Comparison of T1 mapping and fixed T1 method for dynamic contrast-enhanced MRI perfusion in brain gliomas.

OBJECTIVES: To compare dynamic contrast-enhanced MRI (DCE-MRI) data obtained using different prebolus T1 values in glioma grading and molecular profiling. METHODS: We retrospectively reviewed 83 cases of gliomas: 46 lower-grade gliomas (LGG; grades II and III) and 37 high-grade gliomas (HGG; grade IV). DCE-MRI maps of plasma volume fraction (Vp), extravascular-extracellular volume fraction (Ve), and tracer transfer constant from plasma to tissue (Ktrans) were obtained using a fixed T1 value of 1400 ms and a measured T1 obtained with variable flip angle (VFA). Tumour segmentations were performed and first-order histogram parameters were extracted from volumes of interest (VOIs) after co-registration with the perfusion maps. The two methods were compared using Wilcoxon matched-pairs signed-rank test and Bland-Altman analysis. Diagnostic accuracy was obtained and compared using ROC curve analysis and DeLong's test. RESULTS: Perfusion parameters obtained with the fixed T1 value were significantly higher than those obtained with the VFA. As regards diagnostic accuracy, there were no significant differences between the two methods both for glioma grading and molecular classification, except for few parameters of both methods. CONCLUSIONS: DCE-MRI data obtained with different prebolus T1 are not comparable and the definition of a prebolus T1 by T1 mapping is not mandatory since it does not improve the diagnostic accuracy of DCE-MRI. KEY POINTS: • DCE-MRI data obtained with different prebolus T1 are significantly different, thus not comparable. • The definition of a prebolus T1 by T1 mapping is not mandatory since it does not improve the diagnostic accuracy of DCE-MRI for glioma grading. • The use of a fixed T1 value represents a valid alternative to T1 mapping for DCE-MRI analysis.

Hemophagocytic lymphohistiocytosis with neurological presentation: MRI findings and a nearly miss diagnosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease with rarer neurological presentation. When this occurs, diagnosis may be delayed. This report aims to call attention to clinical, laboratory, and radiological features that should prompt the correct diagnosis. A 13-year-old girl presented with progressive increase in intracranial pressure and ataxia. MRI showed a diffuse tumor-like swelling of the cerebellum with tonsillar herniation and patchy white matter post-contrast enhancement. Regression of swelling with steroids ruled out glioma and medulloblastoma, and brain lymphoma was considered. Diagnosis of HLH was reached 2 months after onset when uncontrolled fever and severe elevation of liver enzymes occurred. Two bone marrow biopsies were needed to demonstrate hemophagocytosis. Familial HLH was confirmed by perforin gene mutations. Bone marrow transplantation was performed. The early diagnosis of HLH may be life saving. Awareness of the disease is necessary to investigate its characteristic findings, thus avoiding a delay in diagnosis.

Natural history and management of brainstem gliomas in adults. A retrospective Italian study.

Brainstem gliomas in adults are rare tumors, with heterogeneous clinical course; only a few studies in the MRI era describe the features in consistent groups of patients. In this retrospective study, we report clinical features at onset, imaging characteristics and subsequent course in a group of 34 adult patients with either histologically proven or clinico-radiologically diagnosed brainstem gliomas followed at two centers in Northern Italy. Of the patients 18 were male, 14 female, with a median age of 31. In 21 of the patients histology was obtained and in 20 it was informative (2 pilocytic astrocytoma, 9 low-grade astrocytoma, 8 anaplastic astrocytoma and 1 glioblastoma). Contrast enhancement at MRI was present in 14 patients. In all of the 9 patients who were investigated with MR spectroscopy, the Cho/NAA ratio was elevated at diagnosis. In 8 of the patients, an initial watch and wait policy was adopted, while 24 were treated shortly after diagnosis with either radiotherapy alone [4] or radiotherapy and chemotherapy [20] (mostly temozolomide). Only minor radiological responses were observed after treatments; in a significant proportion of patients (9 out of 15) clinical improvement during therapy occurred in the context of radiologically (MRI) stable disease. Grade III or IV myelotoxicity was observed in 6 patients. After a follow-up ranging from 9 to 180 months, all but 2 patients have progressed and 14 have died (12 for disease progression, 2 for pulmonary embolism). Median overall survival time was of 59 months. Investigation of putative prognostically relevant parameters showed that a short time between disease onset and diagnosis was related to a shorter survival. Compared with literature data, our study confirms the clinical and radiological heterogeneity of adult brainstem gliomas and underscores the need for multicenter trials in order to assess the efficacy of treatments in these tumors.

