Crown-rump length discordance in the first trimester: a predictor of adverse outcome in twin pregnancies?

OBJECTIVES: To evaluate the usefulness of first-trimester crown-rump length (CRL) discordance in predicting adverse outcome in twin pregnancies. METHODS: This retrospective study included a large cohort retrieved from local ultrasound databases at 14 obstetric departments in Denmark, comprising all twin pregnancies with two live fetuses scanned between 11 and 14 weeks' gestation during the period 1 January 2004 to 31 December 2006. The association between CRL discordance ≥ 10 % and adverse outcome was evaluated. RESULTS: Among 1993 twin pregnancies, 1733 were dichorionic (156 (9%) discordant; 1577 (91%) concordant) and 260 were monochorionic (32 (12%) discordant; 228 (88%) concordant). In dichorionic twin pregnancies we found an association between CRL discordance ≥ 10% and preterm delivery before 34 weeks' gestation (P=0.007), birth weight discordance (P=0.001) and mean birth weight (P=0.033). In monochorionic twin pregnancies we found an association between CRL discordance ≥ 10% and birth weight discordance (P=0.02) and mean birth weight (P=0.03). To evaluate CRL discordance as a predictor of fetal loss and preterm delivery before 34 weeks' gestation, receiver-operating characteristics curves were created for each outcome. For CRL discordance ≥ 10% as a predictor of fetal loss and preterm delivery in dichorionic twin pregnancies, sensitivity was 0.17 (95% CI, 0.06-0.28) and 0.14 (95% CI, 0.10-0.18), respectively, and in monochorionic twin pregnancies it was 0.10 (95% CI, 0.03-0.22) and 0.16 (95% CI, 0.06-0.26), respectively. CONCLUSIONS: CRL discordance in twin pregnancies is associated with, but is not a strong predictor of, adverse outcome.

Minor Skin Injuries at School: The Role of the School Nurse.

School nurses routinely provide simple wound care for minor injuries in the school health office. Simple wound care is centered on the principles of moist wound care and only requires a few supplies to be on hand. This article outlines the steps for simple wound care for minor abrasions, cuts, blisters, and burns. Recommendations for referral of more complicated wounds are also provided. Student encounters for minor wound care can also be used by school nurses to provide education on first aid and to teach students, parents, and caregivers about infection prevention and control of the wound.

Influence of chorionicity on perinatal outcome in a large cohort of Danish twin pregnancies.

OBJECTIVE: To assess outcome in twin pregnancies according to chorionicity. METHODS: A cohort was retrieved from local ultrasound databases at 14 obstetric departments in Denmark, comprising all twin pregnancies with two live fetuses scanned between weeks 11 and 14 in the period 1 January 2004 to 31 December 2006. Outcome data were retrieved from the National Board of Health. RESULTS: Among 2038 twin pregnancies, 1757 (86.2%) were dichorionic (DC) and 281 (13.8%) were monochorionic diamniotic (MC). In MC pregnancies, the rate of spontaneous fetal loss in both second and third trimesters was more than threefold higher than the comparable rate in DC pregnancies: 6.0% vs. 1.9% for at least one fetus in the second trimester (P < 0.001) and 2.1% vs. 0.7% in the third trimester (P = 0.03). In 98.4% of DC pregnancies and in 91.1% of MC pregnancies, at least one infant was liveborn. Amongst pregnancies with two live fetuses at 24 weeks, the proportion with two live infants at 28 days after delivery was 97.5% and 95.1%, respectively. CONCLUSIONS: The increased incidence of fetal loss in MC pregnancies compared with DC pregnancies predominantly occurs before 24 weeks' gestation. After this stage, although the risk of intrauterine fetal death is still higher in MC than in DC pregnancies, if both fetuses are alive at 24 weeks, the chance of a woman having two live infants 1 month after delivery is similar in MC and DC pregnancies.

Acute Mesenteric Ischemia Remains a Highly Morbid Diagnosis after Initial Hospitalization Survival.

