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M Hauer-Jensen

Publications and source records attributed to M Hauer-Jensen.

At least 37 records · Page 2Linked to original sources
PubMed1999

Upregulation and spatial shift in the localization of the mannose 6-phosphate/insulin-like growth factor II receptor during radiation enteropathy development in the rat.

BACKGROUND AND PURPOSE: Transforming growth factor beta1 (TGF-beta1) appears to play an important role in the pathogenesis of chronic radiation-induced fibrosis in the intestine and several other organs. TGF-beta1 is secreted as a non-biologically active complex and its function depends on activation. In vitro data suggest that the mannose 6-phosphate/insulin-like growth factor-beta (M6P/IGF-II) receptor is involved in the mechanism of TGF-beta1 activation. Thus, we used a rat model of radiation enteropathy to examine the potential role of the M6P/IGF-II receptor in the in vivo regulation of TGF-beta1 activity and localization. MATERIALS AND METHODS: A scrotal hernia containing a loop of small intestine was created in male rats. The intestine in the scrotum was exposed to 0, 12, or 21 Gy single dose X-radiation. Groups of rats were euthanized 1 day and 2, 6 and 26 weeks after irradiation. Histopathologic injury was assessed with a radiation injury score (RIS). Computerized image analysis was used to identify M6P/IGF-II receptor-positive cells and to quantify extracellular matrix-associated TGF-beta1 immunoreactivity. Changes in urokinase plasminogen activator (uPA), tissue-like plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) immunoreactivity were also assessed. RESULTS: In normal (sham-irradiated) intestine, M6P/IGF-II immunoreactivity was confined to relatively weak, but specific epithelial staining. Irradiated intestine exhibited a highly significant time- and dose-dependent increase in the number of M6P/IGF-II receptor-positive cells (P < 0.001). There was a striking spatial shift of M6P/IGF-II receptor immunoreactivity from epithelium during the early post-radiation phase to stromal cells, most notably fibroblasts during the later stages of injury. Irradiated intestine exhibited distinct co-localization of M6P/ IGF-II receptor-positive cells and extracellular matrix-associated TGF-beta1 in areas of histopathologic injury. There were highly significant associations between the number of M6P/IGF-II receptor-positive stromal cells and TGF-beta1 immunoreactivity (P < 0.001), radiation-induced fibrosis (P < 0.001) and RIS (P < 0.001). Endothelial tPA immunoreactivity decreased significantly after irradiation (P < 0.001), whereas uPA and PAI-1 immunoreactivity levels appeared to be unchanged. CONCLUSIONS: M6P/IGF-II receptor upregulation may be a key factor in the in vivo control of TGF-beta1 activity and responsible for the tissue specificity of TGF-beta1 action after irradiation.

Animals↗
PubMed1999

Molecular cloning and sequence analysis of the 5'-flanking region of the Sprague-Dawley rat thrombomodulin gene.

The 5'-flanking region of the rat thrombomodulin gene was cloned by polymerase chain reaction (PCR) amplification of adaptor-ligated rat genomic DNA fragment libraries, using primers derived from the coding sequences of the thrombomodulin cDNA and adaptor primers. By sequence analysis putative regulatory elements in the promoter domain were shown to include a TATA box and several conserved binding sites for stimulatory protein 1 (SP1) and activator protein 2 (AP2). The transcription factor activator protein 1 (AP1) binding site located in the 5'-flanking region may serve as a negative gene regulatory site for tumor necrosis factor-alpha (TNF-alpha). A potential retinoic acid response element (RARE) and a possible cAMP response element are located in the putative promoter region, suggesting a role for retinoic acid and cAMP in the induction of thrombomodulin gene expression. The rat thrombomodulin gene promoter sequence shows 89% homology to that of mouse and 77% homology to that of human.

Animals↗
PubMed1998

Cellular sources of transforming growth factor-beta isoforms in early and chronic radiation enteropathy.

