Seeding of hepatocellular carcinoma into the stomach wall following endoscopic ultrasound and fine-needle aspiration biopsy.

Delayed gastrointestinal metastasis is a rare complication of hepatocellular carcinoma (HCC). We present the case of a patient who presented with melaena and microcytic anaemia 6 years after receiving an orthotopic liver transplant for hepatitis B-induced HCC. Oesophagogastroduodenoscopy revealed a fungating gastric mass at the lesser curve and histology from biopsies confirmed metastatic recurrence of HCC in the stomach. The route of metastasis is likely due to iatrogenic seeding of tumour cells during pre-transplant endoscopic ultrasound (EUS) and fine needle aspiration (FNA) biopsy. Subsequent positron emission tomography and magnetic resonance imaging failed to reveal further metastatic disease and the patient was managed with a total gastrectomy. This is the first reported description in the literature of needle-track metastasis in the stomach due to liver EUS-FNA for HCC.

Continuous ambulatory peritoneal dialysis versus automated peritoneal dialysis for end-stage renal disease.

BACKGROUND: Peritoneal dialysis (PD) can be performed either manually as in continuous ambulatory peritoneal dialysis (CAPD) or using mechanical devices as in automated PD (APD). APD has been considered to have several advantages over CAPD such as reduced incidence of peritonitis, mechanical complications and greater psychosocial acceptability. OBJECTIVES: To assess the comparative efficacy of CAPD and APD in patients who are dialysed for end-stage renal disease (ESRD). SEARCH STRATEGY: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Renal Group's specialised register and CINAHL. Authors of included studies were contacted, reference lists of identified RCTs and relevant narrative reviews were screened. Date of most recent search: May 2006 SELECTION CRITERIA: RCTs comparing CAPD with APD in patients with ESRD. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two authors onto a standard form. Relative risk (RR) for dichotomous data and a mean difference (MD) for continuous data were calculated with 95% confidence intervals (CI). MAIN RESULTS: Three trials (139 patients) were included. APD did not differ from CAPD with respect to mortality (RR 1.49, 95% CI 0.51 to 4.37), risk of peritonitis (RR 0.75, 95% CI 0.50 to 1.11), switching from original PD modality to a different dialysis modality (RR 0.50, 95% CI 0.25 to 1.02), hernias (RR 1.26, 95% interval 0.32 to 5.01), PD fluid leaks (RR 1.06, 95% CI 0.11 to 9.83), PD catheter removal (RR 0.64, 95% CI 0.27 to 1.48) or hospital admissions (RR 0.96, 95% CI 0.43 to 2.17). There was no difference between either PD modality with respect to residual renal function (MD -0.17, 95% CI -1.66 to 1.32). One study found that peritonitis rates and hospitalisation were significantly less in patients on APD when results were expressed as episodes/patient-year. Another study found that patients on APD had significantly more time for work, family and social activities. AUTHORS' CONCLUSIONS: APD has not been shown to have significant advantages over CAPD in terms of important clinical outcomes. APD may however be considered advantageous in select group of patients such as in the younger PD population and those in employment or education due to its psychosocial advantages. There is a need for a RCT comparing CAPD with APD with sufficiently large patient numbers looking at important clinical outcomes including residual renal function, accompanied by an economic evaluation to clarify the relative clinical and cost-effectiveness of both modalities.

Physical measures for treating depression in dialysis patients.

