Radiobiological impact of dose calculation algorithms on biologically optimized IMRT lung stereotactic body radiation therapy plans.

BACKGROUND: The aim of this study is to evaluate the radiobiological impact of Acuros XB (AXB) vs. Anisotropic Analytic Algorithm (AAA) dose calculation algorithms in combined dose-volume and biological optimized IMRT plans of SBRT treatments for non-small-cell lung cancer (NSCLC) patients. METHODS: Twenty eight patients with NSCLC previously treated SBRT were re-planned using Varian Eclipse (V11) with combined dose-volume and biological optimization IMRT sliding window technique. The total dose prescribed to the PTV was 60 Gy with 12 Gy per fraction. The plans were initially optimized using AAA algorithm, and then were recomputed using AXB using the same MUs and MLC files to compare with the dose distribution of the original plans and assess the radiobiological as well as dosimetric impact of the two different dose algorithms. The Poisson Linear-Quadatric (PLQ) and Lyman-Kutcher-Burman (LKB) models were used for estimating the tumor control probability (TCP) and normal tissue complication probability (NTCP), respectively. The influence of the model parameter uncertainties on the TCP differences and the NTCP differences between AAA and AXB plans were studied by applying different sets of published model parameters. Patients were grouped into peripheral and centrally-located tumors to evaluate the impact of tumor location. RESULTS: PTV dose was lower in the re-calculated AXB plans, as compared to AAA plans. The median differences of PTV(D95%) were 1.7 Gy (range: 0.3, 6.5 Gy) and 1.0 Gy (range: 0.6, 4.4 Gy) for peripheral tumors and centrally-located tumors, respectively. The median differences of PTV(mean) were 0.4 Gy (range: 0.0, 1.9 Gy) and 0.9 Gy (range: 0.0, 4.3 Gy) for peripheral tumors and centrally-located tumors, respectively. TCP was also found lower in AXB-recalculated plans compared with the AAA plans. The median (range) of the TCP differences for 30 month local control were 1.6 % (0.3 %, 5.8 %) for peripheral tumors and 1.3 % (0.5 %, 3.4 %) for centrally located tumors. The lower TCP is associated with the lower PTV coverage in AXB-recalculated plans. No obvious trend was observed between the calculation-resulted TCP differences and tumor size or location. AAA and AXB yield very similar NTCP on lung pneumonitis according to the LKB model estimation in the present study. CONCLUSION: AAA apparently overestimates the PTV dose; the magnitude of resulting difference in calculated TCP was up to 5.8 % in our study. AAA and AXB yield very similar NTCP on lung pneumonitis based on the LKB model parameter sets we used in the present study.

Addressing key issues in the consanguinity-related risk of autosomal recessive disorders in consanguineous communities: lessons from a qualitative study of British Pakistanis.

Currently, there is no consensus regarding services required to help families with consanguineous marriages manage their increased genetic reproductive risk. Genetic services for communities with a preference for consanguineous marriage in the UK remain patchy, often poor. Receiving two disparate explanations of the cause of recessive disorders (cousin marriage and recessive inheritance) leads to confusion among families. Further, the realisation that couples in non-consanguineous relationships have affected children leads to mistrust of professional advice. British Pakistani families at-risk for recessive disorders lack an understanding of recessive disorders and their inheritance. Such an understanding is empowering and can be shared within the extended family to enable informed choice. In a three-site qualitative study of British Pakistanis, we explored family and health professional perspectives on recessively inherited conditions. Our findings suggest, firstly, that family networks hold strong potential for cascading genetic information, making the adoption of a family-centred approach an efficient strategy for this community. However, this is dependent on provision of high-quality and timely information from health care providers. Secondly, families' experience was of ill-coordinated and time-starved services, with few having access to specialist provision from Regional Genetics Services; these perspectives were consistent with health professionals' views of services. Thirdly, we confirm previous findings that genetic information is difficult to communicate and comprehend, further complicated by the need to communicate the relationship between cousin marriage and recessive disorders. A communication tool we developed and piloted is described and offered as a useful resource for communicating complex genetic information.

