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Wound Healing



The potential role of insulin-like growth factors in skeletal muscle regeneration.

MacGregor J, Parkhouse WS. Metabolic Biochemistry Lab, School of Kinesiology, Simon Fraser University, Burnaby, BC.

Can J Appl Physiol 1996 Aug;21(4):236-50

The role of the insulin-like growth factors I and II (IGF-I and IGF-II), previously known as the somatomedins, in general growth and development of various tissues have been known for many years. Thought of exclusively as endocrine factors produced by the liver, and under the control of growth hormone, the somatomedins were known as the intermediaries by which growth hormone exerted its cellular effects during tissue growth and maturation. Eventually it was discovered that virtually every tissue type is capable of autocrine production of the IGFs, and their involvement in skeletal muscle tissue repair and regeneration became apparent. Recent advances in technology have allowed the characterisation of many of the different growth factors believed to play a role in muscle regeneration, and experimental manipulations of cells in culture have provided insight into the effects of the various growth factors on the myoblast. This paper explores the potential role of the IGFs in skeletal muscle regeneration. A critical role of IGF-II in terminal differentiation of proliferating muscle precurser cells following injury is proposed.

Effect of L-arginine on the course of experimental colitis.

Mane J, Fernandez-Banares F, Ojanguren I, Castella E, Bertran X, Bartoli R, Alvarez M, Gassull MA. Research Unit, Pathology, Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.

Clin Nutr 2001 Oct;20(5):415-22

BACKGROUND AND AIMS: L-Arg is the substrate for nitric oxide, and also for L-ornithine which, in turn, is the precursor for the synthesis of collagen and polyamines. By these different metabolic pathways, L-Arg is involved in the mechanisms of inflammation, tissue repair and fibrosis. Thus, the aim of this study was to assess the effect of both different amounts of L-Arg supplementation and L-Arg-free diets upon colonic inflammatory damage and fibrosis in experimental colitis.

METHODS: Sprague-Dawley rats with trinitrobenzene sulphonic acid (TNBS)-induced colitis received increasing doses of L-Arg (30, 100, 500 mg/day), or D-Arg (500 mg/day). In a second experiment, two L-Arg-free diets (one supplemented with L-Gly) were compared to a L-Arg diet. Nitrite/nitrate release in the lumen of the colon and colonic damage were evaluated. In the first experiment, tissue collagen levels and colonic mucosal proliferation were also assessed.

RESULTS: In the acute phase of colitis, intracolonic nitrite/nitrate levels were significantly higher in the 100 and 500 mg supplemented L-Arg groups than in D-Arg group. However, only rats treated with 500 mg of L-Arg showed moderately higher inflammatory and fibrosis colonic scores than the D-Arg treated rats. There was no significant influence of L-Arg-free diets on the course of TNBS-induced colitis. However, L-Arg diet accelerated weight gain both pre- and post-TNBS.

CONCLUSIONS: These results suggest that normal amounts of L-Arg in the diet are not harmful, whereas both absence of L-Arg or supplementation with high doses of this amino acid may be deleterious. In the former this might be due to a decrease of nitrogen retention in injured rats, whereas in the latter it may result from both nitric oxide-mediated tissue damage and collagen deposition. Copyright 2001 Harcourt Publishers Ltd.

Bromelain: biochemistry, pharmacology and medical use.

Maurer HR. Department of Biochemistry, Molecular Biology and Biotechnology, Institute of Pharmacy, Freie Universitat Berlin, Germany.

Cell Mol Life Sci 2001 Aug;58(9):1234-45

Bromelain is a crude extract from the pineapple that contains, among other components, various closely related proteinases, demonstrating, in vitro and in vivo, antiedematous, antiinflammatory, antithrombotic and fibrinolytic activities. The active factors involved are biochemically characterized only in part. Due to its efficacy after oral administration, its safety and lack of undesired side effects, bromelain has earned growing acceptance and compliance among patients as a phytotherapeutical drug. A wide range of therapeutic benefits has been claimed for bromelain, such as reversible inhibition of platelet aggregation, angina pectoris, bronchitis, sinusitis, surgical traumas, thrombophlebitis, pyelonephritis and enhanced absorption of drugs, particularly of antibiotics. Biochemical experiments indicate that these pharmacological properties depend on the proteolytic activity only partly, suggesting the presence of nonprotein factors in bromelain. Recent results from preclinical and pharmacological studies recommend bromelain as an orally given drug for complementary tumor therapy: bromelain acts as an immunomodulator by raising the impaired immunocytotoxicity of monocytes against tumor cells from patients and by inducing the production of distinct cytokines such as tumor necrosis factor-a, Interleukin (Il)-1beta, IL-6, and Il-8. In a recent clinical study with mammary tumor patients, these findings could be partially confirmed. Especially promising are reports on animal experiments claiming an antimetastatic efficacy and inhibition of metastasis-associated platelet aggregation as well as inhibition of growth and invasiveness of tumor cells. Apparently, the antiinvasive activity does not depend on the proteolytic activity. This is also true for bromelain effects on the modulation of immune functions, its potential to eliminate burn debris and to accelerate wound healing. Whether bromelain will gain wide acceptance as a drug that inhibits platelet aggregation, is antimetastatic and facilitates skin debridement, among other indications, will be determined by further clinical trials. The claim that bromelain cannot be effective after oral administration is definitely refuted at this time.

Proinflammatory mediators stimulate neutrophil-directed angiogenesis.

McCourt M, Wang JH, Sookhai S, Redmond HP. Department of Surgery, Professorial Unit, Cork University Hospital, Ireland. Arch Surg 1999 Dec;134(12):1325-31; discussion 1331-2

BACKGROUND: Vascular endothelial growth factor (VEGF; vascular permeability factor) is one of the most potent proangiogenic cytokines, and it plays a central role in mediating the process of angiogenesis or new blood vessel formation. Neutrophils (PMNs) recently have been shown to produce VEGF.

HYPOTHESIS: The acute inflammatory response is a potent stimulus for PMN-directed angiogenesis.

METHODS: Neutrophils were isolated from healthy volunteers and stimulated with lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-alpha), Interleukin 6 (IL-6), and anti-human Fas monoclonal antibody. Culture supernatants were assayed for VEGF using enzyme-linked immunosorbent assays. Culture supernatants from LPS- and TNF-alpha-stimulated PMNs were then added to human umbilical vein endothelial cells and human microvessel endothelial cells and assessed for endothelial cell proliferation using 5-bromodeoxyuridine labeling. Tubule formation was also assessed on MATRIGEL basement membrane matrix. Neutrophils were lysed to measure total VEGF release, and VEGF expression was detected using Western blot analysis.

RESULTS: Lipopolysaccharide and TNF-alpha stimulation resulted in significantly increased release of PMN VEGF (53249 and 48480 pg/mL, respectively; for all, presented as mean SEM) compared with control experiments (324 pg/mL). Interleukin 6 and Fas had no effect. Culture supernatants from LPS- and TNF-alpha-stimulated PMNs also resulted in significant increases (P<.005) in macrovascular and microvascular endothelial cell proliferation and tubule formation. Adding anti-human VEGF-neutralizing polyclonal antibody to stimulated PMN supernatant inhibited these effects. Total VEGF release following cell lysis and Western blot analysis suggests that the VEGF is released from an intracellular store.

