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Biomedical subjects

M Hauer-Jensen

Publications and source records attributed to M Hauer-Jensen.

At least 19 recordsLinked to original sources
PubMed2005

Influence of statins on postoperative wound complications after inguinal or ventral herniorrhaphy.

The lipid-lowering agents, statins, are the most commonly prescribed class of drugs in the western world. Because of their widespread use, many patients undergo surgical procedures while on statins. Statins, in addition to cholesterol-lowering effects, also have anticoagulant, immunosuppressive, and antiproliferative properties that may affect the risk of local wound complications. This study investigated the relationship between statins and postoperative wound complications in a large cohort of patients undergoing inguinal or ventral hernia repair. Data mining was performed in the Veterans Integrated Service Network (VISN)16 Data Warehouse. This database contains clinical and demographic information about all veterans cared for at the ten VA Medical Centers that comprise the South Central VA Healthcare Network in the mid-south region of the US. Aggregate data (age, body mass index, smoking history, gender, race, history of diabetes, statin use, and postoperative wound complications) were obtained for all patients who underwent inguinal or ventral hernia repair during the period October 1, 1996-November 30, 2004. During the period of the query, 10,782 patients (10,676 male, 106 female), 1,242 (11.5%) of whom received statins, underwent herniorrhaphy. Statin use did not affect the risk of wound infection or delayed wound healing. Statin use was, however, associated with an increased rate of local postoperative bleeding complications (P=0.01). When the type of hernia, age, smoking, diabetes, and body mass index were included in a multivariate analysis, statins remained borderline significant as an independent predictor of wound hematoma/postoperative bleeding (P=0.04), odds ratio 1.6 (95% CI 1.03-2.44). Patients who undergo inguinal herniorrhaphy while on statins have an increased risk of postoperative wound hematoma/hemorrhage. Focus on additional factors that may affect the propensity to postoperative bleeding and on meticulous intraoperative hemostasis are particularly important in such patients.

Diabetes Mellitus↗
PubMed2004

Hirudin ameliorates intestinal radiation toxicity in the rat: support for thrombin inhibition as strategy to minimize side-effects after radiation therapy and as countermeasure against radiation exposure.

BACKGROUND: The small bowel is a dose-limiting normal tissue in radiation therapy of malignancies in the abdomen and pelvis, as well as an important determinant of survival after non-therapeutic radiation exposure. Irradiation of normal tissues, including intestine, causes loss of vascular thromboresistance and upregulation of thrombin receptors. Radiation-induced endothelial dysfunction is thought to be involved in both early and delayed radiation responses. Hence, thrombin may be a potential target for ameliorating normal tissue radiation toxicity. OBJECTIVE: To assess direct thrombin inhibition as a protective strategy against small bowel radiation toxicity. METHODS: Rat small intestine was exposed to localized orthovoltage X-radiation. Recombinant hirudin, a direct thrombin inhibitor, or vehicle was infused from 2 days before irradiation to 14 days after irradiation. Structural, cellular, and molecular aspects of intestinal radiation injury were assessed at 2 weeks (early toxicity) and 26 weeks (chronic toxicity) after irradiation. RESULTS: Compared with unirradiated intestine, irradiated intestine showed increased expression of tissue factor, increased immunoreactivity for enzymatically active thrombin, and increased extravascular fibrin(ogen) deposition. Hirudin treatment significantly attenuated radiation-induced mucosal damage (P = 0.04), reactive intestinal wall thickening (P = 0.02), transforming growth factor-beta immunoreactivity levels (P = 0.0002), and collagen III deposition (P = 0.003). The differences between hirudin-treated and control rats were more pronounced at 2 weeks than at 26 weeks after irradiation. Hirudin treatment did not affect postradiation granulocyte infiltration. CONCLUSIONS: Short-term thrombin inhibition attenuates important aspects of intestinal radiation toxicity. Thrombin is a promising target for minimizing normal tissue injury after radiation therapy of cancer, as well as for protecting normal tissues from the adverse effects of non-therapeutic radiation exposure.

Animals↗
PubMed2003

Lichtenstein vs anterior preperitoneal prosthetic mesh placement in open inguinal hernia repair: a prospective, randomized trial.