Dosimetric Comparison of Craniospinal Irradiation Using Different Tomotherapy Techniques.

The objective of this study is to compare the new and conventional tomotherapy treatment techniques and to evaluate dosimetric differences between them. A dosimetric analysis was performed by comparing planning target volume (PTV) median dose, 95% of PTV dose coverage, Paddick conformity index (CI), homogeneity index (HI), whole-body integral dose, and OAR median doses. The beam on time (BOT) and the effect of different jaw sizes and pitch values was studied. The study results indicated that the PTV dose coverage for all the techniques was comparable. Treatment plans using dynamic jaw reduced OAR doses to structures located at the treatment field edge compared to fixed jaw plans. The HT-3DCRT plans resulted in higher OAR doses to kidney, liver, and lung compared to the other techniques, and TD-IMRT provided the best dose sparing to liver compared to other techniques. Whole-body integral dose differences were found to be insignificant among the techniques. BOT was found to be higher for fixed jaw treatment plan compared to dynamic jaw plan and comparable between all treatment techniques with 5-cm dynamic jaw. In studying effect of jaw size, better OAR sparing and HI were found for 2.5-cm jaw but at the expense of doubling of BOT as compared to 5-cm jaw. There was no significant improvement found in OAR sparing when the pitch value was increased. Increasing the pitch from 0.2 to 0.43, the CI was improved, HI improved only for 5-cm jaw size, and BOT decreased to approximately half of its original time.

Examining the family-centred approach to genetic testing and counselling among UK Pakistanis: a community perspective.

WHO advice suggests a family-centred approach for managing the elevated risk of recessively inherited disorders in consanguineous communities, whilst emerging policy recommends community engagement as an integral component of genetic service development. This paper explores the feasibility of the family-centred approach in the UK Pakistani origin community. The study took place within a context of debate in the media, professional and lay circles about cousin marriage causing disability in children. Using qualitative methods, a total of six single-sex focus group discussions (n = 50) were conducted in three UK cities with a high settlement of people of Pakistani origin. Tape-recorded transcripts were analysed using framework analysis. Kinship networks within Pakistani origin communities are being sustained and marriage between close blood relatives continues to take place alongside other marriage options. Study participants were critical of what was perceived as a prevalent notion that cousin marriage causes disability in children. They were willing to discuss cousin marriage and disability, share genetic information and engage with genetic issues. A desire for accurate information and a public informed about genetic issues was articulated whilst ineffective communication of genetic risk information undermined professionals in their support role. This study suggests a community that is embracing change, one in which kinship networks are still active and genetic information exchange is taking place. At the community level, these are conditions supportive of the family-centred approach to genetic testing and counselling.

SU-E-T-439: First Experience of Three Dimensional Conformai Radiotherapy (3DCRT) Planning with Helical Tomotherapy.

