex had a fulminant and fatal course. In polymyositis and inclusion body myositis specimens, the capillaries had a normal overall density and none reacted for membrane attack complex. The findings imply that the capillaries are an early and specific target of the disease process in dermatomyositis.

Early ultrastructural alterations in adult dermatomyositis. Capillary abnormalities precede other structural changes in muscle.

In 6 adults with dermatomyositis, minimally weak or nonweak muscles that showed inconclusive light-microscopic alterations were examined by electron microscopy. In all 6 specimens, this revealed pathologic changes in endomysial capillaries. The endothelial cells harbored microtubular inclusions and microvacuoles in all cases; pale swollen endothelial cells were observed in 3 specimens. There were no significant ultrastructural changes in the muscle fibers. In all cases, a small proportion of muscle capillaries were immunoreactive for complement membrane attack complex neoantigens. The findings imply that in adult dermatomyositis capillary injury precedes muscle fiber damage and infiltration by inflammatory cells, and that the microvasculature is an early and specific target of the disease process in muscle.

Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.

Major histocompatibility complex class I (MHC-I) expression on target cells is a prerequisite for antigen-specific T cell-mediated cytotoxicity (TCMC). Enhanced MHC-I expression has been attributed to interferons (IFNs) released from inflammatory cells. In previous studies, we found evidence of TCMC (invasion of non-necrotic muscle fibers by cytotoxic T cells) in polymyositis (PM) and in inclusion body myositis (IBM). We occasionally found evidence of TCMC in Duchenne dystrophy (DD) but not in dermatomyositis (DM). This study examines the relationships between TCMC, MHC-I expression, and IFN immunoreactivity in these diseases and normal controls. In controls, reactivity for MHC-I was confined to blood vessels. In all diseases, regenerating fibers expressed MHC-I. In IBM, PM and DD, all nonnecrotic muscle fibers invaded by CD8+ cells and some adjacent fibers expressed MHC-I. In DM, myriad muscle fibers expressed MHC-I but none were invaded by CD8+ cells. In all diseases, only a few mononuclear cells and no muscle fiber surfaces were immunoreactive for IFNs. We conclude that MHC-I expression on muscle fibers is necessary but not sufficient for TCMC in myopathy; that the biological significance of increased MHC-I expression in DM remains undefined; and that currently available and appropriately controlled immunocytochemical methods show no relationship between increased MHC-I expression on muscle fibers and local IFN synthesis by mononuclear cells.