Vitamin E analogs limit in vitro oxidant damage to bovine mammary endothelial cells.

Diseases that occur during the transition period are exacerbated when cows are unable to cope with an increased pro-oxidant load that results in oxidative stress. Dairy cattle are routinely supplemented with the vitamin E analog α-tocopherol to mitigate the severity of oxidative stress. Nonetheless, oxidative stress remains a disease predisposing condition for many dairy cattle. A better method of optimizing the antioxidant functions of vitamin E is needed. α-Tocopherol is only 1 of 8 analogs of vitamin E, all of which have varying antioxidant properties in other mammals, albeit a shorter physiological half-life compared with α-tocopherol. A primary bovine mammary endothelial cell oxidant challenge model was used to determine functions of certain vitamin E analogs. The aim of this study was to determine if other analogs, namely γ-tocopherol or γ-tocotrienol, have antioxidative functions in bovine cells and if these functions may protect cellular viability and endothelial function from oxidant damage. Physiological (10 µM) and supraphysiological (50 µM) concentrations of γ-tocopherol and γ-tocotrienol had a greater capacity to reduce accumulated reactive oxygen species derived from a nitric oxide donating pro-oxidant antagonist, when compared with α-tocopherol, after 30 min to 6 h of treatment. Further, γ-tocotrienol (10 µM) decreased cell cytotoxicity to a greater amount than other analogs at like concentrations, whereas γ-tocopherol (10 µM) reduced lipid peroxidation and apoptosis more effectively than other analogs. Last, α-tocopherol (5 and 10 µM) and γ-tocopherol (5 and 10 µM) significantly slowed pro-oxidant induced loss of endothelial cell barrier integrity over a 48-h period using an electrical cell-substrate impedance sensing system. Concerningly, γ-tocotrienol drastically reduced the endothelial barrier integrity at only 5 µM despite no apparent effect on cellular viability at like concentrations. γ-Tocotrienol, however, was also the only analog to show significant cytotoxicity and reductions in viability at supraphysiological doses (25 and 50 µM). Our results suggest that γ-tocopherol has antioxidant activities that reduces cellular damage and loss of function due to oxidant challenge as effectively as α-tocopherol. These data set the foundation for further investigation into the antioxidant properties of vitamin E analogs in other bovine cells types or whole animal models.

Invited review: Cytochrome P450 enzyme involvement in health and inflammatory-based diseases of dairy cattle.

Dairy cattle are at the greatest risk of developing diseases around the time of calving because of compromised immune responses and the occurrence of oxidative stress. Both the development of compromised immunity and oxidative stress are influenced directly or indirectly by the metabolism of polyunsaturated fatty acids (PUFA) and fat-soluble vitamins. The cytochrome P450 (CYP450) family of enzymes is central to the metabolism of both classes of these compounds, but to date, the importance of CYP450 in the health of dairy cattle is underappreciated. As certain CYP450 isoforms metabolize both PUFA and fat-soluble vitamins, potential interactions may occur between PUFA and fat-soluble vitamins that are largely unexplored. For example, one CYP450 that generates anti-inflammatory oxylipids from arachidonic acid additionally contributes to the activation of vitamin D. Other potential substrate interactions between PUFA and vitamins A and E may exist as well. The intersection of PUFA and fat-soluble vitamin metabolism by CYP450 suggest that this enzyme system could provide an understanding of how immune function and oxidant status interconnect, resulting in increased postpartum disease occurrence. This review will detail the known contributions of bovine CYP450 to the regulation of oxylipids with a focus on enzymes that may also be involved in the metabolism of fat-soluble vitamins A, D, and E that contribute to antioxidant defenses. Although the activity of specific CYP450 is generally conserved among mammals, important differences exist in cattle, such as the isoforms primarily responsible for activation of vitamin D that makes their specific study in cattle of great importance. Additionally, a CYP450-driven inflammatory positive feedback loop is proposed, which may contribute to the dysfunctional inflammatory responses commonly found during the transition period. Establishing the individual enzyme isoform contributions to oxylipid biosynthesis and the regulation of vitamins A, D, and E may reveal how the CYP450 family of enzymes can affect inflammatory responses during times of increased susceptibility to disease. Determining the potential effect of each CYP450 on disease susceptibility or pathogenesis may allow for the targeted manipulation of the CYP450 pathways to influence specific immune responses and antioxidant defenses during times of increased risk for health disorders.

