The accuracy of dose calculations by anisotropic analytical algorithms for stereotactic radiotherapy in nasopharyngeal carcinoma.

Nasopharyngeal tumors are commonly treated with intensity-modulated radiotherapy techniques. For photon dose calculations, problems related to loss of lateral electronic equilibrium exist when small fields are used. The anisotropic analytical algorithm (AAA) implemented in Varian Eclipse was developed to replace the pencil beam convolution (PBC) algorithm for more accurate dose prediction in an inhomogeneous medium. The purpose of this study was to investigate the accuracy of the AAA for predicting interface doses for intensity-modulated stereotactic radiotherapy boost of nasopharyngeal tumors. The central axis depth dose data and dose profiles of phantoms with rectangular air cavities for small fields were measured using a 6 MV beam. In addition, the air-tissue interface doses from six different intensity-modulated stereotactic radiotherapy plans were measured in an anthropomorphic phantom. The nasopharyngeal region of the phantom was especially modified to simulate the air cavities of a typical patient. The measured data were compared to the data calculated by both the AAA and the PBC algorithm. When using single small fields in rectangular air cavity phantoms, both AAA and PBC overestimated the central axis dose at and beyond the first few millimeters of the air-water interface. Although the AAA performs better than the PBC algorithm, its calculated interface dose could still be more than three times that of the measured dose when a 2 × 2 cm(2) field was used. Testing of the algorithms using the anthropomorphic phantom showed that the maximum overestimation by the PBC algorithm was 20.7%, while that by the AAA was 8.3%. When multiple fields were used in a patient geometry, the dose prediction errors of the AAA would be substantially reduced compared with those from a single field. However, overestimation of more than 3% could still be found at some points at the air-tissue interface.

The Hong-Ou-Mandel interferometer: a new procedure for alignment.

Two major requirements in the construction of the Hong-Ou-Mandel interferometer are the alignment and length balancing of two optical paths. A new method is presented for meeting these requirements that requires no custom optics or expensive equipment. Using this method, a two photon interferometer sourced by degenerate noncollinear parametric photon pairs was aligned and the optical paths were balanced to within an average of 11.6 microm, yielding two-photon interference features with visibilities of approximately 0.9. The method is applicable to arbitrary noncollinear emission angles, including nondegenerate downconversion situations where the signal and idler emission angles differ.

Rotating and static sources for gamma knife radiosurgery systems: Monte Carlo studies.

Rotating gamma systems (RGSs), GammaART-6000, and its Chinese equivalents, such as OUR and MASEP, etc., are new radiosurgery systems that use rotating 60Co sources instead of the 201 static sources (Leksell gamma knife, LGK). The rotating sources of RGSs simulate an infinite number of beams and promote extremely high target to surface dose ratios. However, the results of Monte Carlo in this study shows that RGS variants (modeled as having the same latitude angles, source to focus distance, and the distance from the source to the end of the collimator as the LGK) have smaller beam profile penumbra in the z direction, while LGK has smaller penumbra in the x and y directions. The differences are more significant in using larger collimators.

Stress induced in heart and other tissues by rat dermal exposure to JP-8 fuel.

Limited information is available regarding the development of systemic organ stress by dermal exposure to JP-8 fuel. In this study, the systemic stress potential of this fuel is evaluated in a rat model subjected to dermal applications of JP-8 for 7 days at 300 microl per day. Tissue histology indicated that JP-8 induces morphological alterations that suggest that tissue stress in the heart is more substantial than stress in the kidney and liver. Immunoblot analysis of tissues revealed increased levels of the inducible heat shock protein 70 (HSP70) in the heart, kidney, and liver after this dermal JP-8 exposure. This exposure also leads to increased levels of heme oxygenase-1 (HO-1/HSP3) in the liver. Additionally during this exposure, a negative regulator of inflammation, IkappaBalpha (inhibitor of NF-kappaB), was increased in the liver, slightly increased in the kidney, and not increased in the heart. Two regions of the rat brain were also examined and HSP70 and IkappaBalpha were increased in the cerebellum but not significantly increased in the cortex. This study indicates dermal JP-8 exposure causes systemic alterations that are associated with cytoprotective activities (e.g., in the liver) as well as potentially toxic mechanisms (heart and kidney).

Screening for vestibular schwannoma by magnetic resonance imaging: analysis of 1821 patients.

