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Biomedical subjects

Martin C Robson

Publications and source records attributed to Martin C Robson.

At least 19 recordsLinked to original sources
PubMed2006

Down-regulating causes of fibrosis with tamoxifen: a possible cellular/molecular approach to treat rhinophyma.

Fibrosis and proliferative scarring are prominent features of the severe forms of rhinophyma. Up-regulation of growth and fibroblast kinetics are hallmarks of fibrosis. Persistent overexpression or dysregulated activation of the fibrogenic isoforms of transforming growth factor beta (TGF-beta) is associated with the increased fibroblast function leading to fibrotic conditions such as rhinophyma. Tamoxifen, a synthetic nonsteroidal antiestrogen, can neutralize or down-regulate TGF-beta. Fibroblast-populated collagen lattices (FPCLs) were constructed from fibroblasts cultured from rhinophyma or normal nasal skin. One-half of each set of FPCLs was treated with Tamoxifen. Lattice contraction was serially measured over 5 days, and the supernatants of the cultures were analyzed for TGF-beta-2 by immunoassay. Tamoxifen significantly decreased fibroblast activity by decreasing contraction of the treated lattices (P < 0.05) and significantly decreased the production/secretion of TGF-beta-2 by rhinophyma fibroblasts (P < 0.001). These results suggest a possible new cellular/molecular approach to the treatment of the fibrotic varieties of rhinophyma.

Case-Control Studies↗
PubMed2006

Wound-healing trajectories as outcome measures of venous stasis ulcer treatment.

Outcome measures of venous ulcer healing are not uniformly accepted. Stringent criteria of 100% closure fail to provide information of healing over the entire span of repair. Wound-healing trajectories (plot of percentage of wound closure versus time of wound treatment) were constructed for 232 patients treated in eight clinical trials at two independent wound care/research centres. Trajectories were constructed for ulcers that totally healed (100% closure) and those that did not (<100% closure) over a 20-week period. Kaplan-Meier survival plots determined the percentage of patients achieving total healing versus time of treatment. The wound-healing trajectories were almost identical for patients achieving complete ulcer healing, as were the trajectories for patients with less than 100% closure. The trajectories for the ulcers healing completely were significantly different from those with <100% closure. Only 60% of all patients achieved 100% closure by 20 weeks. Using linear regression, it was predicted that it would take 31 weeks for all patients to achieve total healing. Total healing is an inadequate outcome measure for healing of venous stasis ulcers. Clinical trials using this measure would require excessive time periods. As wound-healing trajectories for patients treated at two centres mimic one another, shifting the wound-healing trajectory from one of impaired healing to one of a more ideal healing course may be considered a better outcome measure for determining healing of venous stasis ulcers.

Bandages↗
PubMed2004

The prevention of incisional hernia formation using a delayed-release polymer of basic fibroblast growth factor.

OBJECTIVE: We sought to reduce the high incidence of abdominal wall incisional hernias using sustained release growth factor therapy. SUMMARY BACKGROUND DATA: Incisional hernias complicate 11% of abdominal wall closures, resulting in 200,000 incisional hernia repairs in the United States each year. Mechanical improvements alone in mesh, suture material, and surgical technique have failed to reduce the high rate of fascial wound failure. METHODS: Sprague-Dawley rats underwent midline celiotomies that were closed with fast-absorbing suture to induce early biomechanical wound failure and incisional hernia formation. In primary wounds, fascial incisions were closed adjacent to a continuous release polygalactone polymer rod containing basic fibroblast growth factor (bFGF), no growth factor (control-rod), or without rods. In a second group, incisional hernias were repaired with either bFGF or control-rod therapy. Breaking strength was measured on postoperative day (POD) 7, and the incidence of incisional hernia formation was determined on POD 28. RESULTS: Treatment with bFGF rods significantly increased fascial wound breaking strength. In the "hernia-prevention" experiments, incisional hernias developed in 90% of untreated incisions, 60% of control-rod incisions, and only 30% of bFGF-rod incisions (P < 0.05). In the "hernia-treatment" experiments, recurrent incisional hernias developed in 86% of control-rod incisions compared with only 23% of bFGF-rod treated incisions (P < 0.05). Immunohistochemistry demonstrated increased angiogenesis and collagen protein production in bFGF treated incisions. CONCLUSION: The treatment of abdominal fascial incisions with a sustained-release bFGF polymer significantly lowered the incidence of incisional hernias and the recurrence rate after repair.

