Rapamycin-induced impaired wound healing is associated with compromised tissue lactate accumulation and extracellular matrix remodeling.

INTRODUCTION: Extracellular matrix (ECM) remodeling involving matrix metalloproteinases (MMPs) and wound lactate accumulation are essential elements of tissue repair. The aim of this study was to investigate whether rapamycin-induced impaired healing is associated with compromised wound fluid lactate accumulation and altered ECM remodeling. METHODS: Polyvinyl alcohol sponges were subcutaneously implanted in male C57/BL6 mice. Animals were randomized to daily intraperitoneal treatment with either vehicle or 1.5 mg/kg rapamycin. After 7 or 14 days, sponges were harvested to collect wound fluid for subsequent analyses. Wounds were excised for assessment of tensile strength. RESULTS: After 7 days, wound hydroxyproline content was significantly decreased due to rapamycin therapy, whereas the observed difference in tensile strength marginally failed to show statistical significance. In addition, rapamycin reduced wound lactate accumulation and enhanced MMP-2 protein expression, and both MMP-2 and MMP-9 activity. At day 14, wound tensile strength and hydroxyproline content were significantly lower along with an increase in MMP-2 and MMP-9 activity in rapamycin-treated mice. Similarly, wound fluid lactate concentration and MMP-2 protein expression were found to be persistently decreased and increased, respectively. CONCLUSIONS: Rapamycin affects tissue repair by interfering with fundamental mechanisms involved in healing, namely lactate accumulation and ECM remodeling.

Haemodialysis is associated with changes in cutaneous microcirculation in diabetes mellitus.

AIMS: To examine the cutaneous microcirculation on the dorsum of the foot before, during and after haemodialysis in diabetic and non-diabetic patients. METHODS: Fourteen age-matched patients (seven diabetic, seven non-diabetic) without active foot ulceration were studied. Cutaneous microcirculation was assessed using a micro-lightguide spectrophotometer to measure venous oxygen saturation and relative blood flow determined at two tissue depths: 2 and 6 mm. Cumulative relative changes of each parameter during haemodialysis were calculated as area under the curve. Differences between and within the groups were calculated by Mann-Whitney U-test and anova following post hoc testing, respectively. RESULTS: At baseline, relative blood flow at 6 mm tissue depth was significantly greater in diabetic patients (P = 0.048). Thirty minutes after the end of dialysis, relative blood flow at 2 and 6 mm tissue depth was significantly higher in non-diabetic patients (P = 0.048 and P = 0.001). Mean cumulative relative changes in venous oxygen saturation and relative blood flow at 2 mm as well as 6 mm tissue depth were positive for non-diabetic subjects and negative for diabetic patients. CONCLUSIONS: Haemodialysis is associated with changes in cutaneous microcirculation, which differ between people with and without diabetes. In those without diabetes, we found an increase in blood flow during haemodialysis, whereas blood flow was reduced in diabetic patients. This may be the result of abnormal vasomotor regulation due to distal neuropathy.

[Recurrence rates of venous leg ulcers and the special importance of its surgical treatment]. / Rezidivraten des venösen ulkus unter chirurgischer therapie.

BACKGROUND: Venous insufficiency may lead to recurrent leg ulcers. The reason for this observation remains still unclear. In this study we tried to underline the influence of surgical treatment on recurrence rate of venous leg ulcers. PATIENTS AND METHODS: In this study 69 patients were treated in a special wound care centre. Before treatment the angiological status was evaluated using phlebography or duplex scan. Afterwards, patients were scored according to the "Venous Clinical Severity Score" of the American Venous Forum. During the observation period compression therapy was performed and wounds were treated with moist dressings. Necroses were removed by radical debridement and large ulcers were covered by mesh graft tissue transfer. When indicated incompetent veins were treated surgically. RESULTS: The follow-up revealed an overall recurrence rate of 21 % after 30 months. Ulcers treated by radical wound debridement or mesh graft tissue transfer demonstrated a significant lower recurrence rate (p = 0.02 and p = 0.03). According to duplex sonography a correlation was evident among severity of venous insufficiency, the "clinical scoring" (p = 0.04), and the recurrence rate (p = 0.023). After surgical intervention by venous stripping, the insufficiency was improved but the recurrence rate was comparable to that of patients treated without venous surgery (p = 0.44). CONCLUSION: Surgical treatment of venous leg ulcers in modern wound care centres can reduce its recurrence rates. Herein this study a correlation among venous insufficiency evidenced by duplex scan and recurrence rate for leg ulcers could be demonstrated.