Acute mesenteric ischemia (AMI) remains a vascular emergency. Our aim was to explore readmission for AMI. We identified all patients admitted for AMI from the state of California through the Healthcare and Utilization Project from 2005 to 2011. Our primary end point was the rate and etiology for readmission. Our secondary end points were the length of hospitalization and in-hospital mortality. Cox proportional hazard regression was utilized to assess risk of 30-day readmission. There were 534 (9.9%) readmissions at 30 days. The mean age was 67 ± 17 years and 209 (39.1%) were male. The five most common etiologies for readmission were AMI (7.6%), cardiac events (5.3%), severe sepsis (1.2%), dehydration (1.1%), and acute kidney failure (1.1%). Once readmitted, these patients were most likely to experience cardiac catheterizations (25.4%), red blood cell transfusions (23.6%), intubation and mechanical ventilation (17.6%), biopsy of the large intestine (13.9%), reoperation for small bowel resection (10.9%), administration of total parenteral nutrition (10.5%), and transfusion of other blood products (6.9%). This hospitalization was 8.8 ± 12.7 days long. In-hospital mortality was 36 patients (6.7%). On multivariable Cox-regression analysis, severe (hazard ratio [HR]: 2.1 [1.4-3.2], p = 0.0005) and moderate (HR: 1.5 [1.03-2.13], p = 0.04) Elixhauser Comorbidity Group, complications (HR: 1.5 [1.2-1.9], p = 0.0007), and longer index hospitalization (HR: 1.02 [1.01-1.02], p < 0.0001) were predictors of readmission. Conclusion AMI remains a vascular emergency. Readmissions have a significant rate of morbid invasive procedures and can lead to an in-hospital mortality of 6.7%. The adoption of guidelines similar to the European Society for Trauma and Emergency Surgery should be considered.

Direct monitoring of pulmonary disease treatment biomarkers using plasmonic gold nanorods with diffusion-sensitive OCT.

The solid concentration of pulmonary mucus (wt%) is critical to respiratory health. In patients with respiratory disease, such as Cystic Fibrosis (CF) and Chronic Obstructive Pulmonary Disorder (COPD), mucus hydration is impaired, resulting in high wt%. Mucus with high wt% is a hallmark of pulmonary disease that leads to obstructed airways, inflammation, and infection. Methods to measure mucus hydration in situ and in real-time are needed for drug development and personalized therapy. We employed plasmonic gold nanorod (GNR) biosensors that intermittently collide with macromolecules comprising the mucus mesh as they self-diffuse, such that GNR translational diffusion (DT) is sensitive to wt%. GNRs are attractive candidates for bioprobes due to their anisotropic optical scattering that makes them easily distinguishable from native tissue using polarization-sensitive OCT. Using principles of heterodyne dynamic light scattering, we developed diffusion-sensitive optical coherence tomography (DS-OCT) to spatially-resolve changing DT in real-time. DS-OCT enables, for the first time, direct monitoring of changes in nanoparticle diffusion rates that are sensitive to nanoporosity with spatial and temporal resolutions of 4.7 µm and 0.2 s. DS-OCT therefore enables us to measure spatially-resolved changes in mucus wt% over time. In this study, we demonstrate the applicability of DS-OCT on well-differentiated primary human bronchial epithelial cells during a clinical mucus-hydrating therapy, hypertonic saline treatment (HST), to reveal, for the first time, mucus mixing, cellular secretions, and mucus hydration on the micrometer scale that translate to long-term therapeutic effects.

Chronic selective hypertriglyceridemia impairs endothelium-dependent vasodilatation in rats.