BACKGROUND: Depression is the most common psychological problem in the chronic dialysis population. The diagnosis of depression in patients on chronic dialysis is confounded by the fact that several symptoms of uraemia mimic the somatic components of depression. It affects their physical, psychological and social well-being. Furthermore, the frequent occurrence of cardiovascular problems and the pharmacokinetic consequences of renal impairment may make drug treatment of depression difficult. OBJECTIVES: The aim of this systematic review was to assess the efficacy and safety of physical measures in the treatment of depression in patients who are dialysed for end-stage renal disease. SEARCH STRATEGY: A comprehensive search strategy was employed to identify all Randomised Controlled Trials (RCTs) relevant to the treatment of depression in patients on chronic dialysis. The following database were searched - MEDLINE (1966-March 2004), EMBASE (1980-March 2004), PSYCHINFO (1872-March 2004), The Cochrane Library (Issue 1, 2004). Authors of included studies were contacted, reference lists of identified RCTs and relevant narrative reviews were screened. SELECTION CRITERIA: RCTs comparing drugs with placebo or no treatment, or a comparison of drugs against a combination of electroconvulsive therapy and drugs. DATA COLLECTION AND ANALYSIS: Data were abstracted by two investigators independently onto a standard form and subsequently entered into Review Manager 4.2. Relative risk (RR) for dichotomous data and a (weighted) mean difference (WMD) for continuous data were calculated with 95% confidence intervals (95% CI). MAIN RESULTS: Only one trial, with a total of 12 patients and of eight weeks duration was identified. The trial compared fluoxetine against placebo in depressed patients on chronic dialysis. This study did not show any significant difference in depression scores between the treatment and control groups or safety. AUTHORS' CONCLUSIONS: Firm conclusions on the efficacy of physical methods of treatment cannot be made as we identified only one small RCT that was of short duration. More larger and longer term RCTs are needed in this area. Current screening tools for depression are recognised to have poor specificity in the medically ill due to overlap of somatic symptoms of the medical illness. The development of a valid diagnostic tool would be helpful.

Issues in data monitoring and interim analysis of trials.

OBJECTIVES: To address issues about data monitoring committees (DMCs) for randomised controlled trials (RCTs). DATA SOURCES: Electronic databases. Handsearching of selected books. Personal contacts with experts in the field. REVIEW METHODS: Systematic literature reviews of DMCs and small group processes in decision-making; sample surveys of: reports of RCTs, recently completed and ongoing RCTs and policies of major organisations involved in RCTs; case studies of four DMCs; and interviews with experienced DMC members. All focused on 23 prestated questions. RESULTS: Although still a minority, RCTs increasingly have DMCs. There is wide agreement that nearly all trials need some form of data monitoring. Central to the role of the DMC is monitoring accumulating evidence related to benefit and toxicity; variation in emphasis has been reflected in the plethora of names. DMCs for trials performed for regulatory purposes should be aware of any special requirements and regulatory consequences. Advantages were identified for both larger and smaller DMCs. There is general agreement that a DMC should be independent and multidisciplinary. Consumer and ethicist membership is controversial. The chair is recognised as being particularly influential, and likely to be most effective if he or she is experienced, understands both statistical and clinical issues, and is facilitating in style and impartial. There is no evidence available to judge suggested approaches to training. The review suggested that costs should be covered, but other rewards must be so minimal as to not affect decision-making. It is usual to have a minimum frequency of DMC meetings, with evidence that face-to-face meetings are preferable. It is common to have open sessions and a closed session. A report to a DMC should cover benefits and risks in a balanced way, summarised in an accessible style, avoiding excessive detail, and be as current as possible. Disadvantages of blinded analyses seem to outweigh advantages. Information about comparable studies should be included, although interaction with the DMCs of similar ongoing trials is controversial. A range of formal statistical approaches can be used, although this is only one of a number of considerations. DMCs usually reach decisions by consensus, but other approaches are sometimes used. The general, but not unanimous, view is that DMCs should be advisory rather than executive on the basis that it is the trial organisers who are ultimately responsible for the conduct of the trial. CONCLUSIONS: Some form of data monitoring should be considered for all RCTs, with reasons given where there is no DMC or when any member is not independent. An early DMC meeting is helpful, determining roles and responsibilities; planned operations can be agreed with investigators and sponsors/funders. A template for a DMC charter is suggested. Competing interests should be declared. DMC size (commonly three to eight people) is chosen to optimise performance. Members are usually independent and drawn from appropriate backgrounds, and some, particularly the chair, are experienced. A minimum frequency of meetings is usually agreed, with flexibility for more if needed. The DMC should understand and agree the statistical approach (and guidelines) chosen, with both the DMC statistician and analysis statistician competent to apply the method. A DMC's primary purpose is to ensure that continuing a trial according to its protocol is ethical, taking account of both individual and collective ethics. A broader remit in respect of wider ethical issues is controversial; arguably, these are primarily the responsibility of research ethics committees, trial steering committees and investigators. The DMC should know the range of recommendations or decisions open to it, in advance. A record should be kept describing the key issues discussed and the rationale for decisions taken. Errors are likely to be reduced if a DMC makes a thorough review of the evidence and has a clear understanding of how it should function, there is active participation by all members, differences are resolved through discussion and there is systematic consideration of the various decision options. DMCs should be encouraged to comment on draft final trial reports. These should include information about the data monitoring process and detail the DMC membership. It is recommended that groups responsible for data monitoring be given the standard name 'Data Monitoring Committee' (DMC). Areas for further research include: widening DMC membership beyond clinicians, trialists and statisticians; initiatives to train DMC members; methods of DMC decision-making; 'open' data monitoring; DMCs covering a portfolio of trials rather than single trials; DMC size and membership, incorporating issues of group dynamics; empirical study of the workings of DMCs and their decision-making, and which trials should or should not have a DMC.