CONCLUSION: Activated human PMNs are directly angiogenic by releasing VEGF, and this has important implications for inflammation, capillary leak syndrome, wound healing, and tumor growth.

Factors influencing wound healing after surgery for metastatic disease of the spine. McPhee IB; Williams RP; Swanson CE Division of Orthopaedic Surgery, University of Queensland, Brisbane, Australia.

Spine (UNITED STATES) Mar 15 1998 , 23 (6) p726-32; discussion 732-3,

The study group consisted of 53 patients who underwent 75 operations for spine metastases. Patient and tumor demographic factors, preoperative nutritional status, and perioperative adjunctive therapy were retrospectively reviewed.

OBJECTIVE: To determine the risk factors for wound breakdown and infection in patients undergoing surgery for spinal metastases.

SUMMARY OF BACKGROUND DATA: Spinal fusion using spine implants may be associated with an infection rate of 5% or more. Surgery for spine metastases is associated with an infection rate of more than 10%. Factors other than the type of surgery performed may account for the greater infection rate.

METHODS: Data were obtained by reviewing patient records. Age, sex, and neurologic status of the patient; tumor type and site; and surgical details were noted. Adjunctive treatment with corticosteroids and radiotherapy was recorded. Nutritional status was evaluated by determining serum protein and serum albumin concentrations and by total lymphocyte count.

RESULTS: Wound breakdown and infection occurred in 15 of 75 wounds. No patient or tumor demographic factors other than intraoperative blood loss (P < 0.1) were statistically associated with infection. The correlation between preoperative protein deficiency (P < 0.01) or perioperative corticosteroid administration (P < 0.10) and wound infection was significant. There was no statistical correlation between lymphocyte count or perioperative radiotherapy and wound infection.

CONCLUSIONS: The results indicate that preoperative protein depletion and perioperative administration of corticosteroids are risk factors for wound infection in patients undergoing surgery for spine metastases. Perioperative correction of nutritional depletion and cessation of steroid therapy may reduce wound complications.

Nitrogen retention, muscle creatine and orotic acid excretion in traumatized rats fed arginine and glycine enriched diets.

Minuskin ML, Lavine ME, Ulman EA, Fisher H.

J Nutr 1981 Jul;111(7):1265-74

Male, Sprague-Dawley rats were subjected to the trauma of laparotomy under sodium pentothal anesthesia. Apparent N retention (N intake - Urinary N) was studied when these rats were fed a 25% casein diet either unsupplemented or enriched with arginine plus glycine or with ornithine plus glycine. These amino acids occur in particularly high concentrations in skin and connective tissue and might, therefore, be required in greater amounts for tissue repair. In one experiment muscle creatine content and orotic acid excretion in the urine were determined. We found that laparotomy carried out under sodium pentothal anesthesia was a highly reproducible form of trauma which resulted in a significant decrease in apparent N retention. Supplementing a 25% casein based diet with arginine and glycine significantly improved apparent N retention both in untraumatized as well as in traumatized rats. Ornithine was less effective than arginine in improving apparent N retention. Urinary orotic acid excretion was significantly increased in rats fed the unsupplemented casein diet, regardless of the imposition of trauma. Muscle creatine content was significantly increased by the supplementation of the diet with arginine plus glycine. The beneficial effect of arginine-plus-glycine enrichment in traumatized rats does not appear to be due to an arginine deficit needed for the detoxification of ammonia from excess amino acids but may be related to creatine synthesis and turnover.

[The effect of superoxide dismutase on the inflammation induced by periodontal pathogenic bacteria and wound healing of gingival incision] [Article in Japanese]

Misaki H, Suzuki M, Yoshie H, Hara K. Department of Periodontology, Niigata University.

Nippon Shishubyo Gakkai Kaishi 1990 Mar;32(1):93-110

The therapeutic effect of superoxide dismutase (SOD) and the role of O2- were assessed on 3 groups of Wistar rats (total 115). Fifty-four received injections of gingival bacteria or of anaerobically cultured rat dental plaque in their peritoneum, then received both intravenous (i.v.) and intraperitoneal (i.p.) injection of SOD. The rats were killed 48 hours later to collect their peritoneal exudate for cell count and for acid phosphatase activity assessment. Twenty-six received injections of bacteria in their footpads, after which SOD was administered intravenously. These rats were killed at 6 hours, 48 hours and 1 week respectively for histological examination. The gingiva of 26 rats were incised to create artificial lesions. The rats were killed at 24 or 48 hours and examined histologically. The nine remaining rats were used as controls (untreated) for the 3 experiments. The results of the 3 experiments showed that: Injection of SOD reduced exudation and acid phosphatase activity enhanced by the injection of B. gingivalis, at dosages of 1, 5 mg/kg i.p. and 5 mg/kg i.v., but 10 mg/kg i.p. had no apparent effect; i.v. injection of SOD had inhibitory effects on cell infiltration of B. gingivalis into the footpad, and the increase in fibrin and fibroblast formation through time was greater in SOD-administered rats; a decreased cell infiltration rate and increased fibrin network, fibroblast proliferation and gingival tissue regeneration occurred in specimens with artificial lesions given SOD. Apparently SOD has a curative effect on both inflammatory reaction induced by B. gingivalis and periodontal wound healing.

Exogenously regulated stem cell-mediated gene therapy for bone regeneration.

Moutsatsos IK, Turgeman G, Zhou S, Kurkalli BG, Pelled G, Tzur L, Kelley P, Stumm N, Mi S, Muller R, Zilberman Y, Gazit D. Molecular Pathology Laboratory, Hebrew University-Hadassah Medical and Gene Therapy Center, Jerusalem, Israel.

Mol Ther 2001 Apr;3(4):449-61

Regulated expression of transgene production and function is of great importance for gene therapy. Such regulation can potentially be used to monitor and control complex biological processes. We report here a regulated stem cell-based system for controlling bone regeneration, utilizing genetically engineered mesenchymal stem cells (MSCs) harboring a tetracycline-regulated expression vector encoding the osteogenic growth factor human BMP-2. We show that doxycycline (a tetracycline analogue) is able to control hBMP-2 expression and thus control MSC osteogenic differentiation both in vitro and in vivo. Following in vivo transplantation of genetically engineered MSCs, doxycycline administration controlled both bone formation and bone regeneration. Moreover, our findings showed increased angiogenesis accompanied by bone formation whenever genetically engineered MSCs were induced to express hBMP-2 in vivo. Thus, our results demonstrate that regulated gene expression in mesenchymal stem cells can be used as a means to control bone healing.

Spatial and temporal gene expression in chondrogenesis during fracture healing and the effects of basic fibroblast growth factor.

