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Progressive supranuclear palsy (PSP) is rarely confused with other parkinsonian disorders once the vertical gaze palsy appears. Corticobasal degeneration is the most common differential diagnostic entity. We describe three cases diagnosed during life as PSP but found to have another neurologic disorder at autopsy. No explanation for the gaze palsies was found in any case.

A 14-year-old boy with morning glory disc anomaly (MGDA) and normal visual and neurologic function displayed marked carotid artery narrowing on magnetic resonance angiography (MRA). This narrowing disappeared on a follow-up MRA six months later. Optic coherence tomography and scanning laser polarimetry disclosed a normal retinal nerve fiber layer in the eye with MGDA. MGDA has been reported in association with irreversible carotid artery stenosis leading to moya moya disease. This case suggests that mild cases of MGDA may be associated with reversible carotid artery narrowing owing to vasospasm.

Amiodarone is one of the most effective antiarrhythmic drugs currently available. Although a subject of intense controversy, a causal link between amiodarone and optic neuropathy has never been firmly established. Indications for treatment with amiodarone are outlined, and features of the optic neuropathy in patients on amiodarone are compared with those of nonarteritic anterior ischemic optic neuropathy. An approach to patients treated with amiodarone who present with optic neuropathy is outlined, and suggestions for a registry and prospective study of such patients are presented.

With the development of MRI, the natural history of cavernous haemangiomas has been appreciated. This article describes a series of patients with deep cavernous haemangiomas who have presented with acute hydrocephalus. The diagnosis and treatment options are discussed with a review of the literature.

A 34-year-old woman with eclampsia and the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome developed encephalopathy, cardiomyopathy, pulmonary edema, liver failure, and disseminated intravascular coagulation (DIC), all of which resolved. She also had retinal hemorrhages in both eyes and a hemorrhagic infarct in the left occipital lobe that resulted in a permanent right homonymous hemianopia and a persistently depressed acuity of 20/100 OS. This case is unusual in demonstrating permanent visual deficits. In nearly all cases of preeclampsia or eclampsia, visual deficits are reversible. The superimposition of the HELLP syndrome may create more neurologic damage. Clinicians should be alert to patients at risk for HELLP syndrome and manage them aggressively.

Background: Levobupivacaine is an effective local anaesthetic agent for nerve blockade with less systemic toxicity than racemic bupivacaine. The safety and efficacy of levobupivacaine for scalp blockade during awake craniotomy have not been addressed previously., Methods: Serial arterial plasma levobupivacaine concentrations following scalp blockade were measured to 2 h in 10 patients booked for awake craniotomy for epilepsy or tumour surgery. Bilateral scalp blockade providing surgical anaesthesia was achieved with a mean dose of 177 mg (2.5 mg kg(-1), range 1.6-3.2 mg kg(-1)) of levobupivacaine (0.5%, 5 mg ml(-1)) with epinephrine (5 microg ml(-1)) added immediately before the block insertion., Results: The maximum measured plasma levobupivacaine concentration was 1.58 (0.44) microg ml(-1) [mean (SD)] with a mean time to peak plasma concentration of 12 (4) min. There were no episodes in any of the 10 patients of symptoms or signs suggestive of either CNS or CVS toxicity., Conclusions: This study demonstrated a relatively rapid rise of plasma levobupivacaine concentration without evidence of cardiovascular or central nervous system sequelae in a sample population of patients who may be particularly prone to perioperative seizures.

A problem frequently facing researchers examining abundance of expression of a given antigen is measurement. When the antigen is confined to the nucleus, absolute numbers of nuclei or a percentage of nuclei expressing the antigen in a given region can be estimated. When the antigen is localized to cytoplasm, cytoplasmic organelles or processes or membranes, the assessment becomes more difficult. In these settings, an observer/experimenter may assign a density score but intra- and inter-observer agreement using a three-tiered system, and finer resolution than this, is unlikely to be reproducible. Digital image analysis provides an opportunity to minimize observer bias in quantification of immunohistochemical staining. Previously, reported digital methods have mostly employed chromogen-staining methods and often report mean image brightness. We report a method for quantitatively assessing and expressing abundance of expression of an antigen in neural tissue stained with immunofluorescent methods by determining the brightness-area-product (BAP). The described protocol utilizes simple to use commercially available software and calculates BAP rather than mean brightness as a measure more representative of antigen abundance and visual interpretation. Accordingly, we propose this protocol as a useful adjunct to observer interpretation of fluorescent immunohistochemistry and its application to assessment of antigen abundance for varying patterns of antigen localization.

Individuals with seasonal allergic rhinitis (SAR) show a more marked nasal obstructive response (increases in nasal airways resistance or NAR) after provocation with chlorine gas (Cl2) than do nonrhinitic (NR) controls. We were interested in learning whether similar differential responsiveness was apparent after provocation with acetic acid vapor. Sixteen nonsmoking, nonasthmatic subjects, aged 21-63 yr, equally divided by gender and nasal allergy status, were enrolled in a single-blinded crossover study involving exposure to acetic acid (AA) vapor (15 ppm) or air for 15 min on separate days 1 wk apart. NAR was measured in triplicate before, immediately post-, and 15 min postexposure, was normalized to baseline on a given exposure day, and was expressed as Net [NAR/baseline] after acetic acid versus control (air) exposure. After log transformation to achieve normality, the mean loge of Net [NAR/baseline] was 0.22 for SAR subjects and -0.11 for NR subjects immediately postexposure (p<.05); the corresponding values were 0.24 and -0.08, respectively, at 15 min postexposure (p<.05). Inhalation of acetic acid at the (NIOSH-recommended) short-term exposure limit of 15 ppm for 15 min produces differential nasal airflow obstruction among SAR versus NR subjects, with the former showing greater physiologic reactivity to this stimulus. This differential responsiveness is consistent with our previous findings with Cl2, indicating that there may be a generalized susceptibility factor associated with allergic rhinitis. The response occurs with slight subjective nasal irritation.