Bladder training for urinary incontinence in adults.

BACKGROUND: Urinary incontinence is a common and distressing problem. Bladder training aims to increase the interval between voids and is widely used for the treatment of urinary incontinence. OBJECTIVES: To assess the effects of bladder training for the treatment of urinary incontinence. SEARCH STRATEGY: We searched the Cochrane Incontinence Group trials register (January 2003). The reference lists of relevant articles were searched, and trialists contacted for details of other trials. Date of the most recent search: January 2003. SELECTION CRITERIA: Randomised or quasi-randomised trials of bladder training for the treatment of any type of urinary incontinence. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trial quality and independently extracted data. Five primary outcomes were prespecified: participant's perception of cure of urinary incontinence; participant's perception of improvement of urinary incontinence; number of incontinent episodes; number of micturitions; and quality of life. Adverse events were also noted. Three hypotheses were tested: bladder training is better than no bladder training; bladder training is better than other treatments; and combining bladder training with another treatment is better than that other treatment alone. MAIN RESULTS: We assessed 73 reports of 36 potentially relevant trials; 28 reports of ten trials were eligible for inclusion with a total of 1366, predominantly female, participants. Not all participants' with overactive bladder, in five trials had urinary incontinence. Data from five trials with 467 participants, all female, are therefore included in the review. The quality of trials was variable. Few data describing long term follow up are available.Is bladder training better than no bladder training? Data were available for 149 women from two trials comparing bladder training with no bladder training. These described only a limited number of prespecified outcomes, which varied across the two trials. Point estimates of effect favoured bladder training however confidence intervals were wide and no statistically significant differences were found for primary outcome variables.Is bladder training better than other treatments? Only two trials including 125 women compared bladder training with drugs: one with oxybutynin and one with imipramine plus flavoxate. In the former trial the only outcomes demonstrating a statistically significant difference were participant's perception of cure at six months (RR 1.69; 95% CI 1.21 to 2.34) and adverse events (RR 0.03; 95% CI 0.00 to 0.44), both favouring bladder training. In the latter trial participant's perception of cure immediately after treatment just achieved statistical significance (RR 1.50; 95% CI 1.02 to 2.21) favouring bladder training, and this difference was maintained at approximately two months post treatment. One comparison of bladder training with pelvic floor muscle training plus biofeedback included 132 women: none of the differences in the primary outcomes achieved statistical significance.Is combining bladder training with another treatment better than that other treatment alone? One trial compared pelvic floor muscle training plus biofeedback supplemented with bladder training versus pelvic floor muscle training plus biofeedback alone and included 125 women. Of the primary outcomes both participants' perception of improvement and quality of life, both immediately after treatment, achieved statistical significance, favouring the bladder training combined with pelvic floor muscle training and biofeedback group (perception of improvement: RR 1.18; 95% CI 1.01 to 1.39; quality of life: MD -47.20; 95% CI -87.03 to -7.37), this was not sustained at three months. REVIEWER'S CONCLUSIONS: The limited evidence available suggests that bladder training may be helpful for the treatment of urinary incontinence, but this conclusion can only be tentative as the trials were of variable quality and of small size with wide confidence intervals around the point estimates of effect. There was also not enough evidence to determine w evidence to determine whether bladder training was useful as a supplement to another therapy. Definitive research has yet to be conducted: more research is required.