[Symptomatic hypocalcemia after thyroidectomy : Prevention by a combination of prophylaxis and risk-adapted substitution]. / Die symptomatische Hypokalzämie nach Thyreoidektomie : Prävention durch eine Kombination von Prophylaxe und risikoadaptierter Substitution.

BACKGROUND: Treatment of hypocalcemia after thyroidectomy consists of an individual substitution, prophylaxis or a daily administration of calcium/vitamin D3. OBJECTIVE: Does prophylactic therapy combined with a risk-adapted substitution of calcium and vitamin D3 reduce symptomatic hypocalcemia compared to individual substitution? MATERIAL AND METHODS: After implementation of a new algorithm, patient data were prospectively documented and analyzed compared to a historical patient population. The algorithm consisted of a single prophylactic i. v. administration of calcium (1 g calcium gluconate 10% in 250 ml saline) and a risk-adapted oral administration of calcium and vitamin D3 after surgery. Patients without risk (parathyroid hormone, PTH > 15 pg/ml) were not treated. Patients with a low risk (PTH ≥ 6 ≤ 15 pg/ml and Ca > 2.0 mmol/l) received 3 g calcium, patients with a high risk (PTH ≥ 6 ≤ 15 pg/ml and Ca < 2.0 mmol/l) received 3 g calcium and 2â€¯× 0.5 µg vitamin D3 and patients with a very high risk (PTH < 6 pg/ml) got 4 g calcium and 2â€¯× 0.5 µg vitamin D3. RESULTS: In this study 415 patients were included (230 prospectively and 185 retrospectively). Serum calcium of patients with individual substitution increased significantly at day 1 (p = 0.0001) and the number of patients with critical hypocalcemia (Ca < 2.0 mmol/l) decreased by half (27% vs. 12.2%; p = 0.0001). There was a significantly lower rate of symptomatic patients (24.9% vs 13.0%; p = 0.002) and a clear reduction of patients with a prolonged hospitalization (10.8% vs. 6.5%; p = 0.08). The rate of permanent hypocalcemia was comparable (2.2% vs. 2.1%). In the risk groups there was a significantly different rate of hypocalcemia: patients without risk (n = 170) in 2.2%, patients with low risk (n = 36) in 25%, patients with high risk (n = 13) in 69.2% and patients with very high risk (n = 11) in 71%. CONCLUSION: This new treatment regimen is practicable, significantly lowers the symptoms, also in comparison to the literature and shows a clear differentiation between the risk groups.

Increased translocator protein (TSPO) mRNA levels in colon but not in rectum carcinoma.

BACKGROUND: The peripheral-type benzodiazepine receptor or translocator protein (TSPO) is an 18-kDa protein involved in cell proliferation and apoptosis. TSPO was shown to be overexpressed in malignant tumors and cancer cell lines, correlating with enhanced malignant behavior. The present study analyzed the role of TSPO in patients with colorectal carcinomas. METHODS: Tumor tissues and corresponding normal mucosa from 55 patients who underwent resection for colorectal carcinomas were analyzed for TSPO expression in correlation to GAPDH expression(glyceraldehyde-3-phosphate dehydrogenase) using a multiplex RT-PCR assay. RESULTS: TSPO was overexpressed in 67% of the tumors in comparison to corresponding normal mucosa, and positivity as well as expression levels in colon carcinomas were significantly higher than in the rectum carcinomas. In contrast, TSPO expression was not different in intermediate versus high-grade tumors or in lymph node-positive versus -negative patients. CONCLUSION: The differences in TSPO expression between colon and rectum carcinoma may imply that these tumors are of different biological behavior.

[The physiology of wound healing]. / Die Physiologie der Wundheilung.

Wound healing is a complex biological phenomenon. A variety of cellular and biochemical events take place designed to achieve tissue integrity following injury. Even though hypoxia caused by the damaged microvasculature is an important initial stimulus of the healing cascade, adequate tissue perfusion and oxygenation is an absolute pre-requisite for a successful repair since essential wound healing mechanisms such as collagen deposition and bactericidal defence are oxygen dependent reactions. Based upon these findings, there are several ways to overcome the obstacle of tissue hypoxia in clinical practice. Supplemental oxygen is capable of increasing tissue oxygen tension. Following surgery, pain, cold and to little fluids are the main issues of vasoconstriction, impaired tissue perfusion and oxygenation as well. However, all these parameters must be corrected at the same time because any one is sufficient to cause maximal vasoconstriction. A well hydrated, pain free and warm patient should be the main goal of peri- and postoperative surgical care.