Purpose: Proliferation of neural precursors adjacent to the granule cell layer of the dentate gyrus has been identified in previous epilepsy models. Convincingly demonstrating that seizure activity is the stimulant for neurogenesis, rather than neuronal death or other insults inherent to seizure models, is difficult. To address this we derived a rapid electrical amygdala kindling model in mice known to be resistant to seizure-induced neuronal death as an experimental model of focal seizures and to analyze subsequent neurogenesis., Methods: Mice were implanted with bipolar electrodes in the left amygdala and given electrical stimulation (3 s, 100 Hz, 1 ms monophasic square wave pulses every 5 min, 40 in total) while being observed and graded for the development of seizures. Neurogenesis in the hippocampus was assessed by counting bromodeoxyuridine-immunoreactive cells co-labeled for astrocyte (glial fibrillary acidic protein) and neuronal nuclear markers., Results: Bromodeoxyuridine-reactive cell numbers were three-fold higher in stimulated mice compared with controls at 1 week in the subgranular region and at three weeks extensive co-labeling with neuronal nuclear was noted in cells which had migrated into the body of the granule cell layer, while mice receiving stimulation but failing to kindle did not differ significantly from controls. No increase in neuronal death was detected by terminal deoxynucleotidyl transferase-mediated digoxigenin-11-dUTP nick end labeling, Fluorojade or fluorescent examination of hematoxylin and eosin-stained sections in any inter-group comparison., Conclusions: We propose that this kindling paradigm, not previously applied to mice, demonstrates more convincingly than previously the surge in neurogenesis in response to seizures, and the effects of seizures alone in regard to neuronal injury and regeneration.

Background: Seasonal allergic rhinitic (SAR) subjects are more physiologically reactive to airborne irritants than non-rhinitic (NR) subjects; however the mechanism underlying this difference is unclear., Objective: We sought to determine whether irritant-induced nasal airflow limitation involves neuropeptide release into nasal lining fluid, and if so, whether such release occurs differentially by rhinitic status., Methods: Eight SAR and 8 NR subjects were exposed to 1.0 ppm chlorine and filtered air in random order during separate visits; exposures were via nasal mask and lasted 15 min. Rhinomanometry was performed before, immediately post-, and 15 min post-exposure. Following a minimum of 2 weeks' time, exposures and symptom reporting were repeated with nasal lavage pre- and post-exposure. Neuropeptides (substance P, cacitonin gene-related protein, vasoactive intestinal peptide, and neuropeptide Y) as well as markers of plasma leakage (albumin and urea) and glandular secretion (lysozyme and 7F10-mucin) were measured using standard methods., Results: Cl(2) provocation significantly increased nasal airway resistance in SAR but not NR subjects (p<0.05). Neuropeptide levels in nasal lavage fluid, on the other hand, were unaffected, with the exception of a paradoxical increase in vasoactive intestinal peptide in non-rhinitic controls post-Cl(2) provocation., Conclusions: Irritant-induced nasal airflow limitation is more pronounced among SAR than NR subjects. We could not, however, demonstrate a role for neuropeptide release in the nasal congestive response of SAR subjects.

Casitas b-lineage lymphoma (c-Cbl) is an E3 ubiquitin ligase that has an important role in regulating the degradation of cell surface receptors. In the present study we have examined the role of c-Cbl in whole-body energy homeostasis. c-Cbl-/- mice exhibited a profound increase in whole-body energy expenditure as determined by increased core temperature and whole-body oxygen consumption. As a consequence, these mice displayed a decrease in adiposity, primarily due to a reduction in cell size despite an increase in food intake. These changes were accompanied by a significant increase in activity (2- to 3-fold). In addition, c-Cbl-/- mice displayed a marked improvement in whole-body insulin action, primarily due to changes in muscle metabolism. We observed increased protein levels of the insulin receptor (4-fold) and uncoupling protein-3 (2-fold) in skeletal muscle and a significant increase in the phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase. These findings suggest that c-Cbl plays an integral role in whole-body fuel homeostasis by regulating whole-body energy expenditure and insulin action.

Most patients with non-lesional temporal lobe epilepsy (NLTLE) will have the findings of hippocampal sclerosis (HS) on a high resolution MRI. However, a significant minority of patients with NLTLE and electroclinically well-lateralized temporal lobe seizures have no evidence of HS on MRI. Many of these patients have concordant hypometabolism on fluorodeoxyglucose-PET ([18F]FDG-PET). The pathophysiological basis of this latter group remains uncertain. We aimed to determine whether NLTLE without HS on MRI represents a variant of or a different clinicopathological syndrome from that of NLTLE with HS on MRI. The clinical, EEG, [18F]FDG-PET, histopathological and surgical outcomes of 30 consecutive NLTLE patients with well-lateralized EEG but without HS on MRI (HS-ve TLE) were compared with 30 consecutive age- and sex-matched NLTLE patients with well-lateralized EEG with HS on MRI (HS+ve TLE). Both the HS+ve TLE group and the HS-ve TLE patients had a high degree of [18F]FDG-PET concordant lateralization (26 out of 30 HS-ve TLE versus 27 out of 27 HS+ve TLE). HS-ve TLE patients had more widespread hypometabolism on [18F]FDG-PET by blinded visual analysis [odds ratio (OR = + infinity (2.51, -), P = 0.001]. The HS-ve TLE group less frequently had a history of febrile convulsions [OR = 0.077 (0.002-0.512), P = 0.002], more commonly had a delta rhythm at ictal onset [OR = 3.67 (0.97-20.47), P = 0.057], and less frequently had histopathological evidence of HS [OR = 0 (0-0.85), P = 0.031]. There was no significant difference in surgical outcome despite half of those without HS having a hippocampal-sparing procedure. Based on the findings outlined, HS-ve PET-positive TLE may be a surgically remediable syndrome distinct from HS+ve TLE, with a pathophysiological basis that primarily involves lateral temporal neocortical rather than mesial temporal structures.