Statistical assessment of the learning curves of health technologies.

OBJECTIVES: (1) To describe systematically studies that directly assessed the learning curve effect of health technologies. (2) Systematically to identify 'novel' statistical techniques applied to learning curve data in other fields, such as psychology and manufacturing. (3) To test these statistical techniques in data sets from studies of varying designs to assess health technologies in which learning curve effects are known to exist. METHODS - STUDY SELECTION (HEALTH TECHNOLOGY ASSESSMENT LITERATURE REVIEW): For a study to be included, it had to include a formal analysis of the learning curve of a health technology using a graphical, tabular or statistical technique. METHODS - STUDY SELECTION (NON-HEALTH TECHNOLOGY ASSESSMENT LITERATURE SEARCH): For a study to be included, it had to include a formal assessment of a learning curve using a statistical technique that had not been identified in the previous search. METHODS - DATA SOURCES: Six clinical and 16 non-clinical biomedical databases were searched. A limited amount of handsearching and scanning of reference lists was also undertaken. METHODS - DATA EXTRACTION (HEALTH TECHNOLOGY ASSESSMENT LITERATURE REVIEW): A number of study characteristics were abstracted from the papers such as study design, study size, number of operators and the statistical method used. METHODS - DATA EXTRACTION (NON-HEALTH TECHNOLOGY ASSESSMENT LITERATURE SEARCH): The new statistical techniques identified were categorised into four subgroups of increasing complexity: exploratory data analysis; simple series data analysis; complex data structure analysis, generic techniques. METHODS - TESTING OF STATISTICAL METHODS: Some of the statistical methods identified in the systematic searches for single (simple) operator series data and for multiple (complex) operator series data were illustrated and explored using three data sets. The first was a case series of 190 consecutive laparoscopic fundoplication procedures performed by a single surgeon; the second was a case series of consecutive laparoscopic cholecystectomy procedures performed by ten surgeons; the third was randomised trial data derived from the laparoscopic procedure arm of a multicentre trial of groin hernia repair, supplemented by data from non-randomised operations performed during the trial. RESULTS - HEALTH TECHNOLOGY ASSESSMENT LITERATURE REVIEW: Of 4571 abstracts identified, 272 (6%) were later included in the study after review of the full paper. Some 51% of studies assessed a surgical minimal access technique and 95% were case series. The statistical method used most often (60%) was splitting the data into consecutive parts (such as halves or thirds), with only 14% attempting a more formal statistical analysis. The reporting of the studies was poor, with 31% giving no details of data collection methods. RESULTS - NON-HEALTH TECHNOLOGY ASSESSMENT LITERATURE SEARCH: Of 9431 abstracts assessed, 115 (1%) were deemed appropriate for further investigation and, of these, 18 were included in the study. All of the methods for complex data sets were identified in the non-clinical literature. These were discriminant analysis, two-stage estimation of learning rates, generalised estimating equations, multilevel models, latent curve models, time series models and stochastic parameter models. In addition, eight new shapes of learning curves were identified. RESULTS - TESTING OF STATISTICAL METHODS: No one particular shape of learning curve performed significantly better than another. The performance of 'operation time' as a proxy for learning differed between the three procedures. Multilevel modelling using the laparoscopic cholecystectomy data demonstrated and measured surgeon-specific and confounding effects. The inclusion of non-randomised cases, despite the possible limitations of the method, enhanced the interpretation of learning effects. CONCLUSIONS - HEALTH TECHNOLOGY ASSESSMENT LITERATURE REVIEW: The statistical methods used for assessing learning effects in health technology assessment have been crude and the reporting of studies poor. CONCLUSIONS - NON-HEALTH TECHNOLOGY ASSESSMENT LITERATURE SEARCH: A number of statistical methods for assessing learning effects were identified that had not hitherto been used in health technology assessment. There was a hierarchy of methods for the identification and measurement of learning, and the more sophisticated methods for both have had little if any use in health technology assessment. This demonstrated the value of considering fields outside clinical research when addressing methodological issues in health technology assessment. CONCLUSIONS - TESTING OF STATISTICAL METHODS: It has been demonstrated that the portfolio of techniques identified can enhance investigations of learning curve effects. (ABSTRACT TRUNCATED)

