p53 inhibits alpha 6 beta 4 integrin survival signaling by promoting the caspase 3-dependent cleavage of AKT/PKB.

Although the interaction of matrix proteins with integrins is known to initiate signaling pathways that are essential for cell survival, a role for tumor suppressors in the regulation of these pathways has not been established. We demonstrate here that p53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase AKT/PKB. Specifically, we show that the alpha6beta4 integrin promotes the survival of p53-deficient carcinoma cells by activating AKT/PKB. In contrast, this integrin does not activate AKT/PKB in carcinoma cells that express wild-type p53 and it actually stimulates their apoptosis, in agreement with our previous findings (Bachelder, R.E., A. Marchetti, R. Falcioni, S. Soddu, and A.M. Mercurio. 1999. J. Biol. Chem. 274:20733-20737). Interestingly, we observed reduced levels of AKT/PKB protein after antibody clustering of alpha6beta4 in carcinoma cells that express wild-type p53. In contrast, alpha6beta4 clustering did not reduce the level of AKT/PKB in carcinoma cells that lack functional p53. The involvement of caspase 3 in AKT/PKB regulation was indicated by the ability of Z-DEVD-FMK, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in AKT/PKB levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of AKT/PKB in vitro. In addition, the ability of alpha6beta4 to activate AKT/PKB could be restored in p53 wild-type carcinoma cells by inhibiting caspase 3 activity. These studies demonstrate that the p53 tumor suppressor can inhibit integrin-associated survival signaling pathways.

Ozone-Induced Expression of Stress-Related Genes in Arabidopsis thaliana.

Ozone is a major gaseous pollutant that is known to have detrimental effects on plant growth and metabolism. We have investigated the effects of ozone on Arabidopsis thaliana growth and the pattern of expression of several stress-related genes. A. thaliana plants treated with either 150 or 300 parts per billion (ppb) ozone daily for 6 h exhibited reduced growth and leaf curling. Fresh and dry weights of ozone-treated plants were reduced 30 to 48% compared to ambient air controls. RNA blot analyses demonstrated that mRNA levels for glutathione S-transferase (GST), phenylalanine ammonia-lyase (PAL), a neutral peroxidase, and a cytosolic Cu/Zn superoxide dismutase (SOD) were higher in plants treated with 300 ppb ozone than in ambient air-treated controls. The mRNA levels of lipoxygenase and a catalase were not affected by ozone treatment. Of the transcripts examined, GST mRNA levels increased the most, showing a 26-fold induction 3 h after the initiation of ozone treatment. PAL mRNA was also rapidly induced, reaching 3-fold higher levels than controls within 3 h of ozone treatment. The neutral peroxidase and SOD mRNA levels rose more slowly, with both reaching maximum levels corresponding to 5-fold and 3-fold induction, respectively, approximately 12 h after ozone treatment. These studies indicate that ozone-induced expression of stress-related genes in A. thaliana provides an excellent model system for investigating the molecular and genetic basis of ozone-induced responses in plants.

Role of the phytotoxin coronatine in the infection of Arabidopsis thaliana by Pseudomonas syringae pv. tomato.

The role of the phytotoxin coronatine in the virulence of Pseudomonas syringae pv. tomato in Arabidopsis thaliana was evaluated by comparing symptom development, in planta bacterial multiplication, and the induction of defense-related genes in Arabidopsis plants inoculated with the coronatine-producing (Cor+) P. s. pv. tomato strain DC3000 and the coronatine-defective (Cor-) strain DC3661 by either infiltration or dipping methods. The Cor+ strain, P. s. pv. tomato DC3000, caused severe disease symptoms and multiplied by 4-6 logs after inoculation by either infiltration or dipping. P. s. pv. tomato DC3661 failed to produce any disease symptoms and multiplied by only 1-1.5 logs in dipped plants, whereas it caused mild symptoms and multiplied 6 logs over the 4-day experimental period in plants inoculated by infiltration. Parallel experiments using a natural host, tomato, yielded similar results. Analysis of the accumulation of mRNAs encoded by several distinct defense-related genes in Arabidopsis leaves infiltrated with either DC3000 or DC3661 demonstrated that the Cor- strain consistently induced higher levels of these transcripts. These results demonstrate that coronatine production is required under more natural inoculation conditions for the successful infection of Arabidopsis by DC3000, and that coronatine may play a critical role during the early stages of infection by suppressing the activation of defense-related genes.