OBJECTIVES: To study the spectrum of diseases that can be detected by magnetic resonance imaging in patients suspected to have vestibular schwannoma (acoustic neuroma) presenting with sensorineural or mixed hearing loss, and to assess the extent of the problem of hearing loss in a screened population. DESIGN: Retrospective study. SETTING: Diagnostic radiology and imaging department of a regional hospital, Hong Kong. PATIENTS: A total of 1821 consecutive patients from September 1999 to February 2001 with sensorineural or mixed hearing loss were referred by otolaryngologists for magnetic resonance imaging of the internal auditory canal. MAIN OUTCOME MEASURES: Vestibular schwannoma; other cerebellopontine angle masses and other diseases that could account for the patients' hearing loss. RESULTS: In all, 132 (7%) patients had positive findings that could explain their hearing loss. Fifty-four (41%) of the 132 patients had vestibular schwannoma; 39 (30%) had inflammation of the middle ear and mastoids; 17 (13%) had ischaemic foci in the brainstem; 10 (8%) had other cerebellopontine angle masses or tumours; four (3%) had inner ear dysplasia; seven (5%) had vascular loop compression; and one (1%) had chronic cryptococcal meningitis. The overall incidence of vestibular schwannoma detected in this screened population was about 3%. CONCLUSIONS: This study indicates that magnetic resonance imaging is an effective tool to screen for vestibular schwannoma in patients with sensorineural or mixed hearing loss. It can also be used to assess a considerable number of different pathological conditions in patients with audiovestibular disorders.

Anti-cancer and pro-apoptotic effects of an herbal medicine and Saccharomyces cerevisiae product (CKBM) on human hepatocellular carcinoma HepG2 cells in vitro and in vivo.

Hepatocellular carcinoma is a major health problem worldwide. Different treatment strategies have been developed to cope with this problem. Herbal medicine is now widely studied in both Eastern and Western countries. In this study, we used both in vitro and in vivo model to illustrate the anti-tumor effect of a product, CKBM, consisting of herbal medicine and specially processed Saccharomyces cerevisiae. Dose-dependent anti-proliferation effect was observed on in vitro growth of human hepatoma HepG2 cells after 48 hours incubation with CKBM. At the 50% inhibitory concentration (IC50) no significant toxic effect was observed on normal human fibroblasts Hs68 and human liver WRL-68 cells. The results of morphological changes, detection of DNA fragmentation, flow cytometric analysis and Western blot analysis indicated that this anti-tumor effect of CKBM was mediated via the process of apoptosis. In addition, HepG2 cells- bearing nude mice model was used for in vivo anti-tumor study. Our results showed that 14-day treatment with 0.8 ml daily dosage of CKBM could inhibit 54.1% of tumor growth. The plasma activities of enzymes specific for heart and liver, namely creatine kinase, lactate dehydrogenase, aspartate transaminase and alanine transaminase, remained at normal levels, indicated that CKBM did not produce toxicity to the host.

MR Detection of Dilated Deep Medullary Veins in Intracranial Dural Arteriovenous Fistulas with retrograde Leptomeningeal Venous Drainage.

SUMMARY: Patients with dural arteriovenous fistula (DAVF) are at higher risk of developing neurological deficits when there is retrograde leptomeningeal venous drainage. Our aim is to demonstrate the presence of dilated deep medullary veins in the brain on magnetic resonance imaging (MR) in this group of patients, and to assess their clinical significance. Nine patients with angiographically proven DAVF associated with leptomeningeal venous drainage who had MR before treatment were studied.MR was performed in at least two orthogonal planes before and after gadolinium administration. The dural fistula was located at the cavernous sinus in five patients, at the transverse-sigmoid sinus in three and at the tentorium in one. Dilated deep medullary veins were noted in six patients. Of these, four showed parenchymal abnormalities which included intracerebral haematoma, venous infarction, brain oedema and T2 hyperintensity in brainstem. Venous varix was present in one patient. No neurological complication or parenchymal change was observed in the three patients without dilated deep medullary veins. Therefore, in patients with intracranial DAVF associated with leptomeningeal venous recruitment, the MR finding of dilated deep medullary veins suggests a more severe degree of venous hypertension and congestion in the brain. This subgroup of patients has a much higher chance of neurological complications and warrants urgent intervention.

Overexpression of Na+/Ca2+ exchanger alters contractility and SR Ca2+ content in adult rat myocytes.

