Diagnostic Utility of Increased STIR Signal in the Posterior Atlanto-Occipital and Atlantoaxial Membrane Complex on MRI in Acute C1-C2 Fracture.

BACKGROUND AND PURPOSE: Acute C1-C2 fractures are difficult to detect on MR imaging due to a paucity of associated bone marrow edema. The purpose of this study was to determine the diagnostic utility of increased STIR signal in the posterior atlanto-occipital and atlantoaxial membrane complex (PAOAAM) in the detection of acute C1-C2 fractures on MR imaging. MATERIALS AND METHODS: Eighty-seven patients with C1-C2 fractures, 87 with no fractures, and 87 with other cervical fractures with acute injury who had both CT and MR imaging within 24 hours were included. All MR images were reviewed by 2 neuroradiologists for the presence of increased STIR signal in the PAOAAM and interspinous ligaments at other cervical levels. Sensitivity and specificity of increased signal within the PAOAAM for the presence of a C1-C2 fracture were assessed. RESULTS: Increased PAOAAM STIR signal was seen in 81/87 patients with C1-C2 fractures, 6/87 patients with no fractures, and 51/87 patients with other cervical fractures with 93.1% sensitivity versus those with no fractures, other cervical fractures, and all controls. Specificity was 93.1% versus those with no fractures, 41.4% versus those with other cervical fractures, and 67.2% versus all controls for the detection of acute C1-C2 fractures. Isolated increased PAOAAM STIR signal without increased signal in other cervical interspinous ligaments showed 89.7% sensitivity versus all controls. Specificity was 95.3% versus those with no fractures, 83.7% versus those with other cervical fractures, and 91.4% versus all controls. CONCLUSIONS: Increased PAOAAM signal on STIR is a highly sensitive indicator of an acute C1-C2 fracture on MR imaging. Furthermore, increased PAOAAM STIR signal as an isolated finding is highly specific for the presence of a C1-C2 fracture, making it a useful sign on MR imaging when CT is either unavailable or the findings are equivocal.

Low-power inversion recovery MRI preserves brain tissue contrast for patients with Parkinson disease with deep brain stimulators.

BACKGROUND AND PURPOSE: Fast spin-echo short τ inversion recovery sequences have been very useful for MR imaging-guided deep brain stimulation procedures in Parkinson disease. However, high-quality fast spin-echo imaging deposits significant heat, exceeding FDA-approved limits when patients already have undergone deep brain stimulation and need a second one or a routine brain MR imaging for neurologic indications. We have developed a STIR sequence with an ultra-low specific absorption rate that meets hardware limitations and produces adequate tissue contrast in cortical and subcortical brain tissues for deep brain stimulation recipients. MATERIALS AND METHODS: Thirteen patients with medically refractory Parkinson disease who qualified for deep brain stimulation were imaged at 1.5T with a fast spin-echo short τ inversion recovery sequence modified to meet conditional MR imaging hardware and specific absorption rate restrictions. Tissue contrast-to-noise ratios and implant localization were objectively and subjectively compared by 2 neuroradiologists, and image quality for surgical planning was assessed by a neurosurgeon for high and low specific absorption rate images. RESULTS: The mean contrast-to-noise ratio for cerebral tissues without including the contrast-to-noise ratio for ventricular fluid was 35 and 31 for high and low specific absorption rate images. Subjective ratings for low specific absorption rate tissue contrast in 77% of patients were identical to (and in a few cases higher than) those of high specific absorption rate contrast, while the neurosurgical coordinates for fusing the stereotactic atlas with low specific absorption rate MR imaging were equivalent to those of the high specific absorption rate for 69% of patients. CONCLUSIONS: Patients with Parkinson disease who have already had a deep brain stimulation face a risk of neural injury if routine, high specific absorption rate MR imaging is performed. Our modified fast spin-echo short τ inversion recovery sequence conforms to very conservative radiofrequency safety limits, while it maintains high tissue contrast for presurgical planning, postsurgical assessment, and radiologic evaluations with greater confidence for radiofrequency safety.