Widespread basal cytochrome P450 expression in extrahepatic bovine tissues and isolated cells.

Periparturient cattle face increased risk of both metabolic and infectious diseases. Factors contributing to this predisposition include oxidized polyunsaturated fatty acids, also known as oxylipids, whose production is altered during the periparturient period and in diseased cattle. Alterations in the production of oxylipids derived from cytochrome P450 (CYP450) enzymes are over-represented during times of increased disease risk and clinical disease, such as mastitis. Many of these same CYP450 enzymes additionally regulate metabolism of fat-soluble vitamins, such as A, D, and E. These vitamins are essential to maintaining immune health, yet circulating concentrations are diminished near calving. Despite this, a relatively small amount of research has focused on the roles of CYP450 enzymes outside of the liver. The aim of this paper is to describe the relative gene expression of 11 CYP450 in bovine tissues and common in vitro bovine cell models. Eight tissue samples were collected from 3 healthy dairy cows after euthanasia. In vitro samples included primary bovine aortic and mammary endothelial cells and immortalized bovine kidney and mammary epithelial cells. Quantitative real-time-PCR was carried out to assess basal transcript expression of CYP450 enzymes. Surprisingly, CYP450 mRNA was widely expressed in all tissue samples, with predominance in the liver. In vitro CYP450 expression was less robust, with several cell types lacking expression of specific CYP450 enzymes altogether. Overall, cell culture models did not reflect expression of tissue CYP450. However, when CYP450 were organized by activity, certain cell types consistently expressed specific functional groups. These data reveal the widespread expression of CYP450 in individual organs of healthy dairy cows. Widespread expression helps to explain previous evidence of significant changes in CYP450-mediated oxylipid production and fat-soluble vitamin metabolism in organ microenvironments during periods of oxidative stress or disease. As such, these data provide a foundation for targeted functional experiments aimed at understanding the activities of specific CYP450 and associated therapeutic potential during times of increased disease risk.

Contrast-enhanced MR imaging of brain lesions: a large-scale intraindividual crossover comparison of gadobenate dimeglumine versus gadodiamide.

BACKGROUND AND PURPOSE: The higher relaxivity of gadobenate dimeglumine compared with gadodiamide is potentially advantageous for contrast-enhanced brain MR imaging. This study intraindividually compared 0.1-mmol/kg doses of these agents for qualitative and quantitative lesion enhancement. MATERIALS AND METHODS: Adult patients with suggested or known brain lesions underwent 2 identical MR imaging examinations at 1.5T, one with gadobenate dimeglumine and the other with gadodiamide. The agents were administered in randomized order separated by 3-14 days. Imaging sequences and postinjection acquisition timing were identical for the 2 examinations. Three blinded readers evaluated images qualitatively for diagnostic information (lesion extent, delineation, morphology, enhancement, and global preference) and quantitatively for contrast-to-noise ratio (CNR). RESULTS: One hundred thirteen of 138 enrolled patients successfully underwent both examinations. Final diagnoses were intra-axial tumor, metastasis, extra-axial tumor, or other (47, 27, 18, and 21 subjects, respectively). Readers 1, 2, and 3 demonstrated global preference for gadobenate dimeglumine in 63 (55.8%), 77 (68.1%), and 73 (64.6%) patients, respectively, compared with 3, 2, and 3 patients for gadodiamide (P < .0001, all readers). Highly significant (P < .0001, all readers) preference for gadobenate dimeglumine was demonstrated for all qualitative end points and for CNR (increases of 23.3%-34.7% and 42.4%-48.9% [spin-echo and gradient-refocused echo sequences, respectively] for gadobenate dimeglumine compared with gadodiamide). Inter-reader agreement was good for all evaluations (kappa = 0.47-0.69). Significant preference for gadobenate dimeglumine was demonstrated for all lesion subgroup analyses. CONCLUSION: Significantly greater diagnostic information and lesion enhancement are achieved on brain MR imaging with 0.1-mmol/kg gadobenate dimeglumine compared with gadodiamide at an equivalent dose.

A clinical comparison of the safety and efficacy of MultiHance (gadobenate dimeglumine) and Omniscan (Gadodiamide) in magnetic resonance imaging in patients with central nervous system pathology.