PURPOSE: A three-dimensional conformal radiotherapy (3DCRT) has been recently introduced to helical tomotherapy, allowing the user to plan and treat patients that do not require sophisticated IMRT planning and delivery. This study aims to test treatment planning on this modality and evaluate its performance by comparing to conventional LINAC-based 3DCRT planning. METHODS: Four clinical cases (whole brain, extremity, lung, and partial breast irradiation) were retrospectively selected from a Pinnacle planning system (Philips Medical System, Fitchburg, WI) and planned on Tomotherapy (Accuray Inc., Sunnyvale, CA). Computed tomography (CT) images together with contours of target and critical structures were exported from Pinnacle to the Tomotherapy planning station. The same prescription and fractionation scheme was adopted. The pitch factor for all clinical cases was set to 0.287. A 2.5 cm jaw was employed except in the lung case the field size was set to 1.0 cm for better dose conformity. The dose grid size was chosen to be half of that of the planning CT images. On Pinnacle 100% prescription dose was delivered to the treatment isocenter while onTomotherapy it was stipulated that at least 95% of the target volume received the prescribed dose. Comparison between two planning strategies was performed, in terms of dose volume histograms (DVH), dosimetric and radiobiological parameters, for plan quality assessment. RESULTS: Comparison of DVHs reveals that up to 25% healthy tissue sparing in volume can be accomplished with Tomotherapy 3DCRT while the same target coverage is ensured. Dosimetric and radiobiological indices between Tomotherapy and Pinnacle planning agree to within 3.0%. Additional beam modifiers and non-coplanar beams associated with LINAC-based 3DCRT are not needed on Tomotherapy, making it more favorable. CONCLUSIONS: Tomotherapy 3DCRT has similar dosimetric performance when compared to conventional LINAC-based 3DCRT while it is substantially easier to use.

SU-D-217BCD-03: Impact of Jaw Width on the Megavoltage Computed Tomography Image Quality and Imaging Dose with Helical Tomotherapy.

PURPOSE: On-treatment megavoltage computed tomography on Helical Tomotherapy (Accuray Inc., Sunnyvale, CA) is critical for image guided radiotherapy. A strategy was developed to assess the impact of various jaw widths on image quality and imaging dose with Tomotherapy. METHODS: A cheese phantom (Gammex RMI, Middleton, WI) made of water equivalent materials was employed in this study. Three sets of measurements were independently carried out. Firstly, in the imaging dose measurement, the phantom was placed on the couch and aligned with a stationary green laser and beam isocenter. The measurement point was 10 mm up from the cente of the phantom. Three slices on either side of the middle slice were selected. Secondly, two inserts with different rows of holes of various sizes were placed inside the phantom for image contrast and resolution investigation. Lastly, twelve density inserts were placed into the outer holes in the phantom for measurement of the image value to density table (IVDT). A comparison of imaging dose, image resolution and contrast, IVDT table between different jaw configurations was performed to evaluate the imaging system. RESULTS: Imaging dose was 2.93 cGy with a jaw size of one mm as opposed to 1.62 cGy with a four mm jaw, both of which are below the vendor's requirement: 3 cGy. However, image quality is improved significantly with the smaller jaw. Four lines of holes can be readily identified on images using smaller jaw while only three lines visible with the larger jaw. Image contrast is similarly enhanced when reducing the jaw size. On average CT numbers are 6% higher with the smaller jaw than those obtained with the larger one. CONCLUSIONS: Significant improvement in image quality is achieved with the smaller jaw field in Tomotherapy while the imaging dose is kept at a clinically acceptable level.

SU-E-J-182: Patient Specific Assessment of External Radiation Exposure to Bystanders Interacting with Patients Following 131I Therapy.

PURPOSE: Conventional calculation methods of patient release criteria for compliance with NRC regulations are based on the assumption that both patient and bystander are each a single point in space. This study was intended to assess the patient-specific external radiation exposure to a bystander interacting with the patient following radionuclide therapy with 131I. METHODS: 131I-sodium iodide treatment for hyperthyroidism and thyroid cancer and 131I-tositumomab treatment of non-Hodgkin's lymphoma were considered. 131I distribution provided by the patient SPECT image was rendered on the SPECT-fused CT images. The CT images were then imported to a Monte Carlo based simulation code, MCNPX 2.7, as a source phantom. For a target phantom, we employed the adult male hybrid phantom developed at the University of Florida and National Cancer Institute. A single orientation - patient and a bystander facing one another at 1.0 m - was considered. S factors (dose per unit cumulative activity (A)) for each organ in a bystander was obtained from the MC calculations and effective dose (EDE) per A was calculated based on tissue-weighted individual organ doses. The results were compared with the calculations using UF/NCI adult hybrid source/target phantoms and the revised adult ORNL stylized source/target phantoms. RESULTS: EDE per A of the stylized phantom was 1.5% higher than that of the hybrid phantom for uniform source localization in the thyroid. However, EDE per A of the hybrid phantom was 20% less than that of stylized phantoms for a torso source. The difference is attributed to the realistic shape of the frontal body comparing to the simple ellipsoidal trunk of the stylized phantom. CONCLUSIONS: Based on the realistic hybrid phantoms and accurate MC radiation transport calculation tools, patient specific dosimetry for a bystander is feasible. S factors will be calculated using the patient CT image with 131I bio-distributions and hybrid phantoms.

