Virtual 4DCT generated from 4DMRI in gated particle therapy: phantom validation and application to lung cancer patients.

Objective. Respiration negatively affects the outcome of a radiation therapy treatment, with potentially severe effects especially in particle therapy (PT). If compensation strategies are not applied, accuracy cannot be achieved. To support the clinical practice based on 4D computed tomography (CT), 4D magnetic resonance imaging (MRI) acquisitions can be exploited. The purpose of this study was to validate a method for virtual 4DCT generation from 4DMRI data for lung cancers on a porcine lung phantom, and to apply it to lung cancer patients in PT.Approach. Deformable image registration was used to register each respiratory phase of the 4DMRI to a reference phase. Then, a static 3DCT was registered to this reference MR image set, and the virtual 4DCT was generated by warping the registered CT according to previously obtained deformation fields. The method was validated on a physical phantom for which a ground truth 4DCT was available and tested on lung tumor patients, treated with gated PT at end-exhale, by comparing the virtual 4DCT with a re-evaluation 4DCT. The geometric and dosimetric evaluation was performed for both proton and carbon ion treatment plans.Main results. The phantom validation exhibited a geometrical accuracy within the maximum resolution of the MRI and mean dose deviations, with respect to the prescription dose, up to 3.2% for targetD95%, with a mean gamma pass rate of 98%. For patients, the virtual and re-evaluation 4DCTs showed good correspondence, with errors on targetD95%up to 2% within the gating window. For one patient, dose variations up to 10% at end-exhale were observed due to relevant inter-fraction anatomo-pathological changes that occurred between the planning and re-evaluation CTs.Significance. Results obtained on phantom data showed that the virtual 4DCT method was accurate, allowing its application on patient data for testing within a clinical scenario.

Assessment of range uncertainty in lung-like tissue using a porcine lung phantom and proton radiography.

Thoracic tumours are increasingly considered indications for pencil beam scanned proton therapy (PBS-PT) treatments. Conservative robustness settings have been suggested due to potential range straggling effects caused by the lung micro-structure. Using proton radiography (PR) and a 4D porcine lung phantom, we experimentally assess range errors to be considered in robust treatment planning for thoracic indications. A human-chest-size 4D phantom hosting inflatable porcine lungs and corresponding 4D computed tomography (4DCT) were used. Five PR frames were planned to intersect the phantom at various positions. Integral depth-dose curves (IDDs) per proton spot were measured using a multi-layer ionisation chamber (MLIC). Each PR frame consisted of 81 spots with an assigned energy of 210 MeV (full width at half maximum (FWHM) 8.2 mm). Each frame was delivered five times while simultaneously acquiring the breathing signal of the 4D phantom, using an ANZAI load cell. The synchronised ANZAI and delivery log file information was used to retrospectively sort spots into their corresponding breathing phase. Based on this information, IDDs were simulated by the treatment planning system (TPS) Monte Carlo dose engine on a dose grid of 1 mm. In addition to the time-resolved TPS calculations on the 4DCT phases, IDDs were calculated on the average CT. Measured IDDs were compared with simulated ones, calculating the range error for each individual spot. In total, 2025 proton spots were individually measured and analysed. The range error of a specific spot is reported relative to its water equivalent path length (WEPL). The mean relative range error was 1.2% (1.5 SD 2.3 %) for the comparison with the time-resolved TPS calculations, and 1.0% (1.5 SD 2.2 %) when comparing to TPS calculations on the average CT. The determined mean relative range errors justify the use of 3% range uncertainty for robust treatment planning in a clinical setting for thoracic indications.

Novel missense and truncating mutations in FUS/TLS in familial ALS.

BACKGROUND: Mutations in the FUS/TLS gene have been associated with familial amyotrophic lateral sclerosis (FALS). METHODS: We analyzed the presence and frequency of C-terminal FUS/TLS mutations in a German amyotrophic lateral sclerosis (ALS) cohort, including 133 patients with sporadic ALS (SALS) and 58 patients with FALS by sequence analysis of exons 13-15. RESULTS: We identified 2 novel heterozygous FUS/TLS mutations in 4 German ALS families including the novel missense mutation K510R and the truncating mutation R495X. The truncating mutation was associated with an aggressive disease course whereas the K510R mutation showed a mild phenotype with disease duration ranging from 6 to 8 years. No mutation was detected in 133 patients with SALS. CONCLUSIONS: Mutations in FUS/TLS account for 7% (4 of 58) of FALS in our German cohort.

