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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. hrmaurer@zedat.fu-berlin.de
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.
gerhard.schmidmaier@charite.de
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-&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.
gshukla@zoo.uvm.edu
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.
rmaheshwari@usuhs.mil
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. skutek@aol.com
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.
rspiro@fibrogen.com
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. rmhkgyt@ucl.ac.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.
Laura.Tielinen@hus.fi
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. wells@uab.edu
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. cyilmaz@doctor.com
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.
SUGGESTED
READING
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.
cmccoy@caregroup.harvard.edu
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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