Differentiation of BIRADS-4 small breast lesions via Multimodal Ultrasound Tomography.

PURPOSE: To demonstrate the use of a new 3D diagnostic imaging technology, termed Multimodal Ultrasonic Tomography (MUT), for the detection of solid breast lesions < 15 mm in maximum dimension. METHODS AND MATERIALS: 3D MUT imaging was performed on 71 volunteers presenting BIRADS-4 nodules, asymmetrical densities, and architectural distortions in X-ray mammograms, who subsequently underwent biopsy. MUT involved D tomographic imaging of the pendulant breast in a water bath using transmission ultrasound and constructed multimodal images corresponding to refractivity and frequency-dependent attenuation (calibrated relative to water). The multimodal images were fused into composite images and a composite index (CI) was calculated and used for diagnostic purposes. The composite images were evaluated against results of histopathology on biopsy specimens. RESULTS: Histopathology revealed 22 malignant and 49 benign lesions. The pixels of 22 malignant lesions exhibited high values in both refractivity and attenuation, resulting in CI values > 1. In contrast, 99.9% of benign lesions and normal tissue pixels exhibited lower values of at least one of the attributes measured, corresponding to CI values < 1. CONCLUSIONS: MUT imaging appears to differentiate small malignant solid breast lesions as exhibiting CI values >1, while benign lesions or normal breast tissues exhibit CI values <1. KEY POINTS: • MUT was able to detect all 22 biopsy-confirmed malignant lesions. • MUT was able to differentiate the malignant from the benign lesions. • Additional MUT detections outside the biopsy area must be evaluated prospectively.

Model-based physiomarkers of cerebral hemodynamics in patients with mild cognitive impairment.

In our previous studies, we have introduced model-based "functional biomarkers" or "physiomarkers" of cerebral hemodynamics that hold promise for improved diagnosis of early-stage Alzheimer's disease (AD). The advocated methodology utilizes subject-specific data-based dynamic nonlinear models of cerebral hemodynamics to compute indices (serving as possible diagnostic physiomarkers) that quantify the state of cerebral blood flow autoregulation to pressure-changes (CFAP) and cerebral CO2 vasomotor reactivity (CVMR) in each subject. The model is estimated from beat-to-beat measurements of mean arterial blood pressure, mean cerebral blood flow velocity and end-tidal CO2, which can be made reliably and non-invasively under resting conditions. In a previous study, it was found that a CVMR index quantifying the impairment in CO2 vasomotor reactivity correlates with clinical indications of early AD, offering the prospect of a potentially useful diagnostic tool. In this paper, we explore the use of the same model-based indices for patients with amnestic Mild Cognitive Impairment (MCI), a preclinical stage of AD, relative to a control subjects and clinical cognitive assessments. It was found that the model-based CVMR values were lower for MCI patients relative to the control subjects.

Model-based quantification of cerebral hemodynamics as a physiomarker for Alzheimer's disease?

Previous studies have found that Alzheimer's disease (AD) impairs cerebral vascular function, even at early stages of the disease. This offers the prospect of a useful diagnostic method for AD, if cerebral vascular dysfunction can be quantified reliably within practical clinical constraints. We present a recently developed methodology that utilizes a data-based dynamic nonlinear closed-loop model of cerebral hemodynamics to compute "physiomarkers" quantifying the state of cerebral flow autoregulation to pressure-changes (CA) and cerebral CO2 vasomotor reactivity (CVMR) in each subject. This model is estimated from beat-to-beat measurements of mean arterial blood pressure, mean cerebral blood flow velocity and end-tidal CO2, which can be made reliably and non-invasively under resting conditions. This model may also take an open-loop form and comparisons are made with the closed-loop counterpart. The proposed model-based physiomarkers take the form of two indices that quantify the gain of the CA and CVMR processes in each subject. It was found in an initial set of clinical data that the CVMR index delineates AD patients from control subjects and, therefore, may prove useful in the improved diagnosis of early-stage AD.

Closed-loop dynamic modeling of cerebral hemodynamics.

