The increasing threat to European forests from the invasive foliar pine pathogen, Lecanosticta acicola.

European forests are threatened by increasing numbers of invasive pests and pathogens. Over the past century, Lecanosticta acicola, a foliar pathogen predominantly of Pinus spp., has expanded its range globally, and is increasing in impact. Lecanosticta acicola causes brown spot needle blight, resulting in premature defoliation, reduced growth, and mortality in some hosts. Originating from southern regions of North American, it devastated forests in the USA's southern states in the early twentieth century, and in 1942 was discovered in Spain. Derived from Euphresco project 'Brownspotrisk,' this study aimed to establish the current distribution of Lecanosticta species, and assess the risks of L. acicola to European forests. Pathogen reports from the literature, and new/ unpublished survey data were combined into an open-access geo-database (http://www.portalofforestpathology.com), and used to visualise the pathogen's range, infer its climatic tolerance, and update its host range. Lecanosticta species have now been recorded in 44 countries, mostly in the northern hemisphere. The type species, L. acicola, has increased its range in recent years, and is present in 24 out of the 26 European countries where data were available. Other species of Lecanosticta are largely restricted to Mexico and Central America, and recently Colombia. The geo-database records demonstrate that L. acicola tolerates a wide range of climates across the northern hemisphere, and indicate its potential to colonise Pinus spp. forests across large swathes of the Europe. Preliminary analyses suggest L. acicola could affect 62% of global Pinus species area by the end of this century, under climate change predictions. Although its host range appears slightly narrower than the similar Dothistroma species, Lecanosticta species were recorded on 70 host taxa, mostly Pinus spp., but including, Cedrus and Picea spp. Twenty-three, including species of critical ecological, environmental and economic significance in Europe, are highly susceptible to L. acicola, suffering heavy defoliation and sometimes mortality. Variation in apparent susceptibility between reports could reflect variation between regions in the hosts' genetic make-up, but could also reflect the significant variation in L. acicola populations and lineages found across Europe. This study served to highlight significant gaps in our understanding of the pathogen's behaviour. Lecanosticta acicola has recently been downgraded from an A1 quarantine pest to a regulated non quarantine pathogen, and is now widely distributed across Europe. With a need to consider disease management, this study also explored global BSNB strategies, and used Case Studies to summarise the tactics employed to date in Europe.

A practical approach to the evaluation and treatment of an infant with aplasia cutis congenita.

Aplasia cutis congenita (ACC) is a term describing absence of skin at birth. ACC is a rare cutaneous finding, often noted with no other physical abnormalities. The etiology of ACC varies, and there are likely several causes for its development. ACC can be located anywhere on the body. Its clinical appearance and location can alert the clinician to other potential abnormalities and associations. This discussion covers the diagnosis of ACC and its subtypes and associations in order to provide a pragmatic, clinically relevant and patient-centered approach to evaluation and treatment.

Genes and associated peptides involved with aestivation in a land snail.

Some animals can undergo a remarkable transition from active normal life to a dormant state called aestivation; entry into this hypometabolic state ensures that life continues even during long periods of environmental hardship. In this study, we aimed to identify those central nervous system (CNS) peptides that may regulate metabolic suppression leading to aestivation in land snails. Mass spectral-based neuropeptidome analysis of the CNS comparing active and aestivating states, revealed 19 differentially produced peptides; 2 were upregulated in active animals and 17 were upregulated in aestivated animals. Of those, the buccalin neuropeptide was further investigated since there is existing evidence in molluscs that buccalin modulates physiology by muscle contraction. The Theba pisana CNS contains two buccalin transcripts that encode precursor proteins that are capable of releasing numerous buccalin peptides. Of these, Tpi-buccalin-2 is most highly expressed within our CNS transcriptome derived from multiple metabolic states. No significant difference was observed at the level of gene expression levels for Tpi-buccalin-2 between active and aestivated animals, suggesting that regulation may reside at the level of post-translational control of peptide abundance. Spatial gene and peptide expression analysis of aestivated snail CNS demonstrated that buccalin-2 has widespread distribution within regions that control several physiological roles. In conclusion, we provide the first detailed molecular analysis of the peptides and associated genes that are related to hypometabolism in a gastropod snail known to undergo extended periods of aestivation.

