A library of strictly linear poly(ethylene glycol)–poly(ethylene imine) diblock copolymers to perform structure–function relationship of non-viral gene carriers

A library of 39 strictly linear poly(ethylene glycol)–poly(ethylene imine) (PEG-PEI) diblock copolymers was synthesized for the delivery of plasmid DNA using PEG of 2, 5, or 10 kDa in combination with linear PEI with a molecular weight (MW) ranging from 1.5 to 10.8 kDa. In contrast to other approaches, the copolymers demonstrated a clear separation between the hydrophilic PEG and the nucleic acid condensing PEI moieties. Hence, the hypothesis was that PEG may not sterically counteract the interaction between the nucleic acid and PEI and that consequently, the copolymers are perfectly suited to build small and stable polyplexes. Analysis of the polyplexes revealed structure–function relationships and the general guideline was that the PEG domain had a greater influence on the physicochemical properties of the polyplexes than PEI. A PEG content higher than 50% led to small (< 150 nm), nearly neutral polyplexes with favorable stability. The transfection efficacy of these polyplexes was significantly reduced compared to the PEI homopolymer, but was restored by the application of the corresponding degradable copolymer, which involved a redox triggerable PEG domain. In conclusion, valuable design criteria for the optimization of gene delivery carriers, which is only possible through the screening of such a large library, were gained.     

Trends in sociodemographic and health-related indicators in Bangladesh, 1993–2007: will inequities persist?

Objective

To assess levels, trends and gaps between the poorest and the richest in selected health and human development indicators in Bangladesh.

Methods

Data for selected indicators associated with sociodemographic characteristics among ever-married women, contraception use, child vaccination, antenatal care practices and health conditions were extracted from the Bangladesh Demographic and Health Surveys conducted in 1993–94, 1996–1997, 1999–2000, 2004 and 2007. Results for the whole sample and for the poorest and the richest wealth quintiles are presented.

Findings

Positive trends were noted in urbanization, availability of electricity, age at first marriage, use of modern contraception, access to skilled antenatal care, child vaccination, knowledge of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome and overweight and obesity. In contrast, negative trends were seen in factors such as literacy, infant and child mortality, fertility rate, home delivery and malnutrition and underweight. However, changes in these indicators differed between the poorest and richest quintiles. For instance, only the richest quintile experienced rapid urbanization, whereas illiteracy declined more among the poorest. Noteworthy gaps were found in almost all factors. Rich–poor gaps in urbanization, age at marriage, fertility, condom use, home delivery and overweight increased; in contrast, gaps in education, water and sanitation, use of contraception (except condoms) and child vaccination declined.

Conclusion

Persistent inequities in Bangladesh endanger equitable and sustainable human development in the country. Pro-poor development strategies based on the principles of equity and quality should be implemented to narrow existing gaps and further promote holistic and equitable human development.     

Studies in humans and mice implicate neurocan in the etiology of mania

OBJECTIVE Genome-wide association has been reported between the NCAN gene and bipolar disorder. The aims of this study were to characterize the clinical symptomatology most strongly influenced by NCAN and to explore the behavioral phenotype of Ncan knockout (Ncan-/-) mice. METHOD Genotype/phenotype correlations were investigated in patients with bipolar disorder (N=641) and the genetically related disorders major depression (N=597) and schizophrenia (N=480). Principal components and genotype association analyses were used to derive main clinical factors from 69 lifetime symptoms and to determine which of these factors were associated with the NCAN risk allele. These analyses were then repeated using the associated factor(s) only in order to identify the more specific clinical subdimensions that drive the association. Ncan-/- mice were tested using diverse paradigms, assessing a range of behavioral traits, including paradigms corresponding to bipolar symptoms in humans. RESULTS In the combined patient sample, the NCAN risk allele was significantly associated with the "mania" factor, in particular the subdimension "overactivity." Ncan-/- mice were hyperactive and showed more frequent risk-taking and repetitive behaviors, less depression-like conduct, impaired prepulse inhibition, amphetamine hypersensitivity, and increased saccharin preference. These aberrant behavioral responses normalized after the administration of lithium. CONCLUSIONS NCAN preferentially affected mania symptoms in humans. Ncan-/- mice showed behavioral abnormalities that were strikingly similar to those of the human mania phenotype and may thus serve as a valid mouse model.     

Trefoil factors in inflammatory bowel disease

Inflammatory bowel disease(IBD),which comprises ulcerative colitis and Crohn’s disease,is characterized by inflammation of the gastrointestinal tract.The trefoil factors 1,2,and 3(TFF1-3)are a family of peptides that play important roles in the protection and repair of epithelial surfaces,including the gastrointestinal tract.TFFs may be involved in IBD pathogenesis and are a potential treatment option.In the present review,we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression,possible function and pharmacological role in IBD.     

Veränderungen im Chromosomensatz heterolog wachsender Tumoren

Zusammenfassung Der Chromosomensatz einer Walker-Carcinom-Linie, welche auf Ratten, Mäusen und Goldhamstern wächst, wurde untersucht. Die Morphologie der Chromosomen und ihre Zahl ist auf allen drei Tierarten in dieser Tumorlinie gleich. Ein auftretendes submetazentrisches Marker-Chromosom mit heterochromatischem Abschnitt findet sich in gleich hohem Prozentsatz in Tumor-zellen aller drei Tierarten.