Abdominal Muscles↗
PubMed2003

Arresting cell cycles and the effect on wound healing.

Wounds that contain a significant number of fibroblasts that are arrested because of senescence, damaged DNA, or enduring quiescence do not heal. As the arrested population of cells decreases and more cells that divide and contribute to wound repair populate the wound, the wound is more likely to achieve closure. Having an understanding of the regulatory mechanisms within the cell cycle is important to wound repair, particularly chronic wounds. The theory of cellular senescence in chronic wounds is new and has never been tested. Studies seem to show that senescent cells in chronic wounds are a significant part of the wounding process. Senescence is irreversible, and senescent cells are refractory to growth factor therapy. Future growth factor therapies or genetic transfections that are capable of repairing the short circuit in cycling cells or overriding the senescent condition will be important partners in the successful treatment of chronic wound patients.

Cell Cycle↗
PubMed2003

Proliferative scarring.

Proliferative scarring in all organ systems is an enigma. Treatment has been difficult to impossible because the pathobiology of exuberant scarring and fibrosis was unclear. With the concept that proliferative scarring can be viewed on the healing trajectory and dissected into variations of the normal wound healing cellular processes mediated by soluble cytokine messengers, one can begin to understand how excessive scar formation occurs. Realizing that overexpression or dysregulated activity of the fibrogenic isoforms of TGF-beta and its attendant effect on apoptosis may be responsible for proliferative scarring opens the route to propose rational molecular manipulations that can be tested for the prevention or treatment of this enigmatic condition.

Cicatrix↗
PubMed2003

Cytokine manipulation of the wound.

Most individuals expect that healing is an inevitable outcome; wound healing is taken for granted. Although wound healing is perceived as inevitable, it can be fraught with problems and altered at many points. In the past, optimization of wound healing focused on minimizing contamination, accurate tissue approximation, and providing protection. With the advent of recombinant technology, optimization can now include manipulation of the molecular and cellular wound environment. Although the exact manipulative scheme has not yet evolved, it is clear from the multiple attempts reported in this article that understanding and progress is being made.

Acute Disease↗
PubMed2003

Radiated groin wounds: pitfalls in reconstruction.

Reconstruction procedures of soft tissue defects created after tumor excision in the ilioinguinal region which have received prior radiation therapy are associated with serious morbidities. Despite the availability of muscle or myocutaneous flaps, wound infection, wound breakdown, and necrosis occur with relative frequency. Changes in tissues secondary to radiation therapy are chronic and permanent and adversely affect wound healing. Tumors in this region should be considered for primary excision and reconstruction, followed by radiation, if necessary.

Combined Modality Therapy↗
PubMed2002

Tamoxifen decreases fibroblast function and downregulates TGF(beta2) in dupuytren's affected palmar fascia.

BACKGROUND: Dupuytren's contracture is a fibroproliferative disorder that is associated with increased collagen deposition. Isoforms of transforming growth factor beta (TGF(beta)), normally TGF(beta1) and TGF(beta2), are involved in the progressive fibrosis of Dupuytren's disease. It has been suggested that downregulation of TGF(beta) may be useful in the treatment of the condition. Tamoxifen, a synthetic nonsteroidal antiestrogen, is known to modulate the production of TGF(beta). This study examined the role of tamoxifen in decreasing fibroblast function and downregulating TGF(beta2). METHODS: Primary cultures of fibroblasts were obtained from Dupuytren's affected fascia and carpal tunnel affected fascia as a control. Collagen lattices were prepared and populated with the fibroblasts. The fibroblast-populated collagen lattices (FPCL) were then measured for contraction every 24 h for 5 days. Supernatant was obtained from the culture medium following completion of the FPCL portion of the experiment and used for a TGF(beta2) immunoassay. RESULTS: Dupuytren's affected fibroblasts contracted the FPCLs significantly more than carpal tunnel control fibroblasts. Treating the fibroblasts with tamoxifen caused a decreased contraction rate in both Dupuytren's affected fibroblasts and carpal tunnel controls. There was increased TGF(beta2) expression in the Dupuytren's affected fascia group compared to the carpal tunnel control group. Tamoxifen decreased TGF(beta2) expression in Dupuytren's affected fascia group but not in the carpal tunnel control group. CONCLUSION: TGF(beta) appears to be the key cytokine in the fibrogenic nature of Dupuytren's disease. Tamoxifen treatment has been demonstrated to decrease the function of fibroblasts derived from Dupuytren's affected fascia and downregulated TGF(beta2) production in these same fibroblasts. These data suggest a method to manipulate and control Dupuytren's contracture in the clinical setting.