The three mammalian transforming growth factor (TGF)-beta isoforms (TGF-beta1, TGF-beta2, and TGF-beta3) differ in their putative roles in radiation-induced fibrosis in intestine and other organs. Furthermore, tissue specificity of TGF-beta action may result from temporal or spatial changes in production and/or activation. The present study examined shifts in the cell types expressing TGF-beta mRNA relative to TGF-beta immunoreactivity and histopathological injury during radiation enteropathy development. A 4-cm loop of rat small intestine was locally exposed to O, 12, or 21-Gy single doses of x-irradiation. Sham-irradiated and irradiated intestine were procured 2 and 26 weeks after irradiation. Cells expressing the TGF-beta1, TGF-beta2, or TGF-beta3 transcripts were identified by in situ hybridization with digoxigenin-labeled riboprobes. Intestinal wall TGF-beta immunoreactivity was measured using computerized image analysis, and structural radiation injury was assessed by quantitative histopathology. Normal intestinal epithelium expressed transcripts for all three TGF-beta isoforms. Two weeks after irradiation, regenerating crypts, inflammatory cells, smooth muscle cells, and mesothelium exhibited increased TGF-beta1 expression and, to a lesser degree, TGF-beta2 and TGF-beta3 expression. Twenty-six weeks after irradiation, TGF-beta2 and TGF-beta3 expression had returned to normal. In contrast, TGF-beta1 expression remained elevated in smooth muscle, mesothelium, endothelium, and fibroblasts in regions of chronic fibrosis. Extracellular matrix-associated TGF-beta1 immunoreactivity was significantly increased at both observation times, whereas, TGF-beta2 and TGF-beta3 immunoreactivity exhibited minimal postradiation changes. Intestinal radiation injury is associated with overexpression of all three TGF-beta isoforms in regenerating epithelium. Radiation enteropathy was also associated with sustained shifts in the cellular sources of TGF-beta1 from epithelial cells to cells involved in the pathogenesis of chronic fibrosis. TGF-beta2 and TGF-beta3 did not exhibit consistent long-term changes. TGF-beta1 appears to be the predominant isoform in radiation enteropathy and may be more important in the mechanisms of chronicity than TGF-beta2 and TGF-beta3.

Animals↗
PubMed1998

Differential effect of radiation on endothelial cell function in rectal cancer and normal rectum.

BACKGROUND: Chronic radiation injury of the intestine is associated with significant underexpression of a potent physiological anticoagulant, endothelial cell thrombomodulin (TM). This study compared early and late radiation-induced changes in endothelial TM, urokinase plasminogen activator (uPA), and transforming growth factor beta (TGF-beta) in normal rectum and tumors. METHODS: Rectal resection specimens from 27 patients were analyzed: Nine patients underwent primary resection of rectal cancer, 11 tumors were resected after neo-adjuvant radiotherapy, and 7 because of local recurrence after prior resection and adjuvant radiotherapy. TM, uPA, and extracellular matrix-associated TGF-beta, immunoreactivity were assessed using computerized image analysis. RESULTS: Multivariate analysis revealed that tumors had more TM-positive vessels (P = 0.003), more uPA-positive cells (P <0.001), and higher TGF-beta immunoreactivity levels (P <0.001) than normal rectum. Preoperative irradiation was associated with decreased proportions of TM-positive vessels in tumors (P = 0.003) and normal rectum (P <0.001). Irradiated tumors had fewer uPA-positive cells (P = 0.003) and less TGF-beta immunoreactivity (P = 0.001) than unirradiated tumors. The proportion of TM-positive vessels in irradiated rectum from patients with recurrence was decreased (P = 0.03), whereas the recurrent (ie, unirradiated) tumors did not differ from primary tumors in terms of TM, TGF-beta, or uPA immunoreactivity. CONCLUSIONS: The results support a role for endothelial dysfunction in the pathogenesis of radiation proctitis. Maintaining endothelial cell anticoagulant function may be a potential method to optimize the therapeutic ratio of adjuvant radiotherapy of rectal cancer.

