Preservation and redirection of HPV16E7-specific T cell receptors for immunotherapy of cervical cancer

Human papilloma virus (HPV) type 16 infections of the genital tract are associated with the development of cervical cancer (CxCa) in women. HPV16-derived oncoproteins E6 and E7 are expressed constitutively in these lesions and might therefore be attractive candidates for T-cell-mediated adoptive immunotherapy. However, the low precursor frequency of HPV16E7-specific T cells in patients and healthy donors hampers routine isolation of these cells for adoptive transfer. To overcome this problem, we have isolated T cell receptor (TCR) genes from four different HPV16E7-specific healthy donor and patient-derived human cytotoxic T lymphocyte (CTL) clones. We examined whether genetic engineering of peripheral blood-derived CD8+ T cells in order to express HPV16E711-20-specific TCRs is feasible for adoptive transfer purposes. Reporter cells (Jurkat/MA) carrying a transgenic TCR were shown to bind relevant but not irrelevant tetramers. Moreover, these TCR-transgenic Jurkat/MA cells showed reactivity towards relevant target cells, indicating proper functional activity of the TCRs isolated from already available T cell clones. We next introduced an HPV16E711-20-specific TCR into blood-derived, CD8+ recipient T cells. Transgenic CTL clones stained positive for tetramers presenting the relevant HPV16E711-20 epitope and biological activity of the TCR in transduced CTL was confirmed by lytic activity and by interferon (IFN)-gamma secretion upon antigen-specific stimulation. Importantly, we show recognition of the endogenously processed and HLA-A2 presented HPV16E711-20 CTL epitope by A9-TCR-transgenic T cells. Collectively, our data indicate that HPV16E7 TCR gene transfer is feasible as an alternative strategy to generate human HPV16E7-specific T cells for the treatment of patients suffering from cervical cancer and other HPV16-induced malignancies.     

Genotoxicity and physicochemical characteristics of traffic-related ambient particulate matter

Exposure to ambient particulate matter (PM) has been linked to several adverse health effects. Since vehicular traffic is a PM source of growing importance, we sampled total suspended particulate (TSP), PM(10), and PM(2.5) at six urban locations with pronounced differences in traffic intensity. The mutagenicity, DNA-adduct formation, and induction of oxidative DNA damage by the samples were studied as genotoxicological parameters, in relation to polycyclic aromatic hydrocarbon (PAH) levels, elemental composition, and radical-generating capacity (RGC) as chemical characteristics. We found pronounced differences in the genotoxicity and chemical characteristics of PM from the various locations, although we could not establish a correlation between traffic intensity and any of these characteristics for any of the PM size fractions. Therefore, the differences between locations may be due to local sources of PM, other than traffic. The concentration of total (carcinogenic) PAHs correlated positively with RGC, direct and S9-mediated mutagenicity, as well as the induction of DNA adducts and oxidative DNA damage. The interaction between total PAHs and transition metals correlated positively with DNA-adduct formation, particularly from the PM(2.5) fraction. RGC was not associated with one specific PM size fraction, but mutagenicity and DNA reactivity after metabolic activation were relatively high in PM(10) and PM(2.5), when compared with TSP. We conclude that the toxicological characteristics of urban PM samples show pronounced differences, even when PM concentrations at the sample sites are comparable. This implies that emission reduction strategies that take chemical and toxicological characteristics of PM into account may be useful for reducing the health risks associated with PM exposure.     