Recognition of the avirulence gene avrB from Pseudomonas syringae pv. glycinea by Arabidopsis thaliana.

The response of Arabidopsis thaliana land race Columbia to the bacterial pathogen Pseudomonas syringae pv. maculicola 4326 harboring cloned avirulence genes avrB and avrC from P. syringae pv. glycinea and avrA and avrD from P. syringae pv. tomato was examined. Only avrB was recognized by Columbia, as evidenced by attenuation of disease symptoms, slower bacterial multiplication in planta, and differentially greater induction of mRNA for several defense-related genes. This contrasts with two A. thaliana land races where P. s. pv. maculicola strains containing avrB were not recognized. These plants showed typical disease symptoms, and bacterial multiplication in planta was not reduced in response to P. s. pv. maculicola containing avrB. In addition, there was no differential induction of defense-related mRNAs in these susceptible land races after infiltration with bacteria containing or lacking avrB. These results extend previous observations that avirulence genes from pathogens of one host plant can be recognized by "nonhost" plants and provide the genetic framework for analysis of the plant-specified response to the bacterial avrB gene product in A. thaliana.

Treatment of prolactin-secreting macroadenomas with the once-weekly dopamine agonist cabergoline.

Dopamine agonist administration is the primary therapy for macroprolactinomas, but bromocriptine is the only agent approved in the United States. Its use is limited by a high incidence of side effects, a short duration of action, and a lack of effectiveness in some patients. Cabergoline is a long-acting dopamine agonist specific for the D2 receptor that is more effective and better tolerated than bromocriptine in women with microadenomas or idiopathic hyperprolactinemia. However, experience with cabergoline in the treatment of patients with macroadenomas is limited. We report the first study of chronic administration of cabergoline conducted exclusively in patients with macroprolactinomas. Fifteen patients (8 women, 7 men) ages 18-76 yr were studied in an open-label 48-week dose escalation trial of cabergoline administered once per week. Eleven patients had received prior therapy with other dopamine agonists. Mean prolactin (PRL) levels decreased by 93.6%, and normal levels were attained in 73% of patients at doses of 0.5-3.0 mg per week. Three of five patients who had failed to normalize PRL on prior dopamine agonists achieved normal levels. Gonadal function was restored in all hypogonadal men and in 75% of premenopausal women with amenorrhea. Tumor size decreased in 11 of the 15 patients. Side effects were minimal. Of the 5 patients who had experienced side effects in prior dopamine agonists, 4 had none on cabergoline, and the fifth had milder symptoms. During two further years of follow up, the improvement in PRL levels, gonadal function, and tumor size has persisted during cabergoline administration, and three patients have experienced a further decline in PRL and/or tumor size. This study demonstrates the effectiveness and minimal side effects of once-weekly cabergoline for treatment of macroprolactinomas.

The effects of ozone on antioxidant responses in plants.

The response of plants to ozone exposure includes a number of physiological and biochemical changes that are the direct result of selective increases or decreases in gene expression and the resulting changes in the accumulation of the corresponding protein products. Major classes of ozone-induced proteins include antioxidant enzymes and a number of stress-related proteins associated with other biotic and abiotic stresses. In particular, there is a significant overlap in the pattern of gene induction observed in ozone-treated plants and plants exhibiting pathogen defense responses. Current knowledge concerning the specific molecular events associated with the alterations of gene expression caused by ozone and the precise roles of ozone-induced proteins in conferring tolerance to ozone is rather limited. This review summarizes some of the recent results that have been obtained concerning the molecular basis of ozone-induced responses in plants, with an emphasis on studies of the model plant system, Arabidopsis thaliana. These studies demonstrate that ozone-induced responses are caused in part by the activation of a salicylic acid dependent signaling pathway that is also required for the expression of resistance to microbial pathogens.