Increased androgen bioavailability is associated with non-alcoholic fatty liver disease in women with polycystic ovary syndrome.

BACKGROUND: Increased prevalence of abnormal aminotransferase levels and/or ultrasonographic evidence of hepatic steatosis (HS) have been found in women with polycystic ovary syndrome (PCOS). However, factors associated with non-alcoholic fatty liver disease (NAFLD) in PCOS are still under investigation. The aim of this case-control study was to investigate the presence of NAFLD and to assess factors associated with this condition in PCOS patients. METHODS: A prospective study of 57 premenopausal PCOS patients and 60 age- and weight-matched control women, with a history of no or minimal alcohol consumption was conducted. Anthropometric variables, biochemical and hormonal parameters were determined and NAFLD was evaluated by abdominal ultrasonography and biochemical testing, after excluding causes of secondary liver disease. Insulin resistance was assessed by homeostasis model assessment of insulin resistance (HOMA-IR) and free androgen index (FAI) was calculated. RESULTS: PCOS patients had an increased prevalence of HS [21/57 patients (36.8%) versus 12/60 controls (20.0%), P < 0.05] and abnormal (> or =40 IU/l) serum aminotransferase levels [13/57 patients (22.8%) versus 2/60 controls (3.3%), P < 0.01] than controls. All patients and controls with metabolic syndrome had HS. Factors associated with HS were PCOS diagnosis, older age, increased BMI, waist circumference (WC), HOMA-IR and FAI values and decreased high-density lipid cholesterol and sex hormone binding globulin levels. PCOS patients had an OR of 3.55 (95% CI: 1.02-5.35) for HS versus controls, after adjustment for age, BMI and WC. CONCLUSIONS: NAFLD is common in PCOS patients and increased androgen bioavailability may be implicated, in combination with metabolic abnormalities. Liver evaluation is proposed in PCOS patients, especially in those with metabolic syndrome.

Localised gastrocnemius myositis in Crohn's disease.

A19-year-old woman presented with pain and tenderness in both calves associated with pyrexia and neutrophil leukocytosis. Gastrocnemius muscle biopsy showed a non-specific lymphocytic myositis and she was found to have positive c-ANCA, in the absence of other evidence of systemic vasculitis. Subsequent investigation of her gastrointestinal tract revealed extensive Crohn's disease. The myositis responded promptly to treatment with prednisolone 0.5 mg/kg. A review of the literature showed that localised calf pain in the setting of Crohn's disease can be caused by non-specific myositis, granulomatous myositis or vasculitis. It is proposed that the "gastrocnemius myalgia syndrome" be included in the typical - albeit rare - extraintestinal manifestations that may herald the appearance of inflammatory bowel disease.

Chemoprevention of colorectal cancer in inflammatory bowel disease? A potential role for folate.

Patients with ulcerative colitis have an increased risk for developing colon cancer compared to the general population. The risk is related to the extension of the disease and its duration. This risk is the same for Crohn's colitis patients of equal extension and duration. By chemoprevention we mean the use of specific natural or synthetic chemical agents to reverse, suppress or prevent progression to invasive cancer. The chemopreventive agents for colon cancer are either of natural origin (vitamins, minerals, food constituents) or synthetic chemicals (difluoromethyl ornithine) and pharmaceutical agents (aspirin, oltipraz). Apart from folate, no other agent has so far been used in vivo for the prevention of colon cancer in long-standing inflammatory bowel disease. The use of folate was, however, not primarily intended to prevent cancer but to enhance folate absorption in ulcerative colitis. From retrospective studies, within the framework of cancer surveillance programmes, it became evident that folate supplementation may play a positive role as a chemopreventive agent against colorectal cancer in patients with long-standing, extensive ulcerative colitis. There is also evidence suggesting that folate supplementation may contribute to regulation of rectal cell proliferation in ulcerative colitis patients. There is a real need for multicentre, randomized, prospective clinical studies in order to evaluate the promising role of folate in preventing colorectal cancer in patients with long-standing inflammatory bowel disease.

Detection of interferon inhibitors or antagonists in gastrointestinal malignancies.

