[Modern diagnosis and therapy of benign thyroid diseases]. / Moderne Abklärung und Therapie benigner Schilddrüsenerkrankungen.

Modern diagnosis and therapy of benign thyroid diseases Abstract. Benign thyroid diseases continue to be widespread endocrine disorders. Early recognition of their symptoms and exact diagnosis are the prerequisite of targeted therapy and minimal impairment of the patient's well-being. Drug treatment, radioiodine therapy, thermal ablation procedures and surgery have been shown to be successful treatment options. As guidelines for diagnosis and treatment of patients continue to evolve, an interdisciplinary approach ensures optimal diagnosis and management on every step in the care for these patients. We present three clinical scenarios for benign thyroid disease: the symptomatic goitre, the painful thyroid and the thyroid with hyperthyroidism.

Significance of incidental thyroid 18F-fluorocholine uptake in patients with hyperparathyroidism imaged for localizing hyperfunctioning parathyroid glands.

OBJECTIVE: 18F-fluorocholine PET/CT is considered the imaging gold standard for detection of hyperfunctioning parathyroid glands . However, increased uptake might also occur in the thyroid gland. The aim of our study was to assess the incidence and significance of 18F-fluorocholine uptake in the thyroid gland in patients with hyperparathyroidism. MATERIALS AND METHODS: This retrospective study includes 195 consecutive patients with hyperparathyroidism, who underwent 18F-fluorocholine PET/CT, for detection of hyperfunctioning parathyroid glands. PET/CT images were reviewed by two nuclear medicine physicians for the presence of focal or diffuse thyroid uptake. PET/CT results were compared with laboratory parameters, ultrasonography, EU-TIRADS classification in the presence of thyroid nodules, cytology, and final histology. RESULTS: 25 patients (13%) showed 18F-fluorocholine uptake in the thyroid gland: focal thyroid uptake (FTU) in 7 patients (4%), diffuse thyroid uptake (DTU) in 8 patients (4%), and combined uptake (FTU + DTU) in 10 patients (5%), with a total of 20 active thyroid nodules. There was no correlation between EU-TIRADS classification and PET parameters. One highly 18F-fluorocholine active thyroid nodule and one isoactive thyroid nodule turned out to be papillary thyroid cancers in the final histology; 50% of the patients with DTU had Hashimoto's thyroiditis. CONCLUSION: Incidental 18F-fluorocholine uptake in the thyroid gland was observed in 13% of patients. As reported for 18F-FDG, focal 18F-fluorocholine uptake might represent thyroid cancer and should be evaluated with ultrasound and, if indicated, with fine-needle aspiration cytology. Diffuse 18F-fluorocholine uptake most likely represents multinodular goiter or Hashimoto's thyroiditis.

Localization of Brown Tumors With 18 F-Fluorocholine PET/CT Imaging in Severe Primary Hyperparathyroidism.

ABSTRACT: We present the case of a 68-year-old woman with a painful tibial tumor and fatigue. Histology and laboratory studies were consistent with a brown tumor secondary to initially unrecognized, severe primary hyperparathyroidism. 18 F-fluorocholine PET/CT revealed a large hypermetabolic parathyroid mass and multiple bone foci considered as brown tumors. Unilateral neck exploration confirmed a large parathyroid adenoma. Serum calcium and parathyroid hormone levels normalized quickly, and symptoms subsided gradually after parathyroidectomy. Brown tumors are a rare complication of severe hyperparathyroidism. 18 F-fluorocholine PET/CT allows the localization of parathyroid adenomas and brown tumors, and can be used as a single imaging modality.

Cribriform Morular Thyroid Carcinoma - Ultimobranchial Pouch-Related? Deep Molecular Insights of a Unique Case.