RATIONALE AND OBJECTIVES: The safety and diagnostic efficacy of MultiHance (gadobenate dimeglumine) in the central nervous system (CNS) were evaluated in a double-blind, multicenter, phase III clinical trial. METHODS: Two hundred five patients highly suspected of having a CNS lesion (by previous imaging exam) were enrolled at 16 sites in the United States. Patients were randomized to one of three incremental dosing regimens. Magnetic resonance imaging with Omniscan (gadodiamide) at doses of 0.1 and 0.3 mmol/kg was compared with MultiHance (gadobenate dimeglumine) at doses of 0.05 and 0.15 mmol/kg and at 0.1 and 0.2 mmol/kg. RESULTS: Compared with predose images alone, efficacy was demonstrated in each of the gadobenate dimeglumine and gadodiamide groups (single and cumulative doses) as indicated by the level of diagnostic information, number of lesions detected, and contrast-to-noise ratio measurements. The level of diagnostic information from gadobenate dimeglumine at 0.1 mmol/kg was equivalent to that with gadodiamide at the same dose. One of the two blinded reviewers found equivalence between the gadobenate dimeglumine 0.05 mmol/kg dose and gadodiamide at 0.1 mmol/kg. Both reviewers found the level of diagnostic information to be equivalent after the second dose of contrast for all three dosing regimens. The cumulative doses of gadobenate dimeglumine were well tolerated and as safe as gadodiamide. CONCLUSIONS: Gadobenate dimeglumine is comparable to gadodiamide in terms of safety and efficacy for imaging of CNS lesions, with a possible advantage in imaging applications owing to enhanced T1 relaxivity.

Magnetic resonance imaging in patients with central nervous system pathology: a comparison of OptiMARK (Gd-DTPA-BMEA) and Magnevist (Gd-DTPA).

RATIONALE AND OBJECTIVES: The objective of the two pivotal phase 3 studies was to evaluate the safety and efficacy of OptiMARK (Gd-DTPA-bis(methoxyethylamide) [Gd-DTPA-BMEA]) compared with Magnevist (Gd-DTPA) in magnetic resonance imaging of the central nervous system. METHODS: Two multicenter, randomized, double-blind, parallel group studies were conducted in 395 patients with known or suspected central nervous system pathology. Subjects were randomized to receive a single 0.1 mmol/kg intravenous injection of either Gd-DTPA-BMEA or Gd-DTPA. The safety of Gd-DTPA-BMEA and Gd-DTPA was monitored for up to 72 hours after study drug administration. Precontrast and postcontrast administration magnetic resonance scans were acquired using identical imaging planes and techniques. RESULTS: No deaths or unexpected adverse events were reported in either group. A comparison of adverse events by intensity and relation demonstrated no statistically significant differences between the two groups. Gd-DTPA-BMEA and Gd-DTPA were equivalent with respect to confidence in diagnosis, conspicuity, and border delineation. CONCLUSIONS: Gd-DTPA-BMEA and Gd-DTPA demonstrated comparable efficacy profiles, and the safety profiles were considered similar.

Metastatic craniopharyngioma.

We report a unique case of metastatic craniopharyngioma. Initially, the patient had a right frontal craniotomy for resection of a suprasellar mass, which was determined to be an adamantinomatous craniopharyngioma. Seven years later, an MR study of the brain showed two peripheral enhancing lesions adjacent to the dura and contralateral to the craniotomy site. Pathologic examination again showed adamantinomatous craniopharyngioma. Although recurrence, both local and along surgical tracts due to implantation of craniopharyngioma tissue, has been reported, this case raises the possibility of meningeal seeding to remote sites.

Quantitative contrast media dose evaluation for cranial computed tomography.