BACKGROUND/AIMS: The aim of this study was to investigate the IFN-inhibiting activity in sera from patients with gastrointestinal malignancies, exerted in a variety of cellular types, as well as to elucidate the determinants of cellular sensitivity to such IFN-inhibitors. METHODOLOGY: Sera from 16 patients with gastric cancer and 18 with colon cancer were tested, while sera from 37 healthy blood donors were used as controls. All serum samples, collected before any kind of treatment, were tested for IFN-blocking and endogenous IFN-like activity. These activities were determined by assaying the inhibition of the vesicular stomatitis virus specific cytopathic effect in three cell lines: A549 cells, intestine 407 and Chang liver cells. RESULTS: There was no endogenous IFN in any of the serum samples of patients or controls. Concerning the IFN blocking activity of serum, there was no significant difference between gastric and colon cancer, while a marked variability was prominent depending on the cell line used. 76.4% of serum samples exerted IFN-blocking activity in the A549 cells, 47.05% in the Int-407 cell line and 32.3% in the Chang Liver cells. No control sample had IFN-blocking activity in any of the cell lines tested. CONCLUSIONS: The results support a cytokine and cytokine inhibitors network, mediating pathophysiological events at the cellular level as well as the whole organism. The limited responsiveness of many neoplasias, including digestive system cancer, to IFN treatment might be due to the presence of IFN inhibitors in the patient's serum.

Vascular endothelial growth factor (vascular permeability factor) expression in injured rat brain.

We investigated the expression of vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) in stab and freeze brain injury models in rats. Immunohistochemical staining with anti-VEGF antibodies demonstrated an increase in VEGF-positive cells in and around both lesions. Morphologically, the injury-induced VEGF-positive cells resembled astrocytes. Double immunofluorescent staining for the astrocytic marker glial fibrillary acidic protein (GFAP) and VEGF demonstrated directly that VEGF-positive cells which appeared in response to these injuries were astrocytes. VEGF expression in astrocytes was maximal on days 3 and 4 after injury in terms of both cell number and affected area. The increase in VEGF-positive cells was more widespread in the freeze lesion than in the stab wound, and occurred in both the lesioned and nonlesioned hemispheres. VEGF-positive cells were still present 3 weeks after both injuries, but their numbers were reduced and their distribution became limited to the immediate vicinity of the lesions. These observations indicate that astrocytes react to injury by increasing VEGF expression, suggesting that VEGF might participate in the central nervous system response to injury.

The effect of eicosanoids on the expression of MHC genes in cultured human colon cancer cells and mouse colonocytes in vivo.

Eicosanoids have been implicated in the pathogenesis of cancer and are known to regulate the expression of antigens of the major histocompatibility complex (MHC). In human colon cancer, we have recently observed that: (a) the expression of MHC class I and II antigens are markedly reduced; and (b) the levels of PGE2, but not of PGF2 alpha and LTB4, are elevated compared to histologically normal mucosa. Therefore, we investigated the effect of PGE2, PGF2 alpha and LTB4 on the regulation of MHC class I antigens in two human colon adenocarcinoma cell lines and in a murine model of colon cancer. None of these eicosanoids had any significant effect on the expression of MHC class I antigens in the human colonocytes or the transcription rate of class I genes, with the exception of LTB4 which only modestly suppressed the transcription rate. Similarly, 16, 16-dimethyl-PGE2 had no effect on the expression of MHC class I genes in the colonocytes of BALB/c mice treated with the carcinogen dimethylhydrazine. We conclude that PGE2, PGF2 alpha and LTB4 did not affect the expression of MHC class I antigens in cultured human colon adenocarcinoma cells, and 16, 16-dimethyl PGE2 did not affect their expression in mice, even when mice were treated with a colon carcinogen. Thus, these eicosanoids are an unlikely regulator of the observed underexpression of MHC class I antigens in human colon cancer.

Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene.