The dynamics of cerebral hemodynamics have been studied extensively because of their fundamental physiological and clinical importance. In particular, the dynamic processes of cerebral flow autoregulation (CFA) and CO2 vasomotor reactivity have attracted broad attention because of their involvement in a host of pathologies and clinical conditions (e.g., hypertension, syncope, stroke, traumatic brain injury, vascular dementia, Alzheimer's disease, mild cognitive impairment etc.). This raises the prospect of useful diagnostic methods being developed on the basis of quantitative models of cerebral hemodynamics, if cerebral vascular dysfunction can be quantified reliably from data collected within practical clinical constraints. This paper presents a modeling method that utilizes beat-to-beat measurements of mean arterial blood pressure, cerebral blood flow velocity and end-tidal CO2 (collected non-invasively under resting conditions) to quantify the dynamics of CFA and cerebral vasomotor reactivity (CVMR). The unique and novel aspect of this dynamic model is that it is nonlinear and operates in a closed-loop configuration.

Novel technology of multimodal ultrasound tomography detects breast lesions.

OBJECTIVES: To introduce a new three-dimensional (3D) diagnostic imaging technology, termed "multimodal ultrasonic tomography" (MUT), for the detection of breast cancer without ionising radiation or compression. METHODS: MUT performs 3D tomography of the pendulant breast in a water-bath using transmission ultrasound in a fixed-coordinate system. Specialised electronic hardware and signal processing algorithms are used to construct multimodal images for each coronal slice, corresponding to measurements of refractivity and frequency-dependent attenuation and dispersion. In-plane pixel size is 0.25 mm × 0.25 mm and the inter-slice interval can vary from 1 to 4 mm, depending on clinical requirements. MUT imaging was performed on 25 patients ("off-label" use for research purposes only), presenting lesions with sizes >10 mm. Histopathology of biopsy samples, obtained from all patients, were used to evaluate the MUT outcomes. RESULTS: All lesions (21 malignant and four benign) were clearly identified on the MUT images and correctly classified into benign and malignant based on their respective multimodal information. Malignant lesions generally exhibited higher values of refractivity and frequency-dependent attenuation and dispersion. CONCLUSION: Initial clinical results confirmed the ability of MUT to detect and differentiate all suspicious lesions with sizes >10 mm discernible in mammograms of 25 female patients.

The efficacy of licensed-indication use of donepezil and memantine monotherapies for treating behavioural and psychological symptoms of dementia in patients with Alzheimer's disease: systematic review and meta-analysis.

BACKGROUND/AIMS: Behavioural and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD) greatly increase caregiver burden. The abilities of donepezil and memantine to manage BPSD within their licensed indications in AD were compared. METHODS: A systematic review, random effects meta-analysis and Bucher indirect comparison were conducted. RESULTS: Six randomised controlled studies (4 donepezil and 2 memantine) reported use within the licensed indication and had Neuropsychiatric Inventory (NPI) data suitable for meta-analysis. BPSD showed significant improvement with donepezil compared with placebo [weighted mean difference (WMD) in NPI -3.51, 95% confidence interval (CI) -5.75, -1.27], whereas this was not the case for memantine (WMD -1.65, 95% CI -4.78, 1.49). WMD in NPI for donepezil versus memantine favoured donepezil but was not statistically significant (-1.86, 95% CI -5.71, 1.99; p = 0.34). CONCLUSION: Within its licensed indication, donepezil is efficacious for the management of BPSD in AD compared with placebo.

Mixed treatment comparison and meta-regression of the efficacy and safety of prostaglandin analogues and comparators for primary open-angle glaucoma and ocular hypertension.