OBJECTIVE/METHODS: In order to investigate whether selective hypertriglyceridemia impairs endothelium-dependent vasodilatation in the rat hindlimb, rats were selectively bred to establish two strains, one with a pronounced hypertriglyceridemia (HT) and the other with normal plasma levels of triglycerides (LT). RESULTS: Carotid arteries and aortae removed from 3, 6, 9 and 12 month old LT- and HT-rats exhibited a normal morphology. However, marked morphological differences were observed between vessels from 18-20 month old HT- and LT-rats. The endothelium-dependent vasodilator acetylcholine (2 to 50 micrograms/kg), administered into the iliac artery, elicited a concentration-dependent increase in hindlimb blood flow which was not different in 3, 6 and 9 month old LT- or HT-rats but was impaired in 12 and 18-20 month old HT-rats. In contrast the endothelium-independent vasodilator sodium nitroprusside enhanced blood flow in both strains to a similar extent. Neither administration of the nitric oxide (NO) synthase (NOS) substrate, L-arginine, nor the NOS inhibitor NGnitro-L-arginine, affected the responsiveness to endothelium-dependent vasodilators in 12 month old HT-rats. These attenuated responses could not be attributed to a decrease in endothelial NOS expression as Western blot analysis revealed identical levels of this enzyme in the aortae and carotid arteries from LT- and HT-rats. Determination of superoxide anion (O2-) formation however, demonstrated a markedly elevated production of O2- in aortae from HT-rats. CONCLUSION: We conclude that chronic selective hypertriglyceridemia, an independent risk factor in the development and progression of atherosclerosis, leads to an endothelial dysfunction which is associated with an increased vascular O2- production and a subsequent decrease in bioavailable NO.

Induction chemotherapy followed by concurrent chemotherapy and high-dose radiotherapy for locally advanced squamous cell carcinoma of the upper-thoracic and midthoracic esophagus.

The purpose of this study was to evaluate the efficacy and toxicity of an induction chemotherapy schedule followed by high-dose radiotherapy and concurrent chemotherapy for locally advanced squamous cell carcinomas of the upper and midthoracic esophagus. Patients were treated with three courses of fluorouracil, leucovorin, etoposide, and cisplatin-containing induction chemotherapy followed by high-dose external beam radiotherapy to 65 Gy in 6 weeks for T4 and obstructing T3 tumors. Transversable T3 tumors received 60 Gy in 6 weeks by external radiotherapy, followed by two high-dose-rate esophageal brachytherapy fractions of 4 Gy in 5-mm tissue depth. Concurrent to radiotherapy, cisplatin and etoposide were given. Long-term survival of 22 patients was 41% and 31% at 2 and 3 years, respectively, with a median follow-up of 39 months. The probability of locoregional tumor recurrence was 60% at 3 years for all patients and 30% for those with a partial or complete response to induction chemotherapy. Acute toxicity of this schedule was moderate. Long-term survivors had a good swallowing function. This schedule offers a considerable chance of long-term survival for patients with locally advanced squamous cell carcinomas of the upper and midthoracic esophagus. Local in-field recurrences are the main risk after definitive radiochemotherapy. Dose escalation of radiotherapy is possible because of the observed low late toxicity.

[Baseline and contrast-enhanced ultrasound of the liver in tumor patients]. / Sonografische Leberdiagnostik bei Tumorpatienten ohne und mit Kontrastmittel.

In patients with known malignancy, correct detection and characterization of liver lesions has important therapeutic consequences. Conventional sonography is the most commonly used modality for liver imaging in tumor patients. However, it has a lower sensitivity for the detection of liver metastases compared to contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI). The majority of liver metastases are hypoechoic and well defined in baseline ultrasound (US), while detection of isoechoic or small liver metastases <1 cm is difficult and the differentiation of liver metastases from benign liver lesions and other malignant liver tumors can be impossible with baseline US. The use of microbubble-based ultrasound contrast agents and contrast-specific imaging techniques advanced the accuracy of ultrasound in liver imaging. Levovist and SonoVue are the US contrast agents approved for liver imaging in Europe. Compared to Levovist, SonoVue allows continuous imaging of the liver in real-time over a period of up to 5 minutes. As a result, SonoVue became the preferred contrast agent for liver imaging in the recent years, while Levovist became less important. Important for the detection of liver metastases are the portal venous and late phases in which metastases show a wash-out and can be detected as hypoechoic lesions in homogeneous enhanced liver parenchyma. The detection of hepatic metastases is substantially improved by CEUS compared to conventional B-mode sonography. Several studies showed sensitivity in detecting liver metastases comparable to that of contrast-enhanced CT and MRI. Furthermore, the typical enhancement patterns of the different benign and malignant liver lesions allow reliable characterization and differentiation from liver metastases in the majority of cases. This paper provides information about the advantages and expedient application of contrast-enhanced ultrasound (CEUS) in tumor patients.