A 44-year-old female patient with a familial adenomatous polyposis (FAP) was diagnosed with a cribriform morular thyroid carcinoma (CMTC). We observed within the very necrotic tumor a small but distinct poorly differentiated carcinomatous component. As expected, next generation sequencing of both components revealed a homozygous APC mutation and in addition, a TERT promoter mutation. A TP53 mutation was found exclusively in the CMTC part, while the poorly differentiated component showed a clonal evolution, harboring an activating PIK3CA mutation and copy number gains of BRCA2, FGF23, FGFR1, and PIK3CB-alterations which are typically seen in squamous cell carcinoma. The mutational burden in both components was low, and there was no evidence for microsatellite instability. No mutations involving the mitogen-activated protein kinase (MAPK) pathway, typically seen in papillary thyroid carcinomas, were detected. Immunohistochemically, all tumor parts were negative for thyroglobulin, providing further evidence that this entity does not belong to the follicular epithelial cell-derived thyroid carcinoma group. CD5 was negative in the poorly differentiated component, making a relation to intrathyroidal thymic carcinoma rather unlikely. However, since this marker was seen in the morules, a loss in the poorly differentiated component and a relation to the ultimobranchial body cannot be excluded either. After total thyroidectomy and radioiodine ablation, the patient was disease-free with no residual tumor burden on 2-year follow-up.

18F-Fluorocholine-PET combined with contrast-enhanced CT for localizing hyperfunctioning parathyroid glands and optimizing surgical treatment in patients with hyperparathyroidism.

PURPOSE: Hyperparathyroidism (HPT) is a common disorder. A cure can only be achieved by removing all diseased glands. It is critical to localize the hyperfunctioning glands exactly to prevent extensive surgical exploration. The number of false negative/inconclusive results in standard imaging techniques is high. We aimed to evaluate the diagnostic accuracy of 18F-Fluorocholine-PET in combination with contrast-enhanced CT (FCH-PET/CT) and its sensitivity in patients with primary, secondary/tertiary, and familial HPT with negative and/or discordant findings in ultrasound and/or 99mTc-sestamibi scintigraphy/SPECT/CT. METHODS: A total of 96 patients with HPT and negative/equivocal conventional imaging were referred for FCH-PET/CT. In this retrospective, single institution study, 69 patients, who have undergone surgery and histopathologic workup, were analyzed. Of the 69 patients included, 60 patients suffered from primary HPT, four from secondary or tertiary HPT, and five from familial HPT. Sensitivities, positive predictive values, and accuracies were calculated. RESULTS: Sensitivity/positive predictive value (PPV) per lesion was 87.5/98.3% for primary HPT, 75/100% for secondary/tertiary HPT and 25/66.7% for familial HPT. Sensitivity/PPV per patient was 91.5/98.2% for primary HPT, 100/100% for secondary/tertiary HPT and 50/100% for familial HPT. All patients showed normalized serum calcium levels in the postoperative period. The follow-up rate was 97%. Of the patients included in the study, 58 of 60 patients with primary HPT, and four of four patients with secondary/tertiary HPT showed normal calcium and parathyroid hormone (PTH) levels after six months and were cured. Of the patients with familial HPT, four of five patients were cured. CONCLUSION: Diagnostic accuracy of 18F-Fluorocholine-PET/CT for patients with pHPT is excellent. 18F-Fluorocholine-PET/CT is a valuable tool for endocrine surgeons to optimize the surgical treatment of patients with hyperparathyroidism.

European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders.

This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders (PARAT) in 2019, were discussed during two virtual workshops in 2021, and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosing to familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represent areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT, need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborns children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed for a broader clinical audience, and were developed with focus on endocrinologists in training.

M.A.I.D.: a prognostic score estimating probability of healing in chronic lower extremity wounds.