The VHL tumor suppressor gene is inactivated in patients with von Hippel-Lindau disease and in most sporadic clear cell renal carcinomas. Although VHL protein function remains unclear, VHL does interact with the elongin BC subunits in vivo and regulates RNA polymerase II elongation activity in vitro by inhibiting formation of the elongin ABC complex. Expression of wild-type VHL in renal carcinoma cells with inactivated endogenous VHL resulted in unaltered in vitro cell growth and decreased vascular endothelial growth factor (VEGF) mRNA expression and responsiveness to serum deprivation. VEGF is highly expressed in many tumors, including VHL-associated and sporadic renal carcinomas, and it stimulates neoangiogenesis in growing solid tumors. Despite 5-fold differences in VEGF mRNA levels, VHL overexpression did not affect VEGF transcription initiation or elongation as would have been suggested by VHL-elongin association. These results suggest that VHL regulates VEGF expression at a post-transcriptional level and that VHL inactivation in target cells causes a loss of VEGF suppression, leading to formation of a vascular stroma.

Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor.

Brain tumor-associated cerebral edema arises because tumor capillaries lack normal blood-brain barrier function; vascular permeability factor (VPF, also known as vascular endothelial growth factor, VEGF) is a likely mediator of this phenomenon. Clinically, dexamethasone reduces brain tumor-associated vascular permeability through poorly understood mechanisms. Our goals were to determine if suppression of permeability by dexamethasone might involve inhibition of VPF action or expression, and if dexamethasone effects in this setting are mediated by the glucocorticoid receptor (GR). In two rat models of permeability (peripheral vascular permeability induced by intradermal injection of 9L glioma cell-conditioned medium or purified VPF, and intracerebral vascular permeability induced by implanted 9L glioma), dexamethasone suppressed permeability in a dose-dependent manner. Since 80% of the permeability-inducing activity in 9L-conditioned medium was removed by anti-VPF antibodies, we examined dexamethasone effects of VPF expression in 9L cells. Dexamethasone inhibited FCS- and PDGF-dependent induction of VPF expression. At all levels (intradermal, intracranial, and cell culture), dexamethasone effects were reversed by the GR antagonist mifepristone (RU486). Dexamethasone may decrease brain tumor-associated vascular permeability by two GR-dependent mechanisms: reduction of the response of the vasculature to tumor-derived permeability factors (including VPF), and reduction of VPF expression by tumor cells.

Aspirin and aspirin-like drugs induce HLA-DR expression in HT29 colon cancer cells.

Nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the incidence of colon cancer. The underexpression of HLA antigens during colon cancer development is suspected to be a mechanism by which malignant cells escape immune surveillance. We examined whether NSAIDs affect the expression of HLA-DR in HT29 human colon adenocarcinoma cells, which do not express HLA-DR. Aspirin, indomethacin and sulindac induced several-fold the expression of HLA-DR in these cells in a concentration- and time-dependent manner. Aspirin increased HLA-DR alpha steady-state mRNA levels and HLA-DR alpha gene transcription rate. These findings raise the possibility that such a mechanism may be operative in vivo.

Prostaglandin E2 down-regulates the expression of HLA-DR antigen in human colon adenocarcinoma cell lines.

Prostaglandins (PG) have been implicated in the pathogenesis of cancer and play an important role in immune regulation. Colon cancer is associated with elevated levels of PGE2, while aspirin, the prototypical inhibitor of PG synthesis, appears to reduce the incidence of colon cancer by 50%. We have observed that in human colon cancer the expression of HLA class I and II antigens is reduced or lost; loss of HLA antigens is suspected to be a mechanism by which the malignant cell escapes the immune surveillance. We investigated the effect of these eicosanoids on the expression of HLA antigens in human colon adenocarcinoma cell lines. PGE2 down-regulated the expression of the class II antigen HLA-DR in SW1116 cells (65% reduction at 2.8 x 10(-8) M). This effect was dose- and time-dependent, reversible, and specific (PGF2 alpha and LTB4 had no effect; the expression of carcinoembryonic antigen and class I genes were not affected). Aspirin induced the expression of HLA-DR in HT29 cells, a cell line not expressing constitutively HLA-DR. The reduction of HLA-DR by PGE2 was accompanied by reduced messenger RNA (mRNA) levels of HLA-DR alpha and reduced transcription of the corresponding gene. In contrast to HLA-DR, none of these three eicosanoids affected the expression of HLA class I genes, as assessed via determination of protein expression by fluorescence flow cytometric analysis and evaluation of the corresponding class I mRNA levels. We conclude that PGE2 specifically down-regulates the expression of HLA-DR, while it does not affect the expression of class I antigens.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of ethanol on the expression of HLA class I genes in human colon adenocarcinoma cell lines.