The goal of this study was to quantitatively evaluate the CT enhancement characteristics of selected intracranial blood vessels using four different volumes of a contrast medium under otherwise identical conditions in order to help determine a cost-effective dose. In a double blind, prospective manner, 100 patients referred for contrast-enhanced cranial CT were randomly assigned to receive one of four different volumes (50, 75, 100 or 120 ml) of ioversol 320 mg I/ml which was subsequently administered intravenously at a rate of 1 ml/s via a power injector. Unenhanced images were also obtained. Scanning times, slice thickness and other parameters were identical in all patients. Scanning was initiated immediately following delivery of the full volume of contrast. Region of interest Hounsfield unit measurements were acquired in a standardized manner using a 1 mm diameter circle on the pre- and post-contrast scans of the supraclinoid left internal carotid artery (LICA), supraclinoid right internal carotid artery (RICA), basilar artery (BA), and torcular region (TR). The mean enhancement value (in Hounsfield units) for the 50 ml, 75 ml, 100 ml and 120 ml dose groups respectively were as follows for each vessel: LICA 29.9, 41.5, 63.9, 64.6; RICA 30.1, 39.4, 62.6, 65.1; BA 30.0, 41.7, 66.0, 71.9; TR 31.7, 46.8, 68.9, 74.3. There was no statistically significant (p > 0.05) difference in enhancement in any of the four vessels when the 120 ml volume was delivered compared to the 100 ml volume. However, there was a statistically significant (p < 0.05) improvement in enhancement in all four vessels when 100 ml of contrast was administered compared to 75 ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Unilateral cerebral cortical and basal ganglia enhancement following overdosage of nonionic contrast media.

A 69-year-old woman developed seizures after cerebral angiography immediately preceded by coronary angiography. The preceding coronary angiography resulted in hyperconcentration, hyperosmolar loading, and overdosing of the nonionic contrast medium. A CT examination demonstrated gyriform enhancement throughout the left cortex and the left basal ganglia. Preloading with contrast material, as in this case, predisposes to disruption of the blood-brain barrier during selective common carotid or vertebral artery injection with nonionic contrast.

Lumbar epidural lipomatosis: the "Y" sign of thecal sac compression.

PURPOSE: We have identified a specific sign of lumbar thecal sac compression seen in patients with symptomatic lumbar epidural lipomatosis. Recognition of this sign will aid with proper diagnosis of this unusual disorder. METHODS: Computerized Tomography (CT) and Magnetic Resonance Imaging (MRI) examinations of the lumbar spine performed in the evaluation of low back pain over a 24 mo period demonstrated nine patients with excessive fat in the epidural space. Myelography was performed on five of these patients. Detailed analysis of the shape and degree of thecal sac compression was made. RESULTS: Eight of the nine patients with epidural lipomatosis demonstrated a characteristic type of thecal sac compression not seen with other spinal disorders. On cross sectional imaging, the thecal sac has a striking stellate appearance with three rays emanating from a central core. This produces a trifid shape resembling the letter "Y". In two patients scanned following subsequent surgical removal of the epidural fat, the thecal sac had resumed its normal configuration. CONCLUSION: A seemingly specific and easily recognized type of compression of the thecal sac may occur with lumbar epidural lipomatosis. This creates a trifid appearance of the thecal sac; we have termed this the "Y" sign.

MRI evaluation of "solitary" brain metastases with triple-dose gadoteridol: comparison with contrast-enhanced CT and conventional-dose gadopentetate dimeglumine MRI studies in the same patients.

The purpose of this investigation was to compare the sensitivity and safety of high dose gadoteridol (Pro Hance) with routine dose gadopentetate dimeglumine (Magnevist) in the detection of intracranial metastases on magnetic resonance imaging (MRI) when a solitary intracranial lesion was detected on contrast-enhanced cranial computed tomography (CT). Four patients, each with a solitary intracranial metastasis demonstrated on contrast-enhanced CT were studied prospectively with both 0.3 mmol/kg gadoteridol and 0.1 mmol/kg gadopentetate dimeglumine. Images were acquired before and immediately following contrast administration. Both of the MR studies were performed between two and six days of each other and within 1 wk of the cranial CT. Scan parameters and injection rates were identical on both occasions. Patient monitoring for the gadoteridol study included physical examination, vital signs and laboratory tests at several pre-determined times. Eighteen total metastases were demonstrated on MRI compared to the four on CT. Seven were visualized on the unenhanced MR images, nine on the scans using gadopentetate dimeglumine, and all eighteen on the scans using gadoteridol. Additional lesions were seen on the gadoteridol images in all four patients. No adverse events attributable to contrast media occurred. No significant changes in vital signs or laboratory values occurred.

Intracranial extension of basal cell carcinoma of the scalp.

A case of recurrent basal cell carcinoma of the right occipital scalp is reported. Plain film, CT, and MRI examinations of the head demonstrated direct neoplastic invasion through the occipital bone and meninges into the right cerebellar hemisphere.