Nakajima F, Ogasawara A, Goto K, Moriya H, Ninomiya Y, Einhorn TA, Yamazaki M. Department of Orthopaedic Surgery, Chiba University School of Medicine, Japan.

J Orthop Res 2001 Sep;19(5):935-44

Chondrogenesis is an essential component of endochondral fracture healing, though the molecular and cellular events by which it is regulated have not been fully elucidated. In this study, we used a rat model of closed fracture healing to determine the spatial and temporal expression of genes for cartilage-specific collagens. Furthermore, to determine the effects of basic fibroblast growth factor (bFGF) on chondrogenesis in fracture healing, we injected 100 microg recombinant human bFGF into the fracture site immediately after fracture. In normal calluses, pro-alpha1(II) collagen mRNA (COL2A1) was detected in proliferative chondrocytes beginning on day 4 after the fracture, and pro-alpha1(X) collagen mRNA (COL10A1) in hypertrophic chondrocytes beginning on day 7. In FGF-injected calluses, the cartilage enlarged in size significantly. On day 14, both COL2A1- and COL10A1-expressing cells were more widely distributed, and the amounts of COL2A1 and COL10A1 mRNAs were both approximately 2-fold increased when compared with uninjected fractures. Temporal patterns of expression for these genes were, however, identical to those found in normal calluses. The number of proliferating cell nuclear antigen-positive cells was increased in the non-cartilaginous area in the bFGF-injected calluses by day 4. The present molecular analyses demonstrate that a single injection of bFGF enhances the proliferation of chondroprogenitor cells in fracture callus, and thus contributes to the formation of a larger cartilage. However, maturation of chondrocytes and replacement of the cartilage by osseous tissue are not enhanced by exogenous bFGF, and this results in the prolonged cartilaginous callus phase. We conclude that, in the healing of closed fractures of long bones, exogenous bFGF has a capacity to enlarge the cartilaginous calluses, but not to induce more rapid healing.

Lipid peroxides and superoxide dismutase (SOD) induction in skin inflammatory diseases, and treatment with SOD preparations.

Niwa Y. Niwa Institute for Immunology, Kochi-Ken, Japan.

Dermatologica 1989;179 Suppl 1:101-6

In the skin ulcer or severely inflamed and erosive lesions induced due to burn, wounds and other dermatitides, lipid peroxides were markedly increased, with resultant cytotoxic effects in situ. Generally, superoxide dismutase (SOD), which scavenges oxygen radicals or inhibits lipid peroxidation, is adapted to be induced (increased) under oxygen toxicity. For the treatment of not only systemic inflammatory diseases but also skin ulcer lesions, especially due to burn and wounds, liposomal-encapsulated SOD injection was effective. Topical application of free Mn-SOD or Cu, Zn-SOD extracted from bovine, bacterial and other species except for human was also dramatically effective in skin lesions; a burnt patient who was advised to undergo skin transplantation showed complete healing with free SOD cream. In addition, topical application of low molecular weight antioxidants, AOA or Bio-harmony, also showed remarkable effectiveness in these skin lesions. However, SOD dissolved in the vehicle containing greater amounts of vaselinum album (white petrolatum) rapidly lost its activity, and that dissolved in the vehicle with large quantities of water lost its activity within 3 months. In conclusion, SOD should be dissolved in the vehicle before use, however, low molecular weight antioxidant cream can be commercially sold because it does not lose its activity for long periods.

A comparison of topical honey and phenytoin in the treatment of chronic leg ulcers.

Oluwatosin OM, Olabanji JK, Oluwatosin OA, Tijani LA, Onyechi HU. Department of Surgery, University College Hospital, Ibadan, Nigeria.

Afr J Med Med Sci 2000 Mar;29(1):31-4

In view of the reports that phenytoin and honey are useful in the healing of wounds, a comparison of their topical use in the treatment of chronic leg ulcers was carried out. Fifty cases of chronic leg ulceration were studied, each for a period of four weeks. They were assigned into three groups for honey, phenytoin/honey mixture, and phenytoin topical treatment. Overall mean duration of the ulcers was 56.5 months while the mean(s.d.) size was 3339 (5193) mm2. Mean percent reduction in size in the group treated with honey, 27.0 (36.9), was not significantly different (H = 0.26; 2 df; p = 0.88) from that of the mixture group, which was 25.9 (46.4), and from that of the phenytoin group which was 35.5 (53.2). This percent reduction in size was significantly greater, (H = 7.69; 2 df; P = 0.02), during the first week in the phenytoin group than in the other groups. Four of the cases progressed to complete healing at the end of four weeks with phenytoin. Pain score difference (using a graduation scale from 0 to 10) at the end of the four week treatment, was, 1.8 (1.7) in honey group, 2.0 (1.3) in mixture group and 3.6 (2.4) in phenytoin group. This difference was not significant, (H = 3.09; 2 df; P = 0.21). Our study suggests that phenytoin may be superior to honey as a topical agent in the treatment of chronic ulcers.

The musculoskeletal effects of smoking.

Porter SE, Hanley EN Jr. Department of Orthopaedic Surgery, Carolinas Medical Center, Charlotte, NC 28323, USA.

J Am Acad Orthop Surg 2001 Jan-Feb;9(1):9-17

Currently, there are more than 50 million smokers in this country, and approximately 800 billion cigarettes are smoked each year. Smoking is now the leading avoidable cause of morbidity and mortality in the United States. According to one report, over 500,000 deaths per year in the United States alone can be attributed to smoking. For years, orthopaedic surgeons have known about the relationships that putatively exist between smoking and an array of orthopaedic conditions and complications. It has been shown to adversely affect bone mineral density, lumbar disk disease, the rate of hip fractures, and the dynamics of bone and wound healing. Although scientific and clinical information on smoking and its consequences suggests differing degrees of correlation between smoking and orthopaedic conditions, most available data do suggest a real and reproducible relationship. In the past, there have been many individual reports that deal with these relationships separately but very few published comprehensive reviews. This summary of the current literature regarding the relationship between smoking and musculoskeletal diseases and their treatment provides information that can be used clinically by both the practitioner and the patient.

Local application of growth factors (insulin-like growth factor-1 and transforming growth factor-beta1) from a biodegradable poly(D,L-lactide) coating of osteosynthetic implants accelerates fracture healing in rats.

Schmidmaier G, Wildemann B, Bail H, Lucke M, Fuchs T, Stemberger A, Flyvbjerg A, Haas NP, Raschke M. Department of Trauma and Reconstructive Surgery, Charite, Humboldt University of Berlin, Berlin, Germany.

