Evaluation of monte carlo to support commissioning of the treatment planning system of new pencil beam scanning proton therapy facilities.

Objective. To demonstrate the potential of Monte Carlo (MC) to support the resource-intensive measurements that comprise the commissioning of the treatment planning system (TPS) of new proton therapy facilities.Approach. Beam models of a pencil beam scanning system (Varian ProBeam) were developed in GATE (v8.2), Eclipse proton convolution superposition algorithm (v16.1, Varian Medical Systems) and RayStation MC (v12.0.100.0, RaySearch Laboratories), using the beam commissioning data. All models were first benchmarked against the same commissioning data and validated on seven spread-out Bragg peak (SOBP) plans. Then, we explored the use of MC to optimise dose calculation parameters, fully understand the performance and limitations of TPS in homogeneous fields and support the development of patient-specific quality assurance (PSQA) processes. We compared the dose calculations of the TPSs against measurements (DDTPSvs.Meas.) or GATE (DDTPSvs.GATE) for an extensive set of plans of varying complexity. This included homogeneous plans with varying field-size, range, width, and range-shifters (RSs) (n= 46) and PSQA plans for different anatomical sites (n= 11).Main results. The three beam models showed good agreement against the commissioning data, and dose differences of 3.5% and 5% were found for SOBP plans without and with RSs, respectively. DDTPSvs.Meas.and DDTPSvs.GATEwere correlated in most scenarios. In homogeneous fields the Pearson's correlation coefficient was 0.92 and 0.68 for Eclipse and RayStation, respectively. The standard deviation of the differences between GATE and measurements (±0.5% for homogeneous and ±0.8% for PSQA plans) was applied as tolerance when comparing TPSs with GATE. 72% and 60% of the plans were within the GATE predicted dose difference for both TPSs, for homogeneous and PSQA cases, respectively.Significance. Developing and validating a MC beam model early on into the commissioning of new proton therapy facilities can support the validation of the TPS and facilitate comprehensive investigation of its capabilities and limitations.

[Pigmented villonodular synovitis]. / La synovite villonodulaire.

Pigmented villonodular synovitis (PVNS), also known as tenosynovial giant cell tumour is an articular pathology that occurs predominantly in young adults and is caused by an abnormal proliferation of the synovial membrane. The clinical presentation includes pain and joint swelling. MRI represents the best imaging modality to investigate this disease but the histopathology of synovial tissue provides the definitive diagnosis. The management of PVNS is often difficult due to the high risk of relapse after treatment. The objective of this article is to review the literature regarding the diagnosis and therapy of this poorly understood condition.

A review of smoking cessation services in women attending colposcopy clinics in Scotland.

The most common reason for women being referred to colposcopy clinics is an abnormal smear suggesting pre-cancerous change within the cervix. It has been demonstrated that in women with low-grade lesions, smoking cessation led to a reduction in size of the cervical lesion over a 6-month period. Smoking is also recognised as an independent risk factor for treatment failure of cervical intraepithelial neoplasia. As 'stop smoking' services have become an integral part of the colposcopy clinic at St John's Hospital, Livingston, a national survey was undertaken. The aim of the survey was to establish what smoking cessation information, advice and support is available in colposcopy clinics throughout Scotland, and if staff had attended standardised training on raising the issue of smoking. The study demonstrated that 52% of colposcopy clinics in Scotland always establish smoking status but only 37% of clinics discuss the benefits of smoking cessation in relation to abnormal cervical smears. There was inaccurate and inconsistent written and verbal advice given on the benefits of cessation and whether women should cut down or stop smoking completely. The majority of staff had not attended standardised training on how to raise the issue of smoking and very few clinics have established referral pathways for smoking cessation support.

Intra-uterine death resulting from placental metastases in adenocarcinoma of unknown primary.

A thirty-five year old woman presented with bilateral neck, chest wall and back masses. She was 16 weeks pregnant. Lymph node excision revealed metastatic poorly differentiated adenocarcinoma of unknown primary. Abdominal ultrasound showed a mildly enlarged spleen and a 2-3 cm porta hepatis node. All other investigations were negative. The lymph node and cutaneous metastases progressed rapidly so it was decided to initiate systemic chemotherapy with a view to delivery at 28 weeks gestation by Caesarean section. Shortly after the second 3-weekly cycle of cisplatinum chemotherapy the patient suffered severe lower back and hip pain with MRI scan showing multiple bony metastases in the pelvic girdle. Ultrasound revealed the fetus to have been dead for at least 10 days. The products of conception were delivered following medical induction of labour. Two days later the patient suffered a cardiac arrest from which she could not be resuscitated. Placental histology revealed extensive metastases. With the exception of melanoma this has rarely been reported in solid adult malignancy. As a cause of fetal death, placental metastases are extremely rare.

Prevalence of Chlamydia trachomatis infection in small rural town family planning clinics in the central belt of Scotland.

