Beneficial protective effects of 2-allyl amino 4-methyl sulfanyl butyric acid on glucose metabolism and glycoprotein components in streptozotocin induced diabetic rats with molecular modeling.

In the present study, the potential effects of 2-allyl amino 4-methyl sulfanyl butyric acid (AMSB) on the glucose metabolism and glycoprotein components in streptozotocin (STZ) induced experimental diabetic rats were determined. Further, molecular modeling was performed to investigate the modes of AMSB interaction with insulin receptor active sites. The blood glucose and plasma insulin levels were measured in the STZ induced diabetic rats, whereas the glucose metabolism and glycoprotein components were analyzed from the plasma and tissues. After oral treatment of AMSB there was a significant reduction in blood glucose, glucose-6-phosphatase, fructose-1,6-bisphosphatase and glycogen phosphorylase. On the other hand, the activity of the glycoprotein levels, such as hexose, hexosamine, fucose and sialic acid, were significantly reduced. In addition, a significant elevation in plasma insulin, hexokinase, glycogen and glycogen synthase were also observed in the AMSB treated rats. The molecular modeling study revealed that AMSB has a stable binding pattern to the active site of insulin, with a Gscore value of -7.34 Kcal mol-1. From this study we conclude that AMSB has a potent antidiabetic activity in addition to its protective effect on glycoprotein metabolism.

Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome.

RATIONALE: Acute respiratory distress syndrome (ARDS) affects over 200000 people annually in the USA. Despite causing severe, and often refractory, hypoxaemia, the high mortality and long-term morbidity of ARDS results mainly from extra-pulmonary organ failure; however the mechanism for this organ crosstalk has not been determined. METHODS: Using autologous radiolabelled neutrophils we investigated the pulmonary transit of primed and unprimed neutrophils in humans. Flow cytometry of whole blood samples was used to assess transpulmonary neutrophil priming gradients in patients with ARDS, sepsis and perioperative controls. MAIN RESULTS: Unprimed neutrophils passed through the lungs with a transit time of 14.2 s, only 2.3 s slower than erythrocytes, and with <5% first-pass retention. Over 97% of neutrophils primed ex vivo with granulocyte macrophage colony-stimulating factor were retained on first pass, with 48% still remaining in the lungs at 40 min. Neutrophils exposed to platelet-activating factor were initially retained but subsequently released such that only 14% remained in the lungs at 40 min. Significant transpulmonary gradients of neutrophil CD62L cell surface expression were observed in ARDS compared with perioperative controls and patients with sepsis. CONCLUSIONS: We demonstrated minimal delay and retention of unprimed neutrophils transiting the healthy human pulmonary vasculature, but marked retention of primed neutrophils; these latter cells then 'deprime' and are re-released into the systemic circulation. Further, we show that this physiological depriming mechanism may fail in patients with ARDS, resulting in increased numbers of primed neutrophils within the systemic circulation. This identifies a potential mechanism for the remote organ damage observed in patients with ARDS.

Superiority of 18F-FDG PET compared to 111In-labelled leucocyte scintigraphy in the evaluation of fever of unknown origin.

AIM: To compare the accuracy of positron emission tomography (PET) using (18)F-FDG (Fluorodeoxyglucose) PET with (111)In-labelled leucocytes scintigraphy (LS) in patients with fever of unknown origin (FUO). METHODS: Twenty-three consecutive patients with FUO were prospectively studied using whole-body LS and PET. Performance of the two modalities for identifying a cause of FUO was evaluated. Final diagnosis was based on biopsy, microbiological tests, clinical and imaging follow-up. RESULTS: Abnormal tracer uptake was seen in 3/23(13%) and 14/23(61%) patients on LS and PET respectively, suggesting a higher sensitivity (p < 0.01) for the latter. All LS positive cases were identified on PET and confirmed as infection. The causes of FUO in the other PET positive patients were: infection (n = 3), vasculitis (n = 3), non-infectious inflammatory conditions (n = 2) and cancer (n = 1). No specific diagnosis was reached in 2 patients. Of 13 patients without a definite diagnosis following PET and LS, 10 made a spontaneous recovery during the follow-up period and no definite cause for FUO was found on investigation. Still's disease, Polymyalgia rheumatica and Chronic fatigue syndrome/Myalgic encephalomyelitis were diagnosed in the remaining three patients during follow-up. The results thus showed an overall sensitivity of 86% for PET and 20% for LS (p < 0.01). The overall specificity for FDG PET was 78% as against 100% for LS. PET had a PPV of 86% and a NPV of 78% whereas LS had a PPV of 100% and a NPV of 40%. CONCLUSION: PET has a higher sensitivity than LS in identifying the aetiology of FUO. PET/PET-CT, where available, should be used as the non-invasive investigation of choice in the assessment of patients with FUO.