Quantitative and qualitative evaluation of the influence of different table feeds on visualization of peripheral arteries in CT angiography of aortoiliac and lower extremity arteries.

The influence of different table feeds (TF) on vascular enhancement and image quality in patients undergoing lower extremity runoff-CTA for peripheral artery occlusive disease (PAOD), acute ischemia (AI) or abdominal aortic aneurysm (AAA) with PAOD was investigated retrospectively. One hundred eighty-five patients (PAOD: n = 132; AI: n = 40; AAA: n = 13) underwent 16-detector runoff-CTA (120 kV; 140 mAs; rotation time 0.5 s, collimation 16 x 1.5 mm) using different TF (30 mm/s: n = 25; 40 mm/s: n = 91; 48 mm/s: n = 36; 56 mm/s: n = 33). Vascular enhancement of the large arteries was measured every 10 cm along the z-axis from the upper abdomen to the toe. Arterial enhancement in the distal lower leg was compared (ANOVA, Bonferroni post-test). Qualitative assessment of bolus timing was performed independently by two radiologists. The study was IRB approved. In patients with PAOD or AI, enhancement of calf arteries using a TF of 48 mm/s (278 +/- 79 HU) was significantly higher in comparison to two slower TF (30 mm/s: 201 +/- 70 HU, P < 0.001; 40 mm/s: 251 +/- 79 HU, P < 0.05; 56 mm/s: 261 +/- 57 HU, NS) and the fewest noninterpretable arterial segments below the knee were observed with a TF of 48 mm/s (reader 1: 5/121 = 4.1%; reader 2: 4/121 = 3.3%). In patients with AAA, the fewest nondiagnostic segments occurred with a TF of 30 mm/s (2/12 = 17%, both readers) and 40 mm/s (4/24 = 17%, both readers). A TF of 48 mm/s provided the best synchronization of CT data acquisition and contrast bolus propagation and thus the best image quality in patients with PAOD and AI. In patients with AAA, a slower TF of 30 mm/s provided better image quality than faster CT protocols.

Detection of hepatic metastases with low MI real time contrast enhanced sonography and SonoVue.

AIM: SonoVue is the first ultrasound contrast agent which allows repeated continuous examination of the liver in real time. The aim of this study was to compare low mechanical index (MI) real time contrast enhanced ultrasound of the liver, using the contrast agent SonoVue, with conventional B-mode sonography for the detection of hepatic metastases. METHOD: 40 patients with known malignancy and at least one liver lesion on conventional B-mode sonography were included. Conventional B-mode sonography was performed followed by contrast enhanced ultrasound (CEUS) of the liver in the arterial (< 30 sec), portal-venous (40-120 sec) and delayed phase (> 120 sec) after injection of SonoVue. CEUS was performed using contrast specific imaging and low MI (< 0.3). Number, location and size of metastases on baseline and CEUS were compared with CT or MRI (blinded reader). RESULTS: 37 patients had 128 metastases on CT or MRI. Baseline US showed 74 metastases confirmed by reference examination (69%), while CEUS yielded 109 metastases (sensitivity 90%) (p < 0.001). On CEUS, 35 additional metastases not seen on baseline but confirmed by reference imaging were detected in 14 patients (36%). In 8 patients, CEUS showed 13 metastases not seen on reference imaging. CONCLUSION: Detection of hepatic metastases is substantially improved by low MI real time contrast enhanced ultrasound with SonoVue compared to conventional B-mode sonography.

Detection and characterisation of liver metastases.

