Amino acids in oral drug delivery:salts, ion-pairs and transcriptomics

Oral drug delivery is considered the most popular route of delivery because of the ease of administration, availability of a wide range of dosage forms and the large surface area for drug absorption via the intestinal membrane. However, besides the unfavourable biopharmaceutical properties of the therapeutic agents, efflux transporters such as Pglycoprotein (P-gp) and multiple resistance proteins (MRP) decrease the overall drug uptake by extruding the drug from the cells. Although, prodrugs have been investigated to improve drug partitioning by masking the polar groups covalently with pre-moieties promoting increased uptake, they present significant challenges including reduced solubility and increased toxicity. The current work investigates the use of amino acids as ion-pairs for three model drugs: indomethacin (weak acid), trimethoprim (weak base) and ciprofloxacin (zwitter ion) in an attempt to improve both solubility and uptake. Solubility was studied by salt formation while creating new routes for uptake across the membranes via amino acids transporter proteins or dipeptidyl transporters was the rationale to enhance absorption. New salts were prepared for the model drugs and the oppositely charged amino acids by freeze drying and they were characterised using FTIR, 1HNMR, DSC, SEM, pH solubility profile, solubility and dissolution. Permeability profiles were assessed using an in vitro cell based method; Caco-2 cells and the genetic changes occurring across the transporter genes and various pathways involved in the cellular activities were studied using DNA microarrays. Solubility data showed a significant increase in drug solubility upon preparing the new salts with the oppositely charged counter ions (ciprofloxacin glutamate salt exhibiting 2.9x103 fold enhancement when compared to the free drug). Moreover, permeability studies showed a 3 fold increase in trimethoprim and indomethacin permeabilities upon ion-pairing with amino acids and more than 10 fold when the zwitter ionic drug was paired with glutamic acid. Microarray data revealed that trimethoprim was absorbed actively via OCTN1 transporters while MRP7 is the main transporter gene that mediates its efflux. The absorption of trimethoprim from trimethoprim glutamic acid ion-paired formulations was affected by the ratio of glutamic acid in the formulation which was inversely proportional to the degree of expression of OCTN1. Interestingly, ciprofloxacin glutamic acid ion-pairs were found to decrease the up-regulation of ciprofloxacin efflux proteins (P-gp and MRP4) and over-express two solute carrier transporters; (PEPT2 and SLCO1A2) suggesting that a high aqueous binding constant (K11aq) enables the ion-paired formulations to be absorbed as one entity. In conclusion, formation of ion-pairs with amino acids can influence in a positive way solubility, transfer and gene expression effects of drugs.

Eye movement problems and differential diagnosis of the parkinsonian syndromes

Differential clinical diagnosis of the parkinsonian syndromes, viz., Parkinson’s disease (PD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) can be difficult. Eye movement problems, however, are a chronic complication of many of these disorders and may be a useful aid to diagnosis. Hence, the presence in PSP of vertical supranuclear gaze palsy, fixation instability, lid retraction, blepharospasm, and apraxia of eyelid opening and closing is useful in separating PD from PSP. Moreover, atypical features of PSP include slowing of upward saccades, moderate slowing of downward saccades, the presence of a full range of voluntary vertical eye movements, a curved trajectory of oblique saccades, and absence of square-wave jerks. Downgaze palsy is probably the most useful diagnostic clinical symptom of PSP. By contrast, DLB patients are specifically impaired in both reflexive and saccadic execution and in the performance of more complex saccadic eye movement tasks. Problems in convergence in DLB are also followed by akinesia and rigidity. Abnormal ocular fixation may occur in a significant proportion of MSA patients along with excessive square-wave jerks, a mild supranuclear gaze palsy, a gaze-evoked nystagmus, a positioning down-beat nystagmus, mild-moderate saccadic hypometria, impaired smooth pursuit movements, and reduced vestibulo-ocular reflex (VOR) suppression. There may be considerable overlap between the eye movement problems characteristic of the various parkinsonian disorders, but taken together with other signs and symptoms, can be a useful aid in differential diagnosis, especially in the separation of PD and PSP.