Hepatocellular carcinoma with a skull metastasis is a rare clinical entity especially in Western countries. The authors of the present article report a case of solitary skull metastasis from hepatocellular carcinoma in a 75-year-old lady who had no prior history of the primary disease or liver dysfunction. The clinicopathological and radiological features are reviewed and discussed.

A 4-year-old boy presented with complete blindness in his left eye after accidentally walking into a merchandise display hook while shopping in a department store. An ophthalmologic examination revealed no light perception, an amaurotic pupil, and nasal conjunctival injection in the eye. Intravenous steroids did not improve his vision.

Synovial cysts have been well reported as a cause of sciatica, with a sudden acute exacerbation being attributed to haemorrhage and subsequent enlargement of the cyst. Cyst formation is attributed to facet joint degeneration associated with a defect or rupture of the joint capsule. The mechanisms of haemorrhage have not been well described previously. Two cases of haemorrhagic synovial cysts causing acute exacerbation of sciatica are described. Both cases were directly attributable to manipulation of degenerate spines. The MRI and histopathological findings are discussed and we propose a mechanism whereby excessive stress on a degenerate revascularized synovium leads to haemorrhage within synovial cysts.

Object: The aim of this study was to review seizure outcome, imaging modalities used, and complications following surgery in patients with epilepsy who had undergone multimodality image-guided surgery at our institution., Methods: Data from patients with epilepsy who had undergone surgery between April 1999 and October 2001 were reviewed. During this time period, 116 operations were performed in 109 patients with medically refractory epilepsy. Among these patients, 22 were selected to undergo multimodality image-guided surgery primarily on the basis of whether they had no lesion visible on conventional magnetic resonance (MR) imaging sequences, multiple lesions, or one very large lesion that could not be completely resected without the risk of significant postoperative morbidity. A fourth group of patients in whom there was a single lesion in the eloquent cortex, a location associated with a significant risk of postoperative morbidity, was also included in the analysis. This latter group was assessed with the aid of intracranial grid electrodes that were coregistered to the MR image and were used intraoperatively to minimize electrode position error. Other imaging modalities used included positron emission tomography (PET), fluid-attenuated inversion recovery (FLAIR) MR imaging, and subtracted ictal-interictal single-photon positron emission computerized tomography (SPECT) coregistered with MR imaging (SISCOM). After coregistration, images were then downloaded onto an image-guided surgical system and the epileptogenic area was then resected. The mean patient age was 33 years (range 17-46 years), and there was a mean follow up of 27 months (range 14-41 months). Multimodality coregistrations used were as follows: nine PET scans, seven subdural electrode grids, four SISCOM studies, one FLAIR MR image, and one combined PET/subdural grid. Seizure outcome was excellent in 17 patients (77%) and not excellent in five (23%), or favorable in 19 (86%) and unfavorable in three (14%). Six patients (27%) had a transient neurological deficit, one patient (5%) a permanent major deficit, and three patients (15%) a permanent minor deficit. Five patients (24%) had a transient psychiatric problem postoperatively., Conclusions: Multimodality image-guided surgery offers a new perspective in surgery for epilepsy. Functional imaging modalities previously lateralized and often localized a seizure focus, but did not provide enough anatomical information to resect the epileptogenic zone confidently and safely. The coregistration of these modalities to a volumetric MR image and their incorporation into an image-guided system has allowed surgeons to offer surgery to patients who may not previously have been considered eligible, with outcomes comparable to those in patients with more straightforward lesional epilepsy.

Combinations of sodium chloride, phosphate, and dextrose solutions were infused prerigor into lamb carcasses to evaluate effects on tenderness, palatability, color change and microbiological growth during simulated retail display. Each carcass (n=48) was randomly assigned to one of the following: (1) deionized water (dH(2)O), (2) 2% NaCl (S), (3) 3% dextrose (D), (4) 0.5% tri-polyphosphate (P), (5) 2% NaCl and 3% dextrose (SD), (6) 2% NaCl and 0.5% tri-polyphosphate (SP), (7) 0.5% tri-polyphosphate and 3% dextrose (PD), and (8) 2% NaCl, 0.5% tri-polyphosphate, and 3% dextrose (SPD). The right side was pumped to 120% its original green weight and the corresponding left side served as the paired control in a nested design. The SD, SP and SPD solutions improved (P<0.05) Warner-Bratzler shear force values (WBS), sensory panel evaluations for tenderness, decreased cook loss, and increased ultimate pH when compared with their corresponding controls. In addition, no adverse affects on color or microbiological growth were observed for any of the treatments.

