Targeted delivery of a novel group of site-directed transglutaminase inhibitors to the liver using liposomes:a new approach for the potential treatment of liver fibrosis

Liver fibrosis and its end-stage disease cirrhosis are a main cause of mortality and morbidity worldwide. Thus far, there is no efficient pharmaceutical intervention for the treatment of liver fibrosis. Liver fibrosis is characterized by excessive accumulation of the extracellular matrix (ECM) proteins. Transglutaminase (TG)-mediated covalent cross-linking has been implicated in the stabilization and accumulation of ECM in a number of fibrotic diseases. Thus, the use of tissue TG2 inhibitors has potential in the treatment of liver fibrosis. Recently, we introduced a novel group of site-directed irreversible specific inhibitors of TGs. Here, we describe the development of a liposome-based drug-delivery system for the site-specific delivery of these TG inhibitors into the liver. By using anionic or neutral-based DSPC liposomes, the TG inhibitor can be successfully incorporated into these liposomes and delivered specifically to the liver. Liposomes can therefore be used as a potential carrier system for site-specific delivery of the TG2 inhibitors into the liver, opening up a potential new avenue for the treatment of liver fibrosis and its end-stage disease cirrhosis.

Mild cognitive decline. A position statement of the Cognitive Decline Group of the European Innovation Partnership for Active and Healthy Ageing (EIPAHA)

Introduction Mild cognitive impairment (MCI) is a term used to describe a level of decline in cognition which is seen as an intermediate stage between normal ageing and dementia, and which many consider to be a prodromal stage of neurodegeneration that may become dementia. That is, it is perceived as a high risk level of cognitive change. The increasing burden of dementia in our society, but also our increasing understanding of its risk factors and potential interventions, require diligent management of MCI in order to find strategies that produce effective prevention of dementia. Aim To update knowledge regarding mild cognitive impairment, and to bring together and appraise evidence about the main features of clinical interest: definitions, prevalence and stability, risk factors, screening, and management and intervention. Methods Literature review and consensus of expert opinion. Results and conclusion MCI describes a level of impairment in which deteriorating cognitive functions still allow for reasonable independent living, including some compensatory strategies. While there is evidence for some early risk factors, there is still a need to more precisely delineate and distinguish early manifestations of frank dementia from cognitive impairment that is less likely to progress to dementia, and furthermore to develop improved prospective evidence for positive response to intervention. An important limitation derives from the scarcity of studies that take MCI as an endpoint. Strategies for effective management suffer from the same limitation, since most studies have focused on dementia. Behavioural changes may represent the most cost-effective approach.

A new phylogenetic group of Propionibacterium acnes

Immunofluorescence microscopy-based identification of presumptive Propionibacterium acnes isolates, using the P. acnes-specific mAb QUBPa3, revealed five organisms with an atypical cellular morphology. Unlike the coryneform morphology seen with P. acnes types I and II, these isolates exhibited long slender filaments (which formed large tangled aggregates) not previously described in P. acnes. No reaction with mAbs that label P. acnes types IA (QUBPa1) and II (QUBPa2) was observed. Nucleotide sequencing of the 16S rRNA gene (1484 bp) revealed the isolates to have between 99.8 and 99.9 % identity to the 16S rRNA gene of the P. acnes type IA, IB and II strains NCTC 737, KPA171202 and NCTC 10390, respectively. Analysis of the recA housekeeping gene (1047 bp) did reveal, however, a greater number of conserved nucleotide polymorphisms between the sequences from these isolates and those from NCTC 737 (98.9 % identity), KPA171202 (98.9 % identity) and NCTC 10390 (99.1 % identity). Phylogenetic investigations demonstrated that the isolates belong to a novel recA cluster or lineage distinct from P. acnes types I and II. We now propose this new grouping as P. acnes type III. The prevalence and clinical importance of this novel recA lineage amongst isolates of P. acnes remains to be determined.

An evaluation of quinolone prescribing in a group of acute hospitals:Development of an objective measure of usage

Objectives: To develop an objective measure to enable hospital Trusts to compare their use of antibiotics. Design: Self-completion, postal questionnaire with telephone follow up. Sample: 4 hospital trusts in the English Midlands. Results: The survey showed that it was possible to collect data concerning the number of Defined Daily Doses (DDD's) of quinolone antibiotic dispensed per Finished Consultant Episode (FCE) in each Trust.. In the 4 trusts studied the mean DDD/FCE was 0.197 (range 0.117 to 0.258). This indicates that based on a typical course length of 5 days, 3.9% of patient episodes resulted in the prescription of a quinolone antibiotic. Antibiotic prescribing control measures in each Trust were found to be comparable. Conclusion: The measure will enable Trusts to objectively compare their usage of quinolone antibiotics and use this information to carry out clinical audit should differences be recorded. This is likely to be applicable to other groups of antibiotics.