The Maudsley Early Onset Schizophrenia Study:The effect of age of onset and illness duration on fronto-parietal gray matter

Objective: In Early Onset Schizophrenia (EOS; onset before the 18th birthday) late brain maturational changes may interact with disease mechanisms leading to a wave of back to front structural changes during adolescence. To further explore this effect we examined the relationship between age of onset and duration of illness on brain morphology in adolescents with EOS. Subjects and methods: Structural brain magnetic resonance imaging scans were obtained from 40 adolescents with EOS. We used Voxel Based Morphometry and multiple regressions analyses, implemented in SPM, to examine the relationship between gray matter volume with age of onset and illness duration. Results: Age of onset showed a positive correlation with regional gray matter volume in the right superior parietal lobule (Brodmann Area 7). Duration of illness was inversely related to regional gray matter volume in the left inferior frontal gyrus (BA 11/47). Conclusions: Parietal gray matter loss may contribute to the onset of schizophrenia while orbitofrontal gray matter loss is associated with illness duration. © 2008 Elsevier Masson SAS. All rights reserved.

Introduction : the role of quality, production and technological innovation in improving competitive performance

Quality, production and technological innovation management rank among the most important matters of concern to modern manufacturing organisations. They can provide companies with the decisive means of gaining a competitive advantage, especially within industries where there is an increasing similarity in product design and manufacturing processes. The papers in this special issue of International Journal of Technology Management have all been selected as examples of how aspects of quality, production and technological innovation can help to improve competitive performance. Most are based on presentations made at the UK Operations Management Association's Sixth International Conference held at Aston University at which the theme was 'Getting Ahead Through Technology and People'. At the conference itself over 80 papers were presented by authors from 15 countries around the world. Among the many topics addressed within the conference theme, technological innovation, quality and production management emerged as attracting the greatest concern and interest of delegates, particularly those from industry. For any new initiative to be implemented successfully, it should be led from the top of the organization. Achieving the desired level of commitment from top management can, however, be a difficulty. In the first paper of this issue, Mackness investigates this question by explaining how systems thinking can help. In the systems approach, properties such as 'emergence', 'hierarchy', 'commnication' and 'control' are used to assist top managers in preparing for change. Mackness's paper is then complemented by Iijima and Hasegawa's contribution in which they investigate the development of Quality Information Management (QIM) in Japan. They present the idea of a Design Review and demonstrate how it can be used to trace and reduce quality-related losses. The next paper on the subject of quality is by Whittle and colleagues. It relates to total quality and the process of culture change within organisations. Using the findings of investigations carried out in a number of case study companies, they describe four generic models which have been identified as characterising methods of implementing total quality within existing organisation cultures. Boaden and Dale's paper also relates to the management of quality, but looks specifically at the construction industry where it has been found there is still some confusion over the role of Quality Assurance (QA) and Total Quality Management (TQM). They describe the results of a questionnaire survey of forty companies in the industry and compare them to similar work carried out in other industries. Szakonyi's contribution then completes this group of papers which all relate specifically to the question of quality. His concern is with the two ways in which R&D or engineering managers can work on improving quality. The first is by improving it in the laboratory, while the second is by working with other functions to improve quality in the company. The next group of papers in this issue all address aspects of production management. Umeda's paper proposes a new manufacturing-oriented simulation package for production management which provides important information for both design and operation of manufacturing systems. A simulation for production strategy in a Computer Integrated Manufacturing (CIM) environment is also discussed. This paper is then followed by a contribution by Tanaka and colleagues in which they consider loading schedules for manufacturing orders in a Material Requirements Planning (MRP) environment. They compare mathematical programming with a knowledge-based approach, and comment on their relative effectiveness for different practical situations. Engstrom and Medbo's paper then looks at a particular aspect of production system design, namely the question of devising group working arrangements for assembly with new product structures. Using the case of a Swedish vehicle assembly plant where long cycle assembly work has been adopted, they advocate the use of a generally applicable product structure which can be adapted to suit individual local conditions. In the last paper of this particular group, Tay considers how automation has affected the production efficiency in Singapore. Using data from ten major industries he identifies several factors which are positively correlated with efficiency, with capital intensity being of greatest interest to policy makers. The two following papers examine the case of electronic data interchange (EDI) as a means of improving the efficiency and quality of trading relationships. Banerjee and Banerjee consider a particular approach to material provisioning for production systems using orderless inventory replenishment. Using the example of a single supplier and multiple buyers they develop an analytical model which is applicable for the exchange of information between trading partners using EDI. They conclude that EDI-based inventory control can be attractive from economic as well as other standpoints and that the approach is consistent with and can be instrumental in moving towards just-in-time (JIT) inventory management. Slacker's complementary viewpoint on EDI is from the perspective of the quality relation-ship between the customer and supplier. Based on the experience of Lucas, a supplier within the automotive industry, he concludes that both banks and trading companies must take responsibility for the development of payment mechanisms which satisfy the requirements of quality trading. The three final papers of this issue relate to technological innovation and are all country based. Berman and Khalil report on a survey of US technological effectiveness in the global economy. The importance of education is supported in their conclusions, although it remains unclear to what extent the US government can play a wider role in promoting technological innovation and new industries. The role of technology in national development is taken up by Martinsons and Valdemars who examine the case of the former Soviet Union. The failure to successfully infuse technology into Soviet enterprises is seen as a factor in that country's demise, and it is anticipated that the newly liberalised economies will be able to encourage greater technological creativity. This point is then taken up in Perminov's concluding paper which looks in detail at Russia. Here a similar analysis is made of the concluding paper which looks in detail at Russia. Here a similar analysis is made of the Soviet Union's technological decline, but a development strategy is also presented within the context of the change from a centralised to a free market economy. The papers included in this special issue of the International Journal of Technology Management each represent a unique and particular contribution to their own specific area of concern. Together, however, they also argue or demonstrate the general improvements in competitive performance that can be achieved through the application of modern principles and practice to the management of quality, production and technological innovation.