Hospitalization for gastrointestinal adverse events attributable to the use of low-dose aspirin among patients 50 years or older also using non-steroidal anti-inflammatory drugs: a retrospective cohort study.

BACKGROUND: Use of aspirin with non-steroidal anti-inflammatory drugs increases the risk of gastrointestinal ulcers; however, it is not clear if this risk varies with the non-steroidal anti-inflammatory drug used. AIM: To assess the risk of gastrointestinal hospitalizations attributable to aspirin in patients 50 years or older also using non-steroidal anti-inflammatory drugs. METHODS: Administrative data of patients 50 years or older who received a non-steroidal anti-inflammatory drug or acetaminophen prescription between 1998 and 2004 were used. RESULTS: Study patients received 7,412,992 non-steroidal anti-inflammatory drug prescriptions and 5,614,044 acetaminophen prescriptions among which 23% and 32%, respectively, were dispensed to aspirin users. Time-dependent Cox regression models revealed that, compared to patients using acetaminophen (without aspirin), the adjusted hazard ratio (95% CI) among non-users of aspirin were: rofecoxib 1.3 (1.2, 1.5), celecoxib 0.7 (0.6, 0.8), diclofenac 1.5 (1.2, 1.7), ibuprofen 0.9 (0.6, 1.4), naproxen 2.5 (2.1, 3.0) and piroxicam 1.5 (0.8, 2.8); among users of aspirin: rofecoxib 3.2 (2.8, 3.7), celecoxib 1.8 (1.5, 2.1), diclofenac 2.8 (2.2, 3.5), ibuprofen 1.4 (0.8, 2.7), naproxen 2.2 (1.6, 3.0) and piroxicam 2.0 (0.8, 5.4). The risk attributable to aspirin varied from none with naproxen to 61% (53%, 68%) with celecoxib. CONCLUSION: The increase in gastrointestinal hospitalization attributable to aspirin differed with the non-steroidal anti-inflammatory drug used, and seemed higher with cyclo-oxygenase-2 inhibitors than with non-selective non-steroidal anti-inflammatory drugs.

Steroid receptors in epithelial ovarian carcinoma: relation to clinical parameters and survival.

Estrogen receptor (ER) and progestin receptor were measured in samples of tumors obtained at first laparotomy from 97 previously untreated patients suffering with a primary ovarian epithelial tumor, for whom a 3-year follow-up was available. The presence or absence of steroid receptors (threshold arbitrarily fixed at 10 fmol/mg of cytoplasmic protein) was determined by the dextran coated charcoal method and related to a number of patient characteristics such as the residual disease (cutoff, 2 cm), histological type, International Federation of Gynecologists and Obstetricians grade and stage, and age. Results were analyzed by univariate and multivariate methods. (a) The tumor ER positivity was associated with better survival; progestin receptor showed a similar trend but did not reach statistical significance. (b) After stratification for residual tumor the association ER positivity/better survival was still statistically significant in the subset of patients with residual tumor greater than 2 cm. (c) When the median survival times were considered it became apparent that progestin receptor absence nullified the effect associated with positive ER. (d) Multivariate analysis confirmed that among the variables considered the main determinants of prognosis were the size of the residual tumor, serous histological type, and positive ER.

Sexual behavior and hemispheric laterality of the focus in patients with temporal lobe epilepsy.