Correlation of imaging techniques to histopathology in patients with diabetic foot syndrome and clinical suspicion of chronic osteomyelitis. The role of high-resolution ultrasound.

OBJECTIVE: To investigate the role of ultrasound in the diagnosis of osteomyelitis in the diabetic foot compared with magnetic resonance imaging (MRI), bone scintigraphy (BS), and plain film radiography (PFR). RESEARCH DESIGN AND METHODS: We investigated 19 consecutive diabetic patients (2 women, 17 men, age 60.7 +/- 9.8 years, BMI 27.0 +/- 3.8 kg/m2) with clinical suspicion of bone infection of the foot. A high-resolution ultrasound system (Esaote/Biosound, Munich) with a linear array transducer up to 13.0 MHz was used. The prospective and blinded results of each method were compared with histopathology as the reference method after metatarsal resection. RESULTS: In 14 of 19 patients, histopathology confirmed osteomyelitis. Ultrasound showed a sensitivity of 79% (PFR, 69%; BS, 83%; MRI, 100%), a specificity of 80% (PFR, 80%; BS, 75%; MRI, 75%), a positive predictive value of 92% (PFR, 90%; BS, 91%; MRI, 93%), and a negative predictive value of 57% (PFR, 50%; BS, 60%; MRI, 100%). CONCLUSIONS: Our data indicate that ultrasound might have a better diagnostic power for detecting chronic osteomyelitis in the diabetic foot than PFR and has similar sensitivity and specificity as BS. MRI is superior to the other three methods. We conclude that the use of ultrasound in the management of the diabetic foot is worthy of further investigation.

[Possible interventions in impaired wound healing]. / Korrekturmöglichkeiten der gestörten Wundheilung.

Chronic wounds are long-term results of various diseases. Evaluation and therapy of the underlying disorder must be the first goal of a comprehensive wound care protocol. Treatment of local (i.e. wound infection, necrosis, or foreign body) or systemic (i.e. diabetes, immunosuppression, or patient compliance) disturbing factors is the second major step for appropriate wound care. The third major point is wound bed preparation (i.e. debridement, moist wound dressings, or VAC therapy), and wound stimulation. After appropriate wound bed preparation, wounds can be closed by plastic surgery or wound stimulation through various agents (i.e. protease inhibitors, growth factors, or tissue engineering).

[The wound care center in surgery: an interdisciplinary concept for diagnostic and treatment of chronic wounds]. / Die chirurgische Wundsprechstunde. Ein interdisziplinäres, diagnostisches und therapeutisches Konzept für chronische Wunden.

In Germany there is no standardized wound care for patients with chronic wounds in specialized centers. We have established a wound care unit for the past 6 years. The principal concept of therapy was characterized by standardized local surgery, moist wound dressings and concomitant treatment of the underlying disease. We performed local therapy, coordinated the interdisciplinary treatment and developed a new wound documentation system for quality control. We established a close network, integrating general practitioners and home care organizations to realize a mainly outpatient treatment supported by short hospital therapy. Exclusive outpatient treatment was performed in 42% of all patients. According to our prospective data, we achieved an improvement in wound care: 69% of the wounds resistant to therapy for a mean of 30 months healed within 12 months after therapy according to our protocol. Our data strongly supported the importance of local surgery: neither wound depth nor wound infection had any influence on the healing rate, presumably due to radical excisional debridement of necrotic tissue. The presented data justify on medical and economic grounds the establishment of such wound care centers in Germany.

[Network of surgical wound centers using a new electronic data processing documentation system]. / Die Vernetzung chirurgischer Wundzentren mit Hilfe eines neuen EDV-Dokumentationssystems.

UNLABELLED: Care of chronic wounds is of enormous medical, social and economic importance. Nevertheless there is a lack of epidemiological and economical data. A network of ten wound care centers was created and data were documented in a new computerized wound documentation system. METHODS: Treatment was performed according to a comprehensive and standardized wound care protocol. The new documentation system is a network-capable solution. Digital images and planimetry as well as patient and wound related data are recorded. RESULTS: During the first year the ten centers treated and documented already 3281 wounds. There is a wide spectrum of different chronic wounds treated in the participating centers. Despite of long wound duration of several wounds with a median of 5 weeks (range 0-62 years), the healing rate was 80% within 455 days. CONCLUSION: Large amounts of data can be collected and scientifically evaluated in the wound net. This is realized by a new computerized documentation system, which was integrated into the clinical routine and enables clear and standardized documentation. Therefore even large multicenter therapy studies may be performed easily in the wound net and economical data could be collected.

