Rheological characterisation of dextran-concanavalin A mixtures as a basis for a self-regulated drug delivery device.

The rheological characterisation of glucose sensitive mixtures containing dextran and concanavalin A (con A) with and without glucose, was undertaken using oscillatory rheometry at 20 and 37 degrees C so that comparative data could be gathered in the linear viscoelastic (LVE) range. Measurements for a series of mixtures showed that complex viscosity is a function not only of the con A concentration but of the content and molecular weight of the dextran used. The extent of liquefaction on addition of glucose also depended on these factors. The tan delta profiles confirmed the change from semi-solid towards fluid behaviour. This occurs when glucose effects dismantling of the three-dimensional structure of the dextran-con A system by competitive binding to the glucose receptors in the protein. For the mixtures studied, the changes occurred between contents of 0 and 1% (w/w) glucose at 20 and 37 degrees C and form a useful basis for the formulation of a self-regulating delivery device for the control of hyper-and hypoglycaemia in diabetes.     

Apolipoprotein E—associated risk for Alzheimer's disease in the African-American population is genotype dependent

As a part of our ongoing study on Alzheimer's disease (AD) in elderly African Americans, we obtained clinical assessment and apolipoprotein E (ApoE) genotype data on 288 individuals (including 60 with AD). The ApoE σ4 allele frequency was significantly increased in AD patients compared with controls. The age-adjusted odds ratio (OR) for AD in σ4 homozygotes was 4.83 (95% confidence interval [CI], 1.71–13.64) compared with the σ3/σ3 genotype, but the OR for AD with the σ3/σ4 genotype did not reach significance (1.20; 95% CI, 0.58–2.45). These findings suggest that the association between ApoE σ4 and AD is weaker in African Americans than in whites.     

Development of a reconstructed human skin model for angiogenesis

We have previously shown that reconstructed human skin engineered from autologous keratinocytes, fibroblasts, and sterilized donor allodermis stimulates angiogenesis within 5-7 days when placed on well-vascularized wound beds in nude mice. When this reconstructed skin was used clinically in more demanding wound beds, some grafts were lost, possibly due to delayed vascularization. As this reconstructed skin lacks any endothelial cells, our aim in this study was to develop an angiogenic reconstructed skin model in which to explore strategies to improve angiogenesis both in vitro and in vivo. We report that culture of small-vessel human dermal microvascular endothelial cells (HuDMECs) was achieved using magnetic beads coated with an antibody to platelet cell adhesion molecule as a means of purifying the culture. Keratinocytes, fibroblasts, and HuDMECs could be cultured from the same skin biopsy. Initial studies culturing HuDMECs and other sources of endothelial cells with the tissue-engineered skin showed that these cells were capable of slowly entering the dermis under standard culture conditions in vitro. In conclusion, this provides us with a model in which to explore strategies for improving angiogenesis in vitro and also establishes the culture methodologies for the production of reconstructed skin containing autologous keratinocytes, fibroblasts, and endothelial cells.     

2,8-Dihydroxyadenine urolithiasis in a patient with considerable residual adenine phosphoribosyltransferase activity in cell extracts but with mutations in both copies of APRT

We have examined the mutational basis of adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) deficiency (MIM 102600) in a patient of Polish origin who has been passing 2,8-dihydroxyadenine (DHA) stones since birth, but has considerable residual enzyme activity in lymphocyte extracts. The five exons and flanking regions of APRT were amplified by PCR and then sequenced. A single T insertion was identified at the intron 4 splice donor site (TGgtaa to TGgttaa:IVS4+2insT) in one allele from the proband, his mother, and brother. A G-to-T transversion in exon 5 (GTC-to-TTC:c.448G>T, V150F) was identified in the other allele, and this mutation was also present in one allele from the father and the paternal grandmother. Tru91 and AvaII digestions of PCR products spanning exons 4 and 5, respectively, confirmed the mutations. The mother was heterozygous for an intragenic TaqI site, but all other family members were homozygous for the presence of this site. IVS4+2insT, located on the allele containing the TaqI site, has been identified previously in several families from Europe, suggesting a founder effect, but the substitution in exon 5 is a novel mutation. IVS4+2insT is known to result in complete loss of enzyme activity, and our results suggest that V150F produces an enzyme that is nonfunctional in vivo but has considerable residual activity in vitro.     

