A new DOSXYZnrc method for Monte Carlo simulations of 4D dose distributions.

The purpose of this study is to present a novel method for generating Monte Carlo 4D dose distributions in a single DOSXYZnrc simulation. During a standard simulation, individual energy deposition events are summed up to generate a 3D dose distribution and their associated temporal information is discarded. This means that in order to determine dose distributions as a function of time, separate simulations would have to be run for each interval of interest. Consequently, it has not been clinically feasible until now to routinely perform Monte Carlo simulations of dose rate, time-resolved dose accumulation, or electronic portal imaging devices (EPID) cine-mode images for volumetric modulated arc therapy (VMAT) plans. To overcome this limitation, we modified DOSXYZnrc and defined new input and output variables that allow a time-like parameter associated with each particle history to be binned in a user-defined manner. Under the new code version, computation times are the same as for a standard simulation, and the time-integrated 4D dose is identical to the standard 3D dose. We present a comparison of scintillator measurements and Monte Carlo simulations for dose rate during a VMAT beam delivery, a study of dose rate in a VMAT total body irradiation plan, and simulations of transit (through-patient) EPID cine-mode images.

Undiagnosed Partial Ornithine Transcarbamylase Deficiency Presenting Postoperatively as Agitated Delirium.

Partial ornithine transcarbamylase deficiency (pOTCD), an enzymatic defect within the urea cycle, is an increasingly recognized etiology for hyperammonemia of unclear source following a stressor within female adults. Here we present a case of newly diagnosed pOTCD following a systemic stressor and prolonged hospitalization course. From a neurological perspective, prompt recognition provided the patient with a swift and near complete recovery. We briefly review the pertinent literature pertaining to this genetically based condition including historical context and current therapeutic approaches. Given the potential morbidity of prolonged hyperammonemia, neurohospitalists need to be aware of partial ornithine transcarbamylase as an entity.

Haemodialysis is an effective treatment in acute metabolic decompensation of maple syrup urine disease.

Acute metabolic decompensation in maple syrup urine disease can occur during intercurrent illness and is a medical emergency. A handful of reports in the medical literature describe the use of peritoneal dialysis and haemodialysis as therapeutic inventions. We report the only patient from our centre to have haemodialysis performed in this setting. Combined with dietary BCAA restriction and calorific support, haemodialysis allows rapid reduction in plasma leucine concentrations considerably faster than conservative methods.

Dose measurements for dental cone-beam CT: a comparison with MSCT and panoramic imaging.

To date there is a lack of published information on appropriate methods to determine patient doses from dental cone-beam computed tomography (CBCT) equipment. The goal of this study is to apply and extend the methods recommended in the American Association of Physicists in Medicine (AAPM) Report 111 for CBCT equipment to characterize dose and effective dose for a range of dental imaging equipment. A protocol derived from the one proposed by Dixon et al (2010 Technical Report 111, American Association of Physicist in Medicine, MD, USA), was applied to dose measurements of multi-slice CT, dental CBCT (small and large fields of view (FOV)) and a dental panoramic system. The computed tomography dose index protocol was also performed on the MSCT to compare both methods. The dose distributions in a cylindrical polymethyl methacrylate phantom were characterized using a thimble ionization chamber and Gafchromic™ film (beam profiles). Gafchromic™ films were used to measure the dose distribution in an anthropomorphic phantom. A method was proposed to extend dose estimates to planes superior and inferior to the central plane. The dose normalized to 100 mAs measured in the center of the phantom for the large FOV dental CBCT (11.4 mGy/100 mAs) is two times lower than that of MSCT (20.7 mGy/100 mAs) for the same FOV, but approximately 15 times higher than for a panoramic system (0.6 mGy/100 mAs). The effective dose per scan (in clinical conditions) found for the dental CBCT are 167.60 ± 3.62, 61.30 ± 3.88 and 92.86 ± 7.76 mSv for the Kodak 9000 (fixed scan length of 3.7 cm), and the iCAT Next Generation for 6 cm and 13 cm scan lengths respectively. The method to extend the dose estimates from the central slice to superior and inferior slices indicates a good agreement between theory and measurement. The Gafchromic™ films provided useful beam profile data and 2D distributions of dose in phantom.

Mutations in the Complex III Assembly Factor Tetratricopeptide 19 Gene TTC19 Are a Rare Cause of Leigh Syndrome.

We report a patient with Leigh syndrome shown to have two previously undescribed truncating mutations in the TTC19 gene. Our patient is a 4-year-old boy with global developmental delay, language regression at 13 months, and brain MRI showing T2 high-signal lesions involving the putamen, caudate body, and the brainstem, which appear to be progressing. Molecular testing showed our patient is heterozygous for two previously undescribed mutations in the TTC19 gene, c.577G>A (p.Trp186Stop) and c.964_967delGGCT (p.Gly322MetfsX8), both of which are predicted to cause loss of protein function due to either protein truncation or nonsense-mediated mRNA decay. TTC19 encodes tetratricopeptide 19 (TTC19) and is thought to be a complex III (CIII) assembly factor that is embedded on the inner mitochondrial membrane as part of two high-molecular-weight complexes, one of which coincides with CIII. The initial presentations of previously described patients with TTC19 mutations are heterogeneous and can be from childhood to adulthood. In summary, TTC19 mutations have been shown to affect CIII complex function, which results in a heterogeneous clinical phenotype including Leigh syndrome.

