Foot and ankle infections are the most common cause of hospitalization among diabetic patients, and Staphylococcus aureus is a major pathogen implicated in these infections. Patients with insulin-resistant (type 2) diabetes are more susceptible to bacterial infections than nondiabetic subjects, but the pathogenesis of these infections is poorly understood. C57BL/6J-Lepr db /Lepr db (hereafter, db/db) mice develop type 2 diabetes due to a recessive, autosomal mutation in the leptin receptor. We established a S. aureus hind paw infection in diabetic db/db and nondiabetic Lepr +/+ (+/+) mice to investigate host factors that predispose diabetic mice to infection. Nondiabetic +/+ mice resolved the S. aureus hind paw infection within 10 days, whereas db/db mice with persistent hyperglycemia developed a chronic infection associated with a high bacterial burden. Diabetic db/db mice showed a more robust neutrophil infiltration to the infection site and higher levels of chemokines in the infected tissue than +/+ mice. Blood from +/+ mice killed S. aureus in vitro, whereas db/db blood was defective in bacterial killing. Compared with peripheral blood neutrophils from +/+ mice, db/db neutrophils demonstrated a diminished respiratory burst when stimulated with S. aureus. However, bone marrow-derived neutrophils from +/+ and db/db mice showed comparable phagocytosis and bactericidal activity. Our results indicate that diabetic db/db mice are more susceptible to staphylococcal infection than their nondiabetic littermates and that persistent hyperglycemia modulates innate immunity in the diabetic host.
Although Staphylococcus aureus is a major pathogen implicated in diabetic foot infections, little is known about the pathogenesis of this disease. A model of S. aureus infection in the hindpaw of nonobese diabetic (NOD) mice was developed. The experimental infection was exacerbated in diabetic mice (blood glucose levels >19 mmol/l) compared with nondiabetic mice, and the diabetic animals were unable to clear the infection over a 10-day period. Insulin-mediated control of glycemia in diabetic mice resulted in enhanced clearance of S. aureus from the infected tissue. Diabetic mice showed reduced tissue inflammation in response to bacterial inoculation compared with nondiabetic NOD animals, and this was consistent with the novel finding of significantly decreased tissue levels of the chemokines KC and MIP-2 in diabetic mice. Blood from nondiabetic and diabetic NOD mice killed S. aureus in vitro, whereas the bacteria multiplied in blood from diabetic mice with severe hyperglycemia. The impaired killing of S. aureus by diabetic mice was correlated with a diminished leukocytic respiratory burst in response to S. aureus in blood from diabetic animals. This animal model of hindpaw infection may be useful for the analysis of host defects in innate immunity that contribute to recalcitrant diabetic foot infections. Diabetes 54:2904 -2910, 2005 D iabetes afflicts ϳ16 million individuals in the U.S., and it is estimated that 2 million of these individuals will eventually develop chronic foot ulcers and infections (1). The most common cause of hospitalization for diabetic patients is foot infections (1), and the susceptibility of the diabetic host to these infections is multifactorial. Diabetes results in numerous physiologic perturbations in the host such as neuropathy and vasculopathy, and these can play a prominent role in the development of the diabetic foot (2).Staphylococcus aureus is the predominant pathogen in nonlimb-threatening foot infections, particularly in diabetic patients who have not yet received antimicrobial therapy (3-5). Although limb-threatening infections in the diabetic individual are frequently polymicrobial, S. aureus is a major pathogen in these infections (6). Type 1 diabetic patients show more frequent colonization of the nose and skin by S. aureus than nondiabetic and non-insulindependent diabetic individuals (7-9). The emergence of S. aureus strains resistant to multiple antibiotics has made the treatment of staphylococcal infections especially problematic. Methicillin-resistant S. aureus strains have become increasingly prevalent among both nosocomial and community-acquired infections (10,11). Recently, S. aureus isolates resistant to vancomycin, one of the antibiotics of last resort, were recovered from patients with chronic foot ulcers (12,13). Although the increased susceptibility of diabetic patients to bacterial infections is well established, the chronicity associated with these infections remains poorly understood.Many investigations have focused on the nonobese diabetic (NOD) mouse as a...
Diabetes is a frequent underlying medical condition among individuals with Staphylococcus aureus infections, and diabetic patients often suffer from chronic inflammation and prolonged infections. Neutrophils are the most abundant inflammatory cells during the early stages of bacterial diseases, and previous studies have reported deficiencies in neutrophil function in diabetic hosts. We challenged age-matched hyperglycemic and normoglycemic NOD mice intraperitoneally with S. aureus and evaluated the fate of neutrophils recruited to the peritoneal cavity. Neutrophils were more abundant in the peritoneal fluids of infected diabetic mice by 48 h after bacterial inoculation, and they showed prolonged viability ex vivo compared to neutrophils from infected nondiabetic mice. These differences correlated with reduced apoptosis of neutrophils from diabetic mice and were dependent upon the presence of S. aureus and a functional neutrophil respiratory burst. Decreased apoptosis correlated with impaired clearance of neutrophils by macrophages both in vitro and in vivo and prolonged production of proinflammatory tumor necrosis factor alpha by neutrophils from diabetic mice. Our results suggest that defects in neutrophil apoptosis may contribute to the chronic inflammation and the inability to clear staphylococcal infections observed in diabetic patients.
A case of spontaneous dissection of the internal carotid artery is presented and the ten other reported cases are reviewed. It is most common in males aged 35 to 41 years. Of eight patients with neurological symptoms, two had transient hemiplegia and five of six first seen with a severe neurological deficit had prodromal symptoms. Angiography revealed a typical "string sign." A method of surgical treatment is illustrated. The importance of emergency angiography and surgery in patients with acute onset of progressive symptoms of cerebral vascular disease is emphasized by this case. The surgical specimen was studied pathologically by serial section. At its origin the dissection measured 3 mm in width and 0.3 mm in length. Proximally the dissection was in the media but distally it lay at the medial-adventitial interface. There was no evidence of cystic medial necrosis but the muscle and elastic tissue of the media had a disorganized arrangement.
An evaluation of the effect of surgical intervention on foot and ankle radiographic comparisons was performed. In this study, 34 sets of pre-surgical (“premortem”) and post-surgical (“postmortem”) foot and ankle radiographs were retrospectively evaluated simulating a postmortem identification. In each radiographic set, the films were separated by a surgical event to reproduce the effects of an alteration in the anatomy. The radiographs included both matches and mismatches. This study also presents a numerical representation of the reliability of a radiographic match following a surgical procedure. Results indicate that surgical intervention with subsequent healing does not preclude positive identification in foot and ankle radiographic comparisons.
A case of positive identification from decomposed human remains using an unusual foot deformity is presented. Scrutiny of the decedent revealed foot deformities, which upon examination, prompted further inquiry. Radiographic comparisons and defleshing each foot established bilateral talipes equinovarus (TEV, clubfoot). Positive identification was based upon unique skeletal features present in the radiographs.
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