Various studies have described an unusually common incidence of sexual and reproductive dysfunction in patients affected by temporal lobe epilepsy (TLE). The purpose of the present study was to further investigate, by means of an ad hoc questionnaire, the relationship between sexual disorders and the hemispheric laterality of the epileptic focus in men and women with right (R) TLE and left (L) TLE. The results suggest a reduction of sexual interest in patients with R-TLE as compared with L-TLE in both men and women. This effect was fundamentally observed when sexual interest was implicitly explored. No significant difference was found between R-TLE and L-TLE groups concerning most aspects of sexual performance. Various hypotheses are discussed to interpret this effect of hemispheric lateralization on sexual interest.

Progress report on the anorexia induced by drugs believed to mimic some of the effects of serotonin on the central nervous system.

Some agents that increase serotoninergic transmission in the brain show anorectic activity at doses that do not interfere with the behavior of rats and other animal species. These agents reduce food intake by a mechanism that clearly differs from that involved in the anorectic activity of d-amphetamine. d-Fenfluramine, fluoxetine, and sertraline are three drugs that have already been tested and are used in man. These compounds accumulate in the brain and are metabolized through N-dealkylation. They affect the uptake and release of serotonin at different concentrations, with mechanisms that do not completely overlap. There is pharmacological evidence that d-fenfluramine and sertraline exert their anorectic activity by enhancing the stimulation of 5-HT1nonA receptors whereas fluoxetine seems to affect at anorectic doses both serotoninergic and dopaminergic systems. The role of serotonin in controlling food intake will be discussed, and the effects of agents that reduce serotoninergic transmission will also be considered.

Pontine lesions in idiopathic narcolepsy.

Three patients had longstanding (37 to 50 years), highly disabling narcolepsy, poorly controlled by treatment. The clinical histories were typical, consisting of sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, disturbed nocturnal sleep, and HLA-DR2 tissue typing. Polygraphic findings confirmed the diagnosis. Neurologic examination, spinal fluid, and evoked potentials were normal. On MRI scanning, all three patients showed overlapping bilateral and symmetric brainstem T2 hyperintensities circumscribed to the ventrolateral aspect of the midrostral pons. The nature of the lesions remains uncertain but their location corresponded to the pontine oral reticular formation, where the neuronal network generating REM sleep is located. This is the first report of MR signal abnormalities in patients with idiopathic narcolepsy and suggests a causal relationship between the disease and the central pontine lesions.

Diazepam binding inhibitor (DBI) increases after acute stress in rat.

Diazepam binding inhibitor (DBI) acts in brain by binding to GABAA/benzodiazepine receptors (GBR) and to mitochondrial benzodiazepine receptors (MBR). Because DBI acting at MBR, has been shown to be an effector of ACTH-induced steroidogenesis and stress is known to change the level of GBR and MBR, the model of acute noise stress in rats was used to study modifications of DBI and GRB or the content of MBR in various areas of the brain and adrenal gland. It was found that, in the brain of stressed rats, DBI and its processing products (ODN-like immunoreactivity), increased selectively in the hippocampus. This increase in the content of DBI was preceded and followed by a net decrease of GBR and an increase of MBR. Similarly, in adrenal cortex, the content of DBI and MBR increased during the first hour, following acute stress and this increase paralleled the increase in plasma corticosterone. These data suggest that DBI, acting on MBR may regulate steroidogenic function in stress.

Plasma and platelet lipid composition and platelet aggregation by arachidonic acid in women on the pill.

Sensitivity to induction of platelet aggregation by arachidonic acid (AA) and changes in plasma and platelet polyunsaturated fatty acid distribution were studied in seven women before and after six months of oral contraceptive (OC) treatment with a combination of d-norgestrel (0.25 mg) and ethinylestradiol (0.05 mg). Special interest was focused on AA because certain metabolites of fatty acid induce platelets to aggregate and are considered to play a crucial role in thromboembolic processes. In plasma, AA concentrations increased slightly, but significantly, in both the free fatty acid (FFA) and phospholipid fractions; in platelets AA increased in the phospholipid and neutral lipid fractions. The threshold aggregating concentration (TAC) of AA was significantly reduced in platelets of women after six months of OC treatment (0.65 +/- 0.08 versus 0.30 +/- 0.04 mM). This suggests that changes in platelet fatty acid composition may be associated with in vitro changes in platelet sensitivity to AA. Such changes may contribute to the thrombotic tendency associated with OC treatment.