Do the Y-set and double-bag systems reduce the incidence of CAPD peritonitis? A systematic review of randomized controlled trials.

BACKGROUND: Peritonitis is the most frequent serious complication of continuous ambulatory peritoneal dialysis (CAPD). It has a major influence on the number of patients switching from CAPD to haemodialysis and has probably restricted the wider acceptance and uptake of CAPD as an alternative mode of dialysis. This systematic review sought to determine if modifications of the transfer set (Y-set or double-bag systems) used in CAPD exchanges are associated with a reduction in peritonitis and an improvement in other relevant outcomes. METHODS: Based on a comprehensive search strategy, we undertook a systematic review of randomized or quasi-randomized controlled trials comparing double-bag and/or Y-set CAPD exchange systems with standard systems, or comparing double-bag with Y-set systems, in patients with end-stage renal disease (ESRD) treated with CAPD. Only published data were used. Data were abstracted by a single investigator onto a standard form and subsequently entered into Review Manager 4.0.4. Its statistical package, Metaview 3.1, calculated an odds ratio (OR) for dichotomous data and a (weighted) mean difference for continuous data with 95% confidence intervals. RESULTS: Twelve eligible trials with a total of 991 randomized patients were identified. In trials comparing either the Y-set or double-bag systems with the standard systems, significantly fewer patients (133/363 vs 158/263; OR 0.33, 95% CI 0.24-0.46) experienced peritonitis and the number of patient-months on CAPD per episode of peritonitis was consistently greater. When the double-bag systems were compared with the Y-set systems significantly fewer patients experienced peritonitis (44/154 vs 66/138; OR 0.44, 95% CI 0.27-0.71) and the number of patient-months on CAPD per episode of peritonitis was also greater. CONCLUSIONS: Double-bag systems should be the preferred exchange systems in CAPD.

Evidence-based medicine in nephrology: identifying and critically appraising the literature.

BACKGROUND: Uncertainties about best management of end-stage renal disease (ESRD) are reflected in wide variations in practice. Systematic reviews aim to reduce uncertainty by strengthening the evidence base for clinical practice, allowing estimation of the benefits and risks of particular interventions, whilst minimizing the potential for bias. This paper describes the methods and conduct of six systematic reviews of aspects of the management of ESRD, and the yield in terms of trials found. METHODS: Our methodology was based on that recommended by the Cochrane Collaboration (an international initiative set up to perform and disseminate systematic reviews of health care). It involved a systematic search of electronic databases and bibliographic reference lists, together with handsearching of Kidney International for studies relevant to the management of ESRD, followed by a systematic assessment of study quality. RESULTS: Around 12,000 abstracts were assessed which had been identified from electronic sources. Of these, 2085 (18%) were deemed to be reports of possible randomized or quasi-randomized controlled trials relevant to the management of ESRD. Three hundred and forty were relevant to the six specific reviews, and after assessment of the full manuscripts, 39 studies were finally included in our reviews. Reports of a further nine trials, which were identified from other sources, were also included. The broad search adopted allowed the parallel development of a register of trials of all aspects of the management of ESRD. CONCLUSIONS: This study has demonstrated that the methodology of systematic reviews, as promoted by the Cochrane Renal Group, is feasible but has significant resource implications. The development of a register of randomized controlled trials (RCTs) related to the management of ESRD will facilitate this form of research in the future.