Modern liver imaging of cancer patients requires an imaging modality that is not only highly sensitive in detecting lesions but also provides reliable characterisation of lesions and thus allows differentiation of metastases from frequently found benign lesions. Conventional ultrasound (US) has a relatively poor sensitivity and specificity for imaging liver metastases and US used to be inferior to CT and MRI mainly due to a lack of contrast agents. This has changed with the advent of microbubble contrast agents for US. The use of recent contrast agents such as SonoVue (Bracco, Italy) combined with low mechanical index contrast-specific imaging techniques such as Contrast Pulse Sequencing provides dynamic real time imaging of focal liver lesions in the arterial, portal venous and delayed phase. This improves lesion detection and characterisation. To investigate the benefit of SonoVue for detecting liver metastases we studied 40 cancer patients with liver lesions on reference imaging (CT or MRI), 37 of them had metastases. The mean number of reference confirmed metastases per patient increased from 1.85+/-1.79 on conventional ultrasound to 2.73+/-2.50 post SonoVue (p < 0.05). CEUS showed more individual metastases than baseline in 12 (34%) patients. Using CT or MRI as the reference, the mean sensitivity to individual metastases increased from 69% on baseline US to 90% post contrast (p < 0.0005). The role of SonoVue in characterisation of focal liver lesions was evaluated in 63 patients. One lesion was studied per patient. Based on standardised dynamic enhancement criteria for each lesion type, the number of correctly diagnosed lesions improved from 41 (65%) on baseline US to 58 (92%) post contrast (p < 0.001). On CEUS all 27 metastases were correctly diagnosed, while baseline US misinterpreted 2 of these. The number of correctly diagnosed benign lesions (n = 28) increased from 12 (43%) on baseline to 25 (89%) post SonoVue. In conclusion, detection and characterisation of focal liver lesions by US are markedly improved by the use of SonoVue. Contrast agents add a new dimension to sonography allowing it to rival CT and MRI, especially for lesion characterisation.

Liver metastases in cancer: detection with contrast-enhanced ultrasonography.

In patients with known or suspected malignancy, ultrasonography (US) is often the first choice for liver imaging because of its widespread availability and low cost. Compared with contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI), the sensitivity of conventional US for detecting hepatic metastases is relatively poor. The advent of microbubble contrast agents changed this situation. Sensitivity and specificity increased substantially with the use of these contrast agents and contrast-specific imaging modes in recent years. Currently, numerous US imaging methods exist, based on Doppler techniques or harmonic imaging. They exploit the complex nonlinear behavior of microbubbles in a sound field to achieve marked augmentation of the US signal. Although microbubble contrast agents are essentially blood pool agents, some have a hepatosplenic specific late phase. Imaging during this late phase is particularly useful for improving the detection of malignant liver lesions and allows US to perform similarly to spiral CT as shown by recent studies. In addition, this late phase imaging is very helpful for lesion characterization. Low mechanical index imaging with the newer perfluor agents permits real-time imaging of the dynamic contrast behavior during the arterial, portal venous, and late phases and is particularly helpful for lesion characterization. The use of US for hemodynamic studies of the liver transit time may detect blood flow changes induced by micrometastases even before they become visible on imaging. In this field of functional imaging, further research is required to achieve conclusive results, which are not yet available.

Lymphocyte transfer in streptozotocin-induced diabetes: adhesion of donor cells to islet endothelium.

The interaction between intravenously transferred lymphocytes derived from spleens of multiple low-dose streptozotocin-diabetic mice with islet, exocrine pancreatic, and gastric mucosal endothelium of nondiabetic recipient mice was investigated by in vivo microscopy. Donor lymphocytes were stained with acridine red in vitro. The adoptive transfer of these cells from diabetic donor animals resulted in significantly increased lymphocyte rolling (4.46 +/- 1.32%, P < 0.05) and adhesion (3.86 +/- 1.04%, P < 0.05) in islets of nondiabetic recipients that had been pretreated with a single subdiabetogenic dose of streptozotocin. No increased endothelial interaction was noted in nonpretreated recipients or in experiments with nondiabetic donors. Rolling (1.19 +/- 0.61 to 2.71 +/- 0.62%) and adhesion (0.61 +/- 0.33 to 2.80 +/- 0.97%) of donor lymphocytes were low in exocrine pancreatic and gastric mucosal control tissue. It is concluded that, in this animal model, lymphocytes from diabetic donors interact preferentially with recipient islet endothelium. However, additional stimulation of recipient islet endothelium by exogenous factors is necessary to enable transferred cells to adhere to pancreatic islets.

