Mortality Associated With Acute Charcot Foot and Neuropathic Foot Ulceration

To compare the mortality of patients with an acute Charcot foot with a matched population with uninfected neuropathic foot ulcers (NFUs). Data were extracted from a specialist departmental database, supplemented by hospital records. The findings were compared with the results of earlier populations with Charcot foot and uninfected NFUs managed from 1980. Finally, the results of all patients with acute Charcot foot and all control subjects managed between 1980 and 2007 were compared with normative mortality data for the U.K. population. A total of 70 patients presented with an acute Charcot foot (mean age 57.4 +/- 12.0 years; 48 male [68.6%]) between 2001 and 2007; there were 66 matched control subjects. By 1 October 2008, 13 (eight male; 18.6%) patients with a Charcot foot had died, after a median of 2.1 years (interquartile range 1.1-3.3). Twenty-two (20 male; 33.3%) control subjects had also died after a median of 1.3 years (0.6-2.5). There was no difference in survival between the two groups (log-rank P > 0.05). Median survival of all 117 patients with acute Charcot foot managed between 1980 and 2007 was 7.88 years (4.0-15.4) and was not significantly different from the control NFU patients (8.43 years [3.4-15.8]). When compared with normative U.K. population data, life expectancy in the two groups was reduced by 14.4 and 13.9 years, respectively. These data confirm that the mortality in patients presenting to our unit with either an acute Charcot foot and an uninfected neuropathic ulcer was unexpectedly hig

Risks of Nontraumatic Lower-Extremity Amputations in Patients with Type 1 Diabetes: A population-based cohort study in Sweden

OBJECTIVE—The purpose of this study was to estimate the risks of nontraumatic lower-extremity amputations (LEAs) in patients with type 1 diabetes

Increased osteoclastic activity in acute Charcot’s osteoarthopathy: the role of receptor activator of nuclear factor-kappaB ligand

Aims/hypothesis: Our aims were to compare osteoclastic activity between patients with acute Charcot's osteoarthropathy and diabetic and healthy controls, and to determine the effect of the receptor activator of nuclear factor-kappaB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG). Methods: Peripheral blood monocytes isolated from nine diabetic Charcot patients, eight diabetic control and eight healthy control participants were cultured in the presence of macrophage-colony stimulating factor (M-CSF) alone, M-CSF and RANKL, and also M-CSF and RANKL with excess concentrations of OPG. Osteoclast formation was assessed by expression of tartrate-resistant acid phosphatase on glass coverslips and resorption on dentine slices. Results: In cultures with M-CSF, there was a significant increase in osteoclast formation in Charcot patients compared with healthy and diabetic control participants (p=0.008). A significant increase in bone resorption was also seen in the former, compared with healthy and diabetic control participants (p<0.0001). The addition of RANKL to the cultures with M-CSF led to marked increase in osteoclastic resorption in Charcot (from 0.264±0.06% to 41.6±8.1%, p<0.0001) and diabetic control (0.000±0.00% to 14.2±16.5%, p<0.0001) patients, and also in healthy control participants (0.004±0.01% to 10.5±1.9%, p0.0001). Although the addition of OPG to cultures with M-CSF and RANKL led to a marked reduction of resorption in Charcot patients (41.6±8.1% to 5.9±2.4%, p=0.001), this suppression was not as complete as in diabetic control patients (14.2±16.5% to 0.45±0.31%, p=0.001) and in healthy control participants (from 10.5±1/9% to 0.00±0.00%, p<0.0001). Conclusions/interpretation: These results indicate that RANKL-mediated osteoclastic resorption occurs in acute Charcot's osteoarthropathy. However, the incomplete inhibition of RANKL after addition of OPG also suggests the existence of a RANKL-independent pathway

The pathogenesis of Charcot neuroarthropathy: current concepts

The pathogenesis of Charcot neuroarthropathy (CN) has been poorly understood by clinicians and scientists alike. Current researchers have made progress toward understanding the cause of CN and possible treatment options. The authors review the current literature on the pathogenesis of this debilitating disorder and attempt to explain the roles of inflammation, bone metabolism, and advanced glycation end products

Thyrotropin-releasing hormone (TRH) promotes wound re-epithelialisation in frog and human skin

There remains a critical need for new therapeutics that promote wound healing in patients suffering from chronic skin wounds. This is, in part, due to a shortage of simple, physiologically and clinically relevant test systems for investigating candidate agents. The skin of amphibians possesses a remarkable regenerative capacity, which remains insufficiently explored for clinical purposes. Combining comparative biology with a translational medicine approach, we report the development and application of a simple ex vivo frog (Xenopus tropicalis) skin organ culture system that permits exploration of the effects of amphibian skin-derived agents on re-epithelialisation in both frog and human skin. Using this amphibian model, we identify thyrotropin-releasing hormone (TRH) as a novel stimulant of epidermal regeneration. Moving to a complementary human ex vivo wounded skin assay, we demonstrate that the effects of TRH are conserved across the amphibian-mammalian divide: TRH stimulates wound closure and formation of neo-epidermis in organ-cultured human skin, accompanied by increased keratinocyte proliferation and wound healing-associated differentiation (cytokeratin 6 expression). Thus, TRH represents a novel, clinically relevant neuroendocrine wound repair promoter that deserves further exploration. These complementary frog and human skin ex vivo assays encourage a comparative biology approach in future wound healing research so as to facilitate the rapid identification and preclinical testing of novel, evolutionarily conserved, and clinically relevant wound healing promoters

The charcot foot in diabetes.

