RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature

During the past decade, RGD-peptides have become a popular tool for the targeting of drugs and imaging agents to alphavbeta3-integrin expressing tumour vasculature. RGD-peptides have been introduced by recombinant means into therapeutic proteins and viruses. Chemical means have been applied to couple RGD-peptides and RGD-mimetics to liposomes, polymers, peptides, small molecule drugs and radiotracers. Some of these products show impressive results in preclinical animal models and a RGD targeted radiotracer has already successfully been tested in humans for the visualization of alphavbeta3-integrin, which demonstrates the feasibility of this approach. This review will summarize the structural requirements for RGD-peptides and RGD-mimetics as ligands for alphavbeta3. We will show how they have been introduced in the various types of constructs by chemical and recombinant techniques. The importance of multivalent RGD-constructs for high affinity binding and internalization will be highlighted. Furthermore the in vitro and in vivo efficacy of RGD-targeted therapeutics and diagnostics reported in recent years will be reviewed.     

Long-term result of guided nerve regeneration with an inert microporous polytetrafluoroethylene conduit

Thedevelopmentinmicrosurgicaltechniqueshasgreatlyimprovednervefunctionalrecovery .However ,owingtotheinabilitytocoaptateandsuturethousandsofnervefiberstotheirfunctionallysimilarnervefibersandinaccuratesutureofthenervestumps ,regeneratednervefiberspartiallylosethechancetoselectivelyregrowintotheirtargetendoneurialtubes,1 4whichresultsinaninevitablemismatchofmotorandsensorynervefibers .Thus,thecontact guidance basedmicrosurgicalnerverepairhasfailedtoachieveconsistentsatisfactoryfunctionalrecover…     

Psychometric qualities of the rand 36-item health survey 1.0: A multidimensional measure of general health status

The reliability and validity of the RAND 36-Item Health Survey 1.0 were investigated in a population sample of 1,063 inhabitants of a Dutch township, all age 17or older. Confirmatory factor analysisonly partly supported the internal structure of the RAND 36-Item Health Survey 1.0. The internal consistency of the instrument was high. Pointing to high convergent validity, a multitrait-multimelhod matrix revealed that the RAND-36 scales showed higher correlations with corresponding scales from other instruments than with noncorresponding scales. However, indicating low discriminant validity, some of these correlations did not exceed the intercorrelations among the RAND-36 scales. Multivariate analysis of variance (MANOVA) showed significant effects of age for physical functioning, role limitations (physical problem), general health perception and pain, and significant effects of education on physical functioning and general health perception. Significant sex differences were found for mental health only. The results of this study on the psychometric properties of the RAND 36-Item Health Survey 1.0 seem promising. There is a need for further studies investigating its factor structure and cross-cultural equivalence.     

Ovarian Sertoli-Leydig cell tumour with raised serum alpha fetoprotein

Summary A case of ovarian Sertoli-Leydig cell tumour with a raised serum alpha fetoprotein in reported. The patient first presented at the age of 27 years with a history of 6 years' amenorrhoea followed by 3 months irregular vaginal bleeding. A ovarian tumour was found and excised and shown microscopically to be a spindle cell malignant tumour. The patient was treated with chemotherapy and had a complete response. Thirty months after first presentation there was a recurrence in the pelvis which microscopically showed the typical features of a Sertoli-Leydig cell tumour. Six months later a second recurrence had the microscopic appearance of a lipid cell tumour. A raised serum alpha fetoprotein was found at the time of the second recurrence and immunohistochemistry showed this protein in the Leydig and luteinized cells of the recurrent tumours but not in the spindle cells of the original ovarian neoplasm.     

High prevalence of HPV 16 in South African women with cancer of the cervix and cervical intraepithelial neoplasia

Despite the high prevalence of cervical cancer and cervical neoplasias in South Africa, few studies have been performed in this region to establish which human papillomavirus (HPV) types are associated with the development of high-grade cervical intraepithelial neoplasia lesions and cervical cancer. To investigate these prevalence rates, punch biopsies were obtained from 56 women with cervical cancer and 141 women with histologically diagnosed cervical intraepithelial neoplasia 2 or 3 lesions. Nested polymerase chain reaction (PCR) using consensus degenerate PCR primers was performed for the detection of HPV DNA and HPV typing was done by restriction fragment length polymorphism. Forty-seven (94%) of the cervical cancer and 114 (88%) of the cervical intraepithelial neoplasia 2/3 biopsies were positive for HPV DNA. The prevalence rates of the HPV types detected in the cervical cancer biopsies were HPV 16 (82%), HPV 18, (10%), HPV 33 (10%), HPV 31 (2%), HPV 58 (2%), HPV 35 (2%), and HPV 59 (2%). The cervical intraepithelial neoplasia lesions contained HPV 16 (56.6%), HPV 33 (14%), HPV 31 (10.9%), HPV X (7%), HPV 52 (3.9), HPV 58 (3.1%), HPV 35 (2.3%), HPV 18 (1.6%), HPV 11 (0.8%). Five of the nine fragments that were not typed by the RFLP, designated HPV-X, were sequenced to give HPV6 (1/5), HPV 26 (2/5), HPV 68 (1/5), and candHPV 87 (1/5). HPV 58 was detected in one cervical cancer biopsy and four biopsies from cervical intraepithelial neoplasia grade 3 lesions and was shown to be a previously described variant [Williamson and Rybicki (1991) J. Med. Virol. 33:165-171]. In addition, a cervical intraepithelial neoplasia grade 2 lesion was shown to harbour HPV type HAN2294 (cand HPV 87). The results of this study indicate that cervical cancer and cervical intraepithelial neoplasia 2/3 are largely associated with HPV 16 infection in this group of South African women and, therefore, an effective HPV 16 based vaccine should prevent the development of cervical cancer in a large proportion of women from this region of South Africa.     

Dreaming the impossible dream? An exploratory study on the expectations of Dutch clients with multiple problems concerning the co-production of public services

Currently, many policymakers try to encourage client involvement during the public service delivery process and make it a co-production. Clients are encouraged to act as active agents and embrace an integrated approach to address their problems to empower them. However, different studies have raised questions regarding to what extent these ambitions are appropriate for clients with vulnerabilities, such as clients with multiple problems. Aiming to further explore this issue, we studied the expectations of clients with multiple problems concerning the co-production of public services. We interviewed 46 clients with multiple problems at the start of their support trajectory. All 46 participants lived in five districts in Rotterdam, the Netherlands, and were recruited via community-based primary care teams. Our study indicates that co-production ambitions might not resonate with clients with multiple problems. The study shows that these clients’ expectations are driven by their feelings of being overwhelmed and stressed out by their situation, feelings of being a victim of circumstances, bad experiences with public services in the past, their evaluation of what counts as a problem and the envisioned solutions. These clients expect public service providers to take over, fix their main problem(s) and not interfere with other aspects of their lives (not an integrated approach). Although participants seek a ‘normal’ life with, e.g., a house, work, partner, children, holidays, a pet, and no stress (a white picket fence life) as ideal, they do not feel that this is attainable for them. More insight into the rationale behind these expectations could help to bridge the gap between policymakers’ ambitions and clients’ expectations.     

Prevalence of left and balanced coronary arterial dominance decreases with increasing age of patients at