Clinical feasibility of TBI with helical tomotherapy.

Our purpose was to present the clinical feasibility of TBI with helical tomotherapy (HT) in four patients with AML. Treatment planning, delivery, dose verification and summation, toxicity and patient outcomes for each patient are presented. TBI prescription was set in such a manner that 80% of the clinical target volume received 12 Gy in six fractions, at two fractions per day. Dose reconstruction was carried out by recontouring the regions of interest in the daily pretreatment megavoltage computed tomography of each individual fraction and calculating its corresponding dose. A deformable registration model was used for dose summation of all individual fractions. Differences between planned and delivered doses were calculated. Average planned and delivered doses to the regions of interest differed by up to 2.7%. TBI toxicity was limited to radiotherapy oncology group grade 1 dermatitis in all patients and grade 1 headache in one patient. Two patients are alive with no evidence of disease and no GVHD. Two patients died of GVHD, but there was no evidence of disease at the time of death. We conclude that HT simplifies the process of TBI. Dose verification is possible with HT showing small differences between plan and delivered doses.

Modeling of carbon fiber couch attenuation properties with a commercial treatment planning system.

The purpose of this work is to evaluate the modeling of carbon fiber couch attenuation properties with a commercial treatment planning system (TPS, Pinnacle3, v8.0d). A carbon fiber couch (Brain-Lab) was incorporated into the TPS by automatic contouring of all transverse CT slices. The couch shape and dimensions were set according to the vendor specifications. The couch composition was realized by assigning appropriate densities to the delineated contours. The couch modeling by the TPS was validated by absolute dosimetric measurements. A phantom consisting of several solid water slabs was CT scanned, the CT data set was imported into the TPS, and the carbon fiber couch was auto-contoured. Open (unblocked) field plans for different gantry angles and field sizes were generated. The doses to a point at 3 cm depth, placed at the linac isocenter, were computed. The phantom was irradiated according to the dose calculation setup and doses were measured with an ion chamber. In addition, percent depth dose (PDD) curves were computed as well as measured with radiographic film. The calculated and measured doses, transmissions, and PDDs were cross-compared. Doses for several posterior fields (0 degree, 30 degrees, 50 degrees, 75 degrees, 83 degrees) were calculated for 6 and 18 MV photon beams. For model validation a nominal field size of 10 x 10 cm2 was chosen and 100 MU were delivered for each portal. The largest difference between computed and measured doses for those posterior fields was within 1.7%. A comparison between computed and measured transmissions for the aforementioned fields was performed and the results were found to agree within 1.1%. The differences between computed and measured doses for different field sizes, ranging from 5 x 5 cm2 to 25 x 25 cm2 in 5 cm increments, were within 2%. Measured and computed PDD curves with and without the couch agree from the surface up to 30 cm depth. The PDDs indicate a surface dose increase resulting from the carbon fiber couch field modification. The carbon fiber couch attenuation for individual posterior oblique fields (75 degrees) can be in excess of 8% depending on the beam energy and field size. When the couch is contoured in Pinnacle3 its attenuation properties are modeled to within 1.7% with respect to measurements. These results demonstrate that appropriate contouring together with relevant density information for the contours is sufficient for adequate modeling of carbon fiber supporting devices by modern commercial treatment planning systems.