Multi-tissue transcriptomics for construction of a comprehensive gene resource for the terrestrial snail Theba pisana.

The land snail Theba pisana is native to the Mediterranean region but has become one of the most abundant invasive species worldwide. Here, we present three transcriptomes of this agriculture pest derived from three tissues: the central nervous system, hepatopancreas (digestive gland), and foot muscle. Sequencing of the three tissues produced 339,479,092 high quality reads and a global de novo assembly generated a total of 250,848 unique transcripts (unigenes). BLAST analysis mapped 52,590 unigenes to NCBI non-redundant protein databases and further functional analysis annotated 21,849 unigenes with gene ontology. We report that T. pisana transcripts have representatives in all functional classes and a comparison of differentially expressed transcripts amongst all three tissues demonstrates enormous differences in their potential metabolic activities. The genes differentially expressed include those with sequence similarity to those genes associated with multiple bacterial diseases and neurological diseases. To provide a valuable resource that will assist functional genomics study, we have implemented a user-friendly web interface, ThebaDB (http://thebadb.bioinfo-minzhao.org/). This online database allows for complex text queries, sequence searches, and data browsing by enriched functional terms and KEGG mapping.

Characterisation of two conopressin precursor isoforms in the land snail, Theba pisana.

Increased understanding of the molecular components involved in mollusc reproduction may assist in understanding the evolutionary adaptations used by animals, including hermaphrodites, to produce offspring. The neuropeptide conopressin, a member of the vasopressin/oxytocin-like peptide family, can modulate various reproductive activities in invertebrates. In this study, we used the hermaphroditic land snail, Theba pisana, to investigate the presence and tissue-specific distribution of a conopressin gene. Our transcriptomic analysis of T. pisana CNS sheath tissue has revealed two conopressin gene transcripts (Tpi-conopressin-1 and Tpi-conopressin-2), each encoding for precursors containing an identical conopressin nonapeptide and a variable neurophysin. T. pisana conopressins share high identity with other land snails and slugs, as well as other mollusc and vertebrate vasopressin/oxytocin, supported by phylogenetic analysis. Conserved residues in the T. pisana neurophysin are important for peptide binding, and we present molecular dynamic models demonstrating the most likely stable structure of the Tpi-conopressin-1 peptide when associated with neurophysin. RT-PCR shows that Tpi-conopressin-1 is additionally expressed in reproductive tissues, including the dart sac, where abundant spatial expression throughout the sac region is found; this implies a role in 'love' dart synthesis or dart injection during mating. The presence of a conopressin receptor in the CNS sheath indicates CNS neural excitation. In summary, this study represents a detailed molecular analysis of conopressin in a land snail.

Differential peptide expression in the central nervous system of the land snail Theba pisana, between active and aestivated.

Hypometabolism is a physiological state of dormancy entered by many animals in times of environmental stress. There are gaps in our understanding of the molecular components used by animals to achieve this metabolic state. The availability of genomic and transcriptome data can be useful to study the process of hypometabolism at the molecular level. In this study, we use the land snail Theba pisana to identify peptides that may be involved in the hypometabolic state known as aestivation. We found a total of 22 neuropeptides in the central nervous system (CNS) that were differentially produced during activity and aestivation based on mass spectral-based neuropeptidome analysis. Of these, 4 were upregulated in active animals and 18 were upregulated in aestivation. A neuropeptide known to regulate muscle contractions in a variety of molluscs, the small cardioactive peptide A (sCAPA), and a peptide of yet unknown function (termed Aestivation Associated Peptide 12) were chosen for further investigation using temporal and spatial expression analysis of the precursor gene and peptide. Both peptides share expression within regions of the CNS cerebral ganglia and suboesophageal ganglia. Relative transcript abundance suggests that regulation of peptide synthesis and secretion is post-transcriptional. In summary, we provide new insights into the molecular basis of the regulation of aestivation in land snails through CNS peptide control.

Mentoring for new consultants.