Male veterans with unilateral primary inguinal hernia, classified intraoperatively as Gilbert Type III or IV, were randomized to subaponeurotic (Lichtenstein, n=126) or preperitoneal (Read-Rives, n=121) repair under general or spinal anesthesia. The two groups of patients were comparable in age, body weight index, comorbidities, and size and type of hernia. Of the 247 patients enrolled, 224 were followed for at least 2 years (median 82 months, range 24-110 months), 16 were lost to follow-up, and seven died from causes unrelated to the surgery. The average operative time of the Read-Rives repair was 9 min longer than that of the Lichtenstein repair. There were no wound infections, and the frequencies of other short- and long-term complications were low and similar in the two groups. Six patients developed hernia recurrence, five in the Lichtenstein group (4.3%), and one in the Read-Rives group (<1%), ( P=0.21). Both anterior repairs are associated with low postoperative morbidity and recurrence rates. The Lichtenstein repair is technically easier and less time consuming. There is no statistically significant difference in the recurrence rate between the two repairs.

Adolescent↗
PubMed2002

Cytokines in coagulation and thrombosis: a preclinical and clinical review.

The cytokine network is a complex and dynamic system, involved in numerous biological responses in the human body. This review of the current literature describes the role of cytokines and their interaction with the coagulation system, specifically in the maintenance of the thrombo-hemorrhagic balance in vivo in human subjects and in animals. In general, cytokines are thrombogenic, but they are amenable to therapeutic manipulations and hence are a potentially attractive tool in the clinician's armamentarium. Studies of the effects of cytokines in vivo are difficult because cytokines act in a very finite microenvironment and, although their actions are significant, they are transient. Most of the available clinical data related to interactions between cytokines and the coagulation system focuses on the role of tumor necrosis factor-alpha and interleukin-1 in septicemia and septic shock. However, several other cytokines and related proteins, such as platelet activating factor and plasminogen activator inhibitor, are also known to influence coagulation and thrombosis. These factors interact closely with cytokines, and have been included in this review for a better understanding of their interactions with traditional cytokines. Studies that utilize cell culture systems do not accurately model the in vivo status of this complex system and, hence, this review has excluded such studies. The role of the cytokine network in coronary artery disease, angiogenesis, or neoplasia has been addressed elsewhere by other workers and is not discussed here. By emphasizing important in vivo interactions, the intention of this review is to serve as an impetus to further translational research, both clinical and in the laboratory.

Blood Coagulation↗
PubMed2001

Radiation-induced granulocyte transmigration predicts development of delayed structural changes in rat intestine.

We examined whether early radiation-induced granulocyte transmigration (assessed by the fecal transferrin excretion ELISA assay) predicts subsequent development of (consequential) chronic radiation enteropathy. After accounting for the effect of radiation dose, transferrin excretion remained an independent predictor of overall tissue injury, intestinal fibrosis, and mucosal ulcers, but not TGF-beta immunoreactivity.

Animals↗
PubMed2001

Association between decreased pulmonary endothelial cell thrombomodulin and local fibrin deposition in pneumonia.

Thrombomodulin (TM) plays an important role in anticoagulation by forming a complex with thrombin, which subsequently activates protein C. TM is inactivated and downregulated by inflammatory cell mediators. This study examined whether bronchopneumonia is associated with changes in TM immunoreactivity, and whether a decrease in TM is accompanied by evidence of hypercoagulability, i.e. local deposition of fibrin. Double antibody staining for TM and fibrin was performed on lung tissue sections from patients who had died of pneumonia and from patients who had died rapidly, secondary to trauma. Inflammatory changes were assessed histologically and immunohistochemically using antibodies against interleukin-1alpha, tumor necrosis factor-alpha, and myeloperoxidase. Areas with bronchopneumonia exhibited markedly decreased endothelial TM staining of alveolar walls and small vessels. These changes were associated with prominent fibrin immunoreactivity. Some areas exhibited mild to moderate inflammation with little fibrin deposition and variable amounts of TM in adjacent vessels. This study is the first to relate changes of TM immunoreactivity levels to fibrin deposition in a human disease process. These data may have implications for pulmonary pathophysiology in patients with bronchopneumonia.