Precision-grip force changes in the anatomical and prosthetic limb during predictable load increases.

This study examined precision-grip force applied to an instrumented test object held aloft while the weight of the object was predictably varied by transporting and placing loads (50, 100, or 200 g) atop the test object. Transport of the loads was performed either by the subject or the experimenter. Grip force was examined in four non-amputee control subjects and in the anatomical and prosthetic hand of a subject with a prosthetic device. As subjects transported the load, anticipatory grip-force changes occurred in the anatomical hands and prosthetic hand, which were scaled in relation to the load. When the experimenter transported the load to the anatomical hands of control subjects or the prosthetic user, anticipatory increases in grip force occurred that also were scaled in relation to load. However, when the experimenter transported the load to the prosthetic hand, anticipatory grip-force adjustments were absent. During the phase in which the load was being assumed by the postural hand, grip forces in the anatomical hands and prosthetic hand were further scaled to load demands. Ability to adapt grip force in the prosthetic hand during this phase suggested that the subject was utilizing sensory information from the residual limb to adjust grip force. Thus, while anticipatory changes precede the process of adaptation to load changes, actual sensory consequences resulting from added weight remain necessary to fully adapt grip force to load demands, even for the prosthetic user.

Assessment of the learning curve in health technologies. A systematic review.

OBJECTIVE: We reviewed and appraised the methods by which the issue of the learning curve has been addressed during health technology assessment in the past. METHOD: We performed a systematic review of papers in clinical databases (BIOSIS, CINAHL, Cochrane Library, EMBASE, HealthSTAR, MEDLINE, Science Citation Index, and Social Science Citation Index) using the search term "learning curve." RESULTS: The clinical search retrieved 4,571 abstracts for assessment, of which 559 (12%) published articles were eligible for review. Of these, 272 were judged to have formally assessed a learning curve. The procedures assessed were minimal access (51%), other surgical (41%), and diagnostic (8%). The majority of the studies were case series (95%). Some 47% of studies addressed only individual operator performance and 52% addressed institutional performance. The data were collected prospectively in 40%, retrospectively in 26%, and the method was unclear for 31%. The statistical methods used were simple graphs (44%), splitting the data chronologically and performing a t test or chi-squared test (60%), curve fitting (12%), and other model fitting (5%). CONCLUSIONS: Learning curves are rarely considered formally in health technology assessment. Where they are, the reporting of the studies and the statistical methods used are weak. As a minimum, reporting of learning should include the number and experience of the operators and a detailed description of data collection. Improved statistical methods would enhance the assessment of health technologies that require learning.

Through the community looking glass: reevaluating the ethical and policy implications of research on adolescent risk and sociopathology.

Drawing on a conception of scientists and community members as partners in the construction of ethically responsible research practices, this article urges investigators to seek the perspectives of teenagers and parents in evaluating the personal and political costs and benefits of research on adolescent risk behaviors. Content analysis of focus group discussions involving over 100 parents and teenagers from diverse ethnic and socioeconomic backgrounds revealed community opinions regarding the scientific merit, social value, racial bias, and participant and group harms and benefits associated with surveys, informant reports, intervention studies, blood sampling, and genetic research on youth problems. Participants comments highlight new directions for socially responsible research.

Motor performance with a simulated artificial limb.

The present study was conducted to examine performance differences on a reaching and grasping task related to an activity of daily living. This involved either the anatomical limb or a simulated artificial limb. College-aged volunteers (2 men and 4 women), one of whom was left-handed, performed the reaching and grasping task. The apparatus, placed on a table before the seated participant, was a square wooden board which contained a starting key and holes for the insertion and removal of a small Fiberglas dowel. At the beginning of the trial the participant depressed the start key, reached forward and grasped the dowel, and then returned the dowel to a finishing hole located directly in front of the start key. The results of 2 (side) x 2 (type of limb) repeated-measures multivariate analyses of variance on the mean and standard deviation of the movement times showed a significant main effect for type of limb (Wilks lambda 3,3 = .047 and .079, respectively, p < .05). Analyses of variance on mean total transport time, extension time, flexion time, and their standard deviations showed that times were slower and less consistent with the prosthesis for all measures. These results and those of later research should be focused on the development of training principles for both therapists and individuals with an amputation. In addition, the simulated prosthesis is an excellent experimental model for basic and clinical research in the control and acquisition of coordinated movement.