There is increasing evidence of the benefits of having a mentor during the early years as a consultant. Mentoring encourages and provides support to an individual in their professional development. Although there are different forms of mentoring there is recognition that developing a formal mentoring scheme can provide a consistent approach and support within a framework. The Royal College of Physicians of Edinburgh has introduced a mentoring scheme for new consultants that provides a forum for supporting them in their ongoing professional wellbeing. There is potential that the process of mentoring can improve an individual's development, and motivate and encourage them to develop the skills needed to achieve their goals, thus having an impact on ultimately improving their ability to deliver an effective patient-centred service.

The application of water soluble, mega-Stokes-shifted BODIPY fluorophores to cell and tissue imaging.

BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) fluorophores are widely used in bioimaging to label proteins, lipids and nucleotides, but in spite of their attractive optical properties they tend to be prone to self-quenching because of their notably small Stokes shift. Herein, we compare two BODIPY compounds from a recently developed family of naphthyridine substituted BODIPY derivatives, one a visible emitting derivative (BODIPY-VIS) and one a near-infrared emitting fluorophore with a Stokes shift of approximately 165 nm as contrast reagents for live mammalian cells and murine brain tissue. The compounds were rendered water soluble by their conjugation to polyethylene glycol (PEG). Both PEGylated compounds exhibited good cell uptake compared with their parent compounds and confocal fluorescence microscopy revealed all dyes explored to be nuclear excluding, localizing predominantly within the lipophilic organelles; the endoplasmic reticulum and mitochondria. Cytotoxicity studies revealed that these BODIPY derivatives are modestly cytotoxic at concentrations exceeding 10 µM where they induce apoptosis and necrosis. Although the quantum yield of emission of the visible emitting fluorophore was over an order of magnitude greater than the Mega-Stokes shifted probe, the latter showed considerably reduced tendency to self quench and less interference from autofluorescence. The near-infrared probe also showed good penetrability and staining in live tissue samples. In the latter case similar tendency to exclude the nucleus and to localize in the mitochondria and endoplasmic reticulum was observed as in live cells. This to our knowledge is the first demonstration of such a Mega-Stokes BODIPY probe applied to cell and tissue imaging.

The association between postprandial urinary C-peptide creatinine ratio and the treatment response to liraglutide: a multi-centre observational study.

AIMS: The response to glucagon-like peptide 1 receptor agonist treatment may be influenced by endogenous ß-cell function. We investigated whether urinary C-peptide creatinine ratio assessed before or during liraglutide treatment was associated with treatment response. METHODS: A single, outpatient urine sample for urinary C-peptide creatinine ratio was collected 2 h after the largest meal of the day among two separate groups: (1) subjects initiating liraglutide (0.6 â†’ 1.2 mg daily) or (2) subjects already treated with liraglutide for 20-32 weeks. The associations between pretreatment and on-treatment urinary C-peptide creatinine ratio and HbA1c change at 32 weeks were assessed using univariate and multivariate analyses (the ratio was logarithm transformed for multivariate analyses). Changes in HbA1c according to pretreatment urinary C-peptide creatinine ratio quartiles are shown. RESULTS: One hundred and sixteen subjects (70 pretreatment, 46 on treatment) with Type 2 diabetes from 10 diabetes centres were studied. In univariate analyses, neither pretreatment nor on-treatment urinary C-peptide creatinine ratio correlated with HbA1c change (Spearman rank correlation coefficient, r = -0.17, P = 0.17 and r = -0.20, P = 0.19, respectively). In multi-linear regression analyses, entering baseline HbA1c and log urinary C-peptide creatinine ratio, pretreatment and on-treatment log urinary C-peptide creatinine ratio became significantly associated with HbA1c change (P = 0.048 and P = 0.040, respectively). Mean (sd) HbA1c changes from baseline in quartiles 1 to 4 of pretreatment urinary C-peptide creatinine ratio were -3 ± 17 mmol/mol (-0.3 ± 1.6%) (P = 0.52), -12 ± 15 mmol/mol (-1.1 ± 1.4%) (P = 0.003), -11 ± 13 mmol/mol (-1.0 ± 1.2%) (P = 0.002) and -12±17 mmol/mol (-1.1±1.6%) (P=0.016), respectively. CONCLUSIONS: Postprandial urinary C-peptide creatinine ratios before and during liraglutide treatment were weakly associated with the glycaemic response to treatment. Low pretreatment urinary C-peptide creatinine ratio may be more useful than higher values by predicting poorer glycaemic response.