OBJECTIVE: To estimate the prevalence of chlamydia infection in women under 25 attending community-based family planning/sexual health clinics in West Lothian. DESIGN: Two hundred and three women under 25 attending over a six month period were offered a urine test for chlamydia trachomatis. The tests were performed using the ligase chain reaction method. RESULTS: The overall prevalence of infection was 5%. The rate in women under 20 (100 women) was 10% and in the group aged between 20 and 25 (also 100 women) was 3%. CONCLUSION: The prevalence of chlamydia infection in women under 20 years from West Lothian was high. There is no genito urinary medicine (GUM) service in West Lothian. Providing this service should help to improve awareness, detection and management of this common sexually transmitted disease.

Two brothers with varying combinations of severe developmental delay, epilepsy, microcephaly, tetralogy of Fallot and hydronephrosis.

We report on a sib pair who manifest a pattern of anomalies which appears to be unique and for which we are unable to provide a cytogenetic or molecular genetic explanation. While a number of their physical features are distinct, their overall appearance and pattern of neurological impairment suggest they suffer from the same genetic disorder.

Gene-directed enzyme prodrug therapy: quantitative bystander cytotoxicity and DNA damage induced by CB1954 in cells expressing bacterial nitroreductase.

Clones of human colon carcinoma (WiDr), ovarian carcinoma (SK-OV-3), and Chinese hamster V79 cells expressing the nitroreductase enzyme (NR) from E. coli B were 52-, 225- and 177-fold respectively more sensitive to a 24-h incubation with the prodrug 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954) than the parent lines. The IC50s of non-NR-expressing bystander cells were measured in the presence of differing proportions of NR-expressing cells. The shift in IC50 was used to calculate a value for the bystander effect, termed the transmission efficiency (TE), which is the decrease in IC50 due to bystander effect as a percentage of the maximum decrease possible. The percentage of NR-expressing cells for which the TE was 50%, (the TE50) is a single datum of bystander efficacy. WiDr and V79 cell lines, had a similar TE50 of approximately 2%. SK-OV-3 gave a lower value of 0.3%. These TE50 correlate with concentrations of cytosolic NR activity, which is distinguished from endogenous DT diaphorase activity by kinetic differences. A novel method is described which enables both DNA crosslinks and drug-induced single-strand breaks to be simultaneously quantified in a sedimentation assay. Using this technique, bystander DNA damage was demonstrated in V79 cells, of approximately 50% of that in activator cells.

Inhibition of influenza virus transcription by 2'-deoxy-2'-fluoroguanosine.

The nucleoside analog 2'-deoxy-2'-fluoroguanosine (2'-fluorodGuo) is phosphorylated by cellular enzymes and reversibly inhibits influenza virus replication in chick embryo cells within the first 4 h of infection. RNA hybridization studies revealed that primary and secondary transcription of influenza virus RNA were blocked at a compound concentration of 10 microM, but no inhibition of cell protein synthesis was seen even at high compound concentrations (200 microM). In vitro, the triphosphate of 2'-fluorodGuo is a competitive inhibitor of influenza virus transcriptase activity from disrupted virus, with a Ki of 1.0 microM. The cellular polymerases DNA polymerase alpha and RNA polymerase II were only weakly inhibited or were insusceptible to 2'-fluorodGTP. In kinetic studies with the influenza virus transcriptase, 2'-fluorodGTP, in the absence of GTP, blocked elongation of the virus RNA chain. Similarly, by using purified ribonucleoprotein complexes it was found that the addition of a single nucleotide of 2'-fluorodGTP to the virus RNA caused chain termination, which resulted in the blockage of further virus transcription. Furthermore, the specificity for influenza virus transcriptase was confirmed when the transcriptase from partially resistant virus was found to be 10-fold less susceptible to 2'-fluorodGTP (Ki = 13.1 microM).

Circulating lipids and glycaemic control in insulin dependent diabetic children.

The prevalence of dyslipidaemia in children with insulin dependent diabetes mellitus (IDDM) and its relation to glycaemic control was studied in a group of 51 diabetic children and a control population of 132 schoolchildren. The prevalence of dyslipidaemia in the fasting state was increased in the diabetic group (39%) compared with control subjects (17%). Serum cholesterol concentration alone was raised in 25% of diabetic subjects while serum cholesterol and triglycerides were raised in 14%, compared with 16% and 0.7% respectively in control subjects. Serum total cholesterol (5.1 v 4.5 mmol/l), low density lipoprotein cholesterol (3.2 v 2.6 mmol/l), non-esterified fatty acids (0.91 v 0.50 mmol/l), and triglycerides (0.94 v 0.76 mmol/l) were higher in diabetic children. Serum total cholesterol, triglycerides, and apolipoprotein (apo)B concentrations increased with worsening control, while serum high density lipoprotein cholesterol and apoA-I concentrations were unaltered. There were also positive correlations between glycated haemoglobin and total cholesterol, triglycerides, and apoB in diabetic children. Thus, abnormalities in circulating lipids are common in young subjects with IDDM but largely disappear if blood glucose concentrations are reasonably controlled.