OBJECTIVE: To evaluate a wound-based prognostic score for chronic lower extremity wounds suitable for daily routine use capable of predicting long-term healing. SUMMARY BACKGROUND DATA: The main obstacle in the treatment of chronic wounds is to estimate long-term clinical outcome. For diabetic foot ulcers, several ulcer, and nonulcer-related risk factors associated with impaired healing have been described in the past. METHODS: A new chronic lower extremity ulcer score (M.A.I.D.) was created out of 4 clinically defined parameters, namely palpable pedal pulses (I), wound area (A), ulcer duration (D), and presence of multiple ulcerations (M). Palpable pedal pulses were categorized by the absence (scored as 1) or presence (scored as 0) of pedal pulses, while wounds >4 cm were scored as 1 and wounds < or = 4 cm as 0. Ulcers lasting more than 130 days were categorized as 1 and wounds with a duration of <130 days as 0. Patients with multiple ulcerations were graded as 1 (=1) compared with those with single ulcers (=0). M.A.I.D. was calculated by adding these separate scores to a theoretical maximum of 4. RESULTS: Two thousand nineteen consecutive patients with 4004 wounds were included. When patients were divided into subgroups with the same M.A.I.D., we showed a decreasing probability of healing for ulcers with higher M.A.I.D. scores. An increase in the M.A.I.D. by 1 score-point reduced the chance for healing by 37%. Similarly, the higher the ulcer score, the larger the initial wound area, the longer the wound history, and the more likely the occurrence of soft-tissue infection during follow-up. CONCLUSIONS: This new chronic lower extremity ulcer score is capable of anticipating long-term probability of healing by combining 4 clinically assessable parameters. However, adequate and standardized wound care is an indispensable prerequisite for M.A.I.D. to be a valid diagnostic tool in daily clinical routine.

Aging influences wound healing in patients with chronic lower extremity wounds treated in a specialized Wound Care Center.

With the dramatic increase in the aging population, the study and care of wounds in the elderly have become priority topics for both researchers and clinicians. The effects of aging on wound healing in humans have remained controversial. The study was a 5-year epidemiological evaluation of standardized data collected regularly during patients' visits at a specialized Wound Care Center with the aim to determine the key factors influencing the healing of chronic lower extremity wounds. In this analysis of 1,158 chronic wounds, the frequency of wound closure was statistically significantly lower in older patients compared with younger patients. The share of closed wounds decreased by nearly 25% in the elderly patients (>or=70 years). The relationship between the patient's age and the proportion of wound closure was nonlinear. The effect of aging on the frequency of wound closure of chronic wounds became clinically apparent after age 60. The chronicity of the wounds was illustrated by their recurrent nature, their long duration, the presence of multiple wounds, and the frequency of concurrent infection. Comorbidity was documented by the coprevalence of up to three underlying diseases related to impaired wound healing. The present study clearly showed that aging affects chronic wound healing negatively.

[Hypoparathyroidism - un underestimated problem?] / Hypoparathyreoidismus ­ ein unterschätztes Problem?

BACKGROUND: Hypoparathyroidism is a rare and disabilitating disorder characterized by hypocalcemia and low parathyroid hormone levels. Most of the cases occur as a result of the removal of parathyroid glands or damage to the glands during neck surgery. More rare causes include nonsurgical causes such as autoimmune or genetic diseases. METHOD: In this review, a panel of experts presents the current state of diagnosis and therapy of hypoparathyroidism and explains practical aspects of caring for the affected patients. RESULTS: Common signs and symptoms are abnormal sensations and increased excitability in the lower limbs, paresthesia of perioral areas and nocturnal leg cramps. Renal complications frequently occur, but also basal ganglia calcification. Treatment consists of administration of vitamin D analogs in combination with 0.5-1.0 g calcium daily. An adjunctive treatment with the in April 2017 approved recombinant human parathyroid hormone (1-84) is an option for patients whose hypoparathyroidism is difficult to control by conventional treatment alone. Initially and after dose changes follow-up controls should be performed at least every 2 weeks, in well-controlled patients or in the case of chronic progression every 3-6 months.

A new wound-based severity score for diabetic foot ulcers: A prospective analysis of 1,000 patients.