Bone 2001 Apr;28(4):341-50

In vitro and in vivo studies have demonstrated an osteoinductive effect of growth factors such as insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta1 (TGF-beta1). However, for therapeutic use in fracture treatment, questions remain with regard to the local application of these proteins. A controlled, local release of growth factors from a biodegradable polylactide coating of osteosynthetic implants may have a stimulating effect on fracture healing. Such implants could stabilize the fracture and their bioactive surface could function simultaneously as a local drug-delivery system. Previous studies have demonstrated the high mechanical stability of an approximately 10-14-&amp;mgr;m-thick poly(D,L-lactide) (PDLLA) coating on metallic implants, which can even withstand the process of intramedullary insertion. Following an initial peak, 80% of incorporated growth factors IGF-1 and TGF-beta1 were continuously released within 42 days. The effect of locally applied IGF-1 and TGF-beta1 from a biodegradable PDLLA coating of intramedullary implants on fracture healing was investigated in a rat model. Midshaft fractures of the right tibia of 5-month-old female Sprague-Dawley rats (n = 127) were stabilized with coated vs. uncoated titanium Kirschner wires. X-ray examinations and blood analyses were performed, and body weight and body temperature measurements were taken throughout the experimental period. After 28 and 42 days, respectively, tibiae were dissected for mechanical torsional testing and histomorphometrical analyses. X-rays demonstrated an almost completely consolidated fracture, biomechanical testing showed a significantly higher maximum load and torsional stiffness, and histological and histomorphometric analyses demonstrated progressed remodeling after 28 and 42 days in the group treated with growth factors as compared with controls. Interestingly, the PDLLA coating itself revealed a positive effect on fracture healing even without incorporated growth factors. No systemic changes of serum parameters, including IGF-1 and IGF binding proteins, and no differences in body weight and body temperature were observed within and between groups. These findings suggest that the local application of growth factors from a biodegradable PDLLA coating of osteosynthetic implants accelerates fracture healing significantly without systemic side effects.

Asiaticoside-induced elevation of antioxidant levels in healing wounds.

Shukla A, Rasik AM, Dhawan BN Pharmacology Department, Central Drug Research Institute, Lucknow, India.

Phytother Res 1999 Feb;13(1):50-4

Asiaticoside derived from the plant Centella asiatica is known to possess good wound healing activity. Enhanced healing activity has been attributed to increased collagen formation and angiogenesis. Since antioxidants have been reported to play a significant role in the wound healing process we studied the effect of asiaticoside on the levels of certain antioxidants in the wound so as to explore the possible involvement of such a mechanism in the asiaticoside induced wound healing. Asiaticoside application (0.2%, topical) twice daily for 7 days to excision-type cutaneous wounds in rats led to increased enzymatic and non-enzymatic antioxidants, namely superoxide dismutase (35%), catalase (67%), glutathione peroxidase (49%), vitamin E (77%) and ascorbic acid (36%) in newly formed tissues. It also resulted in a several fold decrease in lipid peroxide levels (69%) as measured in terms of thiobarbituric acid reactive substance. However, continued application for 14 days showed no significant difference in these antioxidants compared with their values in vehicle treated wound tissue. It appears from the present study that asiaticosides enhanced induction of antioxidant levels at an initial stage of healing which may be an important contributory factor in the healing properties of this substance.

In vitro and in vivo wound healing activity of asiaticoside isolated from Centella asiatica.

Shukla A, Rasik AM, Jain GK, Shankar R, Kulshrestha DK, Dhawan BN. Pharmacology Division, Central Drug Research Institute, Lucknow, India. gshukla@zoo.uvm.edu1

J Ethnopharmacol 1999 Apr;65(1):1-11

The activity of asiaticoside, isolated from Centella asiatica, has been studied in normal as well as delayed-type wound healing. In guinea pig punch wounds topical applications of 0.2% solution of asiaticoside produced 56% increase in hydroxyproline, 57% increase in tensile strength, increased collagen content and better epithelisation. In streptozotocin diabetic rats, where healing is delayed, topical application of 0.4% solution of asiaticoside over punch wounds increased hydroxyproline content, tensile strength, collagen content and epithelisation thereby facilitating the healing. Asiaticoside was active by the oral route also at 1 mg/kg dose in the guinea pig punch wound model. It promoted angiogenesis in the chick chorioallantoic membrane model at 40 microg/disk concentration. These results indicate that asiaticoside exhibits significant wound healing activity in normal as well as delayed healing models and is the main active constituent of Centella asiatica.

Curcumin enhances wound healing in streptozotocin induced diabetic rats and genetically diabetic mice.

Sidhu GS, Mani H, Gaddipati JP, Singh AK, Seth P, Banaudha KK, Patnaik GK, Maheshwari RK. Center for Combat and Life Sustainment Research, Uniformed Services University of Health Sciences, Bethesda, MD 20814, USA.

Wound Repair Regen 1999 Sep-Oct;7(5):362-74

Tissue repair and wound healing are complex processes that involve inflammation, granulation and tissue remodeling. Interactions of different cells, extracellular matrix proteins and their receptors are involved in wound healing, and are mediated by cytokines and growth factors. Previous studies from our laboratory have shown that curcumin (diferuloylmethane), a natural product obtained from the rhizomes of Curcuma longa, enhanced cutaneous wound healing in rats and guinea pigs. In this study, we have evaluated the efficacy of curcumin treatment by oral and topical applications on impaired wound healing in diabetic rats and genetically diabetic mice using a full thickness cutaneous punch wound model. Wounds of animals treated with curcumin showed earlier re-epithelialization, improved neovascularization, increased migration of various cells including dermal myofibroblasts, fibroblasts, and macrophages into the wound bed, and a higher collagen content. Immunohistochemical localization showed an increase in transforming growth factor-beta1 in curcumin-treated wounds compared to controls. Enhanced transforming growth factor-beta1 mRNA expression in treated wounds was confirmed by in situ hybridization, and laser scan cytometry. A delay in the apoptosis patterns was seen in diabetic wounds compared to curcumin treated wounds as shown by terminal deoxynucleotidyl transferase-mediated deoxyuridyl triphosphate nick end labeling analysis. Curcumin was effective both orally and topically. These results show that curcumin enhanced wound repair in diabetic impaired healing, and could be developed as a pharmacological agent in such clinical settings.

Nitrogen retention in rats fed on diets enriched with arginine and glycine. 1. Improved N retention after trauma.

Sitren HS, Fisher H.

Br J Nutr 1977 Mar;37(2):195-208

1. Nitrogen retention was measured in adult rats (250-350 g) subjected to the trauma of hind-leg fracture and given diets with or without arginine plus glycine supplementation. Observations were also recorded on excretion of creatine, creatinine, allantoin, and orotic acid. Liver and skeletal muscle transaminase activities were also determined. 2. When traumatized rats weighing approximately 250 g were given a diet with 200 g casein/kg, supplemented with 20 g arginine and 10 g glycine/kg (EC diet) or a casein diet made isonitrogenous with the EC diet by addition of aspartic acid (C diet), a 60-70% increase in N retention was observed for the first 5 d post-injury for animals consuming the EC diet. A soya-bean (S) diet, isonitrogenous to the diet containing 20% casein, supplemented with arginine and glycine was as effective as the EC diet in promoting significantly better N retention of traumatized rats (350 g) in comparison to rats given the C diet. 3. When the dietary casein content was reduced to 100 g/kg, supplements of 10 g arginine and 5 g glycine or 20 g arginine and 10 g glycine/kg did not improve N retention. It is suggested that both protein quality and protein quantity are important following injury. 4. An increased excretion of creatine was observed in traumatized rats given the high-protein diets supplemented with arginine and glycine. No consistent changes were noted for urine creatinine. 5. 5. Urine allantoin levels remained stable after leg-fracture in rats consuming either the C or EC diets. Differences in the levels of urine orotic acid were found during both the pre- and post-injury periods in rats given the C, EC or S diets. 6. The mechanisms responsible for the improved N retention of traumatized rats consuming the high-protein diets with supplements of arginine and glycine may be related to the role of arginine both as a constituent of muscle tissue and as an intermediate in the urea cycle. 7. In traumatized rats fed the C or EC diets, liver transaminase activity increased whereas the transaminase activity in skeletal muscle decreased. These results support the recent concept that the increased excretion of N following injury arises from diminished reutilization of amino acids by muscle tissue without an acute increase in the rate of muscle catabolism.