OBJECTIVES: Primary open-angle glaucoma (POAG) is a chronic condition characterised by optic neuropathy and vision loss. Elevated intraocular pressure (IOP) can damage the optic nerve and is a risk factor for glaucoma, thus treatment usually comprises topical hypotensives. This analysis aims to address methodological issues associated with the synthesis of glaucoma clinical trial data, given variations in study methodology and IOP measurement. METHODS: Meta-regression was used to estimate how IOP varies over time for patients receiving treatment. Relative treatment effects were assessed using a random-effects mixed treatment comparison (MTC) in order to preserve randomisation and avoid selection bias. To produce clinically meaningful outputs, these analyses were combined to obtain the mean on-treatment IOP and the proportion of patients achieving different IOP targets at different time points. A further MTC estimated the probability of hyperaemia events. RESULTS: The analysis showed that after 3 months' treatment, between 58 and 83% of patients will have a > or =20% reduction in IOP and 70-93% of patients will have an absolute IOP <20 mmHg. Latanoprost and bimatoprost were found to produce significantly lower on-treatment IOP compared with timolol (p < 0.05); the difference between latanoprost and bimatoprost was not significant. Travoprost produced a lower mean IOP compared with timolol (not significant). Latanoprost-timolol was found to produce significantly lower IOP than latanoprost alone or beta-blockers. The probability of hyperaemia-type events varied between treatments from 14.8 to 63.03%. Latanoprost had significantly lower odds of hyperaemia than travoprost, bimatoprost, travoprost-timolol, or bimatoprost-timolol. CONCLUSION: This analysis suggests that latanoprost and bimatoprost produce a statistically significant reduction in IOP compared with timolol, but are associated with a higher risk of hyperaemia. Out of all the prostaglandins, latanoprost may achieve a good balance between tolerability and IOP efficacy. As with all forms of meta-analysis, the results are based on the assumption that the studies and intervention groupings are sufficiently similar to be compared.

Glycogen synthase kinase-3 and Axin function in a beta-catenin-independent pathway that regulates neurite outgrowth in neuroblastoma cells.

We have sought to determine the roles of beta-catenin and the Wnt signaling pathway in neurite outgrowth using a model cell system, the Neuro-2a neuroblastoma cell line. Activation of the Wnt signaling pathway disrupts a multiprotein complex that includes beta-catenin, Axin, and glycogen synthase kinase-3 (GSK-3), which would otherwise promote the phosphorylation and degradation of beta-catenin. Stabilized beta-catenin accumulates in the cytosol and in the nucleus; in the nucleus it binds to TCF family transcription factors, forming a bipartite transcriptional activator of Wnt target genes. These events can be mimicked by lithium (Li(+)), which inhibits GSK-3 activity. Both Li(+) and the GSK-3 inhibitor SB415286 induced neurite outgrowth of Neuro-2a cells. Li(+)-induced neurite outgrowth did not require beta-catenin-/TCF-dependent transcription, and increasing levels of beta-catenin either by transfection or using Wnt-3A was not sufficient to induce neurite outgrowth. Interestingly, Axin, which is also a substrate for GSK-3, was destabilized by Li(+) and ectopic expression of Axin inhibited Li(+)-induced neurite outgrowth. Deletion analysis of Axin indicated that this inhibition required the GSK-3 binding site, but not the beta-catenin binding site. Our results suggest that a signaling pathway involving Axin and GSK-3, but not beta-catenin, regulates Li(+)-induced neurite outgrowth in Neuro-2a cells.

Development of the health and economic consequences of smoking interactive model.

OBJECTIVE: To describe the health and economic consequences of smoking model, a user friendly, web based tool, designed to estimate the health and economic outcomes associated with smoking and the benefits of smoking cessation. RESULTS: An overview of the development of the model equations and user interface is given, and data from the UK are presented as an example of the model outputs. These results show that a typical smoking cessation strategy costs approximately 1200 pounds sterling per life year saved and 22,000 pounds sterling per death averted. CONCLUSIONS: The model successfully captures the complexity required to model smoking behaviour and associated mortality, morbidity, and health care costs. Furthermore, the interface provides the results in a simple and flexible way so as to be useful to a variety of audiences and to simulate a variety of smoking cessation methods.

Alternative responses to child protective services: emerging issues and concerns.