Objectives: Sensory (eye, nose, and throat) irritation is an important component of non-specific building-related illness ("sick-building syndrome"). Inter-individual variability in susceptibility to upper airway/mucous membrane irritants is suspected epidemiologically, but has been neglected experimentally. We wished to document population variability in nasal irritant sensitivity, as indexed by threshold measurements of sensory acuity. We hypothesized that younger subjects, women, and allergic rhinitis sufferers would display lower sensory thresholds than would older subjects, men, and rhinitis non-sufferers., Methods: We evaluated Sixty human subjects (stratified by age, gender, and seasonal allergy status), using two different test systems: (1) carbon dioxide (detection) and (2) n-propanol (localization). We obtained carbon dioxide (CO2) detection thresholds using an ascending concentration series, presenting 3-s pulses of CO2, paired with air in random order, by nasal cannula. Localization thresholds were obtained by the simultaneous presentation of n-propanol vapor (ascending concentrations in air) and blanks (saturated water vapor in air) to opposite nostrils, with laterality randomized. Threshold data were log-transformed to satisfy normality and analyzed by population marker via ANOVA and linear regression., Results: Test-retest variability was greater for volatile organic compound (VOC) localization than for CO2 detection (r=0.50 and 0.75, respectively); the two measurements were, however, positively correlated (r=0.48; P<0.001). Age predicted both (log-transformed) VOC localization thresholds (P<0.0001) and (log-transformed) CO2 thresholds (P<0.01), with younger age predicting lower thresholds. Female gender predicted lower CO2 detection (P<0.05) but not VOC localization thresholds (P=0.10). Nasal allergies predicted lower VOC localization (P<0.05) but not CO2 detection thresholds (P=0.52)., Conclusions: Consistent with epidemiological reporting patterns in so-called problem buildings, nasal irritant sensitivity appears to be non-randomly distributed in the population, with significant variability predicted by age, gender, and the presence of allergic rhinitis.

The objective of this study was to compare two aspirin prodrugs, isosorbide diaspirinate (ISDA) and a nitroaspirin (ISMNA), with aspirin in terms of effects on dog platelet function after administration of a single oral dose. Groups of six dogs were administered ISDA (2mg kg(-1)), ISMNA (4 mg kg(-1)) or aspirin (2mg kg(-1)). Blood was sampled at 1, 2, 4, 8, 12 and 24 h post-dosing and evaluated for capacity to generate post-clotting thromboxane (TX)B2. The aggregation response to arachidonic acid (AA) (100 microM), ADP (30 microM) or collagen (10 microg mL(-1)) was estimated at each time-point using the whole blood impedance method. Plasma ISMN following oral administration of ISMNA was also measured and compared with plasma ISMN following administration of a physical mixture of ISMN and aspirin. ISDA administration (2 mg kg(-1)) was associated with a significant reduction (P < 0.05) in serum TXB2 at 12 and 24 h (>90%) post-dosing and persistent inhibition of AA-induced platelet aggregation. ISDA administration caused a more marked depression of post-clotting TXB2 levels than aspirin in this study, although its ability to inhibit platelet aggregation was less consistent than that of aspirin. The nitroaspirin ISMNA was least effective at inhibiting platelet aggregation response or TXB2 production. The ISMN AUC(0-24 h) for the ISMNA-treated dogs was 77% of that for the physical mix-treated dogs and the tmax was delayed. This study indicates that the two aspirin esters cause aspirin-like effects on platelet function, probably through aspirin release, when administered orally to dogs.

Upper-respiratory-tract symptoms (nasal irritation, congestion and rhinorrhea) are prevalent complaints in so-called "problem buildings." In epidemiologic studies, symptom reporting is associated with selected subject characteristics, including younger age, female gender, and the presence of allergic rhinitis. The physiologic correlates of these differential reporting patterns, however, are largely unknown. Using dilute chlorine gas as a model upper-respiratory-tract irritant, we studied 52 otherwise healthy volunteers in a sample stratified on age (18-69 yr), gender, and allergy status. In a single-blinded crossover study, subjects had their nasal airway resistance measured preexposure, immediately postexposure, and 15 min postexposure to both filtered air and chlorine (1.0 ppm in air) for 15 min. Allergic rhinitic subjects showed a significantly greater net (chlorine minus air) congestive response at 15 min postexposure than did nonrhinitic controls (p <.01). Advancing age also predicted a greater response immediately post-exposure (p <.01). No gender effect was observed. Significant interindividual variability was evident in the nasal congestive response to irritant (chlorine) provocation. The rhinitis effect was consistent with prior observations, whereas the effect of advancing age was opposite to that hypothesized.

Using a combination of in vivo and in vitro assays, we characterized the sorting pathway and molecular targeting signal for the Arabidopsis 22-kD peroxisome membrane protein (PMP22), an integral component of the membrane of all peroxisomes in the mature plant. We show that nascent PMP22 is sorted directly from the cytosol to peroxisomes and that it is inserted into the peroxisomal boundary membrane with its N- and C-termini facing the cytosol. This direct sorting of PMP22 to peroxisomes contrasts with the indirect sorting reported previously for cottonseed (Gossypium hirsutum) ascorbate peroxidase, an integral PMP that sorts to peroxisomes via a subdomain of the endoplasmic reticulum. Thus, at least two different sorting pathways for PMPs exist in plant cells. At least four distinct regions within the N-terminal one-half of PMP22, including a positively charged domain present in most peroxisomal integral membrane-destined proteins, functions in a cooperative manner in efficient peroxisomal targeting and insertion. In addition, targeting with high fidelity to peroxisomes requires all four membrane-spanning domains in PMP22. Together, these results illustrate that the PMP22 membrane peroxisomal targeting signal is complex and that different elements within the signal may be responsible for mediating unique aspects of PMP22 biogenesis, including maintaining the solubility before membrane insertion, targeting to peroxisomes, and ensuring proper assembly in the peroxisomal boundary membrane.

To evaluate the influence of diet on faecal DNA amplification, 11 captive brown bears (Ursus arctos) were placed on six restricted diets: grass (Trifolium spp., Haplopappus hirtus and Poa pratensis), alfalfa (Lupinus spp.), carrots (Daucus spp.), white-tailed deer (Odocoileus virginianus), blueberries (Vaccinium spp.) and salmon (Salmo spp.). DNA was extracted from 50 faecal samples of each restricted diet, and amplification of brown bear DNA was attempted for a mitochondrial DNA (mtDNA) locus and nuclear DNA (nDNA) locus. For mtDNA, no significant differences were observed in amplification success rates across diets. For nDNA, amplification success rates for salmon diet extracts were significantly lower than all other diet extracts (P < 0.001). To evaluate the accuracy of faecal DNA sex identification when female carnivores consume male mammalian prey, female bears were fed male white-tailed deer. Four of 10 extracts amplified, and all extracts were incorrectly scored as male due to amplification of X and Y-chromosome fragments. The potential biases highlighted in this study have broad implications for researchers using faecal DNA for individual and sex identification, and should be evaluated in other species.