The functional consequences of overexpression of rat heart Na+/Ca2+ exchanger (NCX1) were investigated in adult rat myocytes in primary culture. When maintained under continued electrical field stimulation conditions, cultured adult rat myocytes retained normal contractile function compared with freshly isolated myocytes for at least 48 h. Infection of myocytes by adenovirus expressing green fluorescent protein (GFP) resulted in >95% infection as ascertained by GFP fluorescence, but contraction amplitude at 6-, 24-, and 48-h postinfection was not affected. When they were examined 48 h after infection, myocytes infected by adenovirus expressing both GFP and NCX1 had similar cell sizes but exhibited significantly altered contraction amplitudes and intracellular Ca2+ concentration ([Ca2+]i) transients, and lower resting and diastolic [Ca2+]i when compared with myocytes infected by the adenovirus expressing GFP alone. The effects of NCX1 overexpression on sarcoplasmic reticulum (SR) Ca2+ content depended on extracellular Ca2+ concentration ([Ca2+]o), with a decrease at low [Ca2+]o and an increase at high [Ca2+]o. The half-times for [Ca2+]i transient decline were similar, suggesting little to no changes in SR Ca2+-ATPase activity. Western blots demonstrated a significant (P < or = 0.02) threefold increase in NCX1 but no changes in SR Ca2+-ATPase and calsequestrin abundance in myocytes 48 h after infection by adenovirus expressing both GFP and NCX1 compared with those infected by adenovirus expressing GFP alone. We conclude that overexpression of NCX1 in adult rat myocytes incubated at high [Ca2+]o resulted in enhanced Ca2+ influx via reverse NCX1 function, as evidenced by greater SR Ca2+ content, larger twitch, and [Ca2+]i transient amplitudes. Forward NCX1 function was also increased, as indicated by lower resting and diastolic [Ca2+]i.

Molecular mechanisms of erythropoietin signaling.

Erythropoietin is an obligatory growth factor for red blood cell production. The receptor for erythropoietin contains a single membrane-spanning domain with no intrinsic tyrosine kinase motifs. On binding to erythropoietin, the receptor dimerizes and activates multiple intracellular signaling molecules, including but not limited to JAK2, STAT5, PI 3-kinase, IRS-2, RAS, and Ca2+ channels. This review focuses on cytoplasmic signaling cascades involved in erythropoietin action.

A minimal cytoplasmic subdomain of the erythropoietin receptor mediates p70 S6 kinase phosphorylation.

Erythropoietin (EPO) is a lineage-restricted growth factor that is required for erythroid proliferation and differentiation. EPO stimulates the phosphorylation and activation of p70 S6 kinase (p70 S6K), which is required for cell cycle progression. Here, the minimal cytoplasmic domains of the EPO receptor (EPO-R) required for p70 S6K activation were determined.Ba/F3 cells were stably transfected with wild-type (WT) EPO-R or EPO-R carboxyl-terminal deletion mutants, designated by the number of amino acids deleted from the cytoplasmic tail (-99, -131, -221). Transfected cells were growth factor deprived and then stimulated with EPO. p70 S6K, JAK2, IRS-2, and ERK1/2 phosphorylation/activation were examined. The ability of transfected 3-phosphoinositide-dependent protein kinase 1 (PDK1) to reconstitute p70 S6K phosphorylation in EPO-R mutants also was determined. Phosphorylation and activation of p70 S6K, JAK2, IRS-2, and ERK1/2 in Ba/F3 cells transfected with EPO-R-99 or EPO-R-99Y343F were similar to WT EPO-R. In contrast, EPO-dependent p70 S6K phosphorylation/activation, as well as IRS-2 and ERK1/2 phosphorylation, were minimal or absent in cells transfected with EPO-R-131 or EPO-R-221. JAK2 phosphorylation was reduced significantly in cells transfected with EPO-R-131 and abolished with EPO-R-221. To examine the role of PDK1, a kinase known to phosphorylate p70 S6K, Ba/F3 EPO-R-131 cells were transiently transfected with PDK1. WT constitutively active PDK1 restored p70 S6K phosphorylation in Ba/F3 EPO-R-131 cells but not in Ba/F3 EPO-R-221 cells. The results demonstrate that a minimal cytoplasmic subdomain of the EPO-R extending between -99 and -131 is required for p70 S6K phosphorylation and activation. The results also demonstrate that PDK1 is a critical component in this signaling pathway, which requires the presence of domains between -131 and -221 for its activation of p70 S6K.

Sprint training shortens prolonged action potential duration in postinfarction rat myocyte: mechanisms.