[Stimulation of wound healing with thrombocyte growth factors in treatment of chronic unhealed wounds]. / Stimulation der Wundheilung mit thrombozytären Wachstumsfaktoren bei der Behandlung chronisch nicht-heilender Wunden.

The management of chronic wounds remains a challenge for various medical and surgical specialties. General strategies include local wound care, surgery, skin grafting, debridement, and vascular reconstruction. However, many wounds remain resistant to conventional therapies. Because platelet factors are important in the normal mechanism of wound healing, we report on the topical application of platelet-derived growth factor. Our initial results suggest that the topical application may stimulate and promote healing of chronic wounds.

[Minimally invasive video-assisted thyroidectomy: establishment in a thyroid center]. / Minimalinvasive, videoassistierte Schilddrüsenresektion: Etablierung in einem Schilddrüsenzentrum.

BACKGROUND: This study retrospectively evaluated a series of patients who underwent minimally invasive video-assisted thyroidectomy (MIVAT) during the introduction stage of this surgical technique at the Martha-Maria Hospital in Nuremberg. PATIENTS AND METHODS: The eligibility criteria for MIVAT were a thyroid volume < 25 ml, nodules < 30 mm, no thyroiditis, no preoperative evidence of carcinoma and no previous neck surgery. A retrospective evaluation was performed together with a control group of patients who underwent conventional thyroid surgery during the same time period and included a follow-up for general patient satisfaction and cosmetic results. RESULTS: Between August 2008 and July 2009 a total of 55 patients underwent MIVAT including 8 conversions to open surgery and 45 patients who underwent conventional surgery served as matched controls. No significant differences in terms of perioperative complication rates were found (e.g. recurrent laryngeal nerve palsy, hypocalcemia or secondary hemorrhage). The mean operating time was significantly longer in the MIVAT group (96.8 ± 3.7 min vs. 69.8 ± 2.3 min, p = 0.001) whereas a significant decrease in the mean operating time for hemithyroidectomy after 5 months was observed (98.1 ± 3.77 min vs. 76.0 ± 4.98 min, p = 0.013). Patients in the MIVAT group were more satisfied with the cosmetic outcome (8.5 ± 0.3 vs. 8.2 ± 0.2, p = 0.05) as well as with the overall surgical procedure (9.0 ± 0.3 vs. 8.6 ± 0.2, p = 0.02). CONCLUSION: During introduction of the MIVAT procedure a learning effect can be observed which is hallmarked by a decrease in operating time and conversion rate to open surgery. Moreover, no significant differences in terms of main postoperative complications were found so that MIVAT can be considered a safe and feasible technique under the conditions of correct eligibility criteria.

[Surgical wound consultation]. / Die chirurgische Wundsprechstunde.

Treatment of patients with chronic wounds is characterized by high costs and low efficiency. Epidemiologic data are mainly based on retrospective studies. In 1992, we founded a wound care center and developed a diagnostic and therapeutic algorithm. Prospective data on 293 patients revealed an overall healing rate of 68% (diabetic foot syndrome) and 74% (venous stasis ulcer); mean treatment time was 4.5 months. Relevant prognostic factors were localization of ulcer (0.004), ischemia (0.002), age (0.02) and compliance (0.003), whereas the ulcer grading had no effect on healing.

[Possibilities of demonstration of growth factors in chronic wounds. Demonstration of RNA and protein in wound tissue]. / Nachweismöglichkeiten von Wachstumsfaktoren in chronischen Wunden. RNA- und Protein-Nachweis im Wundgewebe.

Growth factors are important modulators of wound healing. So far, there is little clinical data showing that healing defects in chronic wounds are attribute to deficiency of growth factor expression. Characterization of growth factor expression is necessary to provide new directions toward developing therapies in treating wounds. Present available molecular and immunological techniques allow the analysis of mRNA and protein expression in small amounts of wound material. We analyzed growth factor expression in wound tissue and wound fluid from acute and secondary healing wounds. Wound tissue of secondary healing wounds reveals a higher mRNA growth factor expression compared to acute wound tissue. Secondary healing wounds from our studies demonstrated no deficiency of growth factor expression however, functional analysis may be necessary to determine their activity.

[Ulcus cruris venosum: surgical debridement, antibiotic therapy and stimulation with thrombocytic growth factors]. / Ulcus Cruris Venosum: Chirurgisches Debridement, antibiotische Therapie und Stimulation mit thrombozytären Wachstumsfaktoren.