Purpose: To report a case of bilateral posterior ischemic optic neuropathy (PION) in a healthy young patient after lumbar spine surgery which was initially diagnosed as functional visual loss., Design: Observational case report., Participant: A 33-year-old woman who experienced visual loss in the immediate postoperative period after a lumbar spine fusion., Testing: Serial visual field testing and fundus examinations, ERG., Results: Bilateral PION was confirmed 2 months postoperatively with the development of bilateral optic disc pallor and a normal ERG., Conclusion: Young patients without vascular risk factors may develop bilateral PION after otherwise uncomplicated lumbar spine surgery. In subjects complaining of visual loss in the postoperative period who have a normal fundus and normal neuroimaging, a diagnosis of PION should be suspected, and close follow-up is warranted.

Seasonal allergic rhinitic (SAR) subjects are more sensitive to nasal irritants than nonrhinitic (NR) subjects; however, the mechanism underlying this difference is unclear. This study sought to determine whether irritant-induced nasal congestion involves mast cell degranulation. Eight SAR and eight NR subjects were exposed to both 1.0 parts per million chlorine and filtered air in separate visits; exposures were via nasal mask and lasted 15 min. Rhinomanometry was performed before, immediately after and 15 min after exposure. Following > or = 2 weeks, exposures and symptom reporting were repeated with nasal lavage, rather than rhinomanometry, pre- and postexposure. A separate substudy using rye grass antigen provided a positive control. Mast cell tryptase was measured in nasal lavage fluid from both substudies using an automated fluoroenzyme immunoassay. Chlorine provocation significantly increased nasal airway resistance in SAR but not NR subjects. Conversely, tryptase levels in nasal lavage fluid were unaffected. Nasal allergen challenge significantly increased both nasal obstruction and nasal lavage tryptase in SAR subjects. Irritant-induced nasal congestion is more pronounced among seasonal allergic rhinitic than nonrhinitic subjects. However, unlike nasal allergen challenge, the mechanism of response to chlorine does not appear to involve mast cell degranulation.

Purpose: To present a case of a primary orbital leiomyosarcoma and the corresponding magnetic resonance imaging (MRI) appearance., Design: Observational case report., Methods: Correlation of MRI with clinicopathologic findings., Results: A 56-year-old woman presented with a 10-month history of diplopia in left gaze and left exophthalmos. An enhanced MRI of the left orbit revealed an extraconal, peripheral-enhancing mass measuring 2 cm in maximal diameter with displacement of the medial rectus muscle. The mass was excised, and the diagnosis of leiomyosarcoma was made by pathologic examination., Conclusions: Although computed tomography scan and ultrasound have been the imaging modalities used previously to evaluate cases of primary orbital leiomyosarcoma, MRI can provide important additional information regarding tumor characterization that is useful in the diagnosis and treatment of this rare malignancy., (Copyright 2003 by Elsevier Science Inc.)

The unique tyrosine kinase binding (TKB) domain of Cbl targets phosphorylated tyrosines on activated protein tyrosine kinases (PTKs); this targeting is considered essential for Cbl proteins to negatively regulate PTKs. Here, a loss-of-function mutation (G304E) in the c-Cbl TKB domain, first identified in Caenorhabditis elegans, was introduced into a mouse and its effects in thymocytes and T cells were studied. In marked contrast to the c-Cbl knockout mouse, we found no evidence of enhanced activity of the ZAP-70 PTK in thymocytes from the TKB domain mutant mouse. This finding contradicts the accepted mechanism of c-Cbl-mediated negative regulation, which requires TKB domain targeting of phosphotyrosine 292 in ZAP-70. However, the TKB domain mutant mouse does show aspects of enhanced signaling that parallel those of the c-Cbl knockout mouse, but these involve the constitutive activation of Rac and not enhanced PTK activity. Furthermore, the enhanced signaling in CD4(+)CD8(+) double positive thymocytes appears to be compensated by the selective down-regulation of CD3 on mature thymocytes and peripheral T cells from both strains of mutant c-Cbl mice.

Actinomycin D (ActD) is a transcription inhibitor and has been used in the treatment of certain forms of cancer. ActD has been reported to be a potential inhibitor of human immunodeficiency virus type 1 (HIV-1) replication due to its ability to inhibit reverse transcription. In contrast to what was expected, low concentrations of ActD (1 to 10 nM) upregulated HIV-1 replication 8- to 10-fold in MT-2 cells and had no effect on HIV-2 replication or on HIV-1 replication in MT-4, Jurkat, or peripheral blood mononuclear cells. The upregulation of HIV-1 replication was associated with an increase in HIV-1 transcription and a decrease in CD4 and CXCR4 expression. To further evaluate the effects of ActD on emergence of drug resistance in HIV-1 replication, a series of drug resistance assays were performed. Of interest, treatment of MT-2 cells with ActD also led to a high level of resistance to thymidine analogs (>1,000-fold increase in resistance to zidovudine and >250-fold to stavudine) but not to other nucleoside reverse transcriptases (RT), nonnucleoside RT, or protease inhibitors. This resistance appeared to be due to a suppression of host cell thymidine kinase-1 (TK-1) expression. These results indicate that ActD leads to a novel form of thymidine analog resistance by suppressing host cell TK-1 expression. These results suggest that administration of combination drugs to HIV-1-infected patients may induce resistance to antiretroviral compounds via a modification of cellular factors.