Carpal Tunnel Syndrome↗
PubMed2002

Further evidence for the role of fibrosis in the pathobiology of rhinophyma.

Recent evidence suggests that fibrosis may play an important role in the pathobiology of rhinophyma. The fibrogenic cytokine transforming growth factor (TGF)-beta2 has been reported to be up-regulated in rhinophyma tissue. Of the three common isoforms of TGF-beta, TGF-beta1 and TGF-beta2 are considered fibrogenic, whereas TGF-beta3 has antiscarring properties. To provide further evidence for the role of fibrosis in the pathobiology of rhinophyma, specimens from 8 patients with rhinophyma were compared with nine specimens of normal nasal skin. Immunohistochemistry was used to compare intensity levels of TGFbeta1 and TGFbeta3 proteins, and quantitative reverse transcription-polymerase chain reaction was used to determine messenger ribonucleic acid (mRNA) expression levels of TGFbeta1 and TGFbeta3. TGF-beta1 was elevated significantly in rhinophyma tissue (p < 0.001), whereas TGF-beta3 was no different in the rhinophyma specimens compared with normal nasal skin (p = 0.06). TGFbeta1 mRNA expression was five-fold higher in rhinophyma tissue compared with normal skin (p < 0.001). The mRNA expression of TGF-beta3 was the same for both pathological and normal tissue (p < 0.09). These data, together with previously published observations, present further evidence that fibrosis mediated by the fibrogenic cytokines TGFbeta1 and TGFbeta2 play a role in the pathobiology of rhinophyma and suggest a means of treatment by neutralizing or down-regulating these cytokines.

Aged↗
PubMed2002

Decreasing amputation rates in patients with diabetes mellitus. An outcome study.

The lower-extremity amputation rate in people with diabetes mellitus is high, and the wound failure rate at the time of amputation is as high as 28%. Even with successful healing of the primary amputation site, amputation of part of the contralateral limb occurs in 50% of patients within 2 to 5 years. The purpose of this study was to provide valid outcome data before (control period) and 18 months after (test period) implementation of a multidisciplinary team approach using verified methods to improve the institutional care of wounds. Retrospective medical chart review was performed for 118 control patients and 116 test patients. The amputation rate was significantly decreased during the test period, and the amputations that were required were at a significantly more distal level. No above-the-knee amputations were required in 45 patients during the test period, compared with 14 of 76 patients during the control period. These outcome data suggest that unified care is an effective approach for the patient with diabetic foot problems.

Amputation, Surgical↗
PubMed2002

Mycobacterium kansasii causing carpal tunnel syndrome with concomitant pulmonary Mycobacterium tuberculosis infection.

Mycobacterium kansasii is an uncommon cause of infection of the hand. Other atypical mycobacteria that cause hand infections are M marinium, M avium, M intracellularis, and M chelonei. Such infections usually occur around aquatic areas, though sometimes the source of infection is elusive. Inoculation of the atypical mycobacterium into the host occurs usually from a traumatic break in the skin. Patients commonly report a history of fish tank cleaning, oyster shucking, swinuning, or other aquatic activities. Several drug regimenshave been suggested and used successfully. Surgical intervention is occasionally required for unresponsive or symptomatic cases. Concomitant hand infection and pulmonary tuberculosis is extremely rare. We present a case report of M kansasii infection of the hand and forearm, with carpal tunnel syndrome complicated by concomitant pulmonary M tuberculosis.

Carpal Tunnel Syndrome↗
PubMedDate not supplied

Ratios of activated matrix metalloproteinase-9 to tissue inhibitor of matrix metalloproteinase-1 in wound fluids are inversely correlated with healing of pressure ulcers.