Chronic administration of an aluminium-enriched diet impairs spatial orientation in a sub-group of C57BL6 female mice

Disturbances of spatial orientation are an early clinical component of senile dementia of the Alzheimer type (SDAT). since it has been suggested that an elevated aluminium intake associated with chronic nutritional deficiencies of calcium and magnesium may play an important role in the aetiology of SDAT, we have investigated the effect of such a dietary regime on the spatial orientation abilities of female C57BL6 mice using the Morris swimming pool test. Statistical analysis of the performances of control and experimental groups indicate that the ability to orientate towards a submerged and thus invisible platform is conistently and markedly impaired in the experimental group. The ability to orientate towards a visible platform is also significantly impaired although to a lesser extent. Analysis of the performances of individual animals demonstrate that this impairment of orientation in the experimental group only occurs in a sub-group of animals: the remainder display normal orientational ability.

Local and systemic delivery of a novel group of inhibitors of transglutaminase enzyme: A potential approach for treating of catheter-related complications and liver fibrosis

The present thesis investigates targeted (locally and systemically) delivery of a novel group of inhibitors of enzyme transglutaminases (TGs). TGs are a widely distributed group of enzymes that catalyse the formation of isopeptide bonds between the y-carboxamide group of protein-bound glutamines and the a-amino group of protein-bound lysines or polyamines. The first group of the novel inhibitors tested were the tluorescently labelled inhibitors of Factor XIIIa (FXIIIa). These small, non-toxic inhibitors have the potential to prevent stabilisation of thrombi by FXIIIa and consequently increase the natural rate of thrombolysis, in addition it reduces staphylococcal colonisation of catheters by inhibiting their FXIIIa¬mediated cross-linking to blood clot proteins on the central venous catheter (CVCs) surface. The aim of this work was to incorporate the FXIIIa inhibitor either within coating of polyurethane (PU) catheters or to integrate it into silicone catheters, so as to reduce the incidence of thrombotic occlusion and associated bacterial infection in CVCs. The initial work focused on the incorporation of FXIIIa inhibitors within polymeric coatings of PU catheters. After defining the key characteristics desired for an effective polymeric-coating, polyvinylpyrrolidone (PVP), poly(lactic-co-glycolic acid) (PLGA) or their combination were studies as polymers of choice for coating of the catheters_ The coating was conducted by dip-coating method in a polymer solution containing the inhibitor. Upon incubation of the inhibitor-and polymer-coated strips in buffer, PVP was dissolved instantly, generating fast and significant drug release, whilst PLGA did not dissolve, yielding a slow and an insufficient amount of drug release. Nevertheless, the drug release profile was enhanced upon employing a blend solution of PVP and PLGA. The second part of the study was to incorporate the FXIIIa inhibitor into a silicone elastomer; results demonstrated that FXIIIa inhibitor can be incorporated and released from silicone by using citric acid (CA) and sodium bicarbonate (SB) as additives and the drug release rate can be controlled by the amount of incorporated additives in the silicone matrix. Furthermore, it was deemed that the inhibitor was still biologically active subsequent to being released from the silicone elastomer strips. Morphological analysis confirmed the formation of channels and cracks inside the specimens upon the addition of CA and SB. Nevertheless, the tensile strength, in addition to Young's modulus of silicone elastomer strips, decreased constantly with an increasing amount of amalgamated CA/ SB in the formulations. According to our results, incorporation of FXIIIa inhibitor into catheters and other medical implant devices could offer new perspectives in preventing bio-material associated infections and thrombosis. The use of tissue transglutaminase (T02) inhibitor for treating of liver fibrosis was also investigated. Liver fibrosis is characterized by increased synthesis and decreased degradation of the extracellular matrix (ECM). Transglutaminase-mediated covalent cross-linking is involved in the stabilization of ECM in human liver fibrosis. Thus, TG2 inhibitors may be used to counteract the decreased degradation of the ECM. The potential of a liposome based drug delivery system for site specific delivery of the fluorescent TG2 inhibitor into the liver was investigated; results indicated that the TG2 inhibitor can be successfully integrated into liposomes and delivered to the liver, therefore demonstrating that liposomes can be employed for site-specific delivery of TG2 inhibitors into the liver and TG2 inhibitor incorporating liposomes could offer a new approach in treating liver fibrosis and its end stage disease cirrhosis.