GEO Label:user and producer perspectives on a label for geospatial data

One of the aims of the Science and Technology Committee (STC) of the Group on Earth Observations (GEO) was to establish a GEO Label- a label to certify geospatial datasets and their quality. As proposed, the GEO Label will be used as a value indicator for geospatial data and datasets accessible through the Global Earth Observation System of Systems (GEOSS). It is suggested that the development of such a label will significantly improve user recognition of the quality of geospatial datasets and that its use will help promote trust in datasets that carry the established GEO Label. Furthermore, the GEO Label is seen as an incentive to data providers. At the moment GEOSS contains a large amount of data and is constantly growing. Taking this into account, a GEO Label could assist in searching by providing users with visual cues of dataset quality and possibly relevance; a GEO Label could effectively stand as a decision support mechanism for dataset selection. Currently our project - GeoViQua, - together with EGIDA and ID-03 is undertaking research to define and evaluate the concept of a GEO Label. The development and evaluation process will be carried out in three phases. In phase I we have conducted an online survey (GEO Label Questionnaire) to identify the initial user and producer views on a GEO Label or its potential role. In phase II we will conduct a further study presenting some GEO Label examples that will be based on Phase I. We will elicit feedback on these examples under controlled conditions. In phase III we will create physical prototypes which will be used in a human subject study. The most successful prototypes will then be put forward as potential GEO Label options. At the moment we are in phase I, where we developed an online questionnaire to collect the initial GEO Label requirements and to identify the role that a GEO Label should serve from the user and producer standpoint. The GEO Label Questionnaire consists of generic questions to identify whether users and producers believe a GEO Label is relevant to geospatial data; whether they want a single "one-for-all" label or separate labels that will serve a particular role; the function that would be most relevant for a GEO Label to carry; and the functionality that users and producers would like to see from common rating and review systems they use. To distribute the questionnaire, relevant user and expert groups were contacted at meetings or by email. At this stage we successfully collected over 80 valid responses from geospatial data users and producers. This communication will provide a comprehensive analysis of the survey results, indicating to what extent the users surveyed in Phase I value a GEO Label, and suggesting in what directions a GEO Label may develop. Potential GEO Label examples based on the results of the survey will be presented for use in Phase II.