Purpose: To report a case of monocular blindness resulting from intravascular bullet migration., Design: Observational case report., Methods: A 9-year-old boy presented to the emergency room with a penetrating BB gun injury to the chest., Results: Carotid angiography localized the bullet to the right internal carotid artery. He subsequently suffered blindness in the right eye, a right pupil-involving third nerve palsy, left hemiparesis, and a probable left homonymous hemianopia., Conclusion: BB gun injuries may result in devastating ophthalmologic as well as systemic consequences due to bullet embolization.

Objective: To understand the mechanism underlying the nasal congestive response to irritant challenge., Methods: We exposed 22 subjects--8 with seasonal allergic rhinitis (SAR), 6 with perennial allergic rhinitis (PAR), and 8 normals--to chlorine (Cl2) gas (1.0 ppm x 15 min.) by nasal CPAP mask. Control exposures (filtered air) were carried out on separate days, with counter-balancing of exposure order. Nasal airway resistance (NAR) was measured in triplicate before and after the provocation sequence using active posterior rhinomanometry. For each subject, this experiment was repeated twice, after [double-blinded] pre-treatment with: 1) ipratropium bromide (IB) 0.6% nasal spray, and 2) vehicle., Results: As a group, allergic rhinitics (SAR + PAR) showed greater [Cl2] exposure-related increases in NAR than did normals on placebo (vehicle) pretreatment days (p < 0.05). IB pre-treatment, however, did not have a systematic effect on Cl2-induced congestion., Conclusion: Cholinergic mechanisms do not appear to be responsible for the nasal congestive response to irritant provocation.

Gram-positive bacterial meningitis frequently complicates ventriculo-peritoneal (VP) shunts used for hydrocephalus. Linezolid, an oxazolidinone, is active against Gram-positive cocci, and has excellent CSF penetration. We present a 22-year-old woman who was cured of a Staphylococcus epidermidis VP shunt infection via shunt removal and intravenous linezolid.

Context: Routine cancer screening with prostate-specific antigen (PSA) is controversial, and practice guidelines recommend that men be counseled about its risks and benefits., Objective: To evaluate the process of decision making as men react to and use information after PSA counseling., Design: Written surveys and semistructured qualitative interviews before and after a neutral PSA counseling intervention., Participants: Men 40 to 65 years of age in southeastern Michigan were recruited until thematic saturation--that is, the point at which no new themes emerged in interviews (n = 40)., Results: In a paper survey, 37 of 40 participants (93%) said that they interpreted the counseled information as unfavorable toward PSA. However, 30 participants (75%) said after the intervention that they intended to be tested in the future, including 29 of 30 men (97%) with prior PSA testing. In the interview, many participants cited underlying beliefs as a reason to dismiss the counseled information. Qualitative analysis found the seven most common beliefs cited were fear of cancer, relevance of salient anecdotes and analogies, distrust of statistics, enthusiasm for "prevention," protection from "bad luck," faith in science, and valuing PSA as knowledge for its own sake. Although some beliefs could be interpreted as judgment errors, most were credible on a personal level., Conclusions: Most men who underwent PSA counseling cited underlying beliefs rather than the content of counseled information as the basis for their decisions regarding future PSA screening. If widespread, such beliefs may render clinician counseling and decision support methods less effective. Eliciting patient beliefs prior to counseling may improve the shared decision-making process.

Introduction: vascular endothelial growth factor (VEGF) and tumour necrosis factor alpha (TNF(alpha)) have been specifically implicated in the tissue damage associated with chronic venous disease (CVD). Furthermore, production of both factors is known to be upregulated in vessel wall cells subject to hypertension. The aim of this study was to determine the local venous levels of VEGF and TNF(alpha) in limbs with venous ulcers before and after treatment with graduated compression., Patients and Methods: eight patients with venous ulcers and 8 patients with varicose veins only were included in the study. For ulcer patients, serum samples were taken from the superficial veins in lower limbs and repeated after 4 weeks of treatment with 4-layered graduated compression. Serum from the arms of the same patients served as controls. Determination of the concentrations of VEGF and TNF(alpha) proteins were performed with sandwich enzyme-linked immunosorbent assays., Results: both groups of patients had elevated levels of VEGF and TNF(alpha). In patients with venous ulcers there was a reduction in the levels of both cytokines to below control values with treatment. These changes correlated with healing of the ulcers as determined by reduction in ulcer size., Conclusion: these data, for the first time, suggest a central role for both TNF(alpha) and VEGF in the pathogenesis of venous ulceration which may constitute a causative link between venous hypertension and tissue pathology., (Copyright 2002 Harcourt Publishers Limited.)

Over recent years frameless stereotactic systems have begun replacing framed systems for many neurosurgical procedures. However, little has been published regarding the use of these systems to guide intracranial electrode implantation for epilepsy surgery patients. Here we report our experience utilising such a system to insert depth electrodes and subdural grid electrodes. The SteathStation Image-Guided System (SSIGS) (Sofamor Danek, Memphis TN.) was used to insert bilateral depth electrodes in 13 patients, of whom 5 also underwent the insertion of subdural grids or strip electrodes. Initially, a surgical plan based on an entry and target point on axial and sagittal images was performed for the insertion of electrodes. Navigational views, using three-planar images, were then performed to determine which structures the electrodes would pass through to be correctly placed in the amygdala and hippocampus. The correct site of electrode implantation was confirmed post-operatively by spiral CT scans in 4 patients (which were then co-registered to the pre-implantation MRI using a surface matching technique) and the other 9 patients by post-implantation MRI. The SSIGS was found to have a mean registration error of 2.0 mm (range 1.8-2.5) in 10 cases; in the 3 cases where the error was greater than 2.5 mm a surfacemerge technique was used with a mean error 0.9 (0.8-1.00). The post-implantation MRI or CT-MRI co-registration confirmed an accurate electrode placement in the mesial temporal region in all cases. Seizure onset lateralisation was achieved in 11 patients, all of whom went onto formal resections based on these results. The only long-term complication was a case of osteomyelitis which required removal of the bone flap. 73% of patients had an excellent seizure outcome. Frameless stereotactic systems can be safely used to intracranial electrodes, avoid the disadvantages of the framed system and have the added advantage of the surgeon being able to visualise the trajectory and to adjust this to avoid vital structures. As well they eliminate surgical obstruction to the insertion of subdural grids at the same operation, which may be caused by a framed system.