Cyclic mechanical stretching enhances secretion of Interleukin 6 in human tendon fibroblasts.

Skutek M, van Griensven M, Zeichen J, Brauer N, Bosch U. Laboratory of Histology and Cell Biology, Department of Traumasurgery, Hanover Medical School, 30623 Hanover, Germany.

Knee Surg Sports Traumatol Arthrosc 2001 Sep;9(5):322-6

Accelerated rehabilitation after tendon and ligament injuries is widely accepted to avoid adverse effects of immobilization. However, progressive rehabilitation may also lead to an excessive inflammatory soft tissue response. To investigate the amount of loading necessary to accelerate the healing process without causing damage to the healing tissue, we experimentally stretched human tendon fibroblasts of healthy tendons 15 and 60 min with 1 Hz and an elongation of 5% and measured the secretion of Interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta1 (TGF-beta1), platelet-derived growth factor (PDGF), and fibroblast growth factor basic (bFGF). Secretion of IL-6 was significantly induced by 15 min of cyclic biaxial mechanical stretching after 4 and 8 h observation time and by 60 min stretching and 2 h observation time. The growth factors TGF-beta1, bFGF, and PDGF were secreted by human tendon fibroblasts both in stretched cells and controls; however, no increases were related to mechanical stretching. There was no measurable secretion of TNF-alpha in human tendon fibroblasts. These findings suggest that the inflammatory reaction often seen during physiotherapy after tendon and ligament injuries is caused in part by secretion of IL-6 from the stretched human tendon fibroblasts. IL-6 may cause exaggerated proliferation of fibroblasts and synovial cells as seen in rheumatoid arthritis and arthrofibrosis. However, physiological proliferative reactions leading to repair of injured tissue are also possible. IL-6 measured in the synovial fluid may be an important predictor for monitoring and improving therapeutic strategies in terms of tendon/ligament healing.

Spinal fusion with recombinant human growth and differentiation factor-5 combined with a mineralized collagen matrix.

Spiro RC, Thompson AY, Poser JW. Department of Research, Orquest, Inc., Mountain View, California 94043, USA.

Anat Rec 2001 Aug 1;263(4):388-95

The availability of recombinant osteoinductive growth factors and new osteoconductive matrices offers an alternative to the use of autogenous bone (autograft) for grafting indications. This study evaluates the bone-forming activity of a mineralized collagen matrix combined with recombinant human growth and differentiation factor-5 in a rabbit posterolateral spinal fusion model. The activity of three distinct matrix-growth factor formulations is assessed by radiographic, histologic, and mechanical strength methods. Results show that the radiographic density, histologic quality, and mechanical strength of fusion at 12 weeks post-treatment rank consistently within the treatment groups. Optimal formulations are shown to perform similar to autograft in both the rate and strength of fusion. Fusion rates as high as 80% are observed within specific matrix/growth factor formulations. The average biomechanical strength of treated motion segments in the most efficacious formulation is 82% higher than that obtained with autograft, although this difference is not statistically significant. The fusion mass formed in response to matrix/growth factor formulations is composed of normal trabecular bone with a thin outer cortical plate and modest hematopoietic bone marrow. These results demonstrate that the combination of a mineralized collagen matrix with recombinant human growth and differentiation factor-5 maximizes the inherent conductive and inductive properties of each component, respectively, to provide an effective alternative to autograft for bone grafting procedures. Copyright 2001 Wiley-Liss, Inc.

Interleukin-6 promotes post-traumatic healing in the central nervous system.

Swartz KR, Liu F, Sewell D, Schochet T, Campbell I, Sandor M, Fabry Z. Department of Neurological Surgery, University of Wisconsin, Madison 53706, USA.

Brain Res 2001 Mar 30;896(1-2):86-95

The central nervous system (CNS) is an immune-privileged site where the role of immune cells and mediators in traumatic brain injury is poorly understood. Previously we have demonstrated that Interleukin (IL)-6, a cytokine that acts on a wide range of tissues influencing cell growth and differentiation, is an agonist for vascular endothelial growth factor (VEGF), in in vitro vascularization assays for brain microvessel endothelial cells. In this present work we focus on the role of IL-6 in promoting tissue repair in the CNS in vivo. An aseptic cerebral injury (ACI) was created in the right parietal cortex, using both wild type (C57Bl/6J) and IL-6-deficient (C57Bl/6J-IL-6-/-) mice to study the consequences of the absence of IL-6 on the pathology of brain injuries. We monitored the immediate, early, and late responses to this traumatic injury by characterizing several histologic features in the CNS at days 1, 4, 7 and 14 following injury. Acellular necrosis, cellular infiltration, and re-vascularization were characterized in the injured tissues, and each of these histologic features was individually graded and totaled to assign a healing index. IL-6-deficient mice were found to have a comparatively slower rate of recovery and healing. Furthermore, fluorescein isothiocyanate (FITC)-dextran intravenous injection demonstrated leaky vessels in IL-6-deficient but not in wild type animals following ACI. Additionally, chronic expression of IL-6 in the CNS using transgenic GFAP-IL-6 mice resulted in more rapid healing following ACI. The accelerated tissue repair in GFAP-IL-6 transgenic animals is primarily due to extensive re-vascularization as detected by endothelial cell markers. Combined, this data suggests an important role of IL-6 in tissue repair processes following traumatic injury in the CNS.

Use of magnet therapy to heal an abdominal wound: a case study.

Szor JK; Topp R Toledo Hospital, Ohio, USA.

Ostomy Wound Manage (United States) May 1998 , 44 (5) p24-9 Complementary therapies, in particular magnet therapy, may have benefits to offer in healing chronic wounds. This case study involves a 51 year old paraplegic woman with an abdominal wound that had been present for one year. Traditional approaches to wound care had not achieved complete healing. Prior to surgical intervention, the patient consented to the application of magnet therapy over her usual wound dressing. In one month, the wound completely healed. On the basis of this case, further investigation of magnet therapy for wound healing appears to be warranted.

Role of phenytoin in wound healing--a wound pharmacology perspective.