Aged↗
PubMed1998

Changes in transforming growth factor beta1 gene expression and immunoreactivity levels during development of chronic radiation enteropathy.

Chronic intestinal radiation injury is associated with locally increased TGF-beta1 immunoreactivity that correlates with morphological alterations. However, the underlying mechanisms are not known. This study examined changes in intestinal TGF-beta1 immunoreactivity, steady-state TGF-beta1 mRNA levels, and cellular localization of TGF-beta1 mRNA during development of chronic radiation enteropathy in a rat model. A loop of small bowel was fixed inside the scrotum of orchiectomized male rats. The intestine was subsequently exposed locally to 0, 12 or 21 Gy X radiation. Intestine was procured at 24 h and 2, 6 and 26 weeks and subjected to histopathological analysis, quantitative immunohistochemistry with computerized image analysis, assessment of steady-state TGF-beta1 mRNA levels with quantitative reverse transcriptase polymerase chain reaction, and identification of cell types expressing TGF-beta1 mRNA with in situ hybridization. Intestine from the 21-Gy group exhibited more histopathological injury and increased TGF-beta immunoreactivity 2-26 weeks after irradiation compared to the 12-Gy group and sham-irradiated controls. TGF-beta1 mRNA in irradiated intestine increased up to six times relative to controls at 24 h and 2 weeks, was less at 6 weeks, and did not differ from controls at 26 weeks. In situ hybridization detected TGF-beta1 mRNA in epithelial and Paneth cells in control intestine. Irradiated intestine exhibited additional TGF-beta1 mRNA in inflammatory and fibroblast-like cells. We conclude that there is a radiation-induced shift in the cellular sources of TGF-beta1, and that Tgfb1 gene expression is increased mainly during the early phases of radiation enteropathy, preceding the increase in immunoreactivity and histopathological injury. Translational or post-translational mechanisms are likely involved in sustaining increased TGF-beta1 immunoreactivity levels during the chronic phase of radiation enteropathy.

Animals↗
PubMed1997

Mode of chemotherapy does not affect complications with an implantable venous access device.

BACKGROUND: Few reports have been made regarding the long term safety of implantable venous access devices used for the delivery of chemotherapeutic agents. The authors' goals were to determine the frequency of complications in patients receiving chemotherapy with these devices; to determine whether complications were associated with the mode of chemotherapy delivery (push/bolus or infusional regimens); and to evaluate the influence of other risk factors, including home-based versus hospital-based administration. METHODS: A total of 152 oncology patients at the John L. McClellan Memorial Veterans Administration Medical Center in Little Rock, Arkansas (ages 26-81 years; mean age, 62 years), who underwent surgical placement of an Infus-a-Port (Strato, Inc., Beverly, MA) between May 1, 1992 and May 31, 1994, were evaluated retrospectively for postplacement device complications, such as infection, thrombosis, and mechanical failure. RESULTS: Twenty-seven patients experienced 1 complication each: 17 episodes of device-related sepsis, cellulitis, or fever of unknown origin; 8 episodes of thrombosis or catheter occlusion; 1 episode of drug extravasation; and 1 mechanical failure. Patient age, frequency of port accession, mode of chemotherapy delivery, tumor type, and neutropenia were evaluated as risk factors, but none was statistically significant. Complications were more frequent during the first 90 days after implantation, but they continued to occur throughout the observation period. CONCLUSIONS: Complications attributable to an implantable venous access device were infrequent in this patient population. No differences in complications for patients receiving home-based versus hospital-based chemotherapy administration were noted, opening the possibility of significant time and cost savings with home treatment.

Adult↗
PubMed1997

Increased transforming growth factor beta (TGF-beta) immunoreactivity is independently associated with chronic injury in both consequential and primary radiation enteropathy.