Comparison of magnetic resonance and roentgen ray computed tomography in dementia.

To compare the merits of magnetic resonance imaging (MRI) and roentgen ray computed tomography (CT) in assessing patients with dementia, we examined pairs of MR and CT brain images obtained from 26 patients with Alzheimer's disease (AD), eight patients with vascular or mixed dementia, and two patients with Parkinson's disease plus dementia. Magnetic resonance and CT images were independently rated on a qualitative scale of 0 (normal) to 3 (severely abnormal) in 39 separate brain regions. Ratios of anterolateral and third ventricular linear spans to linear skull spans were measured. Abnormalities in subcortical white matter and in hippocampus, enlargement of basal and sylvian cisterns, and ventriculomegaly were more evident on MR than CT scans, but qualitative ratings in all other brain regions were similar. Linear ventricular span ratios based on MR images did not differ significantly from those measured on CT. White matter abnormalities on MR were high signal foci on T2-weighted images whose pathologic substrate was uncertain; in a single case studied pathologically, no abnormalities were detected in brain regions that contained high signal foci. Dementia severity correlated with periventricular white matter abnormalities on both MR and CT images.

Thalamic hemorrhage: a computed tomographic-clinical correlation.

An analysis has been made of the clinical manifestations in 18 cases of hypertensive thalamic hemorrhage diagnosed by computed tomography (CT). CT scans permitted accurate determination of the site, size, and extension of the hemorrhages. A sensorimotor hemiplegia or hemiparesis was present in all cases. Diagnostic clinical features included limitation of vertical gaze, downward deviation of the eyes, and small unreactive or sluggish pupils. All hemorrhages larger than 3.3 cm in diameter were fatal.

Computed tomography in Hallervorden-Spatz disease.

Computed tomography (CT) in a 34-year-old woman with Hallervorden-Spatz disease (established on the basis of clinicopathologic findings in a sister, and a typical clinical course) showed severe diffuse cerebral atrophy and ventricular enlargement. Ratios between the intercaudate distance and the width of the frontal horns (FH:CC) or the outer tables of the skull (CC:OTcc) exceeded those found in patients with Huntington disease. CT may be helpful diagnostically in progressive cerebral disorders of late childhood or adolescence.

The relation of cerebral vasospasm to the extent and location of subarachnoid blood visualized by CT scan: a prospective study.

In 41 cases of verified ruptured saccular aneurysm, we prospectively predicted the presence or absence of delayed symptomatic cerebral vasospasm. CT criteria quantifying the extent and location of subarachnoid blood (developed in our previous retrospective study) were used in this prospective series of patients. Twenty-two patients had recognizable subarachnoid clots larger than 3 X 5 mm or layers of blood more than 1 mm thick (measured on reproduced images). In 20 of the 22 patients with severe significant clot or thick layer, severe vasospasm was correctly predicted and localized (2 false positives). In 19 patients with no blood, or diffuse blood, or blood outside the subarachnoid space, the absence of severe vasospasm was correctly predicted in 14 (5 false negatives). All of the false-positive and false-negative cases could be explained by inadequate CT technique. The data indicate that the extent and location of blood in the subarachnoid space determine the severity and location of vasospasm and that patients in jeopardy of developing symptomatic cerebral vasospasm can now be identified. Early preventive measures may now be assessed more accurately.

Broca aphasia: pathologic and clinical.