Selective internal radiation therapy with 90Y-SIR-Spheres microspheres for non-resectable colorectal metastases in the liver.

Almost half the patients with colorectal cancer will develop liver metastasis at some stage during their disease. Potentially curative surgical resection is possible in some of these patients. In those patients unsuitable for surgery, treatment with systemic chemotherapy and external radiation therapy is relatively ineffective. Many studies have described the successful use of selective internal radiation therapy (SIRT) with 90Y-SIR-Spheres microspheres in patients with inoperable liver metastasis. The authors report on a patient who has been in complete remission for 1 year after treatment with SIRT.

F18-FDG-PET evaluation of patients for resection of colorectal liver metastases.

BACKGROUND/AIMS: Liver resection is the only treatment which offers long-term survival for patients with colorectal liver metastases. However, the significant mortality and morbidity associated with hepatectomy makes accurate patient selection paramount. Current staging by CT and MRI has limitations, with these modalities delivering a sensitivity and specificity of only 70-80%. Thus some patients may be deprived of long-term survival, and others subjected to futile surgery. METHODOLOGY: We report our experience of the influence of F18-FDG-PET scanning in the management of 31 consecutive patients with colorectal liver metastases referred for liver resection. RESULTS: F18-FDG-PET scanning detected liver and pulmonary metastases with a sensitivity of 96% and 100% respectively, in comparison to corresponding figures of 70% and 83% for CT. Furthermore, the sensitivity of F18-FDG-PET scanning in identifying extra-hepatic and extra-pulmonary disease was 100% in comparison to 20% for CT. Overall, F18-FDG-PET scanning resulted in a significant alteration of management in 29% of patients. CONCLUSIONS: F18-FDG-PET scanning has an important clinical impact on the management of patients being considered for resection of colorectal liver metastases.

P-glycoprotein expression is associated with sestamibi washout in primary hyperparathyroidism.

BACKGROUND: The detection of parathyroid adenomas by (99m)Tc-labelled hexakis 2-methoxyisobutyl isonitrile (sestamibi) scintigraphy is influenced by several factors, including tumour size and serum level of parathyroid hormone (PTH). This study examined the relationship between sestamibi accumulation and multidrug resistance (MDR)-related P-glycoprotein (P-gp) expression in a large series of surgically excised parathyroid tumours. METHODS: Seventy-eight patients underwent dual-phase sestamibi imaging before parathyroidectomy. Expression of P-gp within tumour cells was assessed by immunohistochemistry. Tumour size was measured and the ellipsoid volume calculated. Scan results were analysed in relation to preoperative serum levels of calcium and PTH, P-gp expression and tumour volume. RESULTS: Sixty-four of the 78 sestamibi scans were positive and 14 negative. Smaller adenomas (less than 0.5 cm(3)) were more likely to be sestamibi negative than larger lesions (P = 0.006). Ten of 14 adenomas with negative imaging showed strong P-gp membrane positivity and 45 of 64 lesions with a positive scan did not show P-gp membrane expression, indicating a significant association between high P-gp membrane immunoreactivity and negative sestamibi result (P = 0.006). CONCLUSION: These data suggest an association between P-gp membrane expression and false-negative sestamibi scan result. Inhibition of the P-gp transmembrane pump using MDR modulators may therefore improve the sensitivity of sestamibi scintigraphy.

The use of 18-fluoro-dihydroxyphenylalanine and 18-fluorodeoxyglucose positron emission tomography scanning in the assessment of metaiodobenzylguanidine-negative phaeochromocytoma.