Absence of the septum pellucidum and related disorders.

We present an illustration of the spectrum of intracranial abnormalities associated with absence of the septum pellucidum to better define and illustrate this disorder. CT and 1.5 Tesla MRI examinations of fifteen patients with absence of the septum pellucidum were meticulously analyzed and correlated with clinical and laboratory studies. The findings were compiled and categorized based upon the presence and type of associated radiologic abnormalities. Absence of the septum pellucidum may occur as an isolated abnormality (n = 3). In most patients (n = 12), associated complex developmental abnormalities are present which include heterotopias, hypoplastic falx, ventricular clefts, encephalocele, small pituitary gland, small optic nerves and chiasm, and corpus callosal dysgenesis. Inferior pointing and a squared-off appearance of the frontal horns are frequently noted. These, or other, more severe ventricular configuration deformities are present in all patients. We have portrayed the complete range of findings associated with absence of the septum pellucidum using an illustrative approach to clarify the different patterns of radiologic abnormalities which may be seen with this complex entity.

Percutaneous catheter placement for cyst drainage in the subarachnoid space.

A technique for percutaneous catheter drainage of cystic masses in the subarachnoid space was developed and shown to be safe and effective in an 18-year-old boy with life-threatening, recurrent neuroenteric cysts that compressed the brain stem, cerebellum, and spinal cord. Percutaneous drainage through a C1-C2 approach was performed on 11 separate occasions. Decompression was always accomplished and no infection or other complication occurred, even with continuous catheter drainage for 9 months. This technique provides opportunities for interventional neuroradiologic therapy in the subarachnoid space. It appears to be suited for percutaneous drainage of intraspinal and intracranial cysts when surgery is not indicated due to intractability or inaccessibility.

Primitive neuroectodermal tumor: CT, MRI, and angiographic findings.

Primitive neuroectodermal tumors (PNETs) are uncommon CNS neoplasms found usually in the first decade of life. This article presents a proven case of this lesion in a 14-month-old boy located deep in the left frontal lobe. This lesion was studied by CT, MRI, and cerebral angiography. The radiologic findings of this tumor were assessed and compared with those cases reported in the medical literature.

Prenatal recognition of central nervous system complications of alloimmune thrombocytopenia.

The radiological findings associated with alloimmune thrombocytopenia have not been well described. We present two such cases diagnosed in utero by ultrasound and discuss the radiographic findings of intracranial hemorrhage and hydrocephalus secondary to alloimmune thrombocytopenia. An awareness of this entity and its early diagnosis and intervention may greatly reduce the morbidity and mortality associated with alloimmune thrombocytopenia.

Low-osmolality contrast media: dosage comparison of ioversol and iohexol for cranial computed tomography.

One hundred patients undergoing cranial computed tomography were evaluated in this prospective, randomized, double-blind comparative study. Patients received 50 mL of ioversol 320 (16 g iodine), 75 mL of ioversol 320 (24 g iodine), 100 mL of iohexol 240 (24 g iodine), 100 mL of iohexol 300 (30 g iodine) or 150 mL of iohexol 240 (36 g iodine). Twenty patients were enrolled in each treatment group. No patient in any treatment group experienced any contrast-media-related adverse reaction. Results of this study coupled with our prior work suggests that the lowest dose and optimal concentration of low-osmolality contrast media necessary to produce diagnostic cranial computed tomography is 32 g of iodine administered in a concentration of 320 mg/100 mL iodine.

Optimization of low-osmolality contrast media for cranial CT: a dose comparison of two contrast agents.

A prospective, randomized, double-blind comparative study of 200 patients was made to examine the image quality, safety, and costs of 100 ml of ioversol-320 (32 g iodine) and 150 ml of iohexol-300 (45 g iodine) in patients undergoing cranial CT. We found no statistically significant difference in image quality between the two low-osmolality, nonionic contrast agents at these doses. There was a statistically significant (p = .02) difference in the occurrence of minor to mild adverse effects caused by ioversol (n = 0) as compared with iohexol (n = 5). No patient in either group experienced any major contrast-induced reactions. Contrast media costs were 34% less in patients receiving 32 g of iodine as compared with those receiving 45 g of iodine. This study demonstrates that high-quality cranial CT scans are possible even with a reduced volume of low-osmolality contrast medium, and that the potential cost savings are significant.