Competition, agency and productivity

This article tests a set of hypotheses relating to agency and Schumpeterian views on how competition affects performance. A survey data set of Australian workplaces is used, with the change in labour productivity as the dependent variable. The results show strong support for the idea that intense competition raises productivity growth in managerial workplaces, but not in non-managerial workplaces (i.e. where the principal owner also works). Testing the agency theories in more detail, we find no evidence that the number of competitors, the price elasticity of demand or a proxy for bankruptcy (pre-tax losses) are the mechanisms behind the process. For non-managerial workplaces the results indicate support for the idea that greater demand uncertainty reduces productivity growth. In contrast, for managerial workplaces, greater demand uncertainty tends to raise productivity growth.

Investigating mental health risk assessment in primary care and the potential role of a structured decision support tool, GRiST

Aim: To explore current risk assessment processes in general practice and Improving Access to Psychological Therapies (IAPT) services, and to consider whether the Galatean Risk and Safety Tool (GRiST) can help support improved patient care. Background: Much has been written about risk assessment practice in secondary mental health care, but little is known about how it is undertaken at the beginning of patients' care pathways, within general practice and IAPT services. Methods: Interviews with eight general practice and eight IAPT clinicians from two primary care trusts in the West Midlands, UK, and eight service users from the same region. Interviews explored current practice and participants' views and experiences of mental health risk assessment. Two focus groups were also carried out, one with general practice and one with IAPT clinicians, to review interview findings and to elicit views about GRiST from a demonstration of its functionality. Data were analysed using thematic analysis. Findings Variable approaches to mental health risk assessment were observed. Clinicians were anxious that important risk information was being missed, and risk communication was undermined. Patients felt uninvolved in the process, and both clinicians and patients expressed anxiety about risk assessment skills. Clinicians were positive about the potential for GRiST to provide solutions to these problems. Conclusions: A more structured and systematic approach to risk assessment in general practice and IAPT services is needed, to ensure important risk information is captured and communicated across the care pathway. GRiST has the functionality to support this aspect of practice.

Corticobasal degeneration and dementia

Corticobasal degeneration is a rare, progressive neurodegenerative disorder which significantly impairs movement. The most common initial symptom is asymmetric limb clumsiness with or without accompanying rigidity or tremor. Subsequently, the disease progresses to affect gait and there is a slow progression to influence ipsilateral arms and legs. Apraxia and dementia are the most common cortical signs. Clinical diagnosis of the disorder is difficult as the symptoms resemble those of related neurodegenerative disorders. Histopathologically, there is widespread neuronal and glial pathology including tau-immunoreactive neuronal cytoplasmic inclusions, neuropil threads, oligodendroglial inclusions, astrocytic plaques, together with abnormally enlarged ‘ballooned’ neurons. Corticobasal degeneration has affinities both with the parkinsonian syndromes including Parkinson’s disease, progressive supranuclear palsy, and multiple system atrophy and with the fronto-temporal dementias. Treatment of corticobasal degeneration involves managing and reducing the effect of symptoms.