Cytokines↗
PubMed2001

Influence of Short-Term Octreotide Administration on Chronic Tissue Injury, Transforming Growth Factor beta (TGF-beta) Overexpression, and Collagen Accumulation in Irradiated Rat Intestine.

The somatostatin analog octreotide was recently found to ameliorate radiation-induced tissue injury in rat intestine. The present study addressed whether octreotide reduces chronic intestinal radiation fibrosis, whether enteroprotection is conferred by direct or indirect mechanisms, and whether the effects are dose-dependent. Using a rat model designed for fractionated irradiation, a segment of small intestine was sham-irradiated or exposed to 67.2 Gy X-radiation in 16 daily fractions. Octreotide (0, 2, or 10 microg/kg/h) was administered subcutaneously by osmotic minipumps for 4 weeks, from 2 days before to 10 days after irradiation. Tissue injury was assessed at 2 weeks (early phase) and 26 weeks (chronic phase) by quantitative histopathology and morphometry. Epithelial and smooth muscle cell proliferation was assessed by proliferating cell nuclear antigen staining; connective tissue mast cell hyperplasia by metachromatic staining; and TGF-beta1 and collagen protein and mRNA by quantitative immunohistochemistry, in situ hybridization, and/or real-time fluorogenic probe reverse transcription-polymerase chain reaction. Octreotide conferred dose-dependent protection against early (p = 0.0003) and chronic (p < 0.0001) tissue injury. Octreotide abrogated radiation-induced chronic increases in extracellular matrix-associated TGF-beta (p < 0.0001), collagen I (p = 0.0001), and collagen III (p = 0.0002) immunoreactivity. Octreotide did not affect radiation-induced changes in steady-state TGF-beta1 mRNA levels, mast cell hyperplasia, or smooth muscle cell proliferation. Octreotide reduced crypt epithelial cell proliferation (p = 0.01), but did not otherwise affect unirradiated intestine. Octreotide confers dose-dependent protection against delayed small bowel radiation toxicity and ameliorates radiation fibrosis predominantly by reducing acute mucosal injury. These data strengthen the rationale for using somatostatin analogs as enteroprotective agents in clinical radiation therapy.

Animals↗
PubMed2000

Acute radiation proctitis: a sequential clinicopathologic study during pelvic radiotherapy.

PURPOSE: Rectal toxicity is often dose limiting during pelvic radiation therapy. This prospective study examined the sequential development and associations of clinical, endoscopic, and histopathologic rectal toxicity during ongoing radiation therapy. METHODS AND MATERIALS: Thirty-three patients with nongastrointestinal pelvic carcinomas underwent proctoscopy with biopsy before radiation therapy, after 2 weeks treatment, and toward the end of the treatment course (6 weeks). Symptoms of acute toxicity were recorded, and endoscopic changes were graded. Histologic changes in the surface epithelium, glandular layer, and lamina propria were assessed using an ad hoc scoring system. Macrophage accumulation was evaluated in anti-CD68 stained sections. RESULTS: Pretreatment endoscopy and biopsies were unremarkable. Clinical symptoms progressed toward the end of the treatment course. In contrast, endoscopic pathology was maximal at 2 weeks. Biopsies obtained during treatment exhibited atrophy of the surface epithelium, acute cryptitis, crypt abscesses, crypt distortion and atrophy, and stromal inflammation. Histologic changes, particularly those in the surface epithelium, were consistently more pronounced at 2 weeks than they were at 6 weeks. CONCLUSION: In contrast to clinical symptoms, endoscopic changes stabilize and histologic changes regress from the 2nd to the 6th week of treatment. These results may have implications for the design and timing of prophylactic and therapeutic interventions to reduce radiation proctitis.

Acute Disease↗
PubMed2000

Treatment-time-dependence models of early and delayed radiation injury in rat small intestine.