The loss of HLA antigens by neoplastic cells may allow tumors to escape immune surveillance. We observed reduced expression of HLA antigens during human colon carcinogenesis. Since ethanol, which is associated with human colonic carcinogenesis, modulates the expression of HLA genes, we examined whether it affects the expression of HLA class I genes in human colon adenocarcinoma cell lines. Ethanol (1.7 x 10(-10) M to 1.7 x 10(-1) M), had no effect on the expression of HLA class I antigens on these colonocytes, the corresponding mRNA levels, or the expression of HLA constructs. Our findings do not support the hypothesis that ethanol may modulate the expression of HLA class I genes in human colon cancer cells.

Lithocholic acid inhibits the expression of HLA class I genes in colon adenocarcinoma cells. Differential effect on HLA-A, -B and -C loci.

Loss of HLA antigen expression is considered to be one of the mechanisms whereby tumor cells escape immune surveillance. We recently observed reduced or lost expression of HLA antigens during human colon carcinogenesis. We studied the effect of bile acids (BAs), long implicated in the pathogenesis of colon cancer, on the expression of HLA class I antigens in human colon adenocarcinoma cells. Lithocholic acid (LCA) decreased by 42% the expression of HLA class I antigens on the surface of these cells. This dose-dependent reduction was specific for both the target genes and the chemical structure of LCA, and was not evident in cultured liver cells. None of the other BAs that were tested manifested this effect. LCA, and to a lesser extent deoxycholic acid (DCA), decreased steady-state HLA class I mRNA levels. LCA decreased the rate of transcription of HLA-B (64%) and HLA-C (87%) but not HLA-A; DCA had a similar but less pronounced effect. In transient gene expression (CAT assays) experiments, we evaluated the role of a 0.6-0.7 kb EcoRI/XbaI sequence from the 5' flanking region of HLA-A2, -B7 and -Cw7 genes in the regulation of class I gene expression by LCA. LCA down-regulated by 70% the expression of the reporter gene for all three genes. We interpret these results as indicating a differential regulation of the three HLA loci by LCA. Our findings, demonstrating a profound effect of LCA on HLA class I gene regulation, raise the possibility that such a mechanism may be operative in vivo.

Expression of HLA class I antigens in sporadic adenomas and histologically normal mucosa of the colon.

The loss of HLA antigens by neoplastic cells is considered important for tumor growth and metastasis, inasmuch as it may allow tumors to escape immune surveillance. We have observed reduced expression of HLA antigens in sporadic colon cancer and adenomas from familial adenomatous polyposis patients. We now studied the expression of HLA class I antigens in patients with sporadic adenomas, which are precursors of colorectal cancer. Expression of HLA class I antigens was studied by immunohistochemistry in (a) sporadic colon adenomas, (b) histologically normal mucosa distant from the adenomas, (c) histologically normal colonic mucosa from patients with history of sporadic colon adenomas, and (d) colonic mucosa from normal subjects. HLA class I antigen expression was moderately reduced in 56% and severely reduced in 44% of the adenomas; this reduction was significant when compared to controls (P < 0.0001). The reduction of HLA class I expression in adenomas was related to the grade of dysplasia of the adenomas. HLA class I expression of normal appearing mucosa was decreased in 76% of patients with adenoma (P < 0.0001) and in 54% of patients with history of adenoma (P < 0.005) compared to normal controls. These changes were antigen specific, inasmuch as the expression of carcinoembryonic antigen, a surface antigen, was not affected. Our findings suggest that reduced HLA class I expression is an early event in the cell transformation process from normal to neoplastic state, preceding in many cases the onset of histological changes. HLA class I could be potentially used as a premalignant marker in the colon.