PROBLEM: Increased calls to "do something" about child protective services (CPS) have resulted in proposals or new "paradigms" for services to at-risk or abusive families. These new paradigms call for the reform or revamping of CPS through the development of a community-based alternative response to some reports of child abuse and/or neglect. METHOD: This article reports on outcomes for 1,263 "low" risk CPS referrals diverted to a community-based alternative response system. Data on child, family, and case characteristics and services provided are presented as well as outcomes associated with re-referral and placement post service provision. RESULTS: The risk level and severity of some of the referrals to alternative response systems seems inappropriately high. The rates of re-referral were similar for families who did or did not engage in assessment services, and were highest for families where domestic violence was present. CONCLUSIONS: Criteria for diversion to community alternatives to CPS must be clearly articulated and applied. Both CPS and alternative response system workers must have the skills required to address a family's recognition of the problem and degree of motivation to engage in problem resolution, and to understand their relationship to continued risk of CA/N.

GABAC receptor sensitivity is modulated by interaction with MAP1B.

GABA(C) receptors contain rho subunits and mediate feedback inhibition from retinal amacrine cells to bipolar cells. We previously identified the cytoskeletal protein MAP1B as a rho1 subunit anchoring protein. Here, we analyze the structural basis and functional significance of the MAP1B-rho1 interaction. Twelve amino acids at the C terminus of the large intracellular loop of rho1 (and also rho2) are sufficient for interaction with MAP1B. Disruption of the MAP1B-rho interaction in bipolar cells in retinal slices decreased the EC(50) of their GABA(C) receptors, doubling the receptors' current at low GABA concentrations without affecting their maximum current at high concentrations. Thus, anchoring to the cytoskeleton lowers the sensitivity of GABA(C) receptors and provides a likely site for functional modulation of GABA(C) receptor-mediated inhibition.

The DNA repair inhibitors hydroxyurea and cytosine arabinoside enhance the sensitivity of the alkaline single-cell gel electrophoresis ('comet') assay in metabolically-competent MCL-5 cells.

We have found previously that the metabolically-competent human MCL-5 cell line did not appear to be usefully sensitive to the DNA-damaging effects of several carcinogens, as measured by the alkaline single-cell gel electrophoresis ('comet') assay. We therefore sought to increase its sensitivity by inhibiting DNA repair during exposure to test compounds, using 10 mM hydroxyurea (HU) and 1.8 mM cytosine arabinoside (ara-C), which inhibit DNA resynthesis during nucleotide excision repair. The following compounds were tested, using a 30-min exposure, in the absence or presence of HU/ara-C: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4, 8-DiMeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-9H-pyrido[2,3-b]indole (A[alpha]C), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA[alpha]C), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), benzo[a]pyrene (B[a]P), 3-methylcholanthrene (3-MCA), 7, 12-dimethylbenz[a]anthracene (DMBA), 1-nitropyrene (1-NP), 2-nitrofluorene (2-NF), aniline, o-toluidine, benzene, lindane, bleomycin, cisplatin, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), sodium chromate, chromic chloride, and diethylstilboestrol (DES). We made the following observations. The background level of comet formation was reasonably constant over several months and was increased only slightly, but significantly, in the presence of the DNA-repair inhibitors. All compounds that induced comet formation did so without appreciable cytotoxicity as assessed by trypan blue exclusion. Of the compounds tested, the heterocyclic amines and polycyclic aromatic hydrocarbons (with the exceptions of PhIP and B[a]P) failed to induce convincing levels of comet formation in the absence of repair inhibitors. In their presence the heterocyclic amines tested induced comet formation (with the exception of 8-MeIQx), with widely differing potencies. 1-NP failed to elicit marked comet formation even in the presence of HU/ara-C. Aniline and o-toluidine produced significant levels of comet formation in the absence of HU/ara-C, but in their presence comet formation was markedly increased. Benzene, lindane, bleomycin, cisplatin, MNNG, sodium chromate and chromic chloride induced comet formation in the absence of HU/ara-C, but, with the exception of cisplatin, their presence enhanced comet formation. Neither sucrose nor DES elicited comet formation under the conditions used in this study. Many more agents need to be tested in order to determine how well the comet assay using MCL-5 cells (or modified versions of it) can distinguish genotoxins from non-genotoxins.