The speech disturbance resulting from infarction limited to the Broca area has been delineated; it differs from the speech disorder called Broca aphasia, which results from damage extending far outside the Broca area. Nor does Broca area infarction cause Broca aphasia. The lesions in 20 cases observed since 1972 were documented by autopsy, computerized tomography, or arteriogram; the autopsy records from the Massachusetts General hospital for the past 20 years and the published cases since 1820 were also reviewed. The findings suggest that infarction affecting the Broca area and its immediate environs, even deep into the brain, causes a mutism that is replaced by rapidly improving dyspraxic and effortful articulation, but that no significant distrubance in language function persists. The more complex syndrome traditionally referred to as Broca aphasia, including Broca's original case, is characterized by protracted mutism, verbal stereotypes, and agrammatism. It is associated with a considerably larger infarct which encompasses the operculum, including the Broca area, insula, and adjacent cerebrum, in the territory supplied by the upper division of the left middle cerebral artery.

Neurologic sequelae in the survivors of neonatal intraventricular hemorrhage.

We report our experience with the neurologic sequelae (at a mean follow-up of 24 months) among the 15 surviving infants who have had neonatal intraventricular hemorrhage (IVH) documented by computerized tomographic (CT) brain scan. Neurologically six infants (40%) are normal, six infants (40%) mildly impaired, and three infants (20%) moderate to severely impaired. The neurologic outcome correlated to the degree of hemorrhage seen in the CT scans when IVH was classified into four grades. None of the other neonatal factors examined showed significant correlation with the outcome.

Nuclear magnetic resonance imaging in central nervous system disease.

From the preliminary work of many investigators, it appears that proton nuclear magnetic resonance (NMR) imaging will have wide application in the diagnostic assessment (and potential management) of patients with vascular, neoplastic, and demyelinating diseases of the central nervous system (CNS). Findings in isolated cases and small series suggest that NMR imaging may play a role in the evaluation of patients with other CNS conditions including hydrocephalus, malformations, infections, developmental and metabolic disorders, and degenerative processes. Because of the dynamic nature of disease processes involving the CNS, the precise meaning of NMR image parameters (rho, T1, and T2) remains unclear. A comprehensive study correlating NMR images in neurologic disease with precise neuropathologic examination is required. In the future, with accurate quantitative measurements of these NMR parameters, in vivo imaging may provide insight into the dynamic nature of neurologic disease.

Efficacy of gadoteridol for magnetic resonance imaging of the brain and spine.

RATIONALE AND OBJECTIVES: The efficacy of gadoteridol for contrast enhancement of central nervous system pathology was assessed in a multicenter clinical trial involving 411 patients suspected of having intracranial or spinal pathology. METHODS: Magnetic resonance imaging was performed before and after intravenous administration of 0.10 mmol/kg gadoteridol. Two groups of images were interpreted by one of two neuroradiologists blinded to patient history. The results were analyzed separately. RESULTS: Patients with radiologic evidence of disease demonstrated enhancement of intracranial pathologic lesions in 44 of 63 (70%) and in 91 of 111 (82%) cases, respectively, whereas enhancement of spinal lesions was observed in 36 of 58 (62%) and in 65 of 78 (83%) cases, respectively. Subjectively, postcontrast scans provided more information than precontrast images in 37 of 63 (59%) and 84 of 111 (76%) intracranial cases, respectively, and in 25 of 58 (43%) and 55 of 78 (71%) spinal cases, respectively. Additional information included the subjective sense that there was improved visualization of pathology and definition of lesion borders. CONCLUSIONS: Subjective assessment of magnetic resonance scans suggest gadoteridol is an effective intravenous contrast agent for magnetic resonance imaging.

Lignification induced by pseudomonads harboring avirulent genes on Arabidopsis.