A decision support system for supplier selection and order allocation in stochastic, multi-stakeholder and multi-criteria environments

Integrated supplier selection and order allocation is an important decision for both designing and operating supply chains. This decision is often influenced by the concerned stakeholders, suppliers, plant operators and customers in different tiers. As firms continue to seek competitive advantage through supply chain design and operations they aim to create optimized supply chains. This calls for on one hand consideration of multiple conflicting criteria and on the other hand consideration of uncertainties of demand and supply. Although there are studies on supplier selection using advanced mathematical models to cover a stochastic approach, multiple criteria decision making techniques and multiple stakeholder requirements separately, according to authors' knowledge there is no work that integrates these three aspects in a common framework. This paper proposes an integrated method for dealing with such problems using a combined Analytic Hierarchy Process-Quality Function Deployment (AHP-QFD) and chance constrained optimization algorithm approach that selects appropriate suppliers and allocates orders optimally between them. The effectiveness of the proposed decision support system has been demonstrated through application and validation in the bioenergy industry.

Dyslexia research at the turn of the 21st century:behavioural, neuroimaging and genetic findings

Behavioural studies have shown that dyslexics are a heterogeneous population and between-group comparisons are thus inadequate. Some subjects do not develop dyslexia despite having a deficit implicated in this disorder, which points to protective factors. Dyslexia co-occurs with ADHD, DCD, SLI, and SSD, so that future behavioural studies will need to screen and/or statistically control for other disorders. Studies of multiple cases of DPs with other developmental disorders are necessary. Neuroimaging findings show structural and/or functional brain abnormalities in language areas, V5/MT and the cerebellum. Future neuroimaging studies need to investigate the whole reading network and multiple cases. Six dyslexia risk genes have been found, mostly involved in neural migration, which may suggest dyslexia is a deficit of neuronal migration. However, it is not clear how these genes can restrict migration to specific brain areas. As a complex and heterogeneous disorder, dyslexia is likely to be associated with several mutated genes. ADHD and SSD are characterised by genetic risk factors which are partially shared with dyslexia, resulting in comorbidity. Future genetic studies need to focus on identifying other risk genes and pleiotropic genes involved in comorbidities, and linking genotypes implicated in dyslexia with brain structure. Any theory of dyslexia needs to take into account a multitude of risk and protective factors across behavioural, neural and genetic domains.

Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders

The hippocampus (HC) and adjacent gyri are implicated in dementia in several neurodegenerative disorders. To compare HC pathology among disorders, densities of ‘signature’ pathological lesions were measured at a standard location in eight brain regions of 12 disorders. Principal components analysis of the data suggested that the disorders could be divided into three groups: (1) Alzheimer’s disease (AD), Down’s syndrome (DS), sporadic Creutzfeldt–Jakob disease, and variant Creutzfeldt–Jakob disease in which either β-amyloid (Aβ) or prion protein deposits were distributed in all sectors of the HC and adjacent gyri, with high densities being recorded in the parahippocampal gyrus and subiculum; (2) Pick’s disease, sporadic frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions, and neuronal intermediate filament inclusion disease in which relatively high densities of neuronal cytoplasmic inclusions were present in the dentate gyrus (DG) granule cells; and (3) Parkinson’s disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy in which densities of signature lesions were relatively low. Variation in density of signature lesions in DG granule cells and CA1 were the most important sources of neuropathological variation among disorders. Hence, HC and adjacent gyri are differentially affected in dementia reflecting either variation in vulnerability of hippocampal neurons to specific molecular pathologies or in the spread of pathological proteins to the HC. Information regarding the distribution of pathology could ultimately help to explain variations in different cognitive domains, such as memory, observed in various disorders.