Talas G, Brown RA, McGrouther DA. Department of Plastic and Reconstructive Surgery, University College London Medical School, UK.

Biochem Pharmacol 1999 May 15;57(10):1085-94

Topical agents used for the enhancement of wound healing are designed to act locally and, therefore, do not undergo classic systemic metabolic modification. This commentary reviews the potential role of a vulnerary agent, phenytoin, (PHT), from a wound pharmacology perspective. This agent may have the potential to alter the dynamics of wound healing, suggesting a therapeutic use for the stimulation of chronic wounds. Oral PHT therapy is used widely for the treatment of convulsive disorders, and about half the patients treated develop gingival overgrowth as a side-effect. This apparent stimulatory effect has prompted its assessment in wound healing. Investigations into the mechanisms of gingival overgrowth also provide clues to its action in wound healing, and important similarities and differences are discussed. It appears also that both gingiva and skin are important extrahepatic sites for xenobiotic metabolism, and analysis of the biochemical mechanisms should lead to the design of safer analogues for wound healing. On the other hand, differences between the pharmacokinetics of topical PHT in these tissue situations indicate that different formulations are required for gingival and cutaneous wound healing and during the changing course of wound healing itself.

In vitro modulation of keratinocyte wound healing integrins by zinc, copper and manganese.

Tenaud I, Sainte-Marie I, Jumbou O, Litoux P, Dreno B. Laboratory of Immuno-Dermatology, CHU Hotel-Dieu, Place A. Ricordeau, 44035 Nantes Cedex 01, France.

Br J Dermatol 1999 Jan;140(1):26-34

Although the trace elements zinc, copper and manganese are used in vivo for their healing properties, their mechanism of action is still only partially known. Some integrins expressed by basal layer keratinocytes play an essential part in healing, notably alpha2beta1, alpha3beta1, alpha6beta4 and alphaVbeta5, whose expression and distribution in epidermis are modified during the re-epithelialization phase. This study demonstrates how the expression of these integrins are modulated in vitro by trace elements. Integrin expression was studied in proliferating keratinocytes in monolayer cultures and in reconstituted skin that included a differentiation state. After 48 h incubation with zinc gluconate (0.9, 1.8 and 3.6 microg/mL), copper gluconate (1, 2 and 4 microg/mL), manganese gluconate (0.5, 1 and 2 microg/mL) and control medium, integrin expression was evaluated by FACScan and immunohistochemistry. Induction of alpha2, alpha3, alphaV and alpha6 was produced by zinc gluconate 1.8 microg/mL in monolayers, of alpha2, alpha6 and beta1 by copper gluconate 2 and 4 microg/mL and of all the integrins studied except alpha3 by manganese gluconate 1 microg/mL. Thus, alpha6 expression was induced by all three trace elements. The inductive effect of zinc was particularly notable on integrins affecting cellular mobility in the proliferation phase of wound healing (alpha3, alpha6, alphaV) and that of copper on integrins expressed by suprabasally differentiated keratinocytes during the final healing phase (alpha2, beta1 and alpha6), while manganese had a mixed effect.

Bioactivity of the vascular endothelial growth factor trapped in fibrin clots: production of IL-6 and IL-8 in monocytes by fibrin clots.

Tezono K, Sarker KP, Kikuchi H, Nasu M, Kitajima I, Maruyama I. Second Department of Internal Medicine, Oita Medical University, Oita, Japan.

Haemostasis 2001 Mar-Apr;31(2):71-9

The blood coagulation cascade is activated following vascular-wall injury. The serine protease thrombin is the final protease in this cascade that causes the formation of fibrin from fibrinogen. Thrombin also causes the activation of platelets, which are trapped in a fibrin net followed by hemostasis. Platelets gathered into fibrin clots release several growth factors such as platelet-derived growth factor and transforming growth factor beta. In the present study, we demonstrated that the vascular endothelial growth factor (VEGF) could be bound to fibrin clots in the plasma, and that incubation of the endothelial cells with these VEGF-bound fibrin clots induced proliferation of endothelial cells. Thus, it suggests that clot-bound VEGF may play a role in wound healing through the proliferation of endothelial cells and vascular smooth-muscle cells. On the other hand, a noticeable migration of monocytes was observed when they were cultured on dishes in the presence of VEGF-bound fibrin clots. Moreover, peripheral blood monocytes incubated in the presence of VEGF-bound fibrin clots strikingly increased the production of IL-6 and IL-8, demonstrating that VEGF trapped in fibrin clots not only induces proliferation of human umbilical vein endothelial cells and migration of monocytes but also enhances secretion of IL-6 and IL-8. Thus, our data suggest that fibrin clots that contain several growth factors act as a bioactive reservoir and may play an important role in hemostasis as well as wound healing. Copyright 2001 S. Karger AG, Basel

Inability of transforming growth factor-beta 1, combined with a bioabsorbable polymer paste, to promote healing of bone defects in the rat distal femur.

Tielinen L, Manninen M, Puolakkainen P, Kellomaki M, Tormala P, Rich J, Seppala J, Rokkanen P. Department of Orthopaedics and Traumatology, Helsinki University Central Hospital, Topeliuksenkatu 5, 00260 Helsinki, Finland.

Arch Orthop Trauma Surg 2001;121(4):191-6

The ability of transforming growth factor-beta 1 (TGF-beta 1) to promote bone formation suggests that it may have potential as a therapeutic agent in bone defects. However, there still exists a need for an effective method of delivering TGF-beta 1 to the site of an osseous defect. In the present study, TGF-beta 1 was embedded in a bioabsorbable polymer paste (a blend of an L-lactide oligomer and a copolymer of epsilon-caprolactone and DL-lactide). The release of TGF-beta 1 from the polymer paste was examined in vitro with an enzyme-linked immunosorbent assay, which showed sustained release of active TGF-beta 1 over a 7-day period. Further, the polymer paste was used to fill a bone defect in the rat distal femur. The amount of TGF-beta 1 per rat was 50 micrograms, while in a control group we used an identical polymer paste without the growth factor. After a follow-up of 1 week and 3 weeks, the femurs were examined radiographically, histologically, histomorphometrically, microradiographically, and were also used for tetracycline-labeling studies. TGF-beta 1 did not enhance healing of the bone defect. A combination of growth factors would probably be a more potent osteoinductor than TGF-beta 1 alone.

Prospects for epidermal growth factor in the management of corneal disorders.

Tripathi RC, Raja SC, Tripathi BJ. Department of Ophthalmology and Visual Science, University of Chicago, Illinois.