The responses of Arabidopsis thaliana ecotypes to the bacterial pathogen Pseudomonas syringae pv. maculicola 4326 (Psm4326) harboring cloned avirulence genes avrB and avrRpt2 from P. syringae pv. glycinea were examined. Psm4326 containing avirulent genes, avrB and avrRpt2 induced lignification and peroxidase activities in the bacteria infiltrated leaves of Col-O only and not in Mt-O, Bla-2 and Po-1. However, Arabidopsis ecotypes infiltrated with Psm4326 harboring with and without avirulent genes all showed differential induction of mRNA for peroxidase gene and lignin accumulation up to 24 h after infiltration. Only avrB gene in Col-O showed strong corelationship between peroxidase mRNA expression as well as lignification gradually up to 36 h after infiltration. These results extend previous observations that avirulence genes from pathogens of one host plant can be recognized by non-host plants and provide the genetic framework for analysis of the plant-specific response to the bacterial avirulent gene products in A. thaliana.

Intraventricular noncolloid neuroepithelial cysts.

Symptomatic intraventricular developmental cysts of neuroepithelial origin occurring in the lateral and fourth ventricles are extremely rare. We report the clinical, radiologic, and computed tomographic (CT) findings in three such cases, two occurring in the lateral ventricles and one in the fourth ventricle. Within lateral ventricles, these cysts are distinguished from colloid cysts by their large size, more posterior locations, and CSF-equivalent CT attenuation of their contents. Lack of contrast enhancement on CT and angiographic avascularity are also features. Fenestration in two cases and partial cyst excision in the third case relieved the predominant symptoms. The symptomatology and theories of histogenesis are reviewed and the differential diagnosis discussed.

Magnetic susceptibility effects secondary to out-of-plane air in fast MR scanning.

Areas of signal loss in brain overlying air-containing structures at the skull base are commonly observed on axial fast MR images. The nature of this effect, which can mimic the appearance of cerebral hemorrhage, is investigated in a phantom study and in a normal volunteer. The magnitude of the signal loss is found to be inversely related to the distance of the scanning plane from the air-containing structure and directly related to the echo time.

Selective arteriography of glomus tympanicum and jugulare tumors: techniques, normal and pathologic arterial anatomy.

Glomus tympanicum and jugulare tumors arise within the middle ear and jugular fossa, respectively, but often extend into the adjacent areas of the skull base and posterior fossa. Multiple branches of the external carotid, internal carotid, and vertebral arteries may contribute to the vascular supply of these lesions. The arteriograms of 15 patients with glomus tumors were correlated with the surgical findings to determine if selective arteriography could define precisely the involvement within the middle ear, jugular fossa, and mastoid. The arteriographic mapping correlated well with the surgical findings in nine of 13 cases that had surgery, but a few important limitations were found. Therefore, a new arteriographic projection, called a transcanalicular view, is proposed that separates the middle ear from the jugular fossa, allowing for better visualization and assessment of the tumor blush.

Superselective injection of BCNU through a latex calibrated-leak balloon.

Carmustine (BCNU) has been used extensively to treat glioblastomas by injection through a catheter placed in the cervical internal carotid artery. The technique causes severe pain to the eye and has resulted in ipsilateral blindness. The use of a latex calibrated-leak balloon positioned above the ophthalmic artery in the internal carotid artery or in one of its branches appears to circumvent the ocular complications mentioned. At an infusion rate at 125 ml/hr the balloon does not inflate and does not occlude the artery. This new technique has been used to treat 10 patients without complications.

Hearing loss in skull fractures.

One hundred three cases of skull fractures in or around the temporal bone were reviewed for hearing loss. Of these, 100 patients had skull series, 66 had computed tomographic head scans, and 44 had polytomographic studies of the temporal bone. Hearing loss in head trauma can be grouped into four categories: conductive hearing loss, peripheral sensorineural hearing loss, central sensorineural hearing loss, and combinations of these hearing losses. The cause of conductive hearing loss and peripheral sensorineural hearing loss was usually identified by the type of temporal bone fracture. However, the cause of the central sensorineural hearing loss was more difficult to correlate with the brain lesions shown in the computed tomographic scans.