Gastric chief cell-specific transcription of the pepsinogen A gene.

The molecular mechanisms underlying the regulation of pepsinogen A (PGA) gene expression in mammalian cells are poorly understood. In this paper we describe the structural and functional analysis of the pepsinogen A gene promoter in the pig. By genomic Southern analyses we demonstrate that, in contrast with human PGA genes which are amplified and organized in haplotypes, only a single PGA gene is present per haploid porcine genome. With the aim of identifying promoter elements mediating the gastric mucosa cell-specific transcription of the PGA gene in pig, we isolated a PGA gene from a porcine genomic library. The nucleotide sequence of the first exon and 1.7 kb of the upstream DNA region were determined and compared with the corresponding regions of the human PGA gene encoding isozymogen Pg5. In order to study the promoter activity of the PGA gene a functional assay was developed: we succeeded in obtaining primary monolayer cultures of porcine gastric mucosal chief cells, suitable for transfection. Fragments of 5'-flanking and noncoding first exon sequences of the porcine and human PGA genes were linked to the chloramphenicol acetyltransferase (CAT) gene. The transcriptional activity of these hybrid genes was assessed in transient expression assays upon transfection (lipofection) of gastric and nongastric cells. Whereas PGA 5'-flanking sequences showed no promoter activity in nongastric cell types, the DNA region from -205 to +21 was found to be sufficient to direct expression of the porcine PGA constructs in a cell-specific manner. Further deletion analysis of the proximal promoter fragment identified several regions (-205 to -167, -127 to -67 and +2 to +21) acting synergistically in the transcriptional regulation of the PGA gene. In contrast, all human PGA-CAT constructs used failed to show promoter activity in porcine gastric chief cells, indicating species-specific control of PGA gene expression. In addition, the transcriptional activity of the porcine PGA promoter in chief cells from pig was completely abolished by in vitro CpG methylation. Footprint analyses of the proximal promoter fragment using nuclear extracts from either porcine gastric mucosal chief cells or liver revealed some notable differences between both extracts, which might reflect the interaction with (a) cell-specific factor(s).

Reduction of non-steroidal anti-inflammatory drug induced gastric injury and leucocyte endothelial adhesion by octreotide.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) induce gastric ulcers. AIMS: To assess whether the somatostatin analogue octreotide prevents NSAID induced mucosal gastrointestinal damage in both animals and humans. The effect of octreotide on neutrophil adhesion to the endothelium was also evaluated. METHODS: Male Sprague-Dawley rats were pretreated either with saline (0.3 ml subcutaneously) or octreotide (0.001-1 ng/kg subcutaneously). After 30 minutes gastric ulcers were induced by the intragastric application of NSAIDs (20 mg/kg indomethacin, 200 mg/kg aspirin, 200 mg/kg ibuprofen, or 50 mg/kg diclofenac). Four hours later the rats were killed and gastric mucosal lesions were assessed by computed planimetry. To determine whether octreotide could prevent indomethacin induced injury in humans, 20 healthy volunteers were evaluated in a double blind, placebo controlled study. RESULTS: Octreotide prevented NSAID induced gastric mucosal lesions (p < 0.05). The dose response curve was U shaped and the most effective dose was 0.1 ng/kg. Leucocyte adherence in submucosal venules of the stomach was evaluated by in vivo microscopy. Octreotide (0.1 ng/kg subcutaneously) prevented indomethacin (20 mg/kg intragastric) induced leucocyte adherence in gastric submucosal venules (p < 0.05). Healthy human volunteers received 50 mg indomethacin orally thrice a day concomitantly with either an identical placebo or 0.01 microgram, 0.1 microgram, or 1 microgram octreotide subcutaneously thrice a day for three days. Injury was assessed by endoscopy. There was a negative correlation between the octreotide dose and injury score (p < 0.03 for gastric injury, p < 0.001 for duodenal injury). CONCLUSIONS: Octreotide protects the stomach from NSAID induced gastric injury, probably via its ability to reduce NSAID induced neutrophilic adhesion to the microvasculature. Octreotide also ameliorated indomethacin induced gastric and duodenal injury in humans.