On Projective Plane of Order 13 with a Frobenius Group of Order 39 as a Collineation Group

One of the most outstanding problems in combinatorial mathematics and geometry is the problem of existence of finite projective planes whose order is not a prime power.

The Automorphism Group of the Free Algebra of Rank Two

The theorem of Czerniakiewicz and Makar-Limanov, that all the automorphisms of a free algebra of rank two are tame is proved here by showing that the group of these automorphisms is the free product of two groups (amalgamating their intersection), the group of all affine automorphisms and the group of all triangular automorphisms. The method consists in finding a bipolar structure. As a consequence every finite subgroup of automorphisms (in characteristic zero) is shown to be conjugate to a group of linear automorphisms.

New Symmetric (61,16,4) Designs Invariant Under the Dihedral Group of Order 10

∗ This work has been partially supported by the Bulgarian NSF under Contract No. I-506/1995.

Structure of the Unit Group of FD10

2000 Mathematics Subject Classification: 16U60, 20C05.

Cognitive-behavioural phenotype in a group of girls from 1.2 to 12 years old with the Incontinentia Pigmenti syndrome:recommendations for clinical management

Incontinentia Pigmenti (IP, OMIM#308300) is a rare X-linked genomic disorder (about 1,400 cases) that affects the neuroectodermal tissue and Central Nervous System (CNS). The objective of this study was to describe the cognitive-behavioural profile in children in order to plan a clinical intervention to improve their quality of life. A total of 14 girls (age range: from 1 year and 2 months to 12 years and 10 months) with IP and the IKBKG/NEMO gene deletion were submitted to a cognitive assessment including intelligence scales, language and visuo-spatial competence tests, learning ability tests, and a behavioural assessment. Five girls had severe to mild intellectual deficiencies and the remaining nine had a normal neurodevelopment. Four girls were of school age and two of these showed no intellectual disability, but had specific disabilities in calculation and arithmetic reasoning. This is the first description of the cognitive-behavioural profile in relation to developmental age. We stress the importance of an early assessment of learning abilities in individuals with IP without intellectual deficiencies to prevent the onset of any such deficit.

A computer based approach to improve the dietary and physical activity patterns of a diverse group of adolescents

Diet and physical activity patterns have been implicated as major factors in the increasing prevalence of childhood and adolescent obesity. It is estimated that between 16 and 33 percent of children and adolescents in the United States are overweight (CDC, 2000). Moreover, the CDC estimates that less than 50% of adolescents are physically active on a regular basis (CDC, 2003). Interventions must be focused to modify these behaviors. Facilitating the understanding of proper nutrition and need for physical activity among adolescents is the first step in preventing overweight and obesity and delaying the development of chronic diseases later in life (Dwyer, 2000). The purpose of this study was to compare the outcomes of students receiving one of two forms of education (both emphasizing diet and physical activity), to determine whether a computer based intervention (CBI) program using an interactive, animated CD-ROM would elicit a greater behavior change in comparison to a traditional didactic intervention (TDI) program. A convenience sample of 254 high school students aged 14-19 participated in the 6-month program. A pre-test post-test design was used, with follow-up measures taken at three months post-intervention. ^ No change was noted in total fat, saturated fat, fruit/vegetables, or fiber intake for any of the groups. There was also no change in perceived self-efficacy or perceived social support. Results did, however, indicate an increase in nutrition knowledge for both intervention groups (p<0.001). In addition, the CBI group demonstrated more positive and sustained behavior changes throughout the course of the study. These changes included a decrease in BMI (ppre/post<0.001, ppost/follow-up<0.001), number of meals skipped (ppre/post<0.001), and soda consumption (ppre/post=0.003, ppost/follow-up=0.03) and an increase in nutrition knowledge (ppre/post<0.001, ppre/follow-up <0.001), physical activity (ppre/post<0.05, p pre/follow-up<0.01), frequency of label reading (ppre/follow-up <0.0l) and in dairy consumption (ppre/post=0.03). The TDI group did show positive gains in some areas post intervention, however a return to baseline behavior was shown at follow-up. Findings of this study suggest that compared to traditional didactic teaching, computer-based nutrition and health education has greater potential to elicit change in knowledge and behavior as well as promote maintenance of the behavior change over time. ^

The effect of osteoporosis education on calcium intake and physical activity in a group of community-dwelling Black older adults