Examined the reliability, construct, and concurrent validity of the Parenting Scale (PS), a brief instrument designed to measure dysfunctional parenting practices for parents of young children. In Study 1, 183 primarily African American mothers and their Head Start children completed the PS. The PS, which consists of 3 subscales--Laxness, Overreactivity, and Verbosity--was subjected to confirmatory factor analysis (CFA). Neither the original 3-factor structure, nor a 2-factor structure consisting of the original Laxness and Overreactivity factors, fit the data. A subsequent exploratory factor analysis yielded a 2-factor solution that was generally consistent with the Overreactivity and Laxness subscales identified by Arnold, O'Leary, Wolff, and Acker (1993). The 2-factor CFA solution was replicated with a sample of 216 similar mothers, and the 5-item Overreactivity and Laxness subscales retained internal consistencies above .70. Analysis of the convergent validity of the modified PS and its 2 subscales revealed moderate associations with measures of permissiveness, authoritarianism, involvement, and limit setting. Scores on the PS were not correlated significantly with measures of social desirability, maternal education level, or parent report of internalizing behavior problems. Concurrent validity evidence was obtained by correlating the PS with measures of parenting satisfaction and support, parenting stress, maternal depression, and measures of externalizing child behavior problems.

Many cytokines and growth factors induce transcription of immediate early response genes by activating members of the Signal Transducers and Activators of Transcription (STAT) family. Although significant progress has been made in understanding the events that lead to the activation of STAT proteins, less is known about the regulation of their expression. Here we report that murine embryonic fibroblasts derived from c-Cbl-deficient mice display significantly increased levels of STAT1 and STAT5 protein. In contrast, STAT2 and STAT3 expression, as well as the levels of the tyrosine kinases Jak1 and Tyk2, appear to be regulated independently of c-Cbl. Interestingly, the half-life of STAT1 was unaffected by the presence of c-Cbl, indicating that c-Cbl acts independently of STAT1 degradation. Further analysis revealed similar levels of STAT1 mRNA, however, a dramatically increased rate of STAT1 protein synthesis was observed in c-Cbl-deficient cells. Thus, our findings demonstrate an additional control mechanism over STAT1 function, and also provide a novel biological effect of the Cbl protein family.

Objective: To sample the amount and scope of information available on the internet about three common surgical conditions, identify the sources, and to examine the relevance of the web to the surgical community., Design: Internet search., Setting: General hospital, Republic of Ireland., Material: Three arbitrarily chosen conditions were sought--varicose veins, inguinal hernia, and gallstones. Four commonly used search engines--Yahoo, Altavista, Excite and Lycos, were used to search worldwide, and then sites restricted to the UK and Republic of Ireland., Main Outcome Measures: Quality and quantity of information available., Results: All four search engines retrieved patient-orientated information on the three conditions. The sites accessed from the web page matches generally presented a comprehensive summary of the condition including aetiology, risk factors and clinical features, but gave variable amounts of information on treatment options, surgical complications, comparisons between treatments, and expected outcomes. Online health magazines provided most of the information sites., Conclusion: The internet offers easily-accessible patient-orientated information. Surgeons should make more use of it to satisfy patients' increasing need for information.

The potential roles of an amino acid deletion at codon 67 (Delta67) and a Thr-to-Gly change at codon 69 (T69G) in the reverse transcriptase of human immunodeficiency virus (HIV) type 1 in drug sensitivity and relative replication fitness were studied. Our results suggest that the Delta67 and T69G changes can be categorized as mutations associated with multidrug resistance. The combination of both mutations with an L74I change (Delta67+T69G/L74I) leads to a novel 3'-azido-3'-deoxythymidine resistance motif and compensates for impaired HIV replication.

Objective: Partial liquid ventilation with the perfluorochemical, perflubron, has been shown to improve lung mechanics and enhance gas exchange in the treatment of severe acute lung injury. However, the most effective strategy to provide optimal intrapulmonary distribution of perflubron has not been fully accessed. The objective of this study was to examine the effect of body position (supine vs. rotational) and mode of ventilation (conventional mechanical ventilation [CMV] vs. high-frequency oscillatory ventilation [HFOV]) on perflubron distribution and oxygenation improvement., Design: Prospective, randomized, animal trial., Setting: Research laboratory at a university medical center., Subjects: Twenty healthy piglets (4.5-6.6 kg)., Interventions: Subjects underwent repetitive saline lavage to achieve a uniform degree of lung injury and then were randomized to either CMV or were converted to HFOV. Within each ventilator group, animals were randomized to supine positioning (S) or rotational positioning with alternation between supine and prone position (R) during incremental dosing of three 5-mL/kg doses of perflubron., Measurements and Main Results: Arterial blood gas tensions, hemodynamic variables, and the oxygenation index were recorded after each dose of 5 mL/kg. Lateral cinefluoroscopic images after each dose were digitized for computer analysis of density. A density index was calculated for a 2-cm2 window in three dorsal and three ventral lung regions. Uniformity of distribution was calculated by comparing the mean density among the six regions. Oxygenation improvements were compared between groups. There were no significant differences in hemodynamic variables or gas exchange after lung injury in the four groups. Rotational positioning produced significantly more uniform perflubron distribution during both CMV and HFOV. This effect was independent of the mode of ventilation. The mean ventral density index was affected by rotating position and HFOV mode of ventilation after 10 mL/kg of perflubron, and rotating position was affected only after 15 mL/kg of perflubron. There was a significant reduction in the oxygenation index from baseline to end lavage in both CMV groups, as well as all of the animals that were rotated., Conclusion: Perflubron is more uniformly dispersed when dosed in a rotational fashion with alternation between supine and prone position during incremental dosing. This effect is independent of mode of ventilation. There was no relationship between oxygenation improvements and nondependent perflubron distribution. CMV and rotating dosing both led to a significant decrease in the oxygenation index after a 15 mL/kg dose of perflubron. This information has important impact on the future development of dosing strategies and clinical trial design.