OBJECTIVE: Several well-accepted classification systems are available for diabetic foot ulcers. However, there are only a few and scientifically not validated severity scores. The aim of this study was to establish a new wound-based clinical scoring system for diabetic foot ulcers suitable for daily clinical practice anticipating chances for healing and risk of amputation. RESEARCH DESIGN AND METHODS: Four clinically defined parameters, namely palpable pedal pulses, probing to bone, ulcer location, and presence of multiple ulcerations, were prospectively assessed in 1,000 consecutive patients. In the next step, a new diabetic ulcer severity score (DUSS) was created from these parameters. Palpable pedal pulses were categorized by the absence (scored as 1) or presence (scored as 0) of pedal pulses, while probing to bone was defined as yes (scored as 1) or no (scored as 0). The site of ulceration was defined as toe (scored as 0) or foot (scored as 1) ulcer. Patients with multiple ulcerations were graded as 1 compared with those with single ulcers (scored as 0). The DUSS was calculated by adding these separate gradings to a theoretical maximum of 4. Wounds were followed-up for 365 days or until healing or amputation if earlier. Probability of healing and risk of amputation were calculated by the Kaplan-Meier method. RESULTS: Uni- and multivariate analyses showed a significantly higher probability of healing for patients with palpable pulses, no probing to bone, toe ulcers, and absence of multiple ulcerations. When patients were divided into subgroups with the same DUSS, we found significantly different probabilities for healing. We showed a decreasing probability of healing for ulcers with a high DUSS, concurrent with increasing amputation rates. An increase in the DUSS by one score point reduced the chance for healing by 35%. Similarly, the higher the ulcer score, the larger the initial wound area, the longer the wound history, and the more likely the need for surgery or hospitalization. CONCLUSIONS: The DUSS categorizes different ulcers into subgroups with specific severity and similar clinical outcome. Using this score, the probabilities for healing, amputation, need for surgery, and hospitalization are predictable with high accuracy. This might be useful for the anticipation of health care costs and for comparison of subgroups of patients in clinical studies.

Documentation of 7051 chronic wounds using a new computerized system within a network of wound care centers.

HYPOTHESIS: Wound care can be prospectively recorded on a large scale if a standardized wound documentation system is established. Based on such a documentation system, a network of specialized wound care centers can generate a large and valid database of wound characteristics, wound-healing dynamics, and wound care. DESIGN: A clinical prospective analysis. SETTING: Ten German specialized surgical wound care centers. PATIENTS AND METHODS: In a 2-year pilot phase, 4175 patients with 7051 chronic nonhealing wounds were documented using a new computerized system and treated following defined standards. RESULTS: A total of 1761 diabetic, 1349 venous, 1146 ischemic, 1079 pressure, and 759 postoperative nonhealing wounds and 957 ulcers with other causes were prospectively documented. Chronicity of ulceration was shown by the long wound duration of 433 days (range, 14-1867 days). Wound documentation was well integrated into daily practice, as shown by a mean +/- SD documentation time of 5.7 +/- 2.2 minutes per visit. A multivariate analysis of factors known to interfere with wound healing revealed significant effects of patient compliance, grading of wound depth, and patient age (P<.001 for all). CONCLUSIONS: The German Wound Net achieved, for the first time, centralized and prospective documentation of more than 7000 chronic wounds treated according to defined guidelines. This new concept of a network of specialized wound care centers working with standardized treatment plans and prospective documentation of chronic wounds may open a new dimension for wound-healing studies and may represent an optimal platform for multicenter trials.

Improved production of bioactive glucosylmannosyl-glycerolipid by sponge-associated Microbacterium species.

The marine Microbacterium species HP2 (DSM 12583), isolated from the sponge Halichondria panicea, is able to produce a glucosylmannosyl-glycerolipid when grown on a complex medium with glucose. Optimizing the carbon sources in shake flask experiments has shown that glycerol affords the highest specific glycoglycerolipid production. The product yield approached 300 mg/L or 25 mg/g biomass upon scaling up in a 40-L bioreactor volume. The native diglycosyl-glycerolipid GGL.2 strongly inhibited growth of the tumor cell lines HM02 and Hep G2 (50% inhibition at 0.4 to 3 microg/mL), while the related deacylated compound (GG.2) showed a potent anti-tumor-promoting activity.

Accuracy of parathyroid imaging: a comparison of planar scintigraphy, SPECT, SPECT-CT, and C-11 methionine PET for the detection of parathyroid adenomas and glandular hyperplasia.