Two electrophysiological manifestations of myocardial infarction (MI)-induced myocyte hypertrophy are prolongation of action potential duration (APD) and reduction of transient outward current (I(to)) density. Because high-intensity sprint training (HIST) ameliorated myocyte hypertrophy and improved myocyte Ca(2+) homeostasis and contractility after MI, the present study evaluated whether 6-8 wk of HIST would shorten the prolonged APD and improve the depressed I(to) in post-MI myocytes. There were no differences in resting membrane potential and action potential amplitude (APA) measured in myocytes isolated from sham-sedentary (Sed), MI-Sed, and MI-HIST groups. Times required for repolarization to 50 and 90% APA were significantly (P < 0.001) prolonged in MI-Sed myocytes. HIST reduced times required for repolarization to 50 and 90% APA to values observed in Sham-Sed myocytes. The fast and slow components of I(to) were significantly (P < 0.0001) reduced in MI-Sed myocytes. HIST significantly (P < 0.001) enhanced the fast and slow components of I(to) in MI myocytes, although not to levels observed in Sham-Sed myocytes. There were no significant differences in steady-state I(to) inactivation and activation parameters among Sham-Sed, MI-Sed, and MI-HIST myocytes. Likewise, recovery from time-dependent inactivation was also similar among the three groups. We suggest that normalization of APD after MI by HIST may be mediated by restoration of I(to) toward normal levels.

Dose distributions at extreme irradiation depths of gamma knife radiosurgery: EGS4 Monte Carlo calculations.

The accuracy of the dose planning system (Leksell GammaPlan), used in Gamma Knife (type B) radiosurgery at extreme irradiation depths, was verified using the Monte Carlo technique. EGS4 Monte Carlo calculations were employed to calculate the dose distribution along the x, y and z axes for an irradiation relatively shallow in a spherical bony cavity water phantom. Two different sizes of the collimator helmets, 8 and 18 mm, of the Leksell Gamma Knife Unit were studied. The results of GammaPlan showed good consistency with the Monte Carlo results. Furthermore, small dose enhancements were observed in the skull bone where accurate dose measurements are difficult due to the presence of the air-phantom interface. Therefore, the results of this project can promote confidence to all Gamma Knife centres in the world when using the Leksell GammaPlan.

Expression of angiotensin II type I receptor on erythroid progenitors of patients with post transplant erythrocytosis.

BACKGROUND: The pathogenesis of posttransplant erythrocytosis (PTE) has been elusive. Angiotensin converting enzyme inhibitors (ACEI) are efficacious in lowering the hematocrit of patients with PTE and angiotensin II (AII) type I receptors (AT1R) were recently detected on red blood cell precursors, burst-forming unit-erythroid- (BFU-E) derived cells. The purpose of this study was to determine whether there is increased expression of the AT1R on BFU-E-derived cells of patients with PTE, which might contribute to the pathogenesis of PTE. METHODS: Twelve healthy volunteers and 25 transplant recipients (13 patients with and 12 without PTE) were studied. BFU-E from peripheral blood were cultured in methylcellulose and BFU-E-derived colonies were harvested on day 10. Western blotting was used to detect AT1R and erythropoietin receptor (EpoR) expression. Intracellular free calcium in response to AII and erythropoietin (Epo) was measured with digital video imaging. RESULTS: There were no differences between transplant patients, with and without PTE, with respect to weight, age, sex, blood pressure, serum creatinine, circulating renin, angiotensin II, and Epo levels. Hematocrit, red blood cell number, BFU-E-derived colony number,and size were significantly increased in PTE compared with other two groups. AT1R expression was increased by 44% on the erythroid progenitors of PTE versus non posttransplant erythrocytosis patients and by 32% in PTE patients versus normal volunteers. AT1R expression correlated significantly with the hematocrit in PTE (Spearman r=0.68, P=0.01). In contrast, EpoR expression was equivalent in all groups. The AT1R was functional since a significant increase in [Ca(i)] was observed in Fura-2 loaded day 10 cells when stimulated with AII (182%, P<0.0001). CONCLUSION: An increase in AT1R density was observed in erythroid precursors of transplant patients with PTE compared to those without PTE and normal volunteers, and the level of AT1R expression in PTE correlated significantly with the hematocrit. In contrast, EpoR expression was not different in PTE compared with non posttransplant erythrocytosis or normal controls. This study supports a role for the AT1 receptor signaling pathway in the pathogenesis of PTE.

Sprint training restores normal contractility in postinfarction rat myocytes.