Colony-stimulating factor-1 (CSF-1) activation of the CSF-1 receptor (CSF-1R) causes Cbl protooncoprotein tyrosine phosphorylation, Cbl-CSF-1R association and their simultaneous multiubiquitination at the plasma membrane. The CSF-1R is then rapidly internalized and degraded, whereas Cbl is deubiquitinated in the cytoplasm without being degraded. We have used primary macrophages from gene-targeted mice to study the role of Cbl. Cbl-/- macrophages form denser colonies and, at limiting CSF-1 concentrations, proliferate faster than Cbl+/+ macrophages. Their CSF-1Rs fail to exhibit multiubiquitination and a second wave of tyrosine phosphorylation previously suggested to be involved in preparation of the CSF-1-CSF-1R complex for endocytosis. Consistent with this result, Cbl-/- macrophage cell surface CSF-1-CSF-1R complexes are internalized more slowly, yet are still lysosomally degraded, and the CSF-1 utilization by Cbl-/- macrophages is reduced approximately 2-fold. Thus, attenuation of proliferation by Cbl is associated with its positive regulation of the coordinated multiubiquitination and endocytosis of the activated CSF-1R, and a reduction in the time that the CSF-1R signals from the cell surface. The results provide a paradigm for studies of the mechanisms underlying Cbl attenuation of proliferative responses induced by ligation of receptor tyrosine kinases.

This prospective study was designed to measure the costs and benefits of using a laser rather than electrocautery for soft tissue resection during arthroscopic shoulder decompression. Forty-nine shoulders with refractory Neer stage II impingement (persistent fibrosis and tendinitis) were divided into 2 groups. The composition of the 2 groups was similar with regard to sex, worker's compensation status, dominant arm involvement, duration of symptoms, and length of conservative treatment. In one group, electrocautery was used to ablate the bursa and periosteum, release the coracoacromial ligament, and maintain hemostasis. In the other group, a laser was used in place of electrocautery. Patients had been evaluated preoperatively with 2 functional scoring systems. The patients were reexamined at 1 week and at 1, 2, 3, 6, and 12 months after surgery. There were no differences between the groups with regard to functional outcome or satisfaction. There was also no difference in terms of estimated blood loss or operative time. However, there was a statistically significant difference in total hospital charges between groups, with the laser group having a 23% higher hospital bill. On the basis of these results, it is concluded that there was no medical benefit to laser-assisted arthroscopic subacromial decompression but there was an increased monetary cost.

Background and Purpose: The purpose of this study was to compare the effects of two commonly used stimulating electrode placements on F-wave latency., Subjects: Fifty healthy subjects aged 20 to 47 years were tested., Methods: F-waves were obtained from median and ulnar nerves bilaterally. A total of 200 nerves were tested., Results: A paired t-test indicated a statistically significant difference in F-wave latency between the two stimulating electrode placements. Stepwise linear regression equations demonstrated that our results were consistent with previously published studies., Conclusion and Discussion: Although a statistically significant difference exists between the two techniques, the magnitude of the difference is not likely to be clinically important. Therefore, the most important factor may be to use a consistent technique when investigating potential neuropathies.

The c-Cbl protein is tyrosine phosphorylated and forms complexes with a wide range of signalling partners in response to various growth factors. How c-Cbl interacts with proteins, such as Grb2, phosphatidylinositol 3-kinase, and phosphorylated receptors, is well understood, but its role in these complexes is unclear. Recently, the Caenorhabditis elegans Cbl homolog, Sli-1, was shown to act as a negative regulator of epidermal growth factor receptor signalling. This finding forced a reassessment of the role of Cbl proteins and highlighted the desirability of testing genetically whether c-Cbl acts as a negative regulator of mammalian signalling. Here we investigate the role of c-Cbl in development and homeostasis in mice by targeted disruption of the c-Cbl locus. c-Cbl-deficient mice were viable, fertile, and outwardly normal in appearance. Bone development and remodelling also appeared normal in c-Cbl mutants, despite a previously reported requirement for c-Cbl in osteoclast function. However, consistent with a high level of expression of c-Cbl in the hemopoietic compartment, c-Cbl-deficient mice displayed marked changes in their hemopoietic profiles, including altered T-cell receptor expression, lymphoid hyperplasia, and primary splenic extramedullary hemopoiesis. The mammary fat pads of mutant female mice also showed increased ductal density and branching compared to those of their wild-type littermates, indicating an unanticipated role for c-Cbl in regulating mammary growth. Collectively, the hyperplastic histological changes seen in c-Cbl mutant mice are indicative of a normal role for c-Cbl in negatively regulating signalling events that control cell growth. Consistent with this view, we observed greatly increased intracellular protein tyrosine phosphorylation in thymocytes following CD3epsilon cross-linking. In particular, phosphorylation of ZAP-70 kinase in thymocytes was uncoupled from a requirement for CD4-mediated Lck activation. This study provides the first biochemical characterization of any organism that is deficient in a member of this unique protein family. Our findings demonstrate critical roles for c-Cbl in hemopoiesis and in controlling cellular proliferation and signalling by the Syk/ZAP-70 family of protein kinases.