PURPOSE: Radiation enteropathy is characterized by sustained increase in transforming growth factor beta (TGF-beta) immunoreactivity and connective tissue mast cell (CTMC) hyperplasia that may be responsible for progressive fibrosis and lead to clinical complications. We examined to what extent these chronic molecular and cellular phenomena are associated with acute mucosal breakdown (consequential injury) and/or direct (primary) radiation injury in late-responding compartments. METHODS AND MATERIALS: Rat small intestine was exposed to 50.4 Gy x-irradiation given either over 18 days (2.8 Gy daily or 5.6 Gy every other day) or 9 days (2.8 Gy twice daily or 5.6 Gy daily). Intestinal complications were recorded and groups of animals were euthanized at 2 and 26 weeks to assess subacute and chronic injury. Histopathologic changes were assessed with a radiation injury scoring system (RIS), total TGF-beta immunoreactivity was quantified with computerized image analysis, and CTMC hyperplasia was assessed in toluidine blue-stained sections. RESULTS: TGF-beta immunoreactivity and CTMC hyperplasia colocalized in areas of injury and were highly significantly correlated. Increased fraction size and decreased overall treatment time were associated with increased RIS (p < 0.01 and p < 0.00001), increased TGF-beta immunoreactivity (p = 0.01 andp < 0.001), and degree of CTMC hyperplasia (p = 0.01 and p < 0.001). Postradiation CTMC numbers increased across treatment groups from 2 to 26 weeks (p < 0.01). TGF-beta immunoreactivity was independently associated with chronic intestinal wall fibrosis (p = 0.003). CONCLUSION: This in vivo study supports in vitro evidence linking increased TGF-beta immunoreactivity and mast cell hyperplasia and strongly suggests their involvement in the molecular pathogenesis of both primary and consequential radiation enteropathy.

Animals↗
PubMed1997

Association of granulocyte transmigration with structural and cellular parameters of injury in experimental radiation enteropathy.

Inflammatory cells are involved in the pathogenesis of tissue injury through release of cytokines and biologically active compounds. This study used a novel, noninvasive method to assess the association between granulocyte transmigration and structural and molecular changes in radiation enteropathy. A 4 cm loop of rat small intestine was exposed to 0, 2.8, 12, or 23 Gy localized irradiation. Feces was collected in metabolic cages before and 3, 7, 14, 28, and 42 days after irradiation. Granulocyte marker protein (GMP) was measured in buffer extracts of feces by enzyme-linked immunosorbent assay (ELISA). Irradiated and shielded intestine were procured at 2 and 26 weeks and assessed for histopathologic injury [radiation injury score (RIS)], ED-2 positive macrophages, and interleukin-1 alpha (IL-1 alpha) positive cells. Irradiated intestine exhibited characteristic histopathologic alterations and increased numbers of macrophages and IL-1 alpha positive cells. There was a highly significant dose-dependent increase in post-radiation GMP (P < 0.0001). Maximal GMP excretion occurred 3-7 days after irradiation. Six weeks after irradiation, GMP excretion had returned to normal in the 2.8 and 12 Gy groups, but was still 3.5 times higher in the 23 Gy group than in controls. The associations between early GMP excretion and RIS and fibrosis at 26 weeks were highly significant (P < 0.001 and P < 0.0001, respectively). Post-radiation granulocyte transmigration is dose-dependent and correlates with structural and molecular changes, as well as with subsequent chronic injury. The GMP assay is a sensitive, non-invasive indicator of acute intestinal radiation injury and a promising biological predictor of chronic toxicity. Our data underscore the importance of consequential mechanisms in radiation enteropathy.

Animals↗
PubMed1997

Is the loss of endothelial thrombomodulin involved in the mechanism of chronicity in late radiation enteropathy?