Effects of neonatal cholinergic basal forebrain lesions on excitatory amino acid receptors in neocortex.

The role of cholinergic basal forebrain projections in the modulation of cortical plasticity and associated functional changes is currently the subject of renewed attention. Excitatory amino acid receptors have been identified as mediators of cortical topographic efferent and afferent information. In addition some of these receptors, notably the NMDA and metabotropic [mGluR] type, participate in cortical plasticity. Growing evidence suggests that interactions between cholinergic and glutamatergic systems contribute to cognitive cortical functions and their anatomical and physiological substrates. Though cholinergic and glutamatergic mechanisms have both been shown to be involved in cortical morphogenesis, few studies have attempted to study their interactions in development. The present study investigates the effect of neonatal lesions to the cholinergic basal forebrain on NMDA, AMPA and mGluR receptors in BALB/CByJ mice, at two different developmental ages. We demonstrated previously that nBM lesions at birth result in transient cholinergic depletion for the first two postnatal weeks, substantial morphogenetic alterations in neocortex and cognitive deficits by adulthood. We show here that unilateral neonatal lesions result in decreases in NMDA and AMPA receptors but increases in mGluRs during the second postnatal week (PND 14). At 30 days postnatal, lesion mediated changes were attenuated, compared with PND 14, but significant sex differences in control and nBM lesioned mice were apparent. These data support the notion that cholinergic/glutamatergic interactions are important during early cortical morphogenesis. Moreover, our results highlight the fact that cholinergic as well glutamatergic developmental mechanisms are sexually dimorphic.

Monte Carlo calculations of epithermal boron neutron capture therapy with heavy water.

Much work over the past decade has centred upon the development of epithermal neutron beams for boron neutron capture therapy (BNCT) in an effort to increase thermal-neutron flux penetration and dose homogeneity throughout the brain. While heavy water has been used extensively to improve neutron penetration associated with thermal neutron beams, the effects of heavy water with epithermal neutron beams remain largely unexplored. Applying the Monte Carlo code MCNP to a heterogenous ellipsoidal skull/brain model, the effects of heavy-water replacement are studied for the JRC/ECN Petten HFR epithermal neutron beam. Thermal neutron flux and induced gamma depth dose distributions are calculated for 20% D2O replacement in comparison to standard brain and skull materials. Results are presented for both unilateral and bilateral irradiation. With bilateral irradiation, thermal-neutron flux homogeneity is substantially increased with 20% D2O replacement, thus improving the potential to give lethal doses to boron-10-loaded, disseminated cancer cells whilst avoiding local 'hot spots' to healthy tissue. Additionally, the induced gamma dose is reduced by up to 30%, substantially lowering the background dose to healthy tissue. With bilateral irradiation, 20% D2O replacement increases the therapeutic ratio from 2.25 to 2.75 for over 4 cm depth centred at the midline of the brain. These calculations use documented tumour and blood 10B concentrations for boronophenylalanine (BPA) in humans and recently documented neutron relative biological effectiveness (RBE) values.

The influence of heavy water on boron requirements for neutron capture therapy.

Neutron penetration in tissue is a major limitation of thermal NCT, as such much work has centered upon the epithermal neutron beam in an effort to improve this situation. Further gains in neutron flux penetration, and thus therapeutic ratios, are possible if natural water is replaced with heavy water prior to therapy. Applying MCNP to a heterogeneous ellipsoidal skull/brain model, advantage depth and therapeutic depth parameters are studied as a function of heavy water replacement for a range of tumor to blood boron ratios. Both thermal (0.025 eV) and epithermal (2-7 keV) ideal neutron beams are analyzed. Using 10B ratios in the range of documented human uptake, the thermal advantage depth improved by approximately 0.7 cm for 20% D2O replacement, however, the therapeutic depth increased by less than half this value. For the epithermal beam, both the advantage depth and the therapeutic depth increased by over 1 cm. Effects of heavy water replacement on 10B requirements to therapeutically treat the midline of the brain are also evaluated.