Previous analyses of fluids collected from chronic, nonhealing wounds found elevated levels of inflammatory cytokines, elevated levels of proteinases, and low levels of growth factor activity compared with fluids collected from acute, healing wounds. This led to the general hypothesis that chronic inflammation in acute wounds produces elevated levels of proteinases that destroy essential growth factors, receptors, and extracellular matrix proteins, which ultimately prevent wounds from healing. To test this hypothesis further, pro- and activated matrix metalloproteinases (MMP-2 and MMP-9), tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), and the ratios of MMPs/TIMPs were assayed in fluids and biopsies collected from 56 patients with chronic pressure ulcers. Specimens included ulcers treated for 0, 10, and 36 days with conventional therapy or with exogenous cytokine therapies. Quantitative assay data were correlated with the amount of healing. The average MMP-9/TIMP-1 ratio in fluids from 56 ulcers decreased significantly as the chronic pressure ulcers healed. Furthermore, the average MMP-9/TIMP-1 ratio was significantly lower for fluids collected on day 0 from wounds that ultimately healed well (> or =85% reduction in initial wound volume) compared with wounds that healed poorly (< 50% wound volume reduction). These data show that the ratio of MMP-9/TIMP-1 levels is a predictor of healing in pressure ulcers and they provide additional support for the hypothesis that high levels of MMP activity and low levels of MMP inhibitor impair wound healing in chronic pressure ulcers.

Biopsy↗
PubMedDate not supplied

Significance of cell cycle for wound stratification in clinical trials: analysis of a pressure ulcer clinical trial utilizing cyclin D/cdk4.

During the past 5 years, progress in the treatment of pressure ulcers appears to have reached a plateau. Several factors in the design of recent clinical studies may have contributed to this situation. These factors include the criteria chosen for patient selection, small sample size, and lack of a concisely defined final clinical outcome. Hunt noted that wound stratification according to a patient's physiological characteristics may be a key to quantifying differences among clinical treatments. To address this issue, we examined the expression of cyclin D/cdk4 in pressure ulcer fibroblasts taken from tissues during a recent clinical trial. The treatment groups included patients treated with the following regimens: placebo, granulocyte macrophage-colony stimulating factor alone, basic fibroblast growth factor alone, or granulocyte macrophage-colony stimulating factor and basic fibroblast growth factor given in sequence. Immunocytochemical colocalization of cyclin D and cdk4 showed that, before the initial treatment began, patients were distributed disproportionately among treatment subgroups in regards to the initial expression of these markers. For example, we found that compared with other subgroups, ulcer fibroblasts in the basic fibroblast growth factor treatment group showed a much lower expression of cyclin D/cdk4 at day 0. However, this group exhibited higher levels of expression of this complex after 35 days of treatment. This study shows that measurement of cyclin D/cdk4 expression permits more accurate stratification of patients within treatment subgroups, measurement of a cell's ability to detect the presence of functional cytokines, identification of area(s) of failure within the G1 of the cell cycle, and a basis for critical evaluation of various treatments.

Cell Cycle↗
PubMedDate not supplied

Impediments to drug development.

There is a continual need for new products for wound care, as well as a desire by scientists and clinicians to translate information into wound healing improvements for patients. Pharmaceutical and biotechnology companies devote immense resources to fulfilling these needs and desires. However, there are many impediments to drug development that are poorly understood by caregivers, patients, and the public at large. Among these impediments are the tremendous costs involved, the short patent protection time, and regulatory issues. In addition, there is a marked attrition of potential drugs as they progress through the various stages of development. When the costs, time, regulatory issues, and attrition impediments are overcome, the problems with reimbursement become an impediment. This is especially true in the elderly population in which most chronic wound healing problems occur. Finally, academic societies such as the Wound Healing Society and its members pose an impediment to drug development. There is a need to interact with various governmental agencies and industry to facilitate translating science to patient care. This has not been done with a strong, uniform voice. These are but a few of the impediments that prevent scientific advances from resulting in new products available at the bedside to improve the quality of life of our patients.

Biotechnology↗
PubMedDate not supplied

Effect of cytokine growth factors on the prevention of acute wound failure.

Cytokine growth factor treatment of chronic wounds has met with mixed results. The chronic wound presents a hostile environment to peptides such as growth factors. Cytokine growth factors have not been studied extensively in acute wounds. However, incisional hernias are a major example of acute wound failure that has not been solved by various mechanical approaches. A biological approach to acute wound failure by use of cytokine growth factors may offer a new strategy. A rodent incisional hernia model was used. Seventy-six rats underwent 3-cm midline celiotomies and were closed with fine, fast-absorbing sutures to induce intentional acute wound failure. Group 1 received no other treatment. The midline fascia in Groups 2-10 was infiltrated with 100 microl of vehicle alone or vehicle containing various test cytokine growth factors. Necropsy was performed on postoperative day 28 and the wounds were examined for herniation. Incisional hernias developed in 83 percent (13/16) of untreated incisional and 88 percent (7/8) and 83 percent (5/6) of the two vehicle-treated incisions (PBS and carboxymethylcellulose). Hernia incidences were decreased by priming of the fascial incision with transforming growth factor-beta(2) (12%, 1/8), basic fibroblast growth factor (25%, 2/8) and interleukin-1 beta (50%, 3/6) (p < 0.05). Aqueous platelet-derived growth factor, becaplermin, insulin-like growth factor, and granulocyte macrophage-colony stimulating factor did not significantly decrease the incidence of acute wound failure (p > 0.05). A biological approach to acute wound failure as measured by incisional hernia formation can be useful in reducing the incidence of this complication. Transforming growth factor-beta(2), basic fibroblast growth factor, and interleukin 1 beta all eliminated or significantly reduced the development of incisional hernias in the rat model.