123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy scanning is commonly used in the imaging of phaeochromocytoma (and paraganglioma) to confirm the site of disease and whether any spread has occurred. However, 123I-MIBG imaging is negative in 15% of cases of benign phaeochromocytoma and around 50% of cases of malignant phaeochromocytoma. In recent years, positron emission tomography (PET) scanning using various different radiotracers has been shown to be a good alternative or supplementary investigation in phaeochromocytoma. We present the cases of four patients with symptoms and signs suggestive of phaeochromocytoma, but who had negative 123I-MIBG scans, and illustrate the usefulness of 18-fluoro-dihydroxyphenylalanine PET scanning in their assessment. In one of the patients, we illustrate how fluorodeoxyglucose PETscanning can provide useful information about the extent of malignant disease. These illustrative cases lend further support for the use of PET scanning in the assessment of phaeochromocytoma and suggest that it may have a particularly important role in the investigation of patients in whom 123I-MIBG scanning is negative.

In vivo treatment with the herbal phenylethanoid acteoside ameliorates intestinal inflammation in dextran sulphate sodium-induced colitis.

Recently we demonstrated that in inflammatory bowel disease (IBD) macrophage-oxidative burst activity is increased and NADPH oxidase mRNA is induced. The herbal phenylethanoid acteoside isolated from Plantago lanceolata L. was shown to exhibit anti-oxidative potential. Using the dextran sulphate sodium (DSS)-induced colitis model, in this study we have assessed whether systemic application of acteoside affects colitis. Colitis was induced by DSS in Balb/c mice. Treatment with acteoside (120, 600 microg/mouse/day) was performed intraperitoneally. The colon lengths were determined. Colonic tissue was scored histologically (max. score 8) by a blinded investigator. T cells isolated from mesenteric lymph nodes (MLN) were stimulated with anti-CD3 antibody in the presence of interleukin (IL)-2 (final concentration 10 U/ml). After incubation for 24 h, IL-1beta, IL-6, IL-12 tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma levels in supernatants were analysed by the beadlyte cytokine detection system. Histological scoring of colonic tissue revealed that application of acteoside was followed by a significantly improved histological score. In acute colitis the histological score was 3.2 with acteoside versus 5.2 with phosphate-buffered saline (PBS) (P < 0.02). In chronic colitis both 120 microg (3.3 versus 5.2) or 600 microg acteoside (3.0 versus 5.2) significantly ameliorated colitis (both P < 0.02). Stimulated MLN from mice with chronic DSS-induced colitis treated with acteoside showed a significant down-regulation of IFN-gamma secretion (195 pg/ml with 600 microg acteoside versus 612 pg/ml with PBS, P < 0.02). Inhibition of oxidative burst activity with acteoside reduced mucosal tissue damage in DSS colitis and could be a therapeutic alternative for IBD treatment. Further studies of this agent are warranted.

Antiproliferative activity and induction of apoptosis in human colon cancer cells treated in vitro with constituents of a product derived from Pistacia lentiscus L. var. chia.

In this report, we demonstrate that a 50% ethanol extract of the plant-derived product, Chios mastic gum (CMG), contains compounds which inhibit proliferation and induce death of HCT116 human colon cancer cells in vitro. CMG-treatment induces cell arrest at G(1), detachment of the cells from the substrate, activation of pro-caspases-8, -9 and -3, and causes several morphological changes typical of apoptosis in cell organelles. These events, furthermore, are time- and dose-dependent, but p53- and p21-independent. Apoptosis induction by CMG is not inhibited in HCT116 cell clones expressing high levels of the anti-apoptotic protein, Bcl-2, or dominant-negative FADD, thereby indicating that CMG induces cell death via a yet-to-be identified pathway, unrelated to the death receptor- and mitochondrion-dependent pathways. The findings presented here suggest that CMG (a) induces an anoikis form of cell death in HCT116 colon cancer cells that includes events associated with caspase-dependent pathways; and (b) might be developed into a chemotherapeutic agent for the treatment of human colon and other cancers.

Differential susceptibility to etoposide in clones derived from a human ovarian cancer cell line.