Postgraduate education and training: challenges for the future.

In spite of much attention to the needs of doctors in the training grades over the last decade, the current agenda for change in the NHS is very large and much needs to be done to fit these trainees for the career grade doctors of the future. This article looks briefly at some of the issues facing training grade doctors as they train for a career in the NHS in the first part of the twenty-first century.

Two-dimensional models of tumour angiogenesis and anti-angiogenesis strategies.

There is a very strong link between the vascularization of a tumour and the spread of the disease, both locally and to distant sites (Gimbrone et al., 1974, J. Natl. Cancer Inst. 52, 413-27; Muthukkaruppan et al., 1982, J. Natl. Cancer Inst. 69, 699-704; Ellis & Fiddler, 1995, Lancet 346, 388-9). A tumour becomes vascularized by a process known as angiogenesis. Tumour angiogenesis is initiated by the release of diffusible substances by the tumour, whereby neighbouring capillary vessels are stimulated to grow and eventually penetrate the tumour. Anti-angiogenesis has been proposed as a potential strategy for the treatment of cancer (Folkman, 1995, Nature Med. 1, 21-31; Harris et al., 1996, Breast Cancer Res. Treat. 38, 97-108). In this paper, a mathematical model of the development of the tumour vasculature is presented. By suitable manipulation of the model parameters, we simulate various anti-angiogenesis strategies and we examine the roles that haptotaxis and chemotaxis may play during the growth of the neovasculature. The model is simulated in two space dimensions (on a square domain) so that it is, in theory, experimentally reproducible and any predictions of the model can therefore be tested.

A mathematical model of the first steps of tumour-related angiogenesis: capillary sprout formation and secondary branching.

The growth of a solid tumour is dependent on an adequate supply of nutrients. A tumour can establish a blood supply by inducing neighbouring blood vessels to sprout and grow towards it, a process known as angiogenesis. The tumour cells may secrete a number of diffusible chemicals which stimulate endothelial cell to migrate, to rearrange themselves into capillary tubes or sprouts, and to proliferate. In this paper we focus firstly upon the early stage of angiogenesis wherein the endothelial cells group together in the parent vessel to form the initial capillary-sprout buds. A mathematical model for the formation of the capillary buds is presented which focuses on the potential role that haptotaxis may play. In Section 2 we turn attention to the endothelial cells within the growing and developing capillary sprouts as they migrate towards the tumour cells. Once again the potential role of haptotaxis is focused upon.

The chemotherapy of onchocerciasis XVII. A clinical evaluation of albendazole in patients with onchocerciasis; effects of food and pretreatment with ivermectin on drug response and pharmacokinetics.

Three pharmacokinetic studies were conducted in Ghanaian patients in support of investigations of albendazole and its combination with ivermectin in the treatment of onchocerciasis. These included dose-finding studies, investigations into the influence of a fatty meal on the relative bioavailability of albendazole as assessed by the measurement of concentrations of albendazole sulphoxide and the effect of prior treatment with ivermectin on antiparasitic efficacy and plasma concentrations of albendazole suphoxide. Increasing the dose of albendazole from 800 mg x 3 daily to 1200 mg x 3 daily produced no additional antiparasitic effects although plasma concentrations of albendazole sulphoxide were increased in proportion to dose size. Moreover, the plasma concentration vs time profiles suggest that most of the effects observed may have been due to the first 800 mg dose. Administration of ivermectin had no effect on the pharmacokinetics of albendazole sulphoxide and there was no additive effect on the parasite. Albendazole was well tolerated and its administration 5-7 days after ivermectin produced little additional reaction. Although it is not macrofilaricidal, it does possess important chemosterilant properties which are enhanced by its administration with a fatty breakfast. Under these conditions, the relative bioavailability of albendazole is increased four-fold. These studies support further work with albendazole administered with food either as a single dose, as multiple single doses repeated at intervals of several months and its coadministration with ivermectin. They also encourage the belief that a more potent and bioavailable benzimidazole may be macrofilaricidal or a permanent chemosterilant for Onchocerca volvulus on single dosage.