The diabetic Charcot foot syndrome is a serious and potentially limb-threatening lower-extremity complication of diabetes. First described in 1883, this enigmatic condition continues to challenge even the most experienced practitioners. Now considered an inflammatory syndrome, the diabetic Charcot foot is characterized by varying degrees of bone and joint disorganization secondary to underlying neuropathy, trauma, and perturbations of bone metabolism. An international task force of experts was convened by the American Diabetes Association and the American Podiatric Medical Association in January 2011 to summarize available evidence on the pathophysiology, natural history, presentations, and treatment recommendations for this entity

Examining diabetic heel ulcers through an ecological lens: microbial community dynamics associated with healing and infection

Purpose: While some micro-organisms, such as Staphylococcus aureus, are clearly implicated in causing tissue damage in diabetic foot ulcers (DFUs), our knowledge of the contribution of the entire microbiome to clinical outcomes is limited. We profiled the microbiome of a longitudinal sample series of 28 people with diabetes and DFUs of the heel in an attempt to better characterize the relationship between healing, infection and the microbiome.Methodology: In total, 237 samples were analysed from 28 DFUs, collected at fortnightly intervals for 6 months or until healing. Microbiome profiles were generated by 16S rRNA gene sequence analysis, supplemented by targeted nanopore sequencing.Result/Key findings: DFUs which failed to heal during the study period (20/28, 71.4 %) were more likely to be persistently colonized with a heterogeneous community of micro-organisms including anaerobes and Enterobacteriaceae (log-likelihood ratio 9.56, P=0.008). During clinically apparent infection, a reduction in the diversity of micro-organisms in a DFU was often observed due to expansion of one or two taxa, with recovery in diversity at resolution. Modelling of the predicted species interactions in a single DFU with high diversity indicated that networks of metabolic interactions may exist that contribute to the formation of stable communities.Conclusion: Longitudinal profiling is an essential tool for improving our understanding of the microbiology of chronic wounds, as community dynamics associated with clinical events can only be identified by examining changes over multiple time points. The development of complex communities, particularly involving Enterobacteriaceae and strict anaerobes, may be contributing to poor outcomes in DFUs and requires further investigation

Routine MRI findings of the asymptomatic foot in diabetic patients with unilateral Charcot foot

<p>Abstract</p> <p>Background</p> <p>Imaging studies of bones in patients with sensory deficits are scarce.</p> <p>Aim</p> <p>To investigate bone MR images of the lower limb in diabetic patients with severe sensory polyneuropathy, and in control subjects without sensory deficits.</p> <p>Methods</p> <p>Routine T1 weighted and T2-fat-suppressed-STIR-sequences without contrast media were performed of the asymptomatic foot in 10 diabetic patients with polyneuropathy and unilateral inactive Charcot foot, and in 10 matched and 10 younger, non-obese unmatched control subjects. Simultaneously, a Gadolinium containing phantom was also assessed for reference. T1 weighted signal intensity (SI) was recorded at representative regions of interest at the peritendineal soft tissue, the tibia, the calcaneus, and at the phantom. Any abnormal skeletal morphology was also recorded.</p> <p>Results</p> <p>Mean SI at the soft tissue, the calcaneus, and the tibia, respectively, was 105%, 105% and 84% of that at the phantom in the matched and unmatched control subjects, compared to 102% (soft tissue), 112% (calcaneus) and 64% (tibia) in the patients; differences of tibia vs. calcaneus or soft tissue were highly significant (p < 0.005). SI at the tibia was lower in the patients than in control subjects (p < 0.05). Occult traumatic skeletal lesions were found in 8 of the 10 asymptomatic diabetic feet (none in the control feet).</p> <p>Conclusion</p> <p>MR imaging did not reveal grossly abnormal bone marrow signalling in the limbs with severe sensory polyneuropathy, but occult sequelae of previous traumatic injuries.</p

Enhanced susceptibility to infections in a diabetic wound healing model

<p>Abstract</p> <p>Background</p> <p>Wound infection is a common complication in diabetic patients. The progressive spread of infections and development of drug-resistant strains underline the need for further insights into bacterial behavior in the host in order to develop new therapeutic strategies. The aim of our study was to develop a large animal model suitable for monitoring the development and effect of bacterial infections in diabetic wounds.</p> <p>Methods</p> <p>Fourteen excisional wounds were created on the dorsum of diabetic and non-diabetic Yorkshire pigs and sealed with polyurethane chambers. Wounds were either inoculated with 2 × 10⁸Colony-Forming Units (CFU) of <it>Staphylococcus aureus </it>or injected with 0.9% sterile saline. Blood glucose was monitored daily, and wound fluid was collected for bacterial quantification and measurement of glucose concentration. Tissue biopsies for microbiological and histological analysis were performed at days 4, 8, and 12. Wounds were assessed for reepithelialization and wound contraction.</p> <p>Results</p> <p>Diabetic wounds showed a sustained significant infection (>10⁵CFU/g tissue) compared to non-diabetic wounds (p < 0.05) over the whole time course of the experiment. <it>S. aureus</it>-inoculated diabetic wounds showed tissue infection with up to 8 × 10⁷CFU/g wound tissue. Non-diabetic wounds showed high bacterial counts at day 4 followed by a decrease and no apparent infection at day 12. Epidermal healing in <it>S. aureus</it>-inoculated diabetic wounds showed a significant delay compared with non-inoculated diabetic wounds (59% versus 84%; p < 0.05) and were highly significant compared with healing in non-diabetic wounds (97%; p < 0.001).</p> <p>Conclusion</p> <p>Diabetic wounds developed significantly more sustained infection than non-diabetic wounds. <it>S. aureus </it>inoculation leads to invasive infection and significant wound healing delay and promotes invasive co-infection with endogenous bacteria. This novel wound healing model provides the opportunity to closely assess infections during diabetic wound healing and to monitor the effect of therapeutical agents <it>in vivo</it>.</p