Medication-related pharmacological manipulations of nicotine self-administration in the rat maintained on fixed- and progressive-ratio schedules of reinforcement.

RATIONALE: The use of animal models to study existing medications for smoking cessation can elucidate the mechanism(s) of action of cessation agents and further validate the models for medication development. OBJECTIVE: The objective of the study was to evaluate the response of nicotine self-administration (NSA) to pharmacological agents related to the smoking cessation medication bupropion and to nicotine dosing mimicking nicotine replacement on fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement. MATERIALS AND METHODS: NSA was maintained at a nicotine dose of 30 microg/kg/infusion i.v. in rats trained on FR5 and PR40% schedules. Pharmacological manipulations related to bupropion were examined by treating animals with a dopamine reuptake inhibitor [GBR 12909 (GBR)], a norepinephrine reuptake inhibitor [nisoxetine (NIS)], and a nicotinic antagonist [dihydro-beta-erythroidine (DHbetaE)]. The effect of nicotine replacement was examined on the PR schedule by chronic dosing with osmotic minipumps. RESULTS: Significant treatment effects occurred with NIS and combinations of NIS-DHbetaE and with GBR on response rates. Chronic nicotine dosing reduced self-administration. The two schedules yielded different results with some treatments. CONCLUSIONS: Noradrenergic-nicotinic cholinergic interactions and enhanced responding consequent to dopamine reuptake inhibition may be part of the complex behavioral pharmacology of bupropion-like compounds. Observation of differential results with the two schedules has implication for the use of self-administration techniques to elaborate the mechanisms of dependence as well as drug discovery.

Thyrotoxicosis presenting with headache.

We report three cases of thyrotoxicosis who presented acutely with headache to our neurology service in a 1-year period. In two of these patients there was a pre-existing or subsequent history of migraine. With hindsight, there were other clinical features of thyrotoxicosis but this diagnosis had been missed in primary care. Severe headache can be a striking presenting feature of thyrotoxicosis, but these cases provide reassurance to the clinician that when this does occur, other clinical features of hyperthyroidism are usually present.

The role of the IDDM2 locus in the susceptibility of UK APS1 subjects to type 1 diabetes mellitus.

Autoimmune polyendocrinopathy syndrome type 1 (APS1) is characterized by autoimmune destruction of endocrine tissues and chronic mucocutaneous candidiasis. Type 1 diabetes (T1D) affects 12-25% of patients with APS1, and the prediction of whether this complication will affect an individual is not currently possible. However, alleles of a variable number tandem repeat (VNTR) 5' of the insulin gene are known to influence the development of T1D in the general, non-APS1 population. Therefore, we investigated the prevalence of these IDDM2 alleles in British Caucasian patients with APS1. The study employed genotyping of 33 patients with APS1 for the HphI polymorphism that is in tight linkage disequilibrium with the insulin gene VNTR alleles. Thirty-three patients with APS1 were studied, the mean age was 23.5 years and 24% have T1D. Six of eight (75%) APS1 patients with T1D were homozygous for the class I INS VNTR (susceptibility) allele, compared with eight of 25 (32%) of APS1 patients without T1D (P = 0.042). Our data suggest an association between the development of T1D and homozygosity for the T1D susceptibility class IINS VNTR allele in patients with APS1.

Evaluation of the Cockroft-Gault, Jelliffe and Wright formulae in estimating renal function in elderly cancer patients.