Effect of enalapril on the in vitro and in vivo peptidyl cleavage of a potent VLA-4 antagonist.

BIO1211 is a small peptidyl potent antagonist of the activated form of alpha4beta1 integrin. The effect of enalapril on the in vitro and in vivo cleavage of BIO1211 was investigated. In heparinized blood, plasma and rat liver, lung and intestinal homogenates, BIO1211 was converted rapidly to BIO1588 by hydrolytic cleavage of the terminal dipeptide moiety. This cleavage could be inhibited by EDTA and the ACE inhibitor, enalaprilat, the de-esterified acid derivative of enalapril. Enalaprilat inhibited the hydrolysis of BIO1211 in a concentration-dependent manner with IC(50) values of 2 nM in human and sheep plasma and 10 nM in rat plasma. In rat lung homogenate supernatant, the maximum inhibition of the conversion of BIO1211 to BIO1588 was approximately 80% at 1 microM with no further effect up to 100 microM of enalaprilat. Following a concomitant IV administration of enalapril and BIO1211 at 3 mg/kg each, the AUC and the half-life values of BIO1211 increased 18- and 10-fold, respectively. The AUC of BIO1588 decreased approximately 2-fold with no change in its plasma half-life. When rats were dosed intravenously with enalapril followed by an intratracheal dose of BIO1211, there was approximately 2.5-fold decrease in the AUC of BIO1588 and a 2.4-fold increase in its plasma half-life.

Culicoides mohave (Diptera: Ceratopogonidae): new occurrence records and potential role in transmission of hemorrhagic disease.

Biting midges of the genus Culicoides are important in the transmission of viral diseases affecting wild and domestic ungulates, including bluetongue (BLU) and epizootic hemorrhagic disease (EHD). The primary known vector for these viruses is C. sonorensis Wirth & Jones, however, it has been speculated that other species of Culicoides may also be involved. One potential candidate is C. mohave, a poorly studied species found in inland desert areas of the southwestern United States. In 2000 and 2001, we collected C. mohave and C. sonorensis at six sites in a previously unsurveyed area in the Sonoran Desert of southwestern Arizona and used PCR to detect nucleic acids associated with BLU and EHD viruses. C. mohave was abundant at two low-elevation sites on the study area, but uncommon or absent elsewhere. C. sonorensis commonly occurred along with C. mohave at one site, but was much less abundant. All C. mohave pools were negative for BLU viral RNA, however, 35% yielded positive results for EHD. All C. sonorensis were negative for both BLU and EHD. Our results suggest that C. mohave is a potential vector of EHD virus in this area, however additional studies are needed to determine its ability to transmit EHD.

Maternal hyperglycemia leads to gender-dependent deficits in learning and memory in offspring.

Pregnancy in the diabetic woman has long been associated with an increased risk of congenital malformation in the offspring. However, little is known about the effects of maternal diabetes on development of the central nervous system. To begin to gain an understanding of this problem, diabetes was induced in adult female Sprague-Dawley rats by injection with streptozotocin. Only animals with serum glucose levels greater than 200 mg/dl were used. Diabetic and control females were bred, and all newborn pups were cross-fostered to nondiabetic mothers. At 60 days of age, pups were tested in an elevated plus-maze to assess differences in emotionality and anxiety. There were no significant differences between offspring of diabetic dams and controls on this measure. All pups were then housed individually, put on food restriction, and maintained at 85% of their ad libitum weight. They were then trained in a Lashley III maze, which assesses learning and retention capability. The female offspring of diabetic dams performed poorer than controls, a finding that was supported by inhibitory avoidance data from a separate group of animals. All animals were then trained in a radial-arm maze. Results failed to find differences between experimental and control animals. It was concluded that the diabetic intrauterine environment has gender-specific effects on central nervous system development.

Strong anisotropy of projected 3d moments in epitaxial CrO2 films.