Animals↗
PubMedDate not supplied

Fascial fibroblast kinetic activity is increased during abdominal wall repair compared to dermal fibroblasts.

Abdominal wall fascial wound healing failure is a common clinical problem for general surgeons, manifesting in early postoperative fascial dehiscence as well as delayed development of incisional hernias. We previously reported that abdominal wall fascial incisions normally recover breaking strength faster than simultaneous dermal incisions in a rodent model. The accelerated fascial repair was associated with greater fibroblast cellularity within fascial wounds and increased wound collagen deposition. The current study was designed to determine whether accelerated fascial healing is the result of increased fascial fibroblast kinetic activity as measured by a more efficient fibroblast phenotype for binding to and remodeling a collagen matrix. Using a new model of abdominal wall repair, fibroblast cell cultures were developed from uninjured and wounded fascia and compared to dermal fibroblasts in order to define the fibroproliferative kinetic properties of abdominal wall fibroblasts. Fascial wound fibroblasts produced a more efficient and greater overall collagen lattice compaction compared to dermal fibroblasts. Acute fascial wound fibroblasts also showed enhanced cell proliferation compared to dermal fibroblasts but no significant differences in collagen production when normalized to cell number. These results suggest that fascial fibroblasts express distinct acute repair phenotypes and therefore a specific mechanism for fascial repair following injury.

Abdominal Wall↗
PubMedDate not supplied

Cultured pressure ulcer fibroblasts show replicative senescence with elevated production of plasmin, plasminogen activator inhibitor-1, and transforming growth factor-beta1.

In a 16-patient study, cultured fibroblast populations from normal skin were able to replicate an average of 14.8 +/- 2.2 times before becoming senescent, while fibroblast populations from the ulcer bed reached the end of their replicative life span after 7.2 +/- 1.9 population doublings (p= 0.001). Fibroblast populations from 10 of 16 pressure ulcers became senescent after fewer than five population doublings, whereas when populations of fibroblasts from adjacent normal skin were studied, only 2 of 16 became senescent within this same time period. In addition, only an occasional fibroblast from normal skin stained positively for senescence-associated beta-galactosidase compared to approximately 50% of equally aged ulcer bed fibroblasts (p = 0.0060). Senescent ulcer bed fibroblasts secreted significantly more plasmin than early passage ulcer bed fibroblasts (p= 0.0237), nearly six times as much plasmin as early passage normal skin fibroblasts (p < 0.0001), three and a half times the level of normal skin fibroblasts of the same age (11.52 +/- 4.58 microg/mg protein; p= 0.0003), and more than one and a half times the level of senescent normal skin fibroblasts (p= 0.0525). Senescent pressure ulcer fibroblasts generated significantly more plasminogen activator inhibitor-1 (1179.27 +/- 25.37 ng/mg protein) than normal skin fibroblasts of the same age (132.16 +/- 16.20 ng/mg protein; p = 0.0357). Also, senescent ulcer bed fibroblasts produced higher levels of transforming growth factor-beta1, but these were not significantly different from senescent normal skin fibroblasts. Although senescent ulcer fibroblasts produce elevated levels of plasminogen activator inhibitor-1 and transforming growth factor-beta1, the ratio of these factors to plasmin levels suggests that this may have little influence on extracellular matrix synthesis or maintenance in the chronic wound. These data show that cultured fibroblasts from most patient pressure ulcers profile a wound environment that is associated with an increasing population of senescent fibroblasts; however, factors within the chronic wound environment that promote cellular senescence remain unclear. We have proposed that a prolonged inflammatory response may be a contributing factor to the chronic wound condition.

Cells, Cultured↗