A method for photon beam Monte Carlo multileaf collimator particle transport

Monte Carlo (MC) algorithms are recognized as the most accurate methodology for patient dose assessment. For intensity-modulated radiation therapy (IMRT) delivered with dynamic multileaf collimators (DMLCs), accurate dose calculation, even with MC, is challenging. Accurate IMRT MC dose calculations require inclusion of the moving MLC in the MC simulation. Due to its complex geometry, full transport through the MLC can be time consuming. The aim of this work was to develop an MLC model for photon beam MC IMRT dose computations. The basis of the MC MLC model is that the complex MLC geometry can be separated into simple geometric regions, each of which readily lends itself to simplified radiation transport. For photons, only attenuation and first Compton scatter interactions are considered. The amount of attenuation material an individual particle encounters while traversing the entire MLC is determined by adding the individual amounts from each of the simplified geometric regions. Compton scatter is sampled based upon the total thickness traversed. Pair production and electron interactions (scattering and bremsstrahlung) within the MLC are ignored. The MLC model was tested for 6 MV and 18 MV photon beams by comparing it with measurements and MC simulations that incorporate the full physics and geometry for fields blocked by the MLC and with measurements for fields with the maximum possible tongue-and-groove and tongue-or-groove effects, for static test cases and for sliding windows of various widths. The MLC model predicts the field size dependence of the MLC leakage radiation within 0.1% of the open-field dose. The entrance dose and beam hardening behind a closed MLC are predicted within +/- 1% or 1 mm. Dose undulations due to differences in inter- and intra-leaf leakage are also correctly predicted. The MC MLC model predicts leaf-edge tongue-and-groove dose effect within +/- 1% or 1 mm for 95% of the points compared at 6 MV and 88% of the points compared at 18 MV. The dose through a static leaf tip is also predicted generally within +/- 1% or 1 mm. Tests with sliding windows of various widths confirm the accuracy of the MLC model for dynamic delivery and indicate that accounting for a slight leaf position error (0.008 cm for our MLC) will improve the accuracy of the model. The MLC model developed is applicable to both dynamic MLC and segmental MLC IMRT beam delivery and will be useful for patient IMRT dose calculations, pre-treatment verification of IMRT delivery and IMRT portal dose transmission dosimetry.     

Quantifying the predictability of diaphragm motion during respiration with a noninvasive external marker

The aim of this work was to quantify the ability to predict intrafraction diaphragm motion from an external respiration signal during a course of radiotherapy. The data obtained included diaphragm motion traces from 63 fluoroscopic lung procedures for 5 patients, acquired simultaneously with respiratory motion signals (an infrared camera-based system was used to track abdominal wall motion). During these sessions, the patients were asked to breathe either (i) without instruction, (ii) with audio prompting, or (iii) using visual feedback. A statistical general linear model was formulated to describe the relationship between the respiration signal and diaphragm motion over all sessions and for all breathing training types. The model parameters derived from the first session for each patient were then used to predict the diaphragm motion for subsequent sessions based on the respiration signal. Quantification of the difference between the predicted and actual motion during each session determined our ability to predict diaphragm motion during a course of radiotherapy. This measure of diaphragm motion was also used to estimate clinical target volume (CTV) to planning target volume (PTV) margins for conventional, gated, and proposed four-dimensional (4D) radiotherapy. Results from statistical analysis indicated a strong linear relationship between the respiration signal and diaphragm motion (p<0.001) over all sessions, irrespective of session number (p=0.98) and breathing training type (p=0.19). Using model parameters obtained from the first session, diaphragm motion was predicted in subsequent sessions to within 0.1 cm (1 sigma) for gated and 4D radiotherapy. Assuming a 0.4 cm setup error, superior-inferior CTV-PTV margins of 1.1 cm for conventional radiotherapy could be reduced to 0.8 cm for gated and 4D radiotherapy. The diaphragm motion is strongly correlated with the respiration signal obtained from the abdominal wall. This correlation can be used to predict diaphragm motion, based on the respiration signal, to within 0.1 cm (1 sigma) over a course of radiotherapy.     

Trichothiodystrophy type 4 in an Indian family

Trichothiodystrophy, non‐photosensitive type 4 (TTD4), is a rare genetic disorder with an autosomal recessive mode of inheritance. It is characterized by coarse and brittle hair, anomalies of the tissues derived from the neuro‐ectoderm (skin, hair, and nails) and intellectual disability. We herein report two male siblings aged 13 and 16 years with TTD4 and a known homozygous pathogenic variant, c.229del [p.(Arg77Glyfs*76)] in exon 1 of MPLKIP (NM_138701.3). We herein highlight the clinical and molecular findings of the first reported case of TTD4 in probands of Indian ethnicity.     

Ambient temperature related sleep changes in rats neonatally treated with capsaicin

Ambient temperature related sleep changes in rats neonatally treated with capsaicin. PHYSIOL BEHAV 00(0) 000-000, 2004. The study was conducted on adult male Wistar rats, neonatally treated with capsaicin to destroy the peripheral warm receptors. The sleep-wakefulness was recorded for 5 h at an ambient temperature (T(amb)) of 18, 24, 30 and 33 degrees C on different days. The rectal temperatures (T(r)) of the rats were studied on exposure to 6 and 37 degrees C for 2 h to assess their thermoregulatory ability. The changes in the behavioral thermoregulation were assessed by noting the thermal preference of rats when they were placed in an environmental chamber with 3 interconnected compartments maintained at 24, 27 and 30 degrees C. Slow wave (SWS) and rapid eye movement (REM) sleep were decreased at 18 degrees C and increased at 30 degrees C, in control rats. There was a decrease in REM sleep and no change in SWS when T(amb) was raised from 30 to 33 degrees C. However, in neonatally capsaicin treated rats, sleep was increased even at 33 degrees C, though there was no significant change in sleep when T(amb) was increased from 18 to 24 degrees C. Capsaicin treated rats showed thermoregulatory deficiency at 37 degrees C but the thermal preference was unaltered in these rats. The results suggest that the central warm receptors can produce alteration in sleep at different T(amb), even in absence of peripheral warm receptors. The behavioral thermoregulation was unaffected in these rats, though their ability to defend the body temperature in warm environment was affected.     