Despite the availability of various topical agents and of new technics for surgical correction, venous stasis ulcers are still characterized by high recurrent rates. Experimental data from wound healing studies demonstrate stimulation of wound healing after topical application of various growth factors (TGF beta, PDGF, EGF). The results of clinical studies suggest that topical use of an autologous platelet releasate (PDWHF) containing various growth factors accelerates healing. In this prospective study the stimulating effect of autologous PDWHF on epithelialization of small ulcers (group A, < 5000 mm2) and granulation of large ulcers before mesh grafting (> 5000 mm2) will be demonstrated. Inclusion criteria were the venous aetiology of the ulcer and the failure of conventional therapy for 6 month. Exclusion criteria were arterial occlusive disease, diabetes mellitus, acute wound infection, thrombocytopenia and pregnancy. There were 24 patients with 36 ulcers, caused by postthrombotic syndrome in one-third of cases and in two-thirds by severe insufficiency of the perforating veins. The ulcer had been present for more than in 10 years in 38% of cases, while there were 6 circumferential ulcers. The overall ulcer healing rate was 77% after a mean of 14 weeks. In group A 78% of the patients were healed after a mean of 16 weeks. In group B the mesh graft procedure was successful in 90% of the patients after a mean of 13 weeks. Compared with other conventional therapy studies, we achieved a higher healing rate. PDWHF seems to create ideal granulation tissue for mesh graft, indicated by a high uptake of the skin grafts.(ABSTRACT TRUNCATED AT 250 WORDS)

[The role of a radical surgical debridement and mesh graft tissue transfer for treatment of venous ulcers]. / Uber die Bedeutung des radikalen chirurgischen Debridements mit nachfolgender Spalthauttransplantation bei der Behandlung des venösen Ulkusleidens.

Many studies are published demonstrating remarkable results of skin grafting in venous ulcers, but only a few controlled randomised trials including a low number of patients are available. A review based on two controlled randomised trials concludes that there is no significant benefit for mesh graft tissue transfer compared to standard treatment. However, in all studies no adequate initial radical surgical debridement including fasciectomy for wound bed preparation has been performed. In a prospective study on 57 patients with venous ulceration we found significant lower recurrence rates after mesh graft tissue transfer and radical surgical debridement. In clinical practice the results of mesh graft tissue transfer following surgical debridement in the management of larger chronic venous ulcers have been encouraging, although the evidence-based recommendation is lacking. It may not be the treatment of first choice and should be preserved for large ulcers of long duration or history of recurrence. There is need for more randomised controlled studies comparing also cost effectiveness while ensuring baseline comparability.

[Standardized wound documentation of chronic wounds]. / Die standardisierte Wunddokumentation chronischer Wunden.

Owing to the long periods of treatment and multi-factoral etiology of chronic wounds, standardized wound documentation is necessary to enable judgement of the course of healing. We have developed a documentation system which permits a standardized assessment of chronic wounds by means of defined parameters and graded divisions. Besides containing the diagnostic and therapeutic measures which have been carried out, the documentation should also contain parameters of wound healing. These are the following: wound localisation, size of wound, degree of injury, infection, and wound morphology. Planimetry and photographic documentation complete the documentation. Thus a documented course of healing can be presented, which enables rapid retrospective analysis and, if needed, a change in therapeutic approach at an early stage. This complete, exact documentation is required by modern administration of justice and is a protection against the reversal of the onus of proof in lawsuits. The extent of documentation can be adapted to the individual needs of the institution responsible for treatment. However, a minimal amount of documentation should always include localisation of the wound, size, the diagnostic and therapeutic measures, and complications if any.

[Early plastic coverage increases rate of varicose ulcer healing]. / Die frühe plastische Deckung erhöht die Heilungsrate venöser Ulcera.

Treatment of venous ulcer remains a major clinical problem. In a retrospective study including 83 patients with venous leg ulcers, we demonstrated increased healing rates in patients under 60 years of age and ulcers treated by mesh graft.

[Interdisciplinary treatment concepts in chronic wounds]. / Interdisziplinäre Behandlungskonzepte bei chronischen Wunden.

Interdisciplinary concepts for the treatment of chronic wounds are mandatory because of the multifactorial reasons causing ulceration. This is a report on 6 years' experience at the wound care unit in Tübingen. Patients with chronic wounds (mainly diabetic, venous, and ischemic ulcers) were treated primarily as outpatients according to a standardised and interdisciplinary wound care protocol. Quality control was guaranteed by a standardised wound documentation system. The evaluation of this data demonstrates an overall healing rate of 69% within 52 weeks (mean). Before patients were referred to Tübingen, unsuccessful therapy was characterised by a mean wound duration of 35 weeks. The results presented justify this interdisciplinary wound care unit.