PURPOSE: To compare the accuracy of planar scintigraphy, single photon emission computed tomography (SPECT), SPECT-CT, and positron emission tomography (PET) with C-11 methionine for the pre-operative detection of parathyroid adenomas. MATERIALS AND METHODS: We retrospectively evaluated the pre-operative studies of 60 patients with primary (n=56) and secondary (n=4) hyperparathyroidism. In 25/60 patients (Group 1), only planar scans were obtained, and additional SPECT and SPECT-CT were carried out in 35/60 patients (Group 2). PET or PET-CT with C-11 methionine was conducted in 8/60 patients (Group 3). RESULTS: The results of the planar scans (Group 1) were true positive in 19/25 patients and false negative in 6/25 patients (sensitivity per patient, 76%). Histopathology confirmed 27 adenomas and two hyperplasia. Planar imaging identified 20/29 of these pathologies, whereas 9/29 were missed (sensitivity per adenoma, 69%). SPECT (Group 2) results were true positive in 34/35 patients and false negative in only one case (sensitivity per patient, 97%). On a lesion-based analysis, 38 adenomas were identified, and two were missed (sensitivity per adenoma, 95%). The sensitivities of SPECT and SPECT-CT were equal; however, SPECT-CT provided superior topographic information. C-11 methionine PET (Group 3) results were true positive in all eight patients. In one case, surgery confirmed two ipsilateral adenomas, only one of which was identified by PET (sensitivity per patient, 100%; per adenoma, 88.9%). CONCLUSION: SPECT is superior to planar imaging. SPECT-CT has identical sensitivity compared to SPECT alone, but it provides additional topographic information. The sensitivity of PET appears to be even higher compared to SPECT. In the case of negative scintigraphic findings and proven hyperparathyroidism, additional C-11 methionine PET or PET-CT is recommended.

Fetuin-A induces cytokine expression and suppresses adiponectin production.

BACKGROUND: The secreted liver protein fetuin-A (AHSG) is up-regulated in hepatic steatosis and the metabolic syndrome. These states are strongly associated with low-grade inflammation and hypoadiponectinemia. We, therefore, hypothesized that fetuin-A may play a role in the regulation of cytokine expression, the modulation of adipose tissue expression and plasma concentration of the insulin-sensitizing and atheroprotective adipokine adiponectin. METHODOLOGY AND PRINCIPAL FINDINGS: Human monocytic THP1 cells and human in vitro differenttiated adipocytes as well as C57BL/6 mice were treated with fetuin-A. mRNA expression of the genes encoding inflammatory cytokines and the adipokine adiponectin (ADIPOQ) was assessed by real-time RT-PCR. In 122 subjects, plasma levels of fetuin-A, adiponectin and, in a subgroup, the multimeric forms of adiponectin were determined. Fetuin-A treatment induced TNF and IL1B mRNA expression in THP1 cells (p<0.05). Treatment of mice with fetuin-A, analogously, resulted in a marked increase in adipose tissue Tnf mRNA as well as Il6 expression (27- and 174-fold, respectively). These effects were accompanied by a decrease in adipose tissue Adipoq mRNA expression and lower circulating adiponectin levels (p<0.05, both). Furthermore, fetuin-A repressed ADIPOQ mRNA expression of human in vitro differentiated adipocytes (p<0.02) and induced inflammatory cytokine expression. In humans in plasma, fetuin-A correlated positively with high-sensitivity C-reactive protein, a marker of subclinical inflammation (r = 0.26, p = 0.01), and negatively with total- (r = -0.28, p = 0.02) and, particularly, high molecular weight adiponectin (r = -0.36, p = 0.01). CONCLUSIONS AND SIGNIFICANCE: We provide novel evidence that the secreted liver protein fetuin-A induces low-grade inflammation and represses adiponectin production in animals and in humans. These data suggest an important role of fatty liver in the pathophysiology of insulin resistance and atherosclerosis.

Treatment of periprosthetic soft tissue infection of the groin following vascular surgical procedures by means of a polyvinyl alcohol-vacuum sponge system.

Deep groin infections after prosthetic vascular surgical procedures represent a serious complication of surgical practice. Septicemia and/or erosive hemorrhage can both be consequences. In this situation, removal of the graft appears to be the only option. However, if the infection is detected early (type Szilagyi III), local treatment to eradicate the infection could serve as an alternative. Twenty-four patients with confirmed infection of the soft tissue adjacent to the prosthetic material in the groin were treated locally by implantation of a vacuum sponge system. Duration of this treatment was 2 weeks. All patients showed excellent tissue granulation of the wound area and the microbial stains were negative at the end of therapy. In 21 patients the wound could be primarily closed after explantation of the sponge. Three patients underwent open treatment because of a skin defect. After 12 months, the wounds had healed well in all patients. Histologic evaluation revealed a physiological healing process. Deep soft tissue infections of the groin adjacent to prosthetic vascular material (type Szilagyi III) can be treated effectively and safely with the vacuum sponge system. The treatment is inexpensive, easy to perform, and the initial vascular reconstruction can be preserved.