BACKGROUND: More elderly patients are being treated with chemotherapy. Reliable and accurate measures of renal function are needed to obtain predictable, safe and effective exposure to renally excreted drugs. The Jelliffe, Cockroft-Gault and Wright formulae have been used to evaluate renal function, although they have not been validated in elderly oncology patients. We performed a retrospective evaluation of these formulae using the [51Cr]-ethylenediamine tetraacetic acid ([51Cr]-EDTA) method of measuring glomerular filtration rate (GFR) as the 'gold standard'. PATIENTS AND METHODS: Inclusion criteria were age > or = 70 years and serum creatinine <250 micromol/l, performed within 4 weeks of glomerular filtration rate (GFR) measurement. Creatinine clearance was calculated using the Cockroft-Gault, Jelliffe and Wright formulae. The precision and accuracy of the three formulae were compared with the gold standard. RESULTS: Two hundred and twenty-five patients were evaluated: median age, 74 years (range 70-89); males, 108; females, 117; median creatinine, 84 micromol/l (range 44-186). Correlation coefficients of the Jelliffe, Cockroft-Gault and Wright formulae were similar. In the specific GFR ranges of 50-70, 70-90 and 90-120 ml/min, the bias [mean percentage error (MPE)] was +8%, -4% and -13%, respectively. The degree of bias was greater with the Cockroft-Gault and Jelliffe formulae across the same range of GFR with the MPE being -15%, -25%, -32% and -12%, -19% and -23%, respectively. All three formulae have reduced precision and greater bias at the extremes of GFR. CONCLUSIONS: The Wright formula is the most accurate, precise and least biased formula for the calculation of GFR in elderly patients with a GFR >50 ml/min. These results allow the physician to make a decision regarding the use of the formula based on an expected degree of bias.

A comparative study of mRNA and protein expression of the autoimmune regulator gene (Aire) in embryonic and adult murine tissues.

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive human disorder caused by mutations in the autoimmune regulator gene (AIRE) and characterized by multiple autoimmune diseases. As reports of the tissue expression pattern of the murine Aire gene are discordant, a comprehensive survey of Aire expression was undertaken in adult and embryonic tissues at the mRNA and protein levels using real-time RT-PCR, in situ hybridization, and immunohistochemistry. In the adult, the highest Aire mRNA expression was in the thymus. All the other tissues investigated expressed Aire mRNA at low levels, but it was barely detectable in the adrenal gland. Aire protein expression was observed in the thymus, spleen, and lymph nodes. A common pattern was observed in other tissues, with staining in epithelial cells. An exception to this was the gut, where staining was seen in the mucin spaces. In embryonic tissue, Aire mRNA and protein expression was detected from E14.5 in the thymus. In the fetal liver, unlike the adult, staining was observed at E14.5 and decreased towards term. Thus, Aire is expressed in immunologically relevant tissues and in a restricted number of extra-immunological tissues in the adult. Furthermore, the presence of Aire protein is reported in extra-thymic tissues of the embryo.

Comparison of a commercial reversed passive latex agglutination assay to an enzyme immunoassay for the detection of Shiga toxin-producing Escherichia coli.

A multicenter study was performed to compare the performance of a prototypic reversed passive latex agglutination assay (VTEC Screen "Seiken"; Denka-Seiken, Japan) with the Premier EHEC Enzyme Immunoassay (Meridian Diagnostics, USA) for the detection of Shiga toxin in 554 diarrheal stool samples. Standard culture on sorbitol MacConkey agar and the use of latex agglutination reagents were included to identify the Escherichia coli O157, O26 and O111 serotypes. There was 99% agreement between the VTEC screen and enzyme immunoassay (kappa=0.823). Seventeen samples were positive for toxin by one or both assays. One toxin-positive sample using the enzyme immunoassay and four positive samples using the VTEC Screen could not be confirmed. Serotypes identified included: O157:H7 (n=8), O26 (n=2), O111 (n=1) and O45:H2 (n=1). The VTEC screen is easy to perform and comparable to the Meridian EHEC test for detection of Shiga toxin in clinical samples.

A phase I trial of antibody directed enzyme prodrug therapy (ADEPT) in patients with advanced colorectal carcinoma or other CEA producing tumours.