BACKGROUND: The present study modeled data from a large series of experiments originally designed to investigate the influence of time, dose, and fractionation on early and late pathologic endpoints in rat small intestine after localized irradiation. The objective was to obtain satisfactory descriptions of the regenerative response to injury together with the possible relationships between early and late endpoints. METHODS: Two- and 26-week pathologic radiation injury data in groups of Sprague-Dawley rats irradiated with 27 different fractionation schedules were modeled using the incomplete repair (IR) version of the linear-quadratic model with or without various time correction models. The following time correction models were tested: (1) No time correction; (2) A simple exponential (SE) regenerative response beginning at an arbitrary time after starting treatment; and (3) A bi-exponential response with its commencement linked to accumulated cellular depletion and fraction size (the 'intelligent response model' [INTR]). Goodness of fit of the various models was assessed by correlating the predicted biological effective dose for each dose group with the observed radiation injury score. RESULTS: (1) The incomplete repair model without time correction did not provide a satisfactory description of either the 2- or 26-week data. (2) The models using SE time correction performed better, providing modest descriptions of the data. (3) The INTR model provided reasonable descriptions of both the 2- and 26-week data, confirming a treatment time dependence of both early and late pathological endpoints. (4) The most satisfactory descriptions of the data by the INTR model were obtained when the regenerative response was assumed to cease 2 weeks after irradiation rather than at the end of irradiation. A fraction-size-dependent delay of the regenerative response was also suggested in the best fitting models. (5) Late endpoints were associated with low-fractionation sensitivity and treatment-time dependence even in animal groups that exhibited minimal early mucosal reactions. CONCLUSION: Radiation injury scores in this rat small intestinal experimental model cannot be adequately described without time correction. 'Consequential' mechanisms contribute to the development of late effects, even in animals that do not develop severe early mucosal injuries. The initiation of the regenerative response is subject to a fraction-size-dependent mitotic delay and is linked to the level of accumulated cellular depletion. The response does not cease at the end of therapy but probably continues until maximal healing has taken place.

Animals↗
PubMed2000

Effect of thalidomide on gastrointestinal toxic effects of irinotecan.

Irinotecan is the only accepted second-line treatment for colorectal cancer in the USA. Doses are, however, frequently limited by associated late-onset diarrhoea. Thalidomide has antiangiogenic and immunomodulatory properties and is being investigated as an antineoplastic. We did a pilot study of combination therapy with thalidomide and irinotecan for metastatic colorectal cancer. In an interim analysis of nine patients, thalidomide had almost eliminated the dose-limiting gastrointestinal toxic effects of irinotecan, especially diarrhoea and nausea (each p<0.0001), and eight of nine patients were able to complete the chemotherapy course.

Antineoplastic Agents, Phytogenic↗
PubMed2000

Central venous catheter placement in patients with disorders of hemostasis.

BACKGROUND: Patients requiring central venous access frequently have disorders of hemostasis. The aim of this study was to identify factors predictive of bleeding complications after central venous catheterization in this group of patients. METHODS: A retrospective analysis of all central venous catheters placed over a 2-year period (1997 to 1999) at our institution were performed. The age, sex, clinical diagnosis, most recent platelet count, prothrombin international normalized ratio (INR), activated partial thromboplastin time (aPTT), catheter type, the number of passes to complete the procedure, and bleeding complications were retrieved from the medical records. RESULTS: In a 2-year period, 2,010 central venous catheters were placed in 1,825 patients. Three hundred and thirty placements were in patients with disorders of hemostasis. In 88 of the 330 patients, the underlying coagulopathy was not corrected before catheter placement. In these patients, there were 3 bleeding complications requiring placement of a purse string suture at the catheter entry site. In the remaining 242 patients, there was 1 bleeding complication. Of the variables analyzed, only a low platelet count (<50 x 10(9)/L) was significantly associated with bleeding complications. CONCLUSION: Central venous access procedures can be safely performed in patients with underlying disorders of hemostasis. Even patients with low platelet counts have infrequent (3 of 88) bleeding complications, and these problems are easily managed.

Blood Coagulation Disorders↗
PubMed2000

Recombinant soluble transforming growth factor beta type II receptor ameliorates radiation enteropathy in mice.