A longitudinal study on the maternal–fetal relationship and postnatal maternal sensitivity

Objective: The present study examined whether early signs of maternal sensitivity can be detected during pregnancy by focusing on the maternal–fetal relationship and postnatal maternal sensitivity. Background: Earlier research has identified maternal sensitive behaviour as an important factor for the quality of the mother–infant relationship and the child’s emotional and cognitive development later in life. Research on this topic has predominantly focused on the postnatal period and little is known about early predictors (i.e. during pregnancy) of maternal sensitivity. Methods: Participants were 273 women and their (unborn) infants. Mothers’ attitudes, thoughts and feelings towards the fetus were assessed by the Maternal Antenatal Attachment Scale at 26 weeks of gestation. At the infant’s age of 6 months, maternal sensitivity was assessed in three different situations (i.e. face-to-face play, caregiving and free play) using the NICHD global rating scales. Results: Mothers with a higher quality of the maternal–fetal relationship displayed more maternal sensitivity towards their 6-month-old infant in caregiving and free play situations, even when controlling for covariates such as parity, ethnicity, maternal education, maternal age and the postnatal mother–infant relationship. No associations were found in the face-to-face situation. Conclusion: This study shows that mothers who reported a higher quality of the maternal–fetal relationship were more sensitive while interacting with their infants during caregiving and free play, but not during face-to-face play.     

NetB-producing and beta2-producing Clostridium perfringens associated with subclinical necrotic enteritis in laying hens in the Netherlands

Since 2006 increasing numbers of laying hen flocks with decreased production have been reported in the Netherlands. At necropsy, birds from affected flocks showed multifocal areas of necrosis in the duodenum. Histologically the duodenum had moderate to marked villus atrophy and fusion with crypt hyperplasia and a mixed inflammatory infiltrate within the lamina propria underlying focal areas of degenerative epithelium. Multifocally, free within the intestinal lumen and associated with epithelial necrosis, were marked numbers of large rod-shaped bacteria. Anaerobic culturing and subsequent toxin typing revealed, in 19 out of 73 affected birds, the presence of Clostridium perfringens strains, either type A or type C harbouring the atypical allele of cpb2 and netB. Eighteen out of these 19 birds carried C. perfringens strains capable of producing beta2 toxin in vitro and all of these birds harboured C. perfringens strains capable of producing NetB toxin in vitro. In contrast, specific pathogen free (SPF) birds lacked gross or histological lesions in their duodenum, and C. perfringens type C was isolated from four out of 15 SPF birds tested. One of these isolates harboured the consensus three allele of cpb2 that produced beta2 toxin in vitro. None of the C. perfringens isolates originating from SPF birds harboured netB. These findings might indicate that the NetB toxin produced by C. perfringens is associated with subclinical necrotic enteritis in layers, whereas the involvement of beta2 toxin in subclinical necrotic enteritis, if any, might be variant dependent.     

An economic appraisal of the Australian Medical Sheepskin for the prevention of sacral pressure ulcers from a nursing home perspective

Background  

Many devices are in use to prevent pressure ulcers, but from most little is known about their effects and costs. One such preventive device is the Australian Medical Sheepskin that has been proven effective in three randomized trials. In this study the costs and savings from the use of the Australian Medical Sheepskin were investigated from the perspective of a nursing home.     

Patient organisations and the reimbursement process for medicines: an exploratory study in eight European countries

Background  

Little is known about the role European patient organisations play in the process of deciding on reimbursement for medicines. Therefore we explore the current role of patient organisations in the process of reimbursement for medicines in Western Europe. We focus in particular on collaboration between patient organisations and the pharmaceutical industry in this respect.     

Does normal developmental expression of psychosis combine with environmental risk to cause persistence of psychosis? A psychosis proneness-persistence model

BACKGROUND: Research suggests that low-grade psychotic experiences in the general population are a common but transitory developmental phenomenon. Using two independent general population samples, the hypothesis was examined that common, non-clinical developmental expression of psychosis may become abnormally persistent when synergistically combined with developmental exposures that may impact on behavioural and neurotransmitter sensitization such as cannabis, trauma and urbanicity. METHOD: The amount of synergism was estimated from the additive statistical interaction between baseline cannabis use, childhood trauma and urbanicity on the one hand, and baseline psychotic experiences on the other, in predicting 3-year follow-up psychotic experiences, using data from two large, longitudinal, random population samples from the Netherlands [The Netherlands Mental Health Survey and Incidence Study (NEMESIS)] and Germany [The Early Developmental Stages of Psychopathology (EDSP) study]. RESULTS: The 3-year persistence rates of psychotic experiences were low at 26% in NEMESIS and 31% in EDSP. However, persistence rates were progressively higher with greater baseline number of environmental exposures in predicting follow-up psychotic experiences (chi2=6.9, df=1, p=0.009 in NEMESIS and chi2=4.2, df=1, p=0.04 in EDSP). Between 21% and 83% (NEMESIS) and 29% and 51% (EDSP) of the subjects exposed to both environmental exposures and psychotic experiences at baseline had persistence of psychotic experiences at follow-up because of the synergistic action of the two factors. CONCLUSION: The findings suggest that environmental risks for psychosis act additively, and that the level of environmental risk combines synergistically with non-clinical developmental expression of psychosis to cause abnormal persistence and, eventually, need for care.     