BACKGROUND AND PURPOSE: Radiation enteropathy is characterized by locally elevated levels of inflammatory and fibrogenic cytokines. Microvascular injury may sustain these alterations through persistent local hypercoagulopathy, platelet aggregation, leukocyte adhesion and release of biologically active mediators. This study assessed the relationship of endothelial thrombomodulin (TM), a key regulator of the protein C anticoagulant pathway and marker of endothelial function, with transforming growth factor beta (TGF-beta) immunoreactivity and morphologic alterations in radiation enteropathy. MATERIALS AND METHODS: Small bowel resection specimens from 9 patients with radiation enteropathy were analyzed by computerized quantitative immunohistochemistry using antibodies against TM, von Willebrand factor (vWF) and TGF-beta. Identical measurements were performed on intestinal resection specimens from otherwise healthy penetrating trauma victims and on archived small intestines. A previously validated image analysis technique was used to assess submucosal vessels for TM and vWF immunoreactivity, and the intestinal wall for total extracellular matrix-associated TGF-beta immunoreactivity. RESULTS: Specimens from irradiated patients showed prominent submucosal and subserosal thickening and fibrosis, and obliterative vasculopathy. Control specimens were histopathologically normal. Vascular density and vWF immunoreactivity were similar in radiation enteropathy patients and controls. The image-analysis techniques were highly reproducible, with correlation coefficients for repeated measurements ranging from 0.86 to 0.93. Radiation enteropathy specimens exhibited a highly significant reduction in the number and proportion of TM-positive submucosal vessels per unit area (P < 0.0001) and increased intestinal wall TGF-beta immunoreactivity (P = 0.002). CONCLUSIONS: These data support the theory that sustained endothelial dysfunction is involved in the molecular pathogenesis of radiation enteropathy, and point to TM as important in the chronic nature of radiation enteropathy and a potential target for prophylactic and therapeutic interventions.

Aged↗
PubMed1996

Timing of concomitant boost irradiation affects incidence and severity of intestinal complications.

PURPOSE: In an effort to increase the therapeutic ratio of radiation therapy, so-called "nonstandard" irradiation regimens are being used more frequently. One such regimen, concomitant boost, entails giving a second daily fraction during part of the treatment course, thus reducing the total treatment time and decreasing the opportunity for tumor cell proliferation during treatment. The probability of tumor control is, therefore, increased for a given total dose. Timing of the boost, i.e., whether it is given early or late during the treatment course, affects both normal tissue and tumor response. This study assessed the influence of timing of a second daily boost on the development of intestinal radiation injury in a rat model. METHODS AND MATERIALS: A functionally intact segment of distal ileum was sutured to the inside of the scrotum in 52 orchiectomized, male Sprague-Dawley rats. After a 3-week postoperative recovery period, the intestine contained in the "scrotal hernia" was irradiated. All rats received a total dose of 50.4 Gy, given over a 12-day period as two different boost regimens, daily fractions of 2.8 Gy plus six concomitant boost doses of 2.8 Gy. The early boost group received the additional boost during the first 6 days and the late boost group received the additional boost during the last 6 days. The boost was given 6 h after the daily fraction. Groups of rats were sacrificed at 24 h (acute changes), 2 weeks (subacute changes), and 26 weeks (chronic changes) after the end of the irradiation schedule. Radiation injury was assessed by frequency of radiation-induced complications, histopathologic radiation injury score, collagen content, and epithelial cytokinetics. RESULTS: Radiation injury in the early boost group was significantly more severe than in the late boost group in terms of incidence of complication and histopathologic injury. Relative collagen content of irradiated intestine was significantly increased in the early boost group when compared to the late boost group at 2 weeks and at 26 weeks. Irradiated intestine in the early boost group exhibited decreased labeling index at 2 weeks, whereas irradiated intestine in the late boost group exhibited normal labeling index and increased total crypt cellularity at 2 weeks. CONCLUSION: When small intestine has to be included in the treatment field during radiation therapy, concomitant boost should be given towards the end of the radiation schedule, after the onset of compensatory proliferation, to minimized the risk of subsequent complications.

Animals↗
PubMed1996

Young women with advanced aortoiliac occlusive disease: new insights.