A novel HEXB mutation and its structural effects in juvenile Sandhoff disease.

Mutations in HEXB, encoding the beta-subunit common to hexosaminidases A and B, cause the neurodegenerative condition, Sandhoff disease. A homozygous missense HEXB mutation (p. D459A) was discovered in six patients with a rare juvenile variant: we show that this disrupts a salt bridge between aspartate D459 and arginine 505 at the subunit interface; R505 mutations are reported in late-onset Sandhoff disease. Identification of D459A contributes to diagnosis and molecular understanding of attenuated Sandhoff disease variants.

The effect of gel lubrication on cuff leakage of double lumen tubes during thoracic surgery.

High-volume, low-pressure tracheal cuffs of disposable double lumen tubes may offer limited protection to the dependent lung if fluid leaks through folds in the inflated cuffs. This study was undertaken to determine the incidence of fluid leakage past the tracheal cuff and whether gel lubrication reduces the incidence. Fifty-five patients were randomly assigned to receive a double lumen tube with or without gel lubrication. The dependent lung was intubated. With the patient in the lateral position, methylthionium chloride was administered above the tracheal cuff via a pre-attached catheter. Fibreoptic bronchoscopy was performed to determine if dye had passed the tracheal cuff. Three patients were excluded. Dye leakage was seen in 12/27 and 3/25 patients in the unlubricated and lubricated group, respectively (p = 0.014). Gel lubrication significantly reduces fluid leakage past the tracheal cuff of a double lumen tube and should be considered for all thoracic surgical patients requiring one-lung ventilation.

Juvenile Sandhoff disease--nine new cases and a review of the literature.

Juvenile Sandhoff disease (McKusick 268800) is a rare lysosomal storage disorder with only 12 cases recorded in the literature. This condition is also referred to as the subacute form of hexosaminidase deficiency. We describe 9 new cases of Pakistani origin and compare these with the other published cases. Ataxia and speech abnormalities were the commonest presentation. Constipation and urinary incontinence were frequent and may be due to autonomic neuropathy. Cherry-red spot was not noted in any of our cases. Increased lower limb reflexes were the commonest physical finding. Significant delay in diagnosis may be due to the nonspecific presentation of this condition. Diagnosis was on the basis of hexosaminidase deficiency. Residual enzyme activity did not correlate with the clinical picture. Emerging therapies make early diagnosis of this disorder important.

Probable dystonic reaction after a single dose of cyclizine in a patient with a history of encephalitis.

A patient underwent an emergency Caesarean section under general anaesthesia for an antepartum haemorrhage. Following delivery of a live infant, cyclizine was administered in accordance with departmental anti-emetic protocol. On awakening she was confused, slow to articulate and had slurred speech. A computed tomography (CT) scan, which was performed to exclude an intracranial event, was normal. Her symptoms were suggestive of a lingual-facial-buccal dyskinesia as seen with dopamine antagonists. A presumptive diagnosis of a dystonic reaction to cyclizine was made. She received two doses of procyclidine before her symptoms completely resolved. Cyclizine has had a resurgence in popularity owing to the recent withdrawal of droperidol and anaesthetists should be aware that, although extremely rare, dystonic reactions may occur with this agent.

Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation.

BACKGROUND AND OBJECTIVES: Locus heterogeneity is well established in autosomal recessive primary microcephaly (MCPH) and to date five loci have been mapped. However, the relative contributions of these loci have not been assessed and genotype-phenotype correlations have not been investigated. DESIGN: A study population of 56 consanguineous families resident in or originating from northern Pakistan was ascertained and assessed by the authors. A panel of microsatellite markers spanning each of the MCPH loci was designed, against which the families were genotyped. RESULTS: The head circumference of the 131 affected subjects ranged from 4 to 14 SD below the mean, but there was little intrafamilial variation among affecteds (+/- 1 SD). MCPH5 was the most prevalent, with 24/56 families consistent with linkage; 2/56 families were compatible with linkage to MCPH1, 10/56 to MCPH2, 2/56 to MCPH3, none to MCPH4, and 18/56 did not segregate with any of the loci. CONCLUSIONS: MCPH5 is the most common locus in this population. On clinical grounds alone, the phenotype of families linked to each MCPH locus could not be distinguished. We have also shown that further MCPH loci await discovery with a number of families as yet unlinked.