The significance of 6-8 wk of high-intensity sprint training (HIST) on contractile abnormalities of myocytes isolated from rat hearts with prior myocardial infarction (MI) was investigated. Compared with the sedentary (Sed) condition, HIST attenuated myocyte hypertrophy observed post-MI primarily by reducing cell lengths but not cell widths. At high extracellular Ca(2+) concentration (5 mM) and low pacing frequency (0.1 Hz), conditions that preferentially favored Ca(2+) influx over efflux, MI-Sed myocytes shortened less than Sham-Sed myocytes did. HIST significantly improved contraction amplitudes in MI myocytes. Under conditions that favored Ca(2+) efflux, i.e., low extracellular Ca(2+) concentration (0.6 mM) and high pacing frequency (2 Hz), MI-Sed myocytes contracted more than Sham-Sed myocytes. HIST did not appreciably affect contraction amplitudes of MI myocytes under these conditions. Compared with MI-Sed myocytes, HIST myocytes showed significant improvement in time required to reach one-half maximal contraction amplitude shortening, maximal myocyte shortening and relengthening velocities, and half time of relaxation. Our results indicate that HIST instituted shortly after MI improved cellular contraction in surviving myocytes. Because our previous studies demonstrated that, in post-MI myocytes, HIST improved intracellular Ca(2+) dynamics, enhanced sarcoplasmic reticulum Ca(2+) uptake and Ca(2+) content, and restored Na(+)/Ca(2+) exchange current toward normal, we hypothesized that improvement in MI myocyte contractile function by HIST was likely mediated by normalization of cellular Ca(2+) homeostatic mechanisms.

Spatio-temporal nonlinear modeling of gastric myoelectrical activity.

The accomplishment of a complete digestive process of human stomach is regulated by a spatio-temporally-coordinated electric pattern called gastric myoelectrical activity (GMA). The normal patterns of GMA present temporal evolution from endogenous rhythmic oscillation to bursting of spikes associated with contractions, and also ordered spatial propagation of the oscillating waves. The abnormal patterns of GMA have been observed in temporal dysrhythmia, such as tachygastria, bradygastria and arrhythmia, and in spatial propagation failure, such as retrograde propagation and uncoupling. Different GMA patterns are associated with different gastric symptoms and there exist some nonlinear mechanisms to govern the formation and dynamic evolution of these patterns. However, these mechanisms are so complex that few of them are known by medical observations. The aim of this study is to explore these mechanisms by spatio-temporal modeling of GMA. The single-cell model simulating the formation process of slow waves and spikes, the multi-cell model simulating the propagation process of GMA and the extracellular model simulating the formation of bipolar recordings are presented.

Sprint training normalizes Ca(2+) transients and SR function in postinfarction rat myocytes.

Previous studies have shown that myocytes isolated from sedentary (Sed) rat hearts 3 wk after myocardial infarction (MI) undergo hypertrophy, exhibit altered intracellular Ca(2+) concentration ([Ca(2+)](i)) dynamics and abnormal contraction, and impaired sarcoplasmic reticulum (SR) function manifested as prolonged half-time of [Ca(2+)](i) decline. Because exercise training elicits positive adaptations in cardiac contractile function and myocardial Ca(2+) regulation, the present study examined whether 6-8 wk of high-intensity sprint training (HIST) would restore [Ca(2+)](i) dynamics and SR function in MI myocytes toward normal. In MI rats, HIST ameliorated myocyte hypertrophy as indicated by significant (P

Sequential volume mapping for confirmation of negative growth in vestibular schwannomas treated by gamma knife radiosurgery.

OBJECT: The purpose of this study was to confirm, by using a sequential volume mapping (SVM) technique, that gamma knife radiosurgery (GKS) induces negative growth in vestibular schwannomas (VS). METHODS: Over a period of 5 years, 126 small- to medium-sized (< 15 cm3) VSs were treated using microradiosurgical techniques within a standard protocol. All patient data were collected prospectively. Sequential magnetic resonance imaging was performed every 6 months to assess the volume of the tumor, based on specially developed GammaPlan software. The mean follow-up duration was 22 months. At least three SVM measurements were obtained in 91 patients and at least four were obtained in 62 patients. The mean number of SVM measurements for each patient was 2.54. After GKS, the following patterns of volume change were seen: 1) 57 VSs showed transient increase in volume with a peak at 6 months, followed by shrinkage. Four VSs exhibited prolonged swelling beyond 24 months. Transient swelling and eventual shrinkage were independent of the initial VS volume; 2) 29 VSs showed direct volume shrinkage without swelling; and 3) five VSs showed persistent volume increase. All volume changes were greater than 10%. The overall mean volume reduction was 46.8% at 30 months. CONCLUSIONS: Sequential volume mapping appears to be superior to conventional two-dimensional measurements in monitoring volume changes in VS after GKS. It confirms that transient swelling is common. Ninety-two percent of tumors responded by showing significant volume shrinkage (mean 46.8%). It would seem that GKS can induce volume reduction in VS.