The unprecedented increase in the number of older adults is expected to increase the burden of osteoporosis on the individual and society. Blacks have been understudied in osteoporosis prevention education research. Although the risk of osteoporosis is low in this population, its consequences are significant. This study employs a two-group experimental design (experimental and wait-list control groups) to evaluate the effect of an osteoporosis education on two osteoporosis prevention behaviors (OPBs)—calcium intake (CI) and physical activity (PA), in a group of community-dwelling Black older adults, 50 years and older resident in South Florida. A final sample of 110 (mean age 70.15 years), 90% female and 10% male completed a battery of questionnaires at two assessment periods. The experimental group participated in six weekly education program sessions immediately following baseline assessment, and the wait-list control group received the education following end of program assessment by all participants. The weekly educational sessions were conducted in social settings (church or senior center) employing constructs of the Revised Health Belief Model. The sessions focused on improving CI; osteoporosis knowledge (OKT), self-efficacy (SE), health beliefs (HB) and PA. Findings revealed significantly greater increase in reported CI ( M = 556 mg, Wilks’ λ = .47, F (1,108)=122.97, p< .001, η2=.53), OKT (p< .001), and SE (p< .001) among participants in the experimental compared to the wait-list control group. There was no significant difference between the two groups for PA and most of the HB subscales. OKT and SE were the best predictors of CI, while perceived barrier was a predominant factor predicting PA. Over the study period, a change in SE was the only variable related to changes in both OPBs. Attrition rate was lower than expected, which can be attributed to the settings utilized for the study. These findings support the importance of utilizing a familiar social setting. These results suggested the effectiveness of a program offered in multiple short sessions among this underserved minority population to improve OKT and SE resulting in a change in OPBs (increase in CI). However, there is need to explore alternative strategies to improve PA in this population group.

Developing a leadership identity: A case study exploring a select group of Hispanic women at a Hispanic serving institution

Leadership is a socially constructed concept shaped by the context, values and experiences of society (Klenke, 1996); the historical context of gender and ethnicity in society affects views about leadership and who merits a leadership role. Therefore, developing an understanding of Hispanic women students’ leadership identity development is critical in broadening how we define leadership and develop leadership education. The purpose of this qualitative case study was to explore and describe the leadership identity development of a select group of women leaders at a Hispanic Serving Institution (HSI) in the southeast. A psychosocial approach to the study was utilized. In-depth interviews and focus groups were conducted with 11 self-identified Hispanic women students of sophomore, junior or senior standing with varying degrees of involvement in leadership activities at Florida International University. Participants were asked questions related to four topics; (a) leadership, (b) gender, (c) ethnic identity, and (d) influences that contributed to their understanding of self as leader. Five topics emerged from the data presented by the participants’: (a) encouraging relationships, (b) meaningful experiences, (c) self development, (d) the role of gender, and (e) impact of ethnicity. These themes contributed to the leadership identity development of the participants. Findings indicate that leadership identity development for Hispanic women college students at this HSI is complex. The concept of leadership identity development presented in the literature was challenged as findings indicate that the participants’ experiences living and attending a school in a majority-minority city influenced their development of a leadership identity. The data indicate that leadership is not gender or ethnicity neutral as differences exist in expectations of men and women in leadership roles. Gender expectations posed particular challenges for these women student leaders. The prescriptive nature of stage-based models was problematic as findings indicated leadership identity development a complicated and continuing process influenced strongly by relationships and experiences. This study enhanced knowledge of the ways that Hispanic women students become leaders and the influences that shape their leadership experiences which can assist higher education professionals in developing leadership programs and courses that address gender, multiculturalism and awareness of self as leader.

Charles Perry and a Group of People Outdoors

Charles Edward Perry (Chuck), 1937-1999, was the founding president of Florida International University in Miami, Florida. He grew up in Logan County, West Virginia and received his bachelor's and masters's degrees from Bowling Green State University. He married Betty Laird in 1960. In 1969, at the age of 32, Perry was the youngest president of any university in the nation. The name of the university reflects Perry’s desire for a title that would not limit the scope of the institution and would support his vision of having close ties to Latin America. Perry and a founding corps opened FIU to 5,667 students in 1972 with only one large building housing six different schools. Perry left the office of President of FIU in 1976 when the student body had grown to 10,000 students and the university had six buildings, offered 134 different degrees and was fully accredited. Charles Perry died on August 30, 1999 at his home in Rockwall, Texas. A commemorative plaque on a large coral rock is located in the southeast corner of the Primera Casa building, also called the Charles Perry building, where Perry is now buried.