Intellectual disability and cerebral palsy in a UK community.

OBJECTIVE: The northern English city of Bradford has a population of 370,000. In recent years the Pakistani community has gradually expanded in number, and in 2001 contributed 41.4% of births in the city. There is a very high level of consanguineous marriage in this community, and the main aim of this study was to assess the influence of community endogamy and consanguinity on major disabling childhood diseases. SUBJECTS AND METHODS: More than 300 children are referred to the Child Development Centre each year. Data on neurodegenerative disorders, microcephaly and cerebral palsy were collated and analysed by community of origin and mode of inheritance. RESULTS AND CONCLUSIONS: There was a striking variation in the prevalence of many disabling conditions, but in all cases the Pakistani community was over-represented, suggesting a high prevalence of inherited disease. The large numbers of affected children present a challenge, and adequate resources are needed to improve the delivery of counselling, treatment and care to the community. As child health in Pakistan improves, our experience with the UK Pakistani community suggests that the genetic causes of disability and disease in childhood will assume greater importance.

Compound heterozygosity and nonsense mutations in the alpha(1)-subunit of the inhibitory glycine receptor in hyperekplexia.

The alpha(1)-inhibitory glycine receptor is a ligand-gated chloride channel composed of three ligand-binding alpha1-subunits and two structural beta-subunits that are clustered on the postsynaptic membrane of inhibitory glycinergic neurons. Dominant and recessive mutations in GLRA1 subunits have been associated with a proportion of individuals and families with startle disease or hyperekplexia (MIM: 149400). Following SSCP and bi-directional di-deoxy fingerprinting mutational analysis of 22 unrelated individuals with hyperekplexia and hyperekplexia-related conditions, we report further novel missense mutations and the first nonsense point mutations in GLRA1, the majority of which localise outside the regions previously associated with dominant, disease-segregating mutations. Population studies reveal the unique association of each mutation with disease, and reveals that a proportion of sporadic hyperekplexia is accounted for by the homozygous inheritance of recessive GLRA1 mutations or as part of a compound heterozygote.

Replicating adenoviral vector-mediated transfer of a heat-inducible double suicide gene for gene therapy.

Tumor cells that express a fusion gene of Escherichia coli cytosine deaminase (CD) and herpes simplex virus type 1 thymidine kinase (TK) sequences activate and are subsequently killed by the nontoxic prodrugs 5-fluorocytosine and ganciclovir. We have previously developed a recombinant adenovirus containing the CD-TK fusion gene controlled by the human inducible heat shock protein 70 promoter so that heat at 41 degrees C for 1 hour induces therapeutic gene expression. This adenovirus effectively transduces heat-inducible expression of the CD-TK gene into human prostate carcinoma cells. However, because a limited number of cells in a tumor can actually be infected, we created a replicating adenoviral vector to increase CD-TK gene expression. This vector is a replication-competent, E1B-attenuated adenoviral vector containing the hsp70 promoter-driven CD-TK gene (Ad.E1A(+)HS-CDTK). When human prostate adenocarcinoma DU-145 cells (mutant p53) were infected with the virus at a multiplicity of infection (MOI) of 1 or 10, the viral replication was detected within 2 days at both MOIs. Similar results were observed in human colorectal carcinoma CX-1 cells. When DU-145 cells were infected with the virus at an MOI of 10, incubated for 24 hours, heated at 41 degrees C for 4 hours, and then harvested 20 hours later, Western blot analysis demonstrated that this virus successfully produced viral E1A proteins and heat shock stimulated the CD-TK gene expression by 12.3-fold. In addition, Ad.E1A(+)HS-CDTK effectively suppressed cell proliferation by viral cytopathic effect). Unlike with a replication-incompetent virus (Ad.HS-CDTK), the cytopathic effect of the virus and cytotoxicity in the presence of the prodrugs were still observed even at low MOI (MOI=1.0).