Surv Ophthalmol 1990 May-Jun;34(6):457-62

Epidermal growth factor (EGF) is a naturally occurring mitogen which, in its recombinant form, is under intensive investigation for therapeutic use. Receptor activation by EGF induces up-regulation of synthesis of specific proteins as well as proliferation and differentiation of the corneal epithelium, keratocytes, and endothelium both in vivo and in vitro. With topical application of EGF, corneal wounds could possibly heal within hours, and the strength of the stromal scars is also increased; this may lead to the prospect of sutureless surgery. It may be possible to treat degenerative and dystrophic disorders of the cornea, especially of the endothelium, and to enhance the density of endothelial cells in donor corneas prior to transplantation. Combination therapy with EGF, fibroblast growth factor, and corticosteroids may be advantageous in producing a synergistic effect. It is possible that, with increased knowledge of the pharmacokinetics and the development of appropriate delivery systems, EGF could become an integral part of the next generation of ophthalmic pharmaceuticals.

[Improvement in the healing of colonic anastomoses by vitamin B5 and C supplements. Experimental study in the rabbit] [Article in French]

Vaxman F, Chalkiadakis G, Olender S, Maldonado H, Aprahamian M, Bruch JF, Wittmann T, Volkmar P, Grenier JF. Service de Chirurgie Digestive et Generale B, Hospices Civils de Strasbourg.

Ann Chir 1990;44(7):512-20

To study the effects of vitamins B5 and C on the healing process of colonic anastomoses, 3 groups of 20 rabbits were given daily either placebo (group A), or vitamin B5 (100 mg/kg: group B) or vitamin C (100 mg/kg: group C). After 8 days of supplementation, via a midline incision and under general anaesthesia, 2 colonic segments were removed, and the continuity was restored. On the 3rd post-operative day, the rabbits were killed and the anastomoses were removed. Mechanical properties of both normal colon and anastomoses were determined by using bursting pressure tests, number of burst anastomoses, fibroblast count, hydroxyproline concentration and determination by microanalysis of trace element content: Mg, P, S, Ca, Fe, Cu, Zn and Mn. Vitamin B5 (p = 0.03) and vitamin C (p less than 0.01) both decreased the number of burst anastomoses. Furthermore the required bursting pressure values were higher with vitamin C (p = 0.01) than in controls. Both vitamins restored normal Zn levels at the anastomotic site, whereas these levels decreased on the 3rd post-operative day during the normal healing process of colonic anastomosis. Moreover, vitamins B5 and C increased Fe, Cu and Mn levels, which are intimately all involved in collagen synthesis. Vitamins B5 and C enhance the colonic wound healing process in the rabbit, acting together in synergy in vivo as well as in vitro, as previously demonstrated.

Effect of pantothenic acid and ascorbic acid supplementation on human skin wound healing process. A double-blind, prospective and randomized trial.

Vaxman F, Olender S, Lambert A, Nisand G, Aprahamian M, Bruch JF, Didier E, Volkmar P, Grenier JF. INSERM U 61, Hospices Civils, Strasbourg, France.

Eur Surg Res 1995;27(3):158-66

This study aimed at testing human skin wound healing improvement by a 21-day supplementation of 1.0 g ascorbic acid (AA) and 0.2 g pantothenic acid (PA). 49 patients undergoing surgery for tattoos, by the successive resections procedure, entered a double-blind, prospective and randomized study. Tests performed on both skin and scars determined: hydroxyproline concentrations, number of fibroblasts, trace element contents and mechanical properties. In the 18 supplemented patients, it was shown that in skin (day 8) Fe increased (p < 0.05) and Mn decreased (p < 0.05); in scars (day 21), Cu (p = 0.07) and Mn (p < 0.01) decreased, and Mg (p < 0.05) increased; the mechanical properties of scars in group A were significantly correlated to their contents in Fe, Cu and Zn, whereas no correlation was shown in group B. In blood, AA increased after surgery with supplementation, whereas it decreased in controls. Although no major improvement of the would healing process could be documented in this study, our results suggest that the benefit of AA and PA supplementation could be due to the variations of the trace elements, as they are correlated to mechanical properties of the scars.

Studies on wound healing: effects of calcium D-pantothenate on the migration, proliferation and protein synthesis of human dermal fibroblasts in culture.

Weimann BI, Hermann D. F. Hoffmann-La Roche Ltd, Vitamins Division, Basel, Switzerland.

Int J Vitam Nutr Res 1999 Mar;69(2):113-9

The effect of calcium D-pantothenate on the migration, proliferation and protein synthesis of human dermal fibroblasts from three different donors was investigated. The migration of cells into a wounded area was dose-dependently stimulated by Ca D-pantothenate. The number of cells that migrated across the edge of the wound increased from 32 +/- 7 cells/mm without Ca D-pantothenate to 76 +/- 2 cells/mm with 100 mg/ml Ca D-pantothenate. Moreover, the mean migration distance per cell increased from 0.23 +/- 0.05 mm to 0.33 +/- 0.02 mm. The mean migration speed was calculated to be 10.5 mm/hour without and 15 mm/hour with Ca D-pantothenate. Cell proliferation was also dose-dependently stimulated. The final cell densities were 1.2 to 1.6-fold higher in cultures containing 100 mg/ml Ca D-pantothenate. The protein synthesis was modulated, since two unidentified proteins were more strongly expressed in pantothenate supplemented cultures. In conclusion, Ca D-pantothenate accelerates the wound healing process by increasing the number of migrating cells, their distance and hence their speed. In addition, cell division is increased and the protein synthesis changed. These results suggest that higher quantities of pantothenate are locally required to enhance wound healing.

EGF receptor.

Wells A. Department of Pathology, University of Alabama, Birmingham 35294-0007, USA.

Int J Biochem Cell Biol 1999 Jun;31(6):637-43

The receptor for the epidermal growth factor (EGF) and related ligands (EGFR), the prototypal member of the superfamily of receptors with intrinsic tyrosine kinase activity, is widely expressed on many cell types, including epithelial and mesenchymal lineages. Upon activation by at least five genetically distinct ligands (including EGF, transforming growth factor-alpha (TGF alpha) and heparin-binding EGF (HB-EGF)), the intrinsic kinase is activated and EGFR tyrosyl-phosphorylates itself and numerous intermediary effector molecules, including closely-related c-erbB receptor family members. This initiates myriad signaling pathways, some of which attenuate receptor signaling. The integrated biological responses to EGFR signaling are pleiotropic including mitogenesis or apoptosis, enhanced cell motility, protein secretion, and differentiation or dedifferentiation. In addition to being implicated in organ morphogenesis, maintenance and repair, upregulated EGFR signaling has been correlated in a wide variety of tumors with progression to invasion and metastasis. Thus, EGFR and its downstream signaling molecules' are targets for therapeutic interventions in wound repair and cancer.

New innovations in scar management.

Widgerow AD, Chait LA, Stals R, Stals PJ.