Subcapsular liver hematoma in HELLP syndrome: Evaluation of diagnostic and therapeutic options--a unicenter study.

OBJECTIVE: Subcapsular liver hematoma formation has been reported in less than 2% of pregnancies complicated by HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. The purpose of this study was to identify the main diagnostic and therapeutic options for management of these patients. STUDY DESIGN: In this 10-year retrospective review, we performed a computer-directed search of all cases of confirmed HELLP syndrome with hepatic hematoma treated in the surgical department of our tertiary care referral medical center. RESULTS: Five patients with subcapsular liver hematoma in HELLP syndrome could be identified. All patients received transabdominal ultrasound, computed tomography, or magnetic resonance imaging. Conservative treatment was successful in three patients. Emergency surgical intervention was necessary in two patients, including one liver transplantation. CONCLUSION: The case series shows the full diagnostic spectrum with transabdominal ultrasound, computed tomography, and magnetic resonance imaging, as well as the different therapeutic options varying from conservative therapy to operative management, including liver transplantation.

Age-dependency of insulin-like growth factors, insulin-like growth factor-binding proteins, and acid labile subunit in plasma and wounds of surgical patients.

Wound problems are common in the elderly. We hypothesized that age-related decrements in blood levels of components of the insulin-like growth factor (IGF) system are reflected in the wound environment. In this prospective, observational study IGF-I, IGF-II, IGF-binding protein-2, IGF-binding protein-3, and acid labile subunit were measured by immunoassays in the wound fluid and plasma of young (23.5 +/- 3.3 years) and elderly (78.9 +/- 6.2 years) patients before and daily for 4 days after elective surgery. IGFs, IGFBP-3, and acid labile subunit in plasma were significantly lower in the elderly group (p < 0.0001). The decrements of these proteins in plasma were reflected in corresponding decrements of 25-70% in the wound fluid of elderly patients (p < 0.0001). Additionally, bioavailability of IGF-I was less in the aged. The IGF parameters in the wound displayed a constant ratio with those of blood, suggesting that blood contributes a major share of the IGF that enters the wound during the initial phase of healing. The current data adds to accumulating evidence that a decline in the IGF system in aged patients contributes to the healing deficits observed in the elderly.

Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing.

For many years, lactate has been known to accelerate collagen deposition in cultured fibroblasts and, without detailed explanation, has been presumed to stimulate angiogenesis. Similarly, hypoxia has been linked to angiogenic effects and collagen deposition from cultured cells. Paradoxically, however, wound angiogenesis and collagen deposition are increased by breathing oxygen and decreased by hypoxia. Lactate accumulates to 4-12 mM in wounds for several reasons, only one of which is the result of hypoxia. Oxygen in wounds is usually low but can be increased by breathing oxygen (without change in lactate). We have reported that lactate elicits vascular endothelial growth factor (VECF) from macrophages, as well as collagen, some heat shock proteins, and VECF from endothelial cells, and collagen from fibroblasts, even in the presence of normal amounts of oxygen. Hypoxia exerts many of these same effects in cultured cells. In this study, we elevated extracellular lactate in wounds by implanting purified solid-state, hydrolysable polyglycolide. A steady-state 2-3 mM additional elevation of lactate resulted. With it, there was a significant short-term elevation of interleukin-1beta, a long-term elevation of VECF (2x) and transforming growth factor-beta1 (2-3x), a 50% elevation in collagen deposition, and a large reduction of insulin-like growth factor-1 (- 90%). We propose that lactate induces a biochemical "perception" of hypoxia and instigates several signals that activate growth factor/cytokine signals while the continued presence of molecular oxygen allows endothelial cells and fibroblasts to reproduce and deposit collagen. The data are consistent with ADP-ribosylation effects and oxidant signaling. (WOUND REP REG 2003;11:504-509)