Induction chemotherapy followed by concurrent chemotherapy and high-dose radiotherapy for locally advanced squamous cell carcinoma of the cervical oesophagus.

The efficacy and toxicity of combined radiochemotherapy for locally advanced squamous cell carcinomas of the cervical oesophagus was evaluated retrospectively. Induction chemotherapy consisted of three courses of 5-fluorouracil (5-FU), leucovorin, etoposide and cisplatin (FLEP) or two courses weekly six times of 5-FU and leucovorin combined with biweekly cisplatin. This induction regimen was followed by high-dose external beam radiotherapy up to 60-66 Gy and concurrent chemotherapy with cisplatin and etoposide. Median follow-up of the recruited 17 patients was 37 months (13-73 months). Long-term survival was 24% at 2 and 3 years. The probabilities of locoregional tumour recurrences and distant metastases as sites of first relapse were 67 and 39% at 2 years. Acute and late toxicity of this schedule was moderate. The protocol offers a definitive chance of long-term survival for patients with locally advanced carcinomas of the cervical oesophagus, but local in-field recurrences remain the predominant risk after treatment. Intensification of the regimen seems possible because no dose-limiting late toxicities were observed.

In vivo microscopy of murine islets of Langerhans: increased adhesion of transferred lymphocytes to islets depends on macrophage-derived cytokines in a model of organ-specific insulitis.

Environmental factors contribute to the pathogenesis of type 1 diabetes (insulin-dependent diabetes mellitus). Multiple low doses of streptozotocin (MLDS) induce hyperglycaemia and insulitis in mice. Previously we demonstrated that adhesion of lymphocytes to endothelium of islets is only increased when donor animals were diabetic and recipient mice had received 5 mg/kg streptozotocin (STZ). Therefore we used streptozotocin to evaluate the immunological relevance of such an irritation of islets. Lymphocytes, separated from diabetic mice (MLDS), were fluorescently labelled and injected to recipient mice that had received 5 mg/kg STZ. With in vivo microscopy we measured lymphocyte flow and adherence in islets. Expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) in the pancreas was assessed using immunohistochemistry. Very late antigen-4 (VLA-4) and leucocyte function-associated antigen-1 (LFA-1) expression on transferred lymphocytes was measured with flow cytometry. Pretreatment of recipients with antibodies to cytokines or silica reduced lymphocyte adherence to islet endothelium from 2.04% (goat immunoglobulin G; IgG) or 1.82% (rat IgG) to 0.47, 0.58, 0.39 or 0. 19% for monoclonal antibody (mAb) interferon-gamma (IFN-gamma), polyclonal antibody (pAb) tumour necrosis factor-alpha (TNF-alpha), pAb interleukin (IL)-1alpha or silica, respectively. Reduced adhesion was associated with a decreased expression of VCAM-1 and ICAM-1 in islets of treated recipients compared with mice treated with 5 mg/kg STZ alone. In conclusion, pretreatment of recipients with 5 mg/kg STZ leads to an increased expression of adhesion molecules in the islets and lymphocyte adhesion to islet endothelium in vivo, demonstrating an immune response of the islets. Prevention of increased expression of ICAM-1 or VCAM-1 and reduction of lymphocyte adhesion in islets by silica or antibody indicate an involvement of macrophages and macrophage derived cytokines in the generation of this immune response.