Antibody-directed enzyme prodrug therapy is a targeted therapy in which a prodrug is activated selectively at the tumour site by an enzyme, which has been targeted to the tumour by an antibody (antibody-enzyme conjugate). Previous clinical trials have shown evidence of tumour response, however, the activated drug had a long half-life, which resulted in dose-limiting myelosuppression. Also, the targeting system, although giving high tumour to blood ratios of antibody-enzyme conjugate (10 000 : 1) required administration of a clearing antibody in addition to the antibody-enzyme conjugate. The purpose of this current study therefore was to attempt tumour targeting of the antibody-enzyme conjugate without the clearing antibody, and to investigate a new prodrug (bis-iodo phenol mustard, ZD2767P) whose activated form is highly potent and has a short half-life. Twenty-seven patients were treated with antibody-directed enzyme prodrug therapy using A5CP antibody-enzyme conjugate and ZD2767P prodrug, in a dose-escalating phase I trial. The maximum tolerated dose of ZD2767P was reached at 15.5 mg m(-2)x three administrations with a serum carboxypeptidase G2 level of 0.05 U ml(-1). Myelosuppression limited dose escalation. Other toxicities were mild. Patients' quality of life was not adversely affected during the trial as assessed by the measures used. There were no clinical or radiological responses seen in the study, but three patients had stable disease at day 56. Human anti-mouse antibody and human anti-carboxypeptidase G2 antibody were produced in response to the antibody enzyme conjugate (A5CP). The antibody-enzyme conjugate localisation data (carboxypeptidase G2 enzyme levels by HPLC on tumour and normal tissue samples, and gamma camera analysis of I-131 radiolabelled conjugate) are consistent with inadequate tumour localisation (median tumour: normal tissue ratios of antibody-enzyme conjugate of less than 1). A clearance system is therefore desirable with this antibody-enzyme conjugate or a more efficient targeting system is required. ZD2767P was shown to clear rapidly from the circulation and activated drug was not measurable in the blood. ZD2767P has potential for use in future antibody-directed enzyme prodrug therapy systems.

Trisomy of the short stature homeobox-containing gene (SHOX), resulting from a duplication-deletion of the X chromosome.

The Turner syndrome (TS) is a complex disorder associated with almost invariant short stature and gonadal dysgenesis, as well as a variety of other major organ malformations. Recently, a homeobox-containing gene entitled short-stature homeobox-containing gene (SHOX), was isolated from a minimal short stature gene interval from the pseudoautosomal region of Xp (and Yp). Together with the demonstrable escape of SHOX from X-inactivation, this suggested SHOX to be a strong candidate gene for the short stature component of TS, and as SHOX haploinsufficiency appears to be the molecular basis of a mesomelic short statured skeletal dysplasia (Leri-Weill syndrome), this suggested that SHOX protein expression levels may confer a dosage effect on human stature. However, in this communication we report a normal statured female with gonadal dysgenesis, due to the inheritance of a recombinant duplication-deletion X-chromosome. The karyotype of the proband was 46,X,rec(X)dup(Xp)inv(X)(p11.22q21.2)mat and fluorescent in situ hybridization of her metaphases with a SHOX cosmid confirmed the proband to be trisomic for SHOX. This communication suggests the relationship between levels of SHOX expression and human stature to be more complex than envisaged previously. The presence of normal stature in our patient rather than tall stature is likely to represent the natural variation seen in patients with transcription factor disorders.

GABA mechanisms in the pedunculopontine tegmental nucleus influence particular aspects of nicotine self-administration selectively in the rat.

