Diabetes increases susceptibility to chronic skin ulceration. The etiology of chronic wound formation in diabetic individuals is multifactoral but may be accelerated by changes in the structure and function of the skin secondary to impaired fibroblast proliferation, decreased collagen synthesis, and increased matrix metalloproteinase (MMP) expression. This study explored the effects of all-trans-retinoic acid (RA) on cellular and biochemical features of diabetic human skin in organ culture. Two-mm skin biopsies from hip or ankle were obtained from diabetic subjects and incubated for 9 days in the absence or presence of 2 micro mol/L RA. Hip skin from non-diabetic individuals served as control. Following organ culture incubation, untreated and RA-treated tissue was examined histologically after staining with hematoxylin and eosin. In parallel, organ culture-conditioned medium collected on days 5 and 7 was assayed for levels of active and total MMP-1 (interstitial collagenase) and MMP-9 (gelatinase B). The same organ culture fluids were assayed for the presence of soluble collagen. In comparison with skin from non-diabetic individuals, diabetic skin demonstrated no major differences in overall epidermal thickness or collagen production (both were increased in RA-treated tissue as compared to non-RA-treated tissue). In contrast, levels of MMP-9 (active forms) were elevated in organ culture fluid from diabetic skin as compared to non-diabetic control skin. In the presence of RA, active forms of both MMP-1 and MMP-9 were reduced. Together, these data suggest that RA has the capacity to improve structure and function of diabetic skin, and that a major effect is on reduction of collagen-degrading MMPs.

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In the current study, rats were made diabetic with streptozotocin (STZ) and maintained for 8 weeks, during which time they were treated topically on alternative days with a solution of 0.1% all-trans retinoic acid in a vehicle of 70:30% ethanol/propylene glycol. STZinduced diabetic rats treated with vehicle served as controls. Additional nondiabetic rats were treated with all-trans retinoic acid or vehicle in parallel. At the end of the 8-week period, rats from all four treatment groups were subjected to abrasion wound formation. Wounds healed more rapidly in vehicle-treated nondiabetic skin than in vehicle-treated diabetic skin (96% of the wound surface area closed in nondiabetic rats within 6 days vs. 41% closed in diabetic rats). Wounds in all-trans retinoic acid-treated diabetic skin healed more rapidly than wounds in vehicle-treated diabetic skin (85% of the wound surface area closed in all-trans retinoic acid-treated diabetic rats vs. 41% closed in vehicle-treated diabetic rats). At the histological level, recently healed skin from vehicle-treated diabetic rats was shown to contain a thin, wispy provisional matrix in which many of the embedded cells were rounded and some were pycnotic. In contrast, a much denser provisional matrix with large numbers of embedded spindleshaped cells was observed in healed wounds from diabetic skin that had been pretreated with all-trans retinoic acid. The all-trans retinoic acid-treated diabetic skin was histologically similar to vehicle-treated (or all-trans retinoic acid-treated) skin from nondiabetic animals. In light of these findings, we suggest that prophylactic use of retinoid-containing preparations might be useful in preventing the development of nonhealing skin ulcers resultant from minor traumas in at-risk skin. Diabetes 54:855-861, 2005 D iabetes is responsible for delayed or impaired wound healing, leading in many instances to chronic ulcer formation. Diabetic ulcers of the lower limbs and feet, in particular, are associated with high morbidity and often lead to amputation (1-3). Peripheral neuropathy and peripheral vascular disease are thought to be underlying factors in diabetic wound formation (2-6), but dermal atrophy is likely to be a contributing factor in many cases (6,7). Reduced fibroblast growth, increased expression of matrix-degrading matrix metalloproteinases (MMPs), and decreased matrix synthesis are consequences of chronic vascular disease in diabetic skin as well as in other situations where peripheral vascular disease is present (7-15). Atrophic skin is less resistant than healthy skin to wound formation. In addition, scanty extracellular matrix production during the proliferative phase of wound repair undoubtedly contributes to poor healing (16,17).Past studies have shown that all-trans retinoic acid has the capacity to repair photodamaged skin (18 -19). The repair response includes both increased procollagen production and decreased elaboration of tissue-destructive MMPs. In addition, there is epidermal thickening caused by retinoid-induced ke...

In patients with non specific acute low back pain, without the red flags, a conservative approach is preferable, with assessment in 4–6 weeks. The natural history of low back pain is favorable with improvement over time, thus reassurance to such patients is very important. However, a plain radiograph or more advanced imaging techniques like MRI/CT may be ordered in back pain associated with radiculopathy or spinal stenosis and back pain associated with progressive neurologic deficits. There is limited role of imaging in non specific acute low back pain without the red flags, as the findings correlate poorly with symptoms.

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