PIP: Sensitivity to induction of platelet aggregation by (AA) arachidonic acid and changes in plasma and platelet polyunsaturated fatty acid distribution were studied in 7 women before and after 6 months of (OC) oral contraceptive treatment with a combination of d-norgestrel (0.25 mg) and ethinyl estradiol (0.05 mg). Special interest was focused on AA because certain metabolites of this fatty acid induce platelets to aggregate and are considered to play a crucial role in thromboembolic processes. In plasma, AA concentrations increased slightly, but significantly, in both the free fatty acid and phospholipid fractions; in platelets AA increased in the phospholipid and neutral lipid fractions. The threshold aggregating concentration of AA was signifcantly reduced in platelets of women after 6 months of OC treatment (0.65 + or - 0.08 versus 0.30 + or -0.04 mM). This suggests that changes in platelet fatty acid composition may be associated with in vitro changes in platelet sensitivity to AA. Such changes may contribute to the thrombotic tendency associated with OC treatment.

Amiodarone induced phospholipidosis. Biochemical, morphological and functional changes in the lungs of rats chronically treated with amiodarone.

Amiodarone, an antiarrhythmic drug, causes pulmonary fibrosis in some patients during chronic treatment but the mechanism is unknown. We studied the effects of amiodarone on pulmonary biochemistry, morphology and function at doses of 25 and 50 mg/kg/12 hr given to rats by gavage for four weeks. Plasma and pulmonary phospholipids were significantly augmented, 13% and 88% respectively, in the group given amiodarone 50 mg/kg/12 hr compared to pair-fed controls. Typical phospholipidosis-like light and electron microscopic alterations were seen in the lung, their severity related to the extent of biochemical changes induced by amiodarone. Pulmonary function tests revealed mild but not significant changes in O2 and CO2 alveolar exchange efficiency and lung compliance (P-V curve) of treated animals in comparison to pair fed controls. Plasma average concentrations of amiodarone and its main metabolite, desethylamiodarone, after four weeks were 2.46 +/- 0.18 and 0.73 +/- 0.13 micrograms/ml, respectively, in the 50 mg/kg/12 hr group. In the same group amiodarone and desethylamiodarone concentrations in lung were 163 +/- 26 and 569 +/- 153 times higher than those in plasma. A highly significant correlation was found between amiodarone concentrations in plasma and lung and phospholipid content in the lung. A subgroup of animals received amiodarone 50 mg/kg/12 hr for 8 weeks. The pulmonary phospholipidosis-like lesions were similar to those observed after one month of treatment, no fibrosis was evident on light microscopic examination.

Axonal transport of two major components of the ubiquitin system: free ubiquitin and ubiquitin carboxyl-terminal hydrolase PGP 9.5.

Ubiquitin (Ub), a stress protein thought to target abnormal proteins for degradation, is present in abnormal structures that occur in neuronal perikarya and axons of degenerative diseases including Alzheimer disease. To begin to assess the role of the Ub system in the axon, we studied expression and axonal transport of Ub and other stress proteins, as well as of Ub carboxyl-terminal hydrolase PGP 9.5, in the rat visual system in normal conditions and following heat-shock (HS). In the retina, both the constitutive and inducible forms of HSPs 70 were expressed under normal conditions, while in the superior colliculus the inducible form was detected only following HS. Ub, PGP 9.5 and HSPs 70 were transported in the axon exclusively with the slow component b (SCb), known to carry cytoskeletal and cytoplasmic proteins. The exceedingly long time needed for stress proteins to reach distant axonal locales at the rate of SCb (approximately 3 mm/day) makes it unlikely that they could contribute significantly to the stress response at those sites.

Role of 5-HT receptors in the effect of d-fenfluramine on gastric emptying and feeding behaviour as examined in the runway test.