OBJECTIVES: To identify parameters/factors that may contribute to the differential sensitivity to etoposide in two clones isolated from the human ovarian carcinoma SKOV-3 cell line, which does not express p53 and is resistant to platinum-based regimens. METHODS: Differential sensitivity of the cells to etoposide was monitored by microscopy to observe morphological changes, by flow cytometry analyses to detect cell cycle perturbations, and by molecular/biochemical assays to identify events involved in induction of apoptosis. RESULTS: Etoposide treatment (1) induced apoptosis in one clone, ES, but not in another clone, ER, (2) had no effect on the expression of the antiapoptotic proteins Bcl-2 and Bcl-X(L) in both cell clones, whereas the proapoptotic proteins Bak and Bax were dramatically upregulated in ES, but not ER cells, and (3) induced more extensive processing of procaspase-8, procaspase-9, and the caspase-3-targeted substrates, topoisomerase I and PARP, in ES cells. Ectopic overexpression of Bcl-2 in ES cells failed to inhibit etoposide-induced apoptosis. CONCLUSIONS: The differential susceptibility of ES and ER cells to etoposide-induced apoptosis is associated with differences in several events rather than with a specific single genetic regulator of the apoptotic machinery. We propose that the differential response of ovarian cancer patients to etoposide treatment is associated with the number of etoposide-sensitive cells in the tumor.

16-Detector multislice CT in the detection of stress fractures: a comparison with skeletal scintigraphy.

AIMS: To test the hypothesis that the improved resolution afforded by 16-detector computed tomography (CT) would translate to better stress fracture detection when compared with skeletal scintigraphy. MATERIALS AND METHODS: Thirty-three cases of suspected stress fractures in 26 patients were investigated using skeletal scintigraphy and 16-detector CT performed on the same day. Planar images of the lower limbs were taken 3h post-injection of 400MBq (99m)Tc-methylene diphosphonate ((99m)Tc-MDP). (99m)Tc-MDP uptake was quantified at suspected fracture sites. CT was performed using a 16-detector multisection machine employing 0.75mm detectors and images reconstructed in 0.5mm increments. Examinations were reported independently and discordant results were compared at follow-up. RESULTS: At initial reporting scintigraphy identified fractures in 13 of the 33 cases and CT identified four of the 33. In one case, on review of the CT images, a fracture was present in the distal fibula that was not initially identified. This resulted in eight scintigraphic-positive CT-negative discordant cases. The (99m)Tc-MDP uptake was significantly lower in the discordant fracture group compared with the concordant group (p<0.01). CONCLUSIONS: Despite technological advances in CT, scintigraphy appeared to detect more stress fractures. As such, multidetector CT should not be used as a routine initial investigation in stress fracture detection. The potential use of (99m)Tc-MDP quantification at fracture sites is of interest and may be worth further investigation.

16 detector multislice CT versus skeletal scintigraphy in the diagnosis of wrist fractures: value of quantification of 99Tcm-MDP uptake.

To compare the measured uptake of 99Tcm-methylene diphosphonate (99Tcm-MDP) in those scaphoid fractures seen on both 16 detector multislice CT and scintigraphy, with those seen only on scintigraphy. Over a 12 month period a total of 51 patients with suspected fracture underwent both conventional 99Tcm-MDP scintigraphy and 16 detector multislice CT on the same day. The 99Tcm-MDP uptake was then quantified in patients with identified fracture. This was measured by placing a region of interest (ROI) over the fracture site and the mean and maximum number of counts were compared with those in a similar size ROI placed over background bone activity. A total of 23 fractures were identified on scintigraphy of which 16 were also detected on CT (concordant). In seven cases the fracture was not seen on CT, even in retrospect (discordant). In the discordant cases, follow-up radiographs and MRI (where available) also failed to demonstrate a fracture. The mean fracture count to background bone activity ratio averaged 7.7 (range 3.2-18.5) for concordant fractures and 3.8 (range 1.7-5.3) for discordant fractures (t-test p=0.04). The maximum fracture count to background bone activity ratio averaged 12.7 (range 4.3-27.7) for concordant fractures and 6.3 (range 2.6-9.5) for discordant fractures (t-test p=0.03). It is speculated whether these discordant fractures with less 99Tcm-MDP uptake may represent a less severe injury such as bone bruise.

Hepatocellular carcinoma tumour thrombus in a re-canalised para-umbilical vein: detection by 18-fluoro-2-deoxyglucose positron emission tomography imaging.

This case report describes an unusual site of tumour thrombus in a re-canalised para-umbilical vein, in a patient with hepatocellular carcinoma (HCC) and cirrhosis. The tumour thrombus was suspected on conventional radiography and confirmed using PET imaging, illustrating the complimentary value of structural and functional imaging in achieving the correct diagnosis.