Development of an instrument for the identification of frail older people as a target population for integrated care

Background

Primary care is increasingly interested in the identification of frailty, as it selects the target population for integrated care. However, instruments for the identification of frailty specifically validated for use in primary care are scarce. This study developed the Easycare Two-step Older persons Screening (Easycare-TOS), which provides a valid, efficient, and pragmatic screening procedure to identify frail older people.

Aim

This paper aims to describe the development of the Easycare-TOS and the data from the pilot studies.

Design and setting

Observational pilot study in seven academic GP practices in and around Nijmegen, The Netherlands.

Method

The Easycare-TOS was developed in a cyclic process with the input of stakeholders. In every cycle, the requirements were first defined, then translated into a prototype that was tested in a pilot study. The Easycare-TOS makes optimal use of prior knowledge of the GP, and the professionals’ appraisal is decisive in the frailty decision, instead of a cut-off score. Further, it considers aspects of frailty, as well as aspects of the care context of the patient.

Results

The pilot data have shown that after step 1, two-thirds of the patients do not need further assessment, because they are judged as not frail, based on prior knowledge of the GP. The overall prevalence of frailty in this pilot study is 24%. Most professionals who participated in the pilot studies considered the time investment acceptable and the method to be of added value.

Conclusion

The Easycare-TOS instrument meets the predefined efficiency, flexibility, and acceptability requirements for use as an identification instrument for frailty in primary care.     

The cost-effectiveness of antidepressants for smoking cessation in chronic obstructive pulmonary disease (COPD) patients

Objectives In healthy smokers, antidepressants can double the odds of cessation. Because of its four times lower costs and comparable efficacy in healthy smokers, nortriptyline appears to be favourable compared to bupropion. We assessed which of both drugs was most effective and cost‐effective in stopping smoking after 1 year compared with placebo among smokers at risk or with existing chronic obstructive pulmonary disease (COPD). Methods A total of 255 participants, aged 30–70 years, received smoking cessation counselling and were assigned bupropion, nortriptyline or placebo randomly for 12 weeks. Prolonged abstinence from smoking was defined as a participant's report of no cigarettes from week 4 to week 52, validated by urinary cotinine. Costs were calculated using a societal perspective and uncertainty was assessed using the bootstrap method. Results The prolonged abstinence rate was 20.9% with bupropion, 20.0% with nortriptyline and 13.5% with placebo. The differences between bupropion and placebo [relative risk (RR) = 1.6; 95% confidence interval (CI) 0.8–3.0] and between nortriptyline and placebo (RR = 1.5; 95% CI 0.8–2.9) were not significant. Severity of airway obstruction did not influence abstinence significantly. Societal costs were €1368 (2.5th–97.5th percentile 193–5260) with bupropion, €1906 (2.5th–97.5th 120–17 761) with nortriptyline and €1212 (2.5th–97.5th 96–6602) with placebo. Were society willing to pay more than €2000 for a quitter, bupropion was most likely to be cost‐effective. Conclusions Bupropion and nortriptyline seem to be equally effective, but bupropion appears to be more cost‐effective when compared to placebo and nortriptyline. This impression holds using only health care costs. As the cost‐effectiveness analyses concern some uncertainties, the results should be interpreted with care and future studies are needed to replicate the findings.