Mortality in patients with diabetic neuropathic osteoarthropathy (Charcot foot).

OBJECTIVE: To determine the mortality of a population of patients diagnosed with Charcot neuropathic osteoarthropathy managed by a single specialist unit and to compare the results with a control population. METHODS: We have undertaken a retrospective analysis of all cases of Charcot foot on the comprehensive database which has been maintained at the specialist diabetic foot clinic at the City Hospital, Nottingham since 1982. Survival and the incidence of amputation (major and minor) was compared with a control population referred with uncomplicated neuropathic ulceration. Controls were individually matched for gender, age (+/-2 years), disease type, disease duration (+/-2 years) and year of referral (+/-3 years). RESULTS: Forty-seven cases (21 female, 26 male) of Charcot foot were identified, of whom 18 (38.3%) had Type 1 diabetes. Mean age and disease duration at presentation were 59.2 +/- 13.4 (sd) and 16.2 +/- 11.2 years, compared with 59.7 +/- 12.6 and 16.3 +/- 11.2 years, respectively, in the controls. Twenty-one (44.7%) of those with Charcot had died, after a mean interval of 3.7 +/- 2.8 years. This compared with 16 (34.0%) after a mean 3.1 +/- 2.7 years in the control group. Mean duration of follow-up in the survivors was 4.7 +/- 4.9 years (Charcot) and 5.3 +/- 3.9 years (controls). A total of 11 (23.4%) Charcot patients had had a major amputation on the side of the index lesion, compared with five (10.6%) controls. There was no difference between the two groups (P > 0.05, Chi-square). CONCLUSIONS: The mortality in this group of patients with Charcot foot was higher than expected. Nevertheless, there was no difference between those with Charcot and those with uncomplicated neuropathic ulceration. It is possible that it is neuropathy, rather than Charcot osteoarthropathy, which is independently associated with increased mortality in diabetes. The mechanism underlying any such association is not known. There is a need for a formal, prospective, multicentre study to investigate the life expectancy and cardiovascular risk of those with Charcot osteoarthropathy.     

Cytokines and growth factors in keratinocytes and sweat glands in chronic venous leg ulcers. An immunohistochemical study

The role of growth factors and cytokines in the impaired healing of chronic leg ulcers remains uncertain. The aim of this study was to determine whether changes in the amount and location of cytokines and growth factors may be associated with impaired healing in chronic leg ulcers. Biopsies from leg ulcers of 21 patients and from normal skin of nine healthy volunteers were examined immunohistochemically for selected growth factors and cytokines. Greater staining intensity was found in keratinocytes at the edges of ulcers compared to normal skin, or skin adjacent to the ulcers. Staining at the ulcer edge was more intense in nonhealing ulcers for only vascular endothelial growth factor and platelet-derived growth factor, whereas staining in the adjacent skin was more intense for all factors in the nonhealing phase. For all factors staining was cytoplasmic, suggesting production in these areas. This study shows up-regulation of the production of cytokines and growth factors in keratinocytes of chronic leg ulcers that is greater when the ulcers are nonhealing.     

The mitogenic effect of KGF and the expression of its cell surface receptor on cultured normal and malignant human oral keratinocytes and on contiguous fibroblasts

This study examined the mitogenic response to keratinocyte growth factor (KGF) of normal and tumour-derived human oral keratinocytes in which the degree of cellular differentiation was known and in contiguous fibroblast cultures derived from the malignant epithelial cultures. Keratinocytes, but not fibroblasts, were stimulated by KGF. There by demonstrating epithelial target cell specificity of the ligand. KGF-induced stimulation of the tumour-derived keratinocytes cultured in the absence of the 3T3 fibroblast support broadly correlated with the degree of cellular differentiation; well-differentiated keratinocytes were stimulated more by KGF than their less differentiated counterparts. Malignant oral keratinocytes expressed KGF cell surface receptors (K_D 451-709 pM; receptors/cell 2306-413645), but KGF receptor mRNA did not correlate with either KGF-induced mitogenesis or the degree of epithelial cell differentiation. When the tumour-derived keratinocytes were cultured in the presence of 3T3 fibroblasts, the mitogenic response to KGF was comparable to normal epithelial cells. The results suggest that KGF-mediated growth stimulation may not be significant in providing a selective advantage for the growth of malignant keratinocytes.     

Picotamide inhibition of excess in vitro thromboxane B2 release by colorectal mucosa in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease is associated with increased mucosal release of eicosanoids. Among these, thromboxane A2 has been proposed as a possible inflammatory mediator; its suppression may be a useful therapeutic option. METHODS: Using a tissue incubation technique, we compared release of immunoreactive thromboxane B2 by colonic biopsies from patients with ulcerative colitis, Crohn's disease and controls, and assessed the inhibitory effect of picotamide, a thromboxane synthesis inhibitor-receptor antagonist, which has been widely used in Italy for management of ischaemic heart and cerebrovascular disease. RESULTS: Increased amounts of thromboxane B2 were released from biopsies from patients with active ulcerative colitis (median 238 pg/20 min/mg wet weight (interquartile range 147- 325), n = 12) and active Crohn's disease (252 (174-450), 6) compared with those from patients with quiescent ulcerative colitis (95 (61- 140), 12) or Crohn's disease (105 (57-201), 13), or controls (136 (64- 206), 8). Incubation with picotamide at concentrations between 100 microM and 1 mM reduced thromboxane B2 release (IC50 890 microM). CONCLUSION: Since increased thromboxane A2 production may have pathogenetic importance, thromboxane synthesis inhibitor-receptor antagonists such as picotamide merit therapeutic trial in the management of inflammatory bowel disease.     

Follistatin and activin A production by the male reproductive tract

Follistatin is a binding protein for the activin and inhibin family of hormones, regulating their biological activity. In the male reproductive tract, the interaction of these factors is likely to be involved in the regulation of the proliferation of several cell types. We have investigated the presence of follistatin and activin A in seminal plasma using specific immunoassays and have localized follistatin and activin/inhibin subunits in the adult human testis, prostate and seminal vesicle to establish their likely sources. High concentrations of immunoreactive follistatin were present in seminal plasma in normal men (mean 97.9 ng/ml; 1.43 ng/ml in peripheral plasma) and were similar in men with oligo/azoospermia and following vasectomy. Follistatin immunoreactivity was localized to both Leydig and Sertoli cells of the testis, and to epithelial cells of the prostate gland and seminal vesicle, which are likely to be the predominant sources of the hormone in seminal plasma. Activin A was also present in seminal plasma in normal men but was undetectable following vasectomy, thus deriving from the testis. Consistent with this finding, the betaA-subunit was immunolocalized in Sertoli and Leydig cells but was not present in seminal vesicle or prostate gland. The functional significance of the high concentrations of follistatin secreted into seminal plasma by the prostate gland and/or seminal vesicle is uncertain, but they may regulate the biological activity of testis-derived activin A and inhibin B.