Heat-activated transgene expression from adenovirus vectors infected into human prostate cancer cells.

Replication-deficient adenovirus expression vectors were used to introduce a recombinant DNA construct containing enhanced green fluorescent protein (EGFP) under control of a truncated, human heat shock promoter into human prostate cancer cells growing either exponentially or in plateau phase. This was done to measure controlled, heat shock-induced EGFP expression under conditions relevant to treating human cancers with heat-activated gene therapy. Both the temporal duration and magnitude of EGFP expression increased proportionately with stronger heat shocks (time at temperature) up to maximum values that were induced by 4 h at 41.0 degrees C or 2 h at 42.0 degrees C. Longer heat shocks at either temperature yielded no additional EGFP expression and ultimately reduced it. Maximal EGFP expression was induced in exponential cultures by heat shocks delivered 12-24 h after virus infection. Induction at progressively later postinfection times induced increasingly lower, peak EGFP expression. Maximal EGFP expression could not be induced until 48 h after infection of plateau phase cultures but could still be induced 180 h after virus infection. However, peak EGFP levels in plateau cultures were approximately 25-50% of those observed in identically induced exponential cultures. Ostensibly, the differences in expression from the heat shock promoter observed in exponential and plateau cultures were attributable to cell division diluting the vector within exponential cultures and the lower metabolic activity in serum-starved plateau cultures. For all experimental conditions, EGFP expression induced from the heat shock promoter was comparable with or higher than that from the constitutively active cytomegalovirus promoter over any 24-h period. The experimental results demonstrated that EGFP expression from the heat shock promoter was controllable in both exponential and plateau phase cultures and support the plausibility of using controlled heat shock activation of this promoter as a means of regulating both the spatial and temporal expression of therapeutic DNA constructs within human tissues. The ability to localize and regulate expression from the heat shock promoter may prove particularly advantageous for many cancer applications, especially if the therapeutic products are highly toxic, e.g., proteotoxins or cytokines. However, the results of this study suggest that differential growth conditions within tumors could markedly affect the expression of recombinant DNA under control of both inducible and constitutive promoters. Consequently, inducing schemes may need to be spatially adjusted to obtain the desired therapeutic results in all tumor domains using heat-activated gene therapy.

A gene for ataxic cerebral palsy maps to chromosome 9p12-q12.

Cerebral palsy (CP) has an incidence of approximately 1 in 750 births, although this varies between ethnic groups. Genetic forms of the disease account for about 2% of cases in most countries, but contribute a larger proportion in certain sub-types of the condition and in populations with a large proportion of consanguineous marriages. Ataxic cerebral palsy accounts for 5-10% of all forms of CP and it is estimated that approximately 50% of ataxic cerebral palsy is inherited as an autosomal recessive trait. We have identified a complex consanguineous Asian pedigree with four children in two sibships affected with ataxic cerebral palsy and have used homozygosity mapping to map the disorder in this family. A genome-wide search was performed using 343 fluorescently labelled polymorphic markers and linkage to chromosome 9p12-q12 was demonstrated. A maximum Lod score of 3.4 was observed between the markers D9S50 and D9S167 using multipoint analysis, a region of approximately 23cM. We have identified a family that segregates both ataxic CP and ataxic diplegia and have mapped the genetic locus responsible in this family to chromosome 9p12-q12. The identification of gene(s) involved in the aetiology of CP will offer the possibility of prenatal/premarital testing to some families with children affected with the disorder and will greatly increase our understanding of the development of the control of motor function.