Monte Carlo modelling of neutron depth dose distributions in optimizing prompt gamma in vivo neutron activation analysis systems.

Optimization of prompt gamma in vivo neutron activation analysis systems is best achieved using Monte Carlo simulation. In this study the modelling of the dimensions and materials for source holders and collimators is described and compared with experimentally derived results where feasible. Results show that valid depth doses are obtained by modelling only the central part of an IVNAA system and that the use of borated paraffin as a reflector provides acceptable thermal fluence and depth dose.

Cancer experience in the relatives of an unselected series of breast cancer patients.

First- and second-degree relatives of an unselected series of 402 breast cancer patients have been studied for their cancer experience. In the first-degree relatives an excess of all cancers is seen [overall relative risk (RR) = 1.28, P = 0.002; males RR = 1.26, P = 0.047; females RR = 1.30, P = 0.022). There is a marked excess of sarcoma (RR = 4.26, P = 0.0064); females are at high risk of breast cancer (RR = 2.68, P < 0.0001) and males have an excess of carcinoma of the lip, oral cavity and pharynx (RR = 4.22, P = 0.0032). Second-degree relatives have a non-significant excess of all cancers (RR = 1.14, P = 0.14); females have a borderline excess of breast cancer (RR = 1.53, P = 0.08) and an excess of carcinoma of the kidney (RR = 7.46, P = 0.0012) and males have an excess of carcinoma of the trachea and lung (RR = 1.50, P = 0.032). No excess of prostate or ovarian carcinoma was seen. Relatives are at slightly higher risk if the index patient is diagnosed between the ages of 40 and 49 (first-degree RR = 1.64, P = 0.007; second-degree RR = 1.43, P = 0.02). The excess of cancers, including breast cancers, is not limited to a few high-risk families, but appears to be spread across many. These observations may be accounted for by shared environmental factors within families or a common predisposing gene with low penetrance.

Teatment planning figures of merit in thermal and epithermal boron neutron capture therapy of brain tumours.

The boron neutron capture therapy (BNCT) figures of merit of advantage depth, therapeutic depth, modified advantage depth and maximum therapeutic depth have been studied as functions of 10B tumour to blood ratios and absolute levels. These relationships were examined using the Monte Carlo neutron photon transport code, MCNP, with an ideal 18.4 cm diameter neutron beam incident laterally upon all ellipsoidal neutron photon brain-equivalent model. Mono-energetic beams of 0.025 eV (thermal) and 35 eV (epithermal) were simulated. Increasing the tumour to blood 10B ratio predictably increases all figures of merit. concentration was also shown to have a strong bearing on the figures of merit when low levels were present in the system. This is the result of a non-10B dependent background dose. At higher levels however, the concentration of 10B has a diminishing influence. For boron sulphydryl (BSH), little advantage is gained by extending the blood 10B level beyond 30 ppm, whilst for D,L,-p-boronophenylalanine (BPA) this limit is 10 ppm. To achieve a therapeutic depth of 6 cm (brain mid-line from brain surface) using the thermal beam, a tumour to blood ratio of 25 with 10 ppm 10B in the blood is required for BPA. Similarly, a tumour to blood ratio of 8.5 with 30 ppm blood 10B is required for the maximum therapeutic depth of BSH to reach the brain mid-line. These requirements are five times above current values for these compounds in humans. Applying the epithermal beam under identical conditions, the therapeutic depth reaches the brain mid-line with a tumour to blood 10B ratio of only 5.7 for BPA. For BSH, the maximum therapeutic depth reaches the brain mid-line with a tumour to blood ratio of only 1.9 with 30 ppm in the blood. Human data for these compounds are very close to these requirements.