BACKGROUND & AIMS: Transforming growth factor (TGF)-beta has been implicated in many fibrotic conditions. However, its mechanistic role in radiation toxicity is equivocal despite compelling correlative evidence. This study assessed whether in vivo administration of a soluble TGF-beta type II receptor (TbetaR-II) protein ameliorates intestinal radiation injury (radiation enteropathy). METHODS: A recombinant fusion protein, consisting of the extracellular portion of mouse TbetaR-II and the Fc portion of mouse immunoglobulin (Ig) G, was produced. A 5-cm segment of mouse ileum was exposed to 19 Gy x-radiation. TbetaR-II:Fc fusion protein (1 mg/kg every other day) or mouse IgG was administered from 2 days before to 6 weeks after irradiation. Radiation injury was assessed at 6 weeks using quantitative histology, morphometry, and immunohistochemistry. Collagen was measured colorimetrically, and TGF-beta1 messenger RNA was assessed with fluorogenic probe reverse-transcription polymerase chain reaction. RESULTS: Compared with IgG controls, TbetaR-II:Fc-treated mice exhibited less structural injury, preservation of mucosal surface area, and less intestinal wall fibrosis. Intestinal TGF-beta1 messenger RNA increased in TbetaR-II:Fc-treated mice, whereas TGF-beta immunoreactivity decreased. TbetaR-II:Fc treatment increased crypt cell proliferation but otherwise did not affect unirradiated intestine. CONCLUSIONS: Long-term modulation of TGF-beta with a TbetaR-II:Fc fusion protein is feasible and ameliorates radiation enteropathy. These data confirm the putative role of TGF-beta in intestinal radiation fibrosis.

Animals↗
PubMed2000

Role of mast cells in early and delayed radiation injury in rat intestine.

Mast cell hyperplasia is a characteristic feature of many inflammatory and fibrotic conditions, including intestinal radiation injury (radiation enteropathy). This study used mast cell-deficient rats to define the role of mast cells in the mechanisms underlying early radiation-induced mucosal injury and delayed intestinal wall fibrosis. Mast cell-deficient (Ws/Ws) mutant rats and mast cell-competent (+/+) littermates were used. A 4-cm loop of ileum was exposed to 21 Gy single-dose radiation. Irradiated and unirradiated intestine were examined at 2 or 26 weeks using quantitative histology and morphometry. Quantitative immunohistochemistry was used to assess transforming growth factor beta (Tgfb), myeloperoxidase, and epithelial and smooth muscle cell proliferation. Collagen content was measured colorimetrically, and steady-state Tgfb1 mRNA was determined with fluorogenic probe RT-PCR. Compared to +/+ rats, Ws/Ws animals exhibited strikingly exacerbated mucosal injury but minimal reactive intestinal wall fibrosis. Ws/Ws rats exhibited less radiation-induced intestinal smooth muscle cell proliferation and collagen accumulation than +/+ littermates. Tgfb expression increased to a similar extent in Ws/Ws and +/+ rats. Unirradiated intestine from Ws/Ws and +/+ rats did not differ significantly. Mast cells protected the intestinal mucosa during the early phase of radiation enteropathy and promoted intestinal fibrosis after the breakdown of the mucosal barrier. Mast cells may be required for Tgfb to exert its full fibrogenic effect in radiation enteropathy.

Animals↗
PubMed1999

The synthetic somatostatin analogue, octreotide, ameliorates acute and delayed intestinal radiation injury.

PURPOSE: Reducing intraluminal proteolytic activity attenuates intestinal radiation toxicity. This study assessed whether pharmacological inhibition of exocrine pancreatic secretion protects against early and delayed radiation enteropathy in a preclinical rat model. METHODS AND MATERIALS: Rat ileum was sham-irradiated or exposed to 16 once-daily 4.2 Gy fractions of X-radiation. Vehicle or somatostatin analogue (octreotide, 2 microg/kg/hr) were administered from 2 days prior to 10 days after the end of irradiation. Mucosal injury was monitored noninvasively by assessment of granulocyte transmigration. Radiation injury was assessed at 2 weeks (early phase) and 26 weeks (chronic phase) using quantitative histopathology, immunohistochemistry, and morphometry. RESULTS: Octreotide decreased granulocyte transmigration (p<0.0006), reduced accumulation of myeloperoxidase-positive cells at 2 weeks (p = 0.0002), attenuated structural injury at 2 weeks (p = 0.04) and 26 weeks (p = 0.02), preserved mucosal surface area at 2 weeks (p = 0.0008) and 26 weeks p = 0.0008), and reduced intestinal wall thickening at 26 weeks (p = 0.002). Octreotide did not affect granulocyte transmigration, histology, or mucosal surface area in sham-irradiated controls. CONCLUSION: These results demonstrate the importance of consequential mechanisms in the pathogenesis of chronic radiation enteropathy. Short-term octreotide administration ameliorates acute radiation-induced mucosal injury, as well as chronic structural changes, and should be subject to further preclinical and clinical testing.