We identified a group of 24 young (less than 50 years of age) women with isolated, premature atherosclerotic aortoiliac occlusive disease and attempted to identify distinguishing hemostatic characteristics. Most of these patients (62%) presented with acute thromboembolic events (blue toe syndrome, n = 6; macroemboli, n = 6; or aortoiliac thrombosis, n = 3). Aortoiliac reconstruction (aortoiliac endarterectomy, n = 10, aortobifurcation bypass grafts, n = 6; and percutaneous angioplasty, n = 4) was complicated by early thrombosis in 6 of 20 cases (30%), (1 of 10 endarterectomies, 4 of 6 bypass grafts, and 1 of 4 angioplasties). Fresh thrombus overlying an atherosclerotic plaque was a common finding at surgery. This observation and the relatively high incidence of thromboembolic events led us to hypothesize that a characteristic hemostatic profile might underlie the remarkably similar clinical presentations of these women. Levels of antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant), plasminogen activator inhibitor-1, fibrinogen, antithrombin III, protein C, protein S, plasminogen, prothrombin fragment F1 + 2, and D-dimer were determined for these young women and for 21 age-matched white female control subjects without vascular disease and nine white male patients with aortoiliac occlusive disease (mean 61 years, range 43 to 74 years). The incidence of anticardiolipin antibodies was 42% (8 of 19) in the female patients, which was significantly elevated (p = 0.028). The female (62.5%) and male (100%) patients had significantly elevated D-dimer levels (p < 0.001). Deficiencies of antithrombin III, protein C, and protein S were rare. A unique pattern of premature aortoiliac atherosclerosis exists in some young women. Intra-arterial thromboembolic events are common at presentation and complicate surgical management. The role of antiphospholipid antibodies remains uncertain.

Adult↗
PubMed1996

Association of transforming growth factor beta (TGF-beta) immunoreactivity with specific histopathologic lesions in subacute and chronic experimental radiation enteropathy.

Irradiated intestine consistently exhibits increased immunoreactivity of transforming growth factor beta-1 (TGF-beta 1). It is not known whether this increase occurs secondary to mucosal barrier disruption (consequential injury) or to injury in late-responding tissue compartments (primary radiation enteropathy). This study therefore assessed the association between TGF-beta immunoreactivity and specific consequential and primary histopathologic alterations. A small bowel loop was fixed inside the scrotum in male rats and subsequently exposed to either 18 daily fractions of 2.8 Gy or nine daily fractions of 5.6 Gy orthovoltage X-radiation. Radiation-induced induced intestinal complications were recorded and groups of animals were euthanized 2 and 26 weeks post-irradiation. Radiation injury was assessed with a histopathologic radiation injury score (RIS). Total TGF-beta was detected immunohistochemically and measured with interactive computerized image analysis. The image analysis technique yielded highly reproducible quantitation data. The 2.8-Gy group maintained mucosal integrity and had fewer intestinal complications, lower RIS and lower TGF-beta levels than the 5.6-Gy group. There was highly significant correlation between TGF-beta immunoreactivity and radiation injury at both observation times (P < 0.001 and P < 0.0001). At 2 weeks, TGF-beta immunoreactivity correlated with mucosal ulceration (P = 0.002), epithelial atypia (P = 0.005), and serosal thickening (P = 0.0004). At 26 weeks, TGF-beta levels correlated significantly with six of seven histopathologic parameters, most strikingly with vascular sclerosis (P = 0.0003). We conclude that mucosal barrier breakdown is closely associated with increased TGF-beta immunoreactivity in consequential radiation enteropathy. The highly significant correlation between TGF-beta expression levels and alterations in late-responding tissue compartments also suggest a role for TGF-beta in primary radiation enteropathy.

Acute Disease↗
PubMed1996

Optimal interfraction interval to minimize small bowel radiation injury in treatment regimens with two fractions per day: an experimental study in a rat model.