A prevalence study of antenatal depression among Chinese women

BACKGROUND: There has thus far been no empirical research on the occurrence of antenatal psychiatric morbidity in Chinese population. Epidemiological studies in western societies generally show that depressive episodes occur in 10-20% of pregnant women. Longitudinal studies have demonstrated that antenatal depression is one of the most powerful predictors of postnatal depression. There is also a growing literature that shows that antenatal psychological distress can adversely affect maternal and foetal well being. METHODS: At 38 weeks of pregnancy, 238 consecutive women were invited to return for psychiatric assessment. The participants were interviewed using the non-patient version of the Structured Clinical Interview for DSM-IV (SCID-NP). RESULTS: Seventy women (29%) declined to participate, and another 11 (5%) defaulted the SCID interview. Among the 157 women interviewed, the 1-month prevalence of antenatal depression was 4.4%. The 1-month prevalence of all psychiatric diagnoses was 6.4%. The prevalence of antenatal depression and all psychiatric diagnoses for the entire pregnancy was 6.4% and 8.3%, respectively. LIMITATIONS: About a third of eligible subjects did not participate in the study. CONCLUSIONS: A significant proportion of Chinese women suffer from psychiatric morbidity during pregnancy. Depressive disorders are by far the commonest morbidity in the study population. Given the scope of the morbidity and the potential impact on obstetric and neonatal outcomes, early screening and treatment are warranted.     

The Development of a Multilevel Intervention to Optimise Participant Engagement with an Obesity Prevention Programme Delivered in UK children’s Centres

Prevention Science - Poor participant engagement threatens the potential impact and cost-effectiveness of public health programmes preventing meaningful evaluation and wider application. Although...     

Prospective study of microchimerism in transplant recipients

BACKGROUND: We evaluated peripheral blood microchimerism in 48 consecutive organ transplant recipients (35 kidneys, ten livers, one kidney-liver, one kidney-pancreatic islet, one kidney pancreas) up to 12 months post-transplantation. Patients were categorized according to the presence or absence of rejection episodes, and the patterns of microchimerism in the two groups were then compared. METHODS: DNA was extracted from donor, pre-transplant, and post-transplant peripheral blood samples. Several polymerase chain reaction (PCR)-based assays were developed for the detection of microchimerism. Assay sensitivities ranged from 0.0001 to 3%. RESULTS: Microchimerism was detected only in sex-mismatched cases (male donors and female recipients) using nested PCR for a Y-chromosome marker. There were ten such cases (six kidneys, two livers, and two combined organ transplants). In patients without rejection (n = 7), there was a peak of donor-DNA at 1-3 wk post-transplantation followed by a second peak between 3 wk and 4 months. In patients with biopsy-proven rejection (n = 3), the peaks were absent and the levels of microchimerism were extremely low (< 0.001%). Microchimerism levels declined in all 10 patients and were barely detectable 1 yr post-transplantation. Microchimerism was not detected in the remaining 38 patients despite using a battery of sensitive PCR-based assays. CONCLUSIONS: In our study, microchimerism was detected using the Y-chromosome PCR assay only and the level of donor-DNA in a given patient varied over time. This study highlights the difficulties in establishing a correlation between microchimerism and transplant tolerance.     

Initial UK experience of the levonorgestrel-releasing contraceptive intravaginal ring

A study was performed to establish the tolerance, acceptability and associated efficacy of a levonorgestrel-releasing intravaginal ring (IVR) in a sample of British women requiring contraception. This was achieved with an open non-randomized prospective study of 1710 women aged 18-40 years, recruited in 75 centers geographically spread around the UK using an IVR designed to release 20 g/day of levonorgestrel. Assessments were made at baseline, after 6 weeks, after 3 months and then 3-monthly. After initial insertion of the IVR, it was changed at 3-monthly intervals. A total of 1591 women were eligible for analysis, with 572 available after 12 months and 34 after 24 months of use. Life-table analysis revealed pregnancy rates of 5.1% and 6.5% at 12 months and 24 months, respectively. The IVR was rated as acceptable or very acceptable as a form of contraceptive by 60.7% of women at 12 months. The most common adverse events were menstrual disturbance, headache and vaginal discharge. No significant pattern of biochemical, hematological, microbiological or cytological abnormalities was found but vaginal erythematous lesions were noted at some centers. This IVR was found to be a generally well-accepted method of contraception with a failure rate comparable to some other progestogen-only methods. On this basis, further development of hormone-releasing intravaginal rings is justified.