Animals↗
PubMed1999

cDNA cloning and sequencing, gene expression, and immunolocalization of thrombomodulin in the Sprague-Dawley rat.

Thrombomodulin (TM), in addition to its significance in the protein C anticoagulant pathway and cardiovascular diseases, has recently been shown to play important roles in normal embryonic development, several inflammatory conditions, as well as in tumor biology and in the pathogenesis of chronic radiation toxicity. We cloned and sequenced the cDNA encoding the complete TM protein from the Sprague-Dawley rat. The cDNA sequence consisted of a 78-bp 5' non-coding region and a 1731-bp open reading frame encoding 577 amino acids. Comparison of the deduced amino acid sequences showed Sprague-Dawley rat TM to be 87% homologous with mouse and 70.3% with human TM. In addition to the previously described highly conserved region in the lectin-like domain, another region was found which possessed significant homology among the species and may be involved in regulating cell surface expression of TM. Primers and fluorogenic probe for 5' exonuclease-based real time RT-PCR detection (TaqMan PCR) were constructed based on the cDNA sequence information and used to determine steady-state TM mRNA levels in lung, intestine, kidney, brain, and liver. The highest TM mRNA levels were found in lung and the lowest in liver. Immunohistochemistry confirmed that TM was mainly localized on the endothelium of blood vessels and lymphatics. The alveolar capillaries of lung showed the strongest immunoreactivity, whereas the endothelium of hepatic sinusoids and cerebral cortex were virtually negative.

Amino Acid Sequence↗
PubMed1999

Transperineal 125iodine implantation for treatment of clinically localized prostate cancer: 5-year tumor control and morbidity.

PURPOSE: To evaluate the efficacy and toxicity of transperineal 125I implants for clinically localized prostate cancer in elderly men in a community cancer setting. METHODS AND MATERIALS: From 1988 to 1993, 206 patients, median age 77 years, with localized (Stage T1 and T2), low-grade (Gleason score < or = 7) prostate cancer were treated using pre-planned 125I transperineal implants. Patients were followed for biochemical freedom from disease, overall survival, and treatment-associated morbidity. RESULTS: The 5-year actuarial biochemical freedom from failure rate for all patients available for follow-up was 63%. Specifically, biochemical freedom from failure was 76% in patients with pretreatment PSA < or = 10 ng/ml, compared to 51% of patients with values > 10 ng/ml (median observation time 35 months). Actuarial freedom from failure for patients with PSA < or = 4 ng/ml was 84%. Stage and Gleason score did not predict outcome. PSA nadir was the strongest predictor of long-term biochemical disease-free survival (p < 0.001) with only 2 failures in 62 patients who achieved a posttreatment PSA nadir < or = 0.5 ng/ml. CONCLUSION: Transperineal 125I implants for early prostate cancer are efficacious and feasible for certain populations of elderly patients with favorable prognostic indicators in the community cancer setting. Patients with poor prognostic indicators at diagnosis do not appear to be candidates for treatment with implant alone. ( 1999 El.vit r 'Cio;noo lnc

Aged↗
PubMed1999

Circulating thrombomodulin during radiation therapy of lung cancer.

The endothelial cell glycoprotein, thrombomodulin (TM), is an important physiological anticoagulant. TM is downregulated and released from the cell membrane into the circulation by ionizing radiation and during inflammation. The present study measured plasma TM in 17 patients before, during, and after radiation therapy of lung cancer: nine patients developed radiation pneumonitis, whereas eight matched patients did not. Plasma TM did not change significantly in patients who developed radiation pneumonitis. In contrast, patients who did not develop pneumonitis exhibited a moderate, but statistically significant, decrease in plasma TM antigen during the initial 1-2 weeks, with complete normalization towards the end of treatment. Our study suggests that decreased release of TM during the early phase of radiation therapy may be associated with reduced pulmonary toxicity. The use of plasma TM as a marker of pulmonary toxicity needs further study.

Adult↗