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Summary The chromosome-sets of a Walker carcinoma line were studied while growing in rats, mice, and gold hamsters. The morphology of the chromosomes and their number for this tumor-line were the same in all three types of animals. A submetacentric marker-chromosome appearing with heterochromatic segments was found in the same high percentage in the tumor cells of all three types of animal.

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Der Deutschen Forschungsgemeinschaft danken wir für die Unterstützung bei Durchführung der Arbeit.     

Cathepsin D: screening for new polymorphisms using single-strand conformation polymorphism analysis.

Cathepsin D (CTSD) is a lysosomal protease involved in the pathogenesis of several diseases such as breast cancer and possibly Alzheimer's disease (AD). Previous findings revealed a significant association between the T allele of the 224 C/T (A58V) polymorphism in exon 2 of the CTSD gene and late onset AD. The exonic regions of the CTSD gene were screened for further polymorphic variations using polymerase chain reaction and single-strand conformation polymorphism analysis. In addition to the known 224 C/T polymorphism and two silent mutations in exons 3 and 4 we detected two new polymorphisms in introns 5 and 8. Combination of these sequence variations results in three different haplotypes; one of these haplotypes is due to the new polymorphism in intron 5. We detected no further missense mutations except for the known 224 C/T polymorphism in exon 2. Thus, if sequence variations within the CTSD gene influence the risk for various diseases, the pathogenic mechanism is likely to be linked to the amino acid substitution in the profragment of CTSD.     

Double positivity for HPV DNA/p16 in tonsillar and base of tongue cancer improves prognostication: Insights from a large population‐based study

The aim was to explore the overall survival (OS) for palatine tonsillar squamous cell carcinoma (TSCC), subdivided, according to certainty of tonsillar tumour origin, into specified tonsillar squamous cell carcinomas (STSCCs) and nonspecified tonsillar squamous cell carcinomas (NSTSCCs), and base of tongue squamous cell carcinoma (BSCC) when stratifying for HPV DNA status, p16 expression and combined HPV/p16 status. We included all patients (n = 797) diagnosed with TSCCs and BSCCs in Eastern Denmark as registered in the Danish Head and Neck Cancer Group (DAHANCA) database and the Danish Pathology Databank, 2000–2010. Patients were treated according to national guidelines (radiotherapy +/? concomitant cisplatin). All specimens were analysed using HPV DNA PCR and p16 immunohistochemistry. Clinical information was retrieved from the DAHANCA database and the Danish National Patient Registry. Information on vital status was obtained from the Danish Civil Registration System. We observed improved OS for HPV+/p16+ BSCCs compared to HPV?/p16? (hazard ratio for death [HR], 0.15; 95% CI, 0.09–0.24). Among STSCCs, HPV+/p16+ showed the lowest HR (0.19, 95% CI, 0.13–0.29); whereas, HPV?/p16+ showed an intermediate HR (0.39; 95% CI, 0.22–0.70). For NSTSCCs, HPV+/p16+ and HPV?/p16+ showed similar OS (HRs, 0.39; 95% CI, 0.26–0.59; and 0.48; 95% CI, 0.24–0.95, respectively). Combined HPV+/p16+ was a significantly better prognostic marker in BSCCs and STSCCs than HPV DNA and p16, alone (all p‐values < 0.05). Whereas, combined testing in NSTSCC was not better than p16 (p = 0.53), alone. In conclusion, double positivity for HPV/p16 in conjunction with the certainty of tumour site improved prognosis.     

Relationship between haemoglobin A1C values and recurrent cardiac events: A retrospective, longitudinal cohort study

OBJECTIVE: This study set out to analyse the impact of baseline glycosylated haemoglobin A1c (HbA1c) values on the incidence of recurrent cardiac events in patients prescribed optimal secondary prevention medications and receiving aggressive cardiac risk factor management. METHODS: This was a retrospective study conducted at Kaiser Permanente Colorado and included adults followed by a clinical pharmacy specialist-managed cardiac risk service (CPCRS) with an incident cardiac event and an HbA1c value measured within 1 year prior or 60 days after the incident cardiac event was identified. Cox proportional hazards models were constructed to assess the relationship between HbA1c levels and recurrent cardiac events (assessed as continuous and categorical measures) after adjustment for potential confounding variables. RESULTS: Of 5663 patients identified within an incident cardiac event between January 1999 and March 2005, 1270 (22.4%) patients had a baseline HbA1c value recorded. Of these 1270 patients, 215 (16.9%) had a recurrent cardiac event. Compared with the 'no recurrent event' cohort, the 'recurrent event' cohort were younger, less likely to have undergone an initial coronary artery bypass graft, and more likely to have undergone percutaneous coronary intervention with or without stent. The recurrent event cohort was also less likely to have purchased an HMG-CoA reductase inhibitor ('statin') [p = 0.043] at the time of the incident cardiac event. There was no significant difference in mean baseline HbA1c value between the cohorts. There were also no significant differences between the cohorts when categorized by baseline HbA1c <7% as referent compared with > or =7% to <8%, > or =8% to <9%, > or =9 to <10%, and > or =10%. Moreover, there was no significant difference between cohorts when HbA1c values <7% were compared with values >7% in the unadjusted analysis. Results remained non-significant after adjustment for sex, incident cardiac event type, baseline age, ss-blocker use, statin use and hyperlipidaemia. CONCLUSION: The results of this study suggest that an abnormal HbA1c is not predictive of recurrent cardiac events among patients with cardiovascular disease when other cardiovascular risk factors are being aggressively treated and appropriate secondary prevention medications are being taken. However, larger studies are warranted to validate these findings.