Aesthetic Plast Surg 2000 May-Jun;24(3):227-34

As current aesthetic surgical techniques become more standardized and results more predictable, a fine scar may be the demarcating line between acceptable and unacceptable aesthetic results. With this in mind, a scar management program has been adopted based on the modalities of wound support, hydration, and hastened maturity, all factors gleaned from scientific evidence published over the past 25 years. Tension on a scar in one axis will result in a stretched scar, probably initiated by neutrophils and their neutral proteases [18,26]. Tension on a scar from many directions or intermittently will result in a hypertrophic scar, possibly initiated by lymphocytes but definitely related to a prolongation of the inflammatory process, with increased fibroblast activity and overabundant extracellular matrix secretion [24,26]. The common initiating factor is the tension on the scar, and the critical element needed to counteract this tension is scar support. Clinical experience has shown us that the most reliable way to support a scar is by using microporous tape. Hydration is a second beneficial influence on scar control and is the basis of the use of silicone sheeting and gel [7,29,36]. Alpha Centella cream has two main components. The first is an extract from the plant Bulbine frutescens. This increases hydration under the tape by leaving a layer of fatty vesicles of glycoprotein on the skin surface. This also has antibacterial properties. The second component is the principal terpenoids extracted from the Centella asiatica plant. These include Asiatic acid, madecassic acid, and asiaticoside. Centella asiatica has been documented to aid wound healing in a large number of scientific reports [5,12,21,22,33,34,40]. The most beneficial effect appears to be the stimulation of maturation of the scar by the production of type I collagen [4,19] and the resulting decrease in the inflammatory reaction and myofibroblast production. Thus these components have been incorporated into the formulation of a scar management program. This publication reviews much of the available literature relating to scar management and describes the formulation and use of a scar management program based on this information.

Nutritional intake and physical activity in leg ulcer patients.

Wissing U; Unosson M; Lennernas MA; Ek AC

Department of Caring Sciences, Faculty of Health Sciences, University of Linkoping, Sweden.

J Adv Nurs (England) Mar 1997, 25 (3) p571-8

The aim of the study was to describe the nutritional intake, meal patterns, physical activity and need for help in nine women living in their own homes and being treated for venous leg ulcers. Food habits were identified by use of interviews and food diaries completed by the women during a period of seven days. The intake of energy and nutrients from 304 eating events during seven days was calculated and meal patterns were evaluated using a qualitative system for meal classification. Physical activity and the degree of need were identified with the help of interviews. The intakes of energy and key nutrients for wound healing, such as protein, vitamin C and zinc, were not optimal according to the Swedish nutrition recommendations, although food habits were well organized. Most of the women had hardly any physical activities and the need of help and support varied, from daily visits to visits every second week.

Prevalence of magnesium and zinc deficiencies in nursing home residents in Germany.

Worwag M, Classen HG, Schumacher E. Department of Pharmacology and Toxicology of Nutrition, University of Hohenheim, Stuttgart, Germany.

Magnes Res. 1999 Sep;12(3):181-9.

In a multicentric study with 345 seniors over 70 years old we investigated magnesium and zinc levels in serum together with the prevalence of their typical symptoms of deficiency in nursing home residents (NHR) and non-nursing home residents (nNHR). In addition calcium, sodium and potassium levels in serum were determined as well as creatinine and albumin. Considering all seniors 33 per cent exhibited hypomagnesemia and 19 per cent hypozincemia. Zinc levels of female and male NHR were significantly lower than levels of nNHR. Hypomagnesemia was significantly associated with calf cramps and with diabetes mellitus. Hypozincemia was significantly associated with impaired wound healing.

The contribution of vitamin C to healing of experimental fractures.

Yilmaz C, Erdemli E, Selek H, Kinik H, Arikan M, Erdemli B. Department of Orthopaedics and Traumatology, University of Ankara Medical School, Turkey.

Arch Orthop Trauma Surg 2001 Jul;121(7):426-8

The benefits of various minerals and vitamins on fracture healing have been demonstrated in animal models. Vitamin C is an essential substance in fracture healing but has not been studied previously on an experimental basis. Sixteen rats were grouped randomly into control and vitamin C-supplemented groups. The right tibias of all rats were fractured by digital manipulation. One group received single high dose of vitamin C intramuscularly. On the 5th, 10th, 15th, and 20th days, two rats from each group were killed and the tibias examined under light microscopy. It was seen that the vitamin C-supplemented group went through the stages of fracture healing faster compared with the control group.

Activation of a mouse macrophage cell line by acemannan: the major carbohydrate fraction from Aloe vera gel.

Zhang L, Tizard IR. Department of Veterinary Pathobiology, Texas A & M University College Station 77843, USA.

Immunopharmacology 1996 Nov;35(2):119-28

Acemannan is the name given to the major carbohydrate fraction obtained from the gel of the Aloe vera leaf. It has been claimed to have several important therapeutic properties including acceleration of wound healing, immune stimulation, anti-cancer and anti-viral effects. However, the biological mechanisms of these activities are unclear. Because of this wide diversity of effects, it is believed that they may be exerted through pluripotent effector cells such as macrophages. The effects of acemannan on the mouse macrophage cell line, RAW 264.7 cells were therefore investigated. It was found that acemannan could stimulate macrophage cytokine production, nitric oxide release, surface molecule expression, and cell morphologic changes. The production of the cytokines IL-6 and TNF-alpha were dependent on the dose of acemannan provided. Nitric oxide production, cell morphologic changes and surface antigen expression were increased in response to stimulation by a mixture of acemannan and IFN-gamma. These results suggest that acemannan may function, at least in part, through macrophage activation.


Drotrecogin alfa (recombinant human activated protein C) for the treatment of severe sepsis.

McCoy C, Matthews SJ. Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.

Clin Ther. 2003 Feb;25(2):396-421.

BACKGROUND: The search for a life-preserving drug to treat sepsis has increased understanding of the pathogenesis of the process but produced little in the way of successful treatments. The prospective, randomized, double-blind, placebo-controlled, Phase III, multicenter Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial suggested that drotrecogin alfa--recombinant human activated protein C--significantly improved 28-day mortality rates in acute sepsis (P = 0.005).

OBJECTIVES: The goals of this drug review were to summarize the recent findings regarding the pathogenesis of sepsis and septic shock, as well as the results of select immunomodulator drug trials, and to offer a comprehensive review of the mechanism of action, pharmacokinetic profile, efficacy and safety profile, and pharmacoeconomics of drotrecogin alfa.

METHODS: The English-language literature was searched using the EMBASE and MEDLINE databases. In EMBASE, the subject headings drotrecogin, activated protein C, and sepsis were used to search publications from 1980 through September 2002. In MEDLINE, the MeSH heading protein C and subject heading sepsis were used to search publications from 1966 through September 2002. Published abstracts of recent meetings and proceedings of the US Food and Drug Administration were also reviewed.

RESULTS: Drotrecogin alfa mimics the endogenous protein depleted during acute sepsis. Its activity as an antithrombotic, anti-inflammatory, and profibrinolytic agent appears to diminish the negative outcomes of acute sepsis, notably mortality at 28 days. The results of the PROWESS trial support this finding. A bleeding risk was noted during Phase II and III trials despite efforts to exclude those patients at high risk of bleeding.

CONCLUSIONS: Drotrecogin alfa is the first adjunctive agent for the treatment of sepsis to display clinically and statistically significant effects on mortality rates at 28 days. Many questions remain regarding which patients are ideal candidates for treatment. New research and treatment guidelines are necessary to address these questions.

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