Successful implementation of a nurse-led teaching programme to independently administer subcutaneous methotrexate in the community setting to children with Crohn's disease.

BACKGROUND: Methotrexate is increasingly used as a third line immunosuppression agent in children with Crohn's disease (CD). Methotrexate is traditionally administered in the hospital setting. AIM: To set up a nurse-led education programme to teach children/their parents to administer subcutaneous methotrexate in the community. METHODS: All patients were given methotrexate over a 16-month period. Patient demographics including previous treatments were collected. A competency based teaching package was implemented by the inflammatory bowel disease nurse. Distances and travel times together with costings were calculated. RESULTS: Thirty two patients (19 male; 13 female) with a median treatment age of 11.96 years (IQR 10.67-13.92) were studied. Thirty of 32 (17 children, 13 parents) were independently administering methotrexate. The median return journey distance to hospital was 23 miles (IQR 14.4-42.4) taking a median time of 52 min (IQR 41.0-73.5) for each injection. The total patient travel saving was £10,537 (average £730 per patient) and nursing time saving was £12,808 with home administration (total saving £23,345). CONCLUSIONS: This paediatric study demonstrates that methotrexate injections can be given successfully in the majority (94%) of patients with CD independently in the community, resulting in significant time and money savings for patients and health professionals alike.

Effect of CCK receptor antagonists on the antinociceptive, reinforcing and gut motility properties of morphine.

1. The ability of a selective CCKA receptor antagonist PD 140548 and a selective CCKB receptor antagonist CI-988 (formerly PD 134308) to modulate the various in vivo properties of morphine was investigated in the rat. 2. PD 140548 dose-dependently (0.001-1.0 mg kg-1, i.p.) antagonised the development of conditioned place preference to morphine (2.0 mg kg-1, s.c.). In contrast, CI-988 (0.01-1.0 mg kg-1, i.p.) did not affect this morphine-induced behaviour. Neither of the CCK receptor antagonists blocked or generalised to the morphine (3.0 mg kg-1, i.p.) discriminative stimulus. 3. CI-988 (0.001-10.0 mg kg-1, s.c.) at doses of 0.05 and 0.1 mg kg-1 (s.c.), potentiated the antinociceptive action of a threshold dose of morphine (5.0 mg kg-1, i.p.) in a radiant heat model of acute nociception, the rat tail flick test. Furthermore, at 0.01 mg kg-1 it potentiated the antinociceptive action of morphine (3.0 mg kg-1) during the acute phase of the rat paw formalin test. And at doses of 0.01 and 0.1 mg kg-1 it also potentiated the antinociceptive action of morphine (1.0 mg kg-1) during the tonic phase of the formalin test. However, in both models, higher doses of CI-988 were ineffective. In contrast, PD 140548 (0.001-10 mg kg-1, s.c.) was only active at a dose of 1.0 mg kg-1 (s.c.) and only in the tonic phase of the formalin test. Neither CI-988 nor PD 140548 possessed any intrinsic antinociceptive action in either of the tests. Chronic treatment with CI-988 (0.01 mg kg-1, s.c.) prevented the development of tolerance to morphine antinociception (4 mg kg-1, s.c.) following a 6 day period of twice daily injections of morphine escalating from 1 to 16 mg kg-1 (i.p.). 4. Morphine dose-dependently (1-10 mg kg-1, s.c.) reduced the distance travelled by a charcoal meal in the rat intestine. Neither PD 140548 (0.01-1.0 mg kg-1, i.p.) nor CI-988 (0.01-1.0 mg kg-1, i.p.) potentiated or suppressed this inhibitory action of morphine. 5. In conclusion, the results of the present study indicate that CCKA and CCKB receptors modulate different properties of morphine. Thus, whilst a selective CCKA receptor antagonist blocked the rewarding properties of morphine, a selective CCKB receptor antagonist potentiated the antinociceptive action. However, neither compound displayed a potential for modulating the influence of morphine on gastro-intestinal motility. It is suggested that these findings may have important implications for development of CCK receptor antagonists as analgesic adjuncts to the therapeutic use of morphine.

Differential modulation of kappa and mu opioid antinociception by the glycine/NMDA receptor agonist D-serine.

D-Serine, a selective agonist for the strychnine-insensitive glycine allosteric site associated with the NMDA receptor-ion channel complex, was found to modulate differentially the antinociception produced by kappa and mu-opioid receptor agonists in the rat formalin test. D-Serine (100 micrograms, i.c.v.) attenuated the antinociception produced by the selective kappa-opioid agonist, enadoline (0.003-0.1 mg kg-1, s.c.) against the tonic, but not acute, phase of the formalin response. Conversely, D-serine potentiated the antinociception produced by morphine (0.3-10 mg kg-1, s.c.) against both the acute and tonic phases. These results demonstrate an important interaction between the opioid and NMDA/glycine systems in the control of nociceptive information possibly at different levels of the neuraxis.