In one experiment, the effect of d-fenfluramine (DF) on gastric emptying was studied in rats treated i.p. with metergoline, a non-selective serotonin (5-HT) receptor antagonist, ritanserin, a selective 5-HT2 and 5-HT1C receptor antagonist, and xylamidine, a 5-HT antagonist which has poor access to the brain. Metergoline (1 mg/kg) but not ritanserin (0.5 mg/kg) or xylamidine (3 mg/kg) blocked the effect of 2.5 mg/kg DF studied 2 and 4 h after injection. In a second experiment, we studied the ability of metergoline to antagonise the effect of DF, administered after a meal, on runway performance, food intake and gastric emptying assessed 4 h later. Metergoline at a dose of 1 mg/kg did not antagonise the effect of DF (2.5 mg/kg) on runway performance but completely blocked the effect on gastric emptying. The data clearly show that DF delays gastric emptying by indirectly activating 5-HT1 receptors; this effect is not important for the ability of DF to reduce runway performance and food intake when the drug is injected after a pre-feeding period. While there is evidence that DF hastens the termination of the meal by a 5-HT mechanism, the data suggest that DF may prolong the satiating effect of food during the post-absorptive phase by mechanisms other than 5-HT.

MR of diffusion slowing in global cerebral ischemia.

PURPOSE: To investigate the causal connections between ischemia and the hyperintensity in diffusion-weighted MR images that has been associated with it. METHODS: Diffusion-weighted and T2-weighted MR imaging were used in a feline global cerebral ischemia/reperfusion model. Single 30-minute vascular occlusions followed by reperfusion were studied. Global occlusions were used to avoid interpretive complications associated with the temporally unstable hemodynamics of the penumbral zones around focal occlusions and the possible growth of the ischemic and penumbral regions with time. RESULTS: Diffusion-weighted hyperintensity and the associated diffusional slowing were not attributable exclusively to the cessation of blood flow because: 1) it does not appear abruptly at the onset of ischemia; 2) it resolves slowly early in reperfusion; and 3) it reappears after prolonged reperfusion. CONCLUSION: The times during which diffusion-weighted hyperintensity is manifested during ischemia, and recovers with reperfusion, point to a role for energy metabolism failure.

MR imaging and proton MR spectroscopy in adult Krabbe disease.

We present the MR imaging findings in four patients (two pairs of siblings from two unrelated families) with adult Krabbe disease. In the first family, clinical presentation mimicked familial spastic paraplegia. Their MR images showed selective, increased signal intensity on T2-weighted sequences along the corticospinal tracts, most prominently in the proband and barely detectable in her brother. Proton MR spectroscopy showed increased choline and myo-inositol in the affected white matter. In the second family, the clinical presentation differed in that the signs of pyramidal tract involvement were asymmetrical, with concomitant asymmetry on MR images in one. In adults, Krabbe disease may present on MR imaging with selective pyramidal fiber involvement.

Quantitative proton MR spectroscopic imaging in acute disseminated encephalomyelitis.

Serial MR imaging and quantitative proton MR spectroscopic imaging (MRSI) findings of a 4-year-old boy with acute disseminated encephalomyelitis (ADEM) are reported. Over a 2-month period characterized by an initial illness and two relapses, each with full recovery, MR imaging exhibited the appearance and disappearance of multifocal lesions throughout the CNS that correlated only partly with the neurologic impairment. During one relapse, MRSI revealed low levels of N-acetylaspartate (NAA) within the regions of prolonged T2 signal intensity. All other metabolites were normal. At follow-up, the MR imaging and MRSI abnormalities had fully resolved. MRSI might play an important role in the diagnosis of ADEM, as well as in the elucidation of underlying pathophysiologic processes in this poorly defined disorder of children. This case demonstrates that reduced levels of NAA are not always associated with neuronal loss, irreversible tissue damage, or poor neurologic outcome.

Comparative studies on the anorectic activity of d-fenfluramine in mice, rats, and guinea pigs.