RATIONALE: The pedunculopontine tegmental nucleus (PPTg) is part of the neuronal circuit activated by self-administered nicotine. The cholinergic neurons of the PPTg comprise a prominent projection to midbrain dopamine neurons. However, anatomical studies of Fos expression suggest that nicotine targets primarily non-cholinergic neurons in the PPTg, especially GABAergic and glutamatergic neurons. OBJECTIVE: The objective of these experiments was to examine the role of GABA manipulations in the PPTg on nicotine self-administration. METHODS AND RESULTS: Rats trained to self-administer nicotine or cocaine intravenously were prepared with brain microcannulae directed to the PPTg. Intra-PPTg microinfusions of the GABA agonists muscimol (10-50 ng) and baclofen (30-60 ng) reduced nicotine self-administration maintained on a fixed-ratio schedule of reinforcement (30 microg/kg per infusion); self-administration of cocaine (0.3 mg/kg per infusion) under an identical schedule was not affected. Muscimol and baclofen were also examined after intra-PPTg microinfusion in animals trained to self-administer nicotine on a progressive-ratio schedule (10 and 30 microg/kg per infusion). Progressive-ratio responding was sensitive to pharmacological manipulations such as a change in the nicotine dose available for self-administration, or intra-PPTg microinfusion of the nicotinic antagonist dihydro-beta-erythroidine (30 microg). However, nicotine self-administration on a progressive-ratio schedule was not altered by intra-PPTg microinfusions of GABA agonists. CONCLUSIONS: These data confirm that the PPTg is involved in nicotine self-administration, a conclusion that is independent of the schedule of reinforcement that is used. GABAergic mechanisms in the PPTg play a selective role in nicotine reinforcement compared to cocaine, and that role is restricted to the characteristics of reinforcement measured by fixed-ratio responding.

Mathematical model of antibody targeting: important parameters defined using clinical data.

Antibody-targeted therapy of cancer has shown benefits in the treatment of some cancers but selective delivery has not been optimized. Many parameters influence antibody targeting; some will have a greater effect than others and their effects will generally be interrelated. They include effects of blood flow and pressure, vascular permeability, venous and lymphatic drainage, permeation through extravascular spaces, antibody clearance, specificity, affinity and resistance to degradation. Quantitative data about the behaviour of targeting systems can be collected, and it is possible to describe the system in terms of compartments interconnected by equations defining the passage of targeting agents between them. A mathematical model of antibody targeting can thus be built. We have collected data on the time course of the distribution of four different antibody molecules of molecular weight 27, 100 and 150 kDa directed against carcinoembryonic antigen in patients with colorectal cancer. Laboratory data were used for parameters which could not be measured in patients. These data have been used to test the validity of the model for man and to develop it so that it is consistent with the diverse clinical data. The model is then used to understand the effects of changes to a parameter on tumour targeting efficiency and to select those parameters which have the greatest effect in therapy. Affinity of antibody, flow of antibody through the tumour and rate of elimination of antibody from the tumour were shown to be the most powerful parameters determining antibody localization. These concepts can be used to determine design parameters for antibody-targeted cancer therapy.

The clinical application of a dual head gamma camera with coincidence detection in 20 women with suspected ovarian cancer.

OBJECTIVE: To assess the effectiveness of a dual head coincidence gamma camera in identifying ovarian cancer as a less expensive alternative to the traditional 2-[18F] fluoro-2-deoxy-D-glucose (18FDG) system using positron emission tomography. DESIGN: Prospective study. POPULATION: Twenty consecutive women suspected of having ovarian carcinoma. Inclusion was based on abnormal serum CA125 (reference range is 0-35 units/L), ultrasound, computerised tomography or clinical findings. METHODS: Women underwent assessment before staging laparotomy. Two nuclear medicine physicians, who were blinded to the pre-operative assessment, reported on 18FDG- dual head coincidence gamma camera imaging. MAIN OUTCOME MEASURES: The histology and operative staging were compared with the 18FDG- dual head coincidence gamma camera findings. RESULTS: Twelve women had pelvic malignancies (nine primary and three recurrences), seven women had benign pathology and one patient had a borderline malignancy. We were able to image accurately all malignant pelvic masses with dual head coincidence gamma camera, as well as accurately demonstrate disease spread. Two of the benign pelvic masses localised 18FDG. The positive predictive value for detecting malignancy was 86%. CONCLUSIONS: Dual head coincidence gamma camera offers accurate and affordable imaging in suspected ovarian masses, with improved specificity over CA125, ultrasound and computerised tomography. These results are similar to those obtained on more expensive dedicated PET systems. We report on a series of patients believed to have primary or recurrent carcinoma and recognise the need to include patients more likely to have benign lesions to assess false positive results. However, we believe that dual head coincidence gamma camera is useful in the pre-operative assessment of women with suspected ovarian cancer.