Predicting dyslexia using prereading skills:the role of sensorimotor and cognitive abilities

Background: It is well established that phonological awareness, print knowledge and rapid naming predict later reading difficulties. However, additional auditory, visual and motor difficulties have also been observed in dyslexic children. It is examined to what extent these difficulties can be used to predict later literacy difficulties. Method: An unselected sample of 267 children at school entry completed a wide battery of tasks associated with dyslexia. Their reading was tested 2, 3 and 4 years later and poor readers were identified (n = 42). Logistic regression and multiple case study approaches were used to examine the predictive validity of different tasks. Results: As expected, print knowledge, verbal short-term memory, phonological awareness and rapid naming were good predictors of later poor reading. Deficits in visual search and in auditory processing were also present in a large minority of the poor readers. Almost all poor readers showed deficits in at least one area at school entry, but there was no single deficit that characterised the majority of poor readers. Conclusions: Results are in line with Pennington’s (2006) multiple deficits view of dyslexia. They indicate that the causes of poor reading outcome are multiple, interacting and probabilistic, rather than deterministic. Keywords: Dyslexia; educational attainment; longitudinal studies; prediction; phonological processing.

Novel, isoform-selective, cholecystokinin A receptor antagonist inhibits colon and pancreatic cancers in preclinical models through novel mechanism of action

Colon and pancreatic cancers contribute to 90,000 deaths each year in the USA. These cancers lack targeted therapeutics due to heterogeneity of the disease and multiple causative factors. One important factor that contributes to increased colon and pancreatic cancer risk is gastrin. Gastrin mediates its actions through two G-protein coupled receptors (GPCRs): cholecystokinin receptor A (CCK-A) and CCK-B/gastrin receptor. Previous studies have indicated that colon cancer predominantly expresses CCK-A and responds to CCK-A isoform antagonists. However, many CCK-A antagonists have failed in the clinic due to poor pharmacokinetic properties or lack of efficacy. In the present study, we synthesized a library of CCK-A isoform-selective antagonists and tested them in various colon and pancreatic cancer preclinical models. The lead CCK-A isoform, selective antagonist PNB-028, bound to CCK-A at 12 nM with a 60-fold selectivity towards CCK-A over CCK-B. Furthermore, it inhibited the proliferation of CCK-A-expressing colon and pancreatic cancer cells without affecting the proliferation of non-cancerous cells. PNB-028 was also extremely effective in inhibiting the growth of MAC-16 and LoVo colon cancer and MIA PaCa pancreatic cancer xenografts in immune-compromised mice. Genomewide microarray and kinase-array studies indicate that PNB-028 inhibited oncogenic kinases and angiogenic factors to inhibit the growth of colon cancer xenografts. Safety pharmacology and toxicology studies have indicated that PNB-028 is extremely safe and has a wide safety margin. These studies suggest that targeting CCK-A selectively renders promise to treat colon and pancreatic cancers and that PNB-028 could become the next-generation treatment option.

Additive and multiplicative properties of scoring methods for preference aggregation

The paper reviews some additive and multiplicative properties of ranking procedures used for generalized tournaments with missing values and multiple comparisons. The methods analysed are the score, generalised row sum and least squares as well as fair bets and its variants. It is argued that generalised row sum should be applied not with a fixed parameter, but a variable one proportional to the number of known comparisons. It is shown that a natural additive property has strong links to independence of irrelevant matches, an axiom judged unfavourable when players have different opponents.

A study of the relationship between U.S. hotel companies and travel agency companies: Determinants of the success of the relationship

The primary objectives of this study were to describe the relationship that U.S. hotel companies have with travel agency companies and to identify the determinants of a successful relationship.^ The unit of analysis was hotel companies operating in U.S. One hundred and three hotel companies contributed information for this research. The data were collected through a questionnaire developed from previous empirical studies and from interviews with hospitality management professors and hotel sales and marketing directors.^ Simple and multiple regression analyses indicated that in order to have successful relationships with travel agency companies, hotel companies should (a) show more commitment or dedication to working with the travel agents, (b) have more trust in the travel agents themselves, and (c) be less dependent on any one travel agent for their business.^ Additionally, the results suggest that hotel companies who coordinate activities with travel agents companies and who communicate with them in a timely, accurate, adequate, complete and credible manner have more successful interorganizational relationships than those who do not.^ Furthermore, hotel companies who share proprietary sales and any other information with travel agents reported better relationships. (Abstract shortened by UMI.) ^