The present study compares the anorectic activity of d-fenfluramine and its metabolite d-norfenfluramine in three animal species. d-Fenfluramine and d-norfenfluramine show anorectic activity at increasing doses (ED50) in rats, guinea pigs, and mice, d-norfenfluramine being more active than d-fenfluramine in all three species. Equiactive anorectic activities are reached with different brain levels of d-fenfluramine and d-norfenfluramine, guinea pigs being the most sensitive species, followed by rats then mice. The metabolite most probably plays a major role in the anorectic effect of d-fenfluramine in guinea pigs, contributes to the anorectic activity in rats, but adds little to the action of the parent drug in mice. The different sensitivity to d-fenfluramine and d-norfenfluramine in these three species does not appear to be explained by a number of biochemical parameters, including serotonin uptake or release, receptor subtypes, or 3H-d-fenfluramine binding and uptake.

Progress in assessing the role of serotonin in the control of food intake.

There is evidence that serotonin inhibits food intake, particularly intake of carbohydrate and that induced by activation of catecholamine-containing neurons in different brain circuits. An agent that has contributed considerably to the hypothesis of a role of serotonin in feeding is fenfluramine, used as an anorexigenic drug in obese people. Experiments using synaptosomal preparations for studying monoamine uptake and release have shown that d-norfenfluramine preferentially releases serotonin from a reserpine-insensitive compartment. Studies on brain monoamine release and metabolism in intact animals have shown that d and l isomers of fenfluramine at relatively low doses have a specific action on brain serotonin and catecholamines, respectively. Several findings suggest that d-fenfluramine and d-norfenfluramine cause anorexia by increasing the availability of serotonin at postsynaptic receptors. Evidence has recently been provided that d-fenfluramine uses preferentially serotonin1 sites, particularly of the serotonin1B type, in the rat brain to cause anorexia in this animal species. Activation of serotonin1A sites by agents such as 8-OH-DPAT and buspirone instead has been shown to cause overeating. It is suggested that serotonin1B sites in the hypothalamus and serotonin1A sites in the serotonin neurons of the midbrain raphe nuclei mediate these effects. Evidence is provided that [3H]d-fenfluramine binding to rat brain membranes is different from serotonin uptake sites ([3H]imipramine binding) and serotonin receptors. It is, however, displaced by some drugs using serotonin to cause anorexia, raising the possibility that it is somewhat related to serotonin mechanisms involved in feeding control. These studies provide evidence that the serotoninergic system in the brain is a likely target for drugs affecting food intake and suggest new ways to develop novel and potent strategies for the treatment of clinical hyperphagia and anorexia.

Adriamycin causes hyperlipemia as a consequence of nephrotoxicity.

Adriamycin induced hyperlipemia: its features and mechanism(s) in rats were investigated. Massive hyperlipemia occurred 14-21 days after a single dose of adriamycin (7.5 mg/kg i.v.). All lipoprotein fractions were affected. Mild but significant changes in tissues were observed (liver and intestine triglycerides and kidney phospholipids were reduced). Lipid synthesis and secretion was decreased, as shown by the Triton WR1339 test 7 days after treatment, but subsequently returned to normal. Mitochondrial oxidation of long-chain fatty acids was markedly reduced in kidney, and a slight reduction was also observed in heart. Lipoprotein lipase activity was reduced in adipose tissue. These results suggest that adriamycin hyperlipemia is due to reduced lipid storage and utilization. Carnitine did not counteract hyperlipemia and proteinuria after adriamycin. Analogies to hyperlipemia following puromycin aminonucleoside-induced nephrotoxicity are discussed.

Accumulation and metabolism of uneven fatty acids present in single cell protein.

Liquipron and Toprina, obtained by growing yeasts (Candida maltosa and Candida lipolytica) on n-hydrocarbons, were investigated to ascertain the biological significance and possible toxicological implications of their high content of uneven fatty acids (UFA). It was confirmed that the extent to which UFA accumulate in adipose tissue of rats fed the 2 products reflects only partially their UFA contents. The presence of UFA in rat tissues does not appear to alter intermediate metabolism. The capacity of liver mitochondria ot oxidize palmitic acid was similar in control and in Liquipron-treated rats. Palmitic acid and heptadecanoic acid did not compete for oxidation when mixed at concentrations which reflect their presence in the tissues of animals fed high levels of Liquipron.