Case report: False negative 16 detector multislice CT for scaphoid fracture.

We discuss a case of a 19-year-old man with scaphoid trauma. We describe the imaging findings on three sets of radiographs, bone scintigraphy, CT and MRI. CT failed to identify a scaphoid fracture, which was present on 6 week radiographs, MRI and scintigraphy. The case illustrates that despite multidetector technology, CT still relies upon cortical and or trabecular displacement to demonstrate fractures.

A review of the surgical management of metastatic gastrointestinal stromal tumours (GISTs) on imatinib mesylate (Glivec).

Gastrointestinal stromal tumours (GISTs) are defined as a group of C-KIT positive mesenchymal tumours of the gastrointestinal tract. Although they may arise throughout the gut, the commonest sites are stomach and small intestine. Over 80% of metastases are to the liver and omentum. Targeted therapy (imatinib) can inhibit C-KIT and thereby aberrant tumoural proliferation. Imatinib may induce shrinkage of lesions and cystic change. Such physical changes often correspond with reduced metabolic activity demonstrated by (18-FDG)PET scans. These changes may enable metastatectomy reducing tumour pain and the risk of haemorrhage and rupture in the short term. In the long term, resection may lessen the risk of recurrence by removing potentially resistant clones. The precise role of palliative resection for GIST metastases on imatinib remains unclear. Imatinib has changed the natural history of metastatic GISTs, with increased survival times. Surgery remains an important management strategy in the metastatic setting because complete pathological responses are rare with imatinib. Surgery is likely to provide the best palliation, greatest reduction in tumour burden and eliminate resistant clones. A multidisciplinary team approach with expertise concentrated in a few centres specialising in the management of these rare tumours is vital to the successful outcome. Future issues regarding the management of differential response of the metastases to imatinib are highlighted. With the emergence of techniques enabling identification of the precise mutational status of the C-KIT oncogene, the imatinib/surgery sequence could be tailored to the type of C-KIT mutation.

Large renal cell carcinoma isometabolic with normal liver on F-18 FDG PET scan.

Positron emission tomography (PET) using F-18 fluorodeoxyglucose (FDG) is a very effective imaging modality in the diagnosis, staging, and monitoring of a variety of malignant conditions. The principle of imaging is based on the enhanced utilization of glucose by cancer. In this report, we describe a patient with renal cell carcinoma who showed FDG uptake isometabolic to normal liver.

Cerebral neutrophil recruitment, histology, and outcome in acute ischemic stroke: an imaging-based study.

BACKGROUND AND PURPOSE: Evidence now exists for a pathogenic role for neutrophils in acute cerebral ischemia. We have studied the patterns and temporal profile of cerebral neutrophil recruitment to areas of acute ischemic stroke (IS) and have attempted to correlate this with neurological status and outcome. METHODS: Patients with cortical middle cerebral artery (MCA) IS were recruited within 24 hours of clinical onset. Neutrophil recruitment was studied using indium-111 (111In) troponolate-labeled neutrophils, planar imaging, and single-photon emission computed tomography (SPECT). Volume of brain infarction was calculated from concurrent computed tomography (CT). Hematoxylin and eosin sections were obtained postmortem (n=2). Outcome was measured using Barthel, Rankin, and National Institute of Health Stroke (NIHSS) scales. RESULTS: Fifteen patients were studied. Significant 111In-neutrophil recruitment to ipsilateral hemisphere, as measured by asymmetry index (AI), was demonstrated within 24 hours of onset in 9 patients; this response was heterogenous between patients and on repeated measurement attenuated over time. Histologically, recruitment was confirmed within intravascular, intramural, and intraparenchymal compartments. Interindividual heterogeneity in neutrophil response did not correlate with infarct volume or outcome. In an exploratory analysis, neutrophil accumulation appeared to correlate significantly with infarct expansion (Spearman rho=0.66; P=0.03, n=12). CONCLUSIONS: Neutrophils recruit to areas of ischemic brain within 24 hours of symptom onset. This recruitment attenuates over time and is confirmed histologically. While neutrophil accumulation may be associated with either the magnitude or the rate of infarct growth, these results require confirmation in future studies.