Soft x-ray magnetic circular dichroism (XMCD) spectra have been investigated for different crystallographic projections of CrO2. Strong anisotropic orbital Cr 3d contributions and a change of sign of the XMCD signal is observed and attributed to t(2g) majority states near the Fermi level. Additionally, moment analysis exhibits anisotropic behavior in the projected spin contributions of CrO2 assigned to a strong magnetic dipole term T(z), consistent with an intrinsic magnetic easy axis behavior along the CrO2 [001] axis. A reduced projected isotropic Cr 3d spin moment has been interpreted in terms of hybridization with oxygen.

Photon beats from a single semiconductor quantum dot.

Single-photon interference is observed on the ultranarrow long-term stable exciton resonance of an individual semiconductor quantum dot. This interference is related to the fine-structure splitting and allows direct conclusions about the coherence properties of the exciton. When selectively addressing a particular dot by quasiresonant phonon-assisted excitation, despite a rapid orientation relaxation on a 1-ps time scale, coherence is partly maintained. No significant further decoherence occurs when the ground state is reached until the exciton recombines radiatively (approximately 300 ps).

The effect of diabetes mellitus on endocrine and reproductive function.

The adverse effects of diabetes on the circulatory, visual, renal, and peripheral nervous system are commonly recognized and have been extensively studied. The effects of decreased insulin secretion or resistance to insulin action on endocrine glands have not been as carefully documented. Both clinical and animal research have demonstrated that diabetes mellitus is commonly associated with altered thyroid, adrenal and gonadal function. Some of these changes are reversed with insulin replacement therapy, but endocrine function is not always restored to normal even with rigorous glycemic control. Patients with poorly controlled diabetes exhibit basal and stimulated growth hormone (GH) hypersecretion, while patients with good metabolic control still present with diurnal and exercise-induced GH hypersecretion. In contrast, diabetes suppresses GH secretion in the rat. It is unclear why GH secretion is altered, but clinical and experimental evidence exists for diabetes-associated changes in GH-releasing hormone and somatostatin release as well as for changes in the pituitary response to these hypothalamic hormones. The thyroid hormones, T3 and T4, are usually suppressed in both humans and experimental animals with diabetes. This effect of diabetes appears to involve changes in hypothalamic thyrotropin-releasing hormone (TRH) secretion as well as changes in pituitary thyrotropin (TSH) release and direct effects at the level of the thyroid gland. Adrenal cortical function is often enhanced in diabetes, most likely due to alterations in glucocorticoid feedback responses. There is much conflicting data on adrenal medullary function in diabetes; responses to stress and exercise, however, are often abnormal. Finally, male and female reproductive function is often disrupted in diabetes. Data from animal studies suggest that the major cause is altered hypothalamic LHRH secretion secondary to diabetes-induced changes in hypothalamic neurotransmitter metabolism.

Effects of streptozotocin-induced diabetes on neuroendocrine responses to ovariectomy and estrogen replacement in female rats.

The effects of streptozotocin-induced (STZ) diabetes on the negative feedback regulation of LH and FSH were evaluated in adult female rats. Rats were injected with STZ (50 mg/kg) or vehicle and ovariectomized 10 days later. Estrogen (EB; 100 micrograms/kg) or oil injections were given on alternate days, starting on the day of ovariectomy. Blood samples for LH, FSH and PRL assay were taken on days 10, 13, 15 and 17. The rats were decapitated on day 17. One hour prior to sacrifice, one half of the animals were injected with alpha-methyl-p-tyrosine for determination of catecholamine turnover rates. Pituitaries were incubated to determine basal secretion rates. Rats treated with STZ exhibited the expected weight loss and elevation of plasma glucose levels. At the time of ovariectomy, FSH, but not LH or PRL, was depressed in the diabetic rats. The postovariectomy rise in LH and FSH was severely attenuated in the diabetic rats. EB treatment was more effective in lowering LH and FSH levels in the diabetic as compared to the control rats. Median eminence (ME) norepinephrine (NE) and dopamine (DA) turnover was higher in the oil-treated diabetic rats than oil-treated controls. EB also caused a greater decrease in ME NE and DA turnover in the diabetic rats. EB was more effective in decreasing in vitro LH secretion and increasing in vitro PRL secretion from pituitaries of control as compared to STZ-treated animals. These results demonstrated that STZ-induced diabetes leads to an attenuation of LH and FSH release after ovariectomy and potentiates the negative feedback effects of EB.(ABSTRACT TRUNCATED AT 250 WORDS)