Isolation of the ERG2 gene, encoding sterol delta 8-->delta 7 isomerase, from the rice blast fungus Magnaporthe grisea and its expression in the maize smut pathogen Ustilago maydis.

The Magnaporthe grisea ERG2 gene, encoding delta 8-->delta 7 sterol isomerase, was isolated from a genomic library by heterologous hybridization to a fragment of the Ustilago maydis ERG2 gene. The isolated gene contained a reading frame of 745 bp which encoded a protein of 221 amino acids. The coding region was interrupted by a single putative 79-bp-long intron. The deduced amino-acid sequence exhibited similarity to the ERG2 gene products of U. maydis and of Saccharomyces cerevisiae, particularly in the central region of the proteins. The NH2-terminal of all three proteins contained a long stretch of amino acids that were strongly hydrophobic, suggesting that they may function by anchoring the protein to a membrane surface. The M. grisea ERG2 gene complemented a U. maydis deletion mutant in which the ERG2 gene had been removed using a one-step gene replacement procedure. The delta 8-->delta 7 sterol isomerase produced by the M. grisea ERG2 gene exhibited a level of sensitivity to the sterol biosynthesis inhibitor, tridemorph, similar to that of the enzyme derived from the U. maydis ERG2 gene.

Lipid levels in schoolchildren in north east England: effects of feeding and age.

Serum total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein (apo) A-I and apoB concentrations were estimated and low-density lipoprotein (LDL) cholesterol levels were calculated in 132 children aged 11.4-17.3 years. The effect of feeding was investigated by estimating postprandial values and also by studying the effects of a test meal. The distribution of all data was consistent with Gaussian apart from triglycerides which was log normal. Overall fasting values were [mean (standard deviation; SD)] cholesterol 4.5 (0.8) mmol/L, HDL cholesterol 1.5 (0.4) mmol/L, LDL cholesterol 2.6 (0.8) mmol/L, apoA-I 1.5 (0.3) g/L, apoB 1.0 (0.4) g/L and triglycerides 0.76 (0.38-1.51) mmol/L, the values for triglycerides being mean (95% confidence intervals). Girls had higher triglycerides than boys [0.82 (0.43-1.54) versus 0.70 (0.36-1.33)] and different effects of age on lipids were found, HDL cholesterol being negatively correlated with age in boys (r = -0.37; P < 0.001), but not in girls, and apoA-I being negatively correlated with age in boys (r = -0.31; P = 0.006), but positively correlated with age in girls (r = 0.32; P = 0.008). Triglycerides rose and HDL cholesterol fell following feeding and inconsistent effects were seen on apoA-I and apoB.

Rapid purification and characterisation of HIV-1 reverse transcriptase and RNaseH engineered to incorporate a C-terminal tripeptide alpha-tubulin epitope.

The C-termini of p66 and p51 forms of HIV-1 reverse transcriptase have been engineered to contain a Glu-Glu-Phe sequence recognized by a monoclonal antibody to alpha-tubulin, YL1/2. Mutated RTs were purified in a single step using peptide elution from columns of immobilized YL1/2. The known sequence requirements of the YL1/2 epitope are consistent with protein eluting from the column with an intact C-terminus. Kinetic parameters of these mutated RTs are essentially unchanged from wild-type enzyme. The p15 RNaseH domain has been purified using this method and shown to have low enzyme activity compared to the parental p66 subunit.

Haemophilus influenzae infections in siblings: the need for prophylaxis.

An 8 month old child developed Haemophilus influenzae meningitis 12 days after his elder brother had developed epiglottitis. There is not at present in the United Kingdom a recognised policy for prophylactic treatment of contacts of patients with H influenzae infection. Variations in clinical practice were confirmed by the result of a survey of paediatricians in the Northern region.

Do education groups help diabetics and their parents?

The importance of education in the management of diabetes is recognised but has rarely been assessed in children. In a longitudinal controlled study we have examined the effect of a programme of education on the knowledge, diet, and concentration of glycated haemoglobin A1c in a group of diabetics. The programme took the form of two packages of education each consisting of four weekly meetings, in which small groups of parents and older children were led in a discussion of different aspects of diabetes. Only one of the 119 families who began the study failed to complete it. Family knowledge about diabetes improved as a result of the programme, although this was poorly retained in the fathers. A trend to improvement in several aspects of diet was noted but did not reach significance. A significant fall in glycated haemoglobin A1c was apparent seven months after the education in children aged 11 years and over. Those whose initial control was poor improved most. We conclude that such meetings should be considered as a useful adjunct to regular diabetic clinics.