Choriocarcinoma with negative urinary and serum beta human chorionic gonadotropin (betaHCG)--a case report

This was a rare case where a patient presented clinically as a case of post abortal sepsis and ultrasound showing the picture of an intramural degenerating fibroid. Her serum and urine both were negative for beta human chorionic gonadotropin (betaHCG). Patient succumbed to choriocarcinoma 1 month later. Failure to detect urinary and serum betaHCG lead to maternal mortality due to the choriocarcinoma. The failure to detect, certain degradation products of HCG which may predominate in gestational trophoblastic neoplasia, by many common HCG testing kits lead to the error of diagnosis. Only 3 of the 7 common commercial serum HCG tests appropriately detects nicked HCG and its free betaHCG, DPC immulite assay, being the most sensitive method. Though of rare occurrence, this awareness is important for diagnosis and follow-up of gestational trophoblastic neoplasia and could have been life saving in our case.     

Morphine stimulates superoxide formation by glomerular mesangial cells

Focal glomerulosclerosis is the predominant glomerular lesion in heroin addicts. We studied whether morphine, a metabolite of heroin, could directly affect the formation of superoxide by glomerular mesangial cells. Mesangial cells preincubated with morphine (10^–8 M) showed a higher (P<0.001) production of superoxide when compared to control cells (control) 401±21 vs. morphine 610±41 nM/mg protein/h). This effect of morphine on mesangial cells was dose dependent. Naloxone, an opiate antagonist, attenuated morphine-induced formation of Superoxide by mesangial cells [control, 317±4; morphine (10^–8 M), 573±9; and naloxone (10^–8 M) + morphine (10^–8 M), 333±6 nM/mg protein/h]. We conclude that morphine enhances formation of superoxide by mesangial cells and this effect of morphine seems to be mediated through opiate receptors. Since superoxide has been demonstrated to cause mesangiolysis, we propose that morphine may be playing a role in the induction of mesangial injury in patients with opiate abuse.This work was supported by National Institute of Health Grant R01-DA-06753.     

Anti-subnucleosome reactivities in systemic lupus erythematosus (SLE) patients and their first-degree relatives

Antibodies specific for dsDNA appear to have different genetic origins and pathogenic consequences, compared with histone/dsDNA-specific antibodies, in a recently described murine model. The purpose of this study was to examine if this is also true in human lupus. Sera from 40 SLE families (comprising 40 probands and 153 first-degree relatives), and 45 normal adult controls were assayed for the levels of anti-dsDNA, anti-H1/dsDNA, anti-H2A/H2B/dsDNA, and anti-H3/H4/dsDNA autoantibodies by ELISA. Both the probands and the first-degree relatives exhibited significantly increased levels of antinuclear antibodies (ANA) targeting the different subnucleosomal epitopes. Importantly, probands with anti-dsDNA antibodies had a significantly higher incidence of renal disease compared with those with just anti-H2A/H2B/dsDNA antibodies, in resonance with murine studies. The frequency of anti-dsDNA and anti-H2A/H2B/DNA ANA among the first-degree relatives was 11.8% and 18.3%, respectively. Surprisingly, whereas probands with anti-dsDNA ANA had families with several seropositive members, first-degree relatives of patients with anti-H2A/H2B/DNA ANA (but not anti-dsDNA ANA) were uniformly ANA-free. These findings suggest that anti-dsDNA ANA in lupus may not only have worse disease associations, they may also have very different genetic origins, compared with anti-H2A/H2B/DNA (or anti-nucleosome) ANA.     

Microdissection genotyping of archival fixative treated tissue for Gaucher disease

The genetic diagnosis of Gaucher disease by molecular methods is complicated by the existence of a highly homologous transcribed pseudogene (96% identity) that is found in close proximity to the true gene on chromosome 1q21. In addition, the pseudogene sequence can mimic disease-causing mutations in the true gene. Selective polymerase chain reaction (PCR) amplification of the true gene can be accomplished in extracted DNA from fresh-frozen samples by designing oligonucleotide primers to hybridize to defined regions that are not present in the pseudogene. This standard molecular approach, which entails amplification of relatively long segments of intact DNA, is not feasible in archival, paraffin-embedded, solid-tissue specimens in which the negative effects of chemical fixation result in DNA strand scission and breakdown of nucleic acid. A novel approach, specifically created for use with archival, fixative-treated tissue specimens, was developed for detection and characterization of common mutations of Gaucher disease. Three separate robust PCR reactions were formulated, 2 for selective amplification of portions of only the true gene exons 2 and 9, with a third reaction targeting exon 10, wherein both the true and pseudogene were coamplified. In the latter, DNA sequencing was used to determine the presence of true and pseudogene allele content in addition to identification of base sequence alterations. This method, requiring a single, 4-microm-thick histologic section, was successfully applied to archival paraffin block tissue specimens that had been in storage for up to 75 years. It was capable of accurately genotyping common Gaucher disease mutations as well as discovering a novel mutation and genetic polymorphism. We recommend our approach when only fixative-treated tis sue is available for molecular genotyping.