BACKGROUND: Normal tissue damage in fractionated radiotherapy is influenced by a number of factors including sublethal damage repair and cellular proliferation. The therapeutic benefit of regimens with multiple fractions per day may thus be offset by increased normal tissue injury if there is insufficient time between daily fractions. We examined the influence of interfraction interval on radiation injury of the intestine, an organ at significant risk during treatment of abdominal and pelvic tumors. METHODS: A total of 150 male rats were orchiectomized, and a functionally intact loop of small bowel was sutured to the inside of the scrotum. The intestine within this 'artificial hernia' was irradiated twice daily for 9 days with 2.8 Gy fractions at intervals of 0, 2, 4, 6, or 8 h. Animals were observed for development of radiation-induced intestinal complications and euthanized at either 2 weeks and 26 weeks for subsequent histopathologic examination of irradiated and shielded intestine. RESULTS: Increasing the interfraction interval from 0 to 6 h was associated with a statistically significant reduction in intestinal complications (from 53% to 0%, P < 0.001), and in Radiation Injury Score (RIS) (from 10 to 6, P < 0.01) in long-term observed animals. Extending the interfraction interval to 8 h did not confer additional benefit. CONCLUSION: An interfraction interval of 6 h minimizes the risk of chronic radiation enteropathy in this rat model.

Animals↗
PubMed1996

Can the NASCET technique for measuring carotid stenosis be reliably applied outside the trial?

PURPOSE: The North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the Asymptomatic Carotid Artery Study (ACAS) both confirmed the effectiveness of carotid endarterectomy for preventing stroke in patients who have significant carotid stenosis. A uniform technique for measuring carotid stenosis from an arteriogram (% stenosis = [1 - minimum residual lumen/normal distal cervical internal carotid artery diameter] x 100) was used in both trials, with reproducibility internally validated. The reliability of this measurement when used outside the trials for defining carotid stenosis has not been validated. Imprecise calculation of carotid stenosis can result in a 50% overestimation of significant carotid disease and potential overuse of carotid surgery. This is a prospective study of the reliability of carotid stenosis measurements performed by practicing physicians of different specialties and different levels of clinical experience. METHODS: Two vascular surgeons and two interventional radiologists (one resident and one staff member per specialty), blinded to results, calculated the percent stenosis from 219 consecutive arteriograms performed to evaluate extracranial carotid artery occlusive disease; 72 random films were reread by each individual. The interpretations were grouped as < 60% or > or = 60% stenosis (ACAS) and as < 30%, 30% to 69%, and > or = 70% stenosis (NASCET). Interobserver and intraobserver agreement were analyzed with the kappa statistic and Pearson correlation coefficients. RESULTS: Interobserver reliability in categorizing carotid stenosis revealed excellent agreement for both ACAS (kappa = 0.825 to 0.903) and NASCET groups (kappa = 0.729 to 0.793). Interobserver correlation coefficients ranged from 0.91 to 0.95. Intraobserver agreement was also highly reproducible for both the ACAS (kappa = 0.732 to 0.970) and NASCET categories (kappa = 0.634 to 0.805). Intraobserver correlation coefficients ranged from 0.89 to 0.95. CONCLUSION: The NASCET technique for quantification of carotid stenosis can be easily learned by physicians and reliably implemented for appropriate identification of candidates for carotid endarterectomy.

Angiography, Digital Subtraction↗
PubMed1996

Relationship between intestinal fibrosis and histopathologic and morphometric changes in consequential and late radiation enteropathy.

Intestinal fibrosis is a marked feature of late radiation enteropathy. This study assessed the time dose fractionation relationships of radiation-induced fibrosis in order to elucidate possible pathogenetic mechanisms. In 290 male Sprague-Dawley rats, a loop of small bowel was transposed to the left side of the scrotum. Three weeks later, the transposed segment was irradiated with either single dose or various fractionated regimens. The animals were observed for radiation-induced intestinal complications and killed in groups, 2 and 26 weeks after completion of irradiation. A semiquantitative histopathologic radiation injury score, morphometry of the submucosa, submucosal arterioles, intestinal surface area, and relative collagen content were used as endpoints. Fibrosis, measured by collagen assay and radiation injury score, increased with total dose, increasing fraction size and reduction in overall treatment time. This paralleled the results of morphometric assessment of mucosal surface area. Differences in vascular morphometry were only statistically significant in response to changes in total dose and fraction size and not with changes in overall treatment time. We conclude that fibrosis increases with increasing observation time, increasing fraction size, increasing total dose, and reduction of interfraction interval. Consequential injury, occurring as a result of disruption of mucosal integrity, seems to be an important mechanism for development of intestinal fibrosis. In contrast, vascular injury is relatively independent of this mechanism.

Animals↗
PubMed1996

Influence of fraction size on the development of late radiation enteropathy. An experimental study in the rat.

The use of large fraction sizes in radiotherapy may be associated with an increased risk of complications from late responding normal tissues. However, in the intestine, chronic injury may develop either as primary late effect or secondary to disruption of mucosal integrity as so-called consequential injury. Mucosal damage is relatively less sensitive to changes in fraction size than late reacting, slowly proliferating cells. The relationship between fraction size and chronic radiation enteropathy in a given situation may thus depend on which of the two mechanisms that predominates. Most previous studies of the influence of fraction size on radiation injury are confounded by differences in treatment time. The present study was therefore designed to assess subacute and chronic radiation enteropathy after three different fractionation regimens where fraction size was the only experimental variable. A total of 96 male Sprague-Dawley rats were orchiectomized and a functionally intact loop of small intestine was transposed into the left scrotum. These 'scrotal hernias' containing intestine were subsequently exposed to 50.4 Gy localized fractionated irradiation over 18 days with either 2.8 Gy every 24 h, 4.2 Gy every 36 h, or 5.6 Gy every 48 h. Control animals were sham irradiated. The animals were observed for development of intestinal complications (intestinal obstruction or enterocutaneous fistula formation) up to 6 months after irradiation. Histologic damage was assessed in groups of animals at 2 weeks (subacute injury) and 26 weeks (chronic injury), using a previously validated radiation injury score (RIS). RIS increased significantly with increasing fraction size at both observation times. However, the increase was more pronounced at 26 weeks than at 2 weeks. Increased chronic injury was characterized by increased incidence and severity of mucosal ulceration, serosal thickening, vascular sclerosis and intestinal wall fibrosis. We conclude that increasing fraction size increases both subacute and, even more markedly, chronic injury in the intestine. With the fractionation regimens used here, the chronic radiation enteropathy develops as a combined consequential and primary late effect, but the primary mechanism predominates.

Acute Disease↗
PubMed1996

When should the "infected" subcutaneous infusion reservoir be removed?

Subcutaneous central venous infusion reservoirs (central venous catheters) are one of the primary devices for administration of intravenous chemotherapy. Usually these devices have few problems, and they provide dependable long term central venous access. Infection of these catheters is a significant problem that usually requires removal. When infection is suspected, it is often difficult to make this determination without actually removing the catheter. Thorough preoperative evaluation may help the surgeon decide which catheters are infected and should be removed. A total of 817 subcutaneous infusion reservoirs were placed at our institution from January 1, 1990 through November 1, 1994. During the same time period, 143 catheters were removed, 63 for suspected infection. The charts of these 63 patients were reviewed to determine to what extent available preoperative information could be used to predict which catheters were infected, thus avoiding unnecessary removal. Twenty-three preoperative parameters were assessed, including physical exam, body temperature, leukocyte count, platelet count, blood cultures from the catheter and peripheral blood, time from placement to removal, whether or not the catheter was functional, and whether it was currently in use. Forty catheters (65%) removed for suspected infection were infected, as demonstrated by a positive culture from the catheter or the wound. Staphylococcus was the most common microorganism. Physical exam (local erythema, tenderness, or swelling) correlated significantly with catheter infection (P = 0.0238). In contrast, blood culture data and the other clinical and laboratory parameters showed no significant association with catheter infection. We conclude that physical exam is the best indicator of catheter infection. Commonly used parameters such as fever, leukocytosis, and positive blood cultures are nonspecific, may not be due to catheter infection, and were not significant in our study. Removal and subsequent restoration of long term intravenous access is associated with significant morbidity and expense. Clinical decision making should not be based on isolated laboratory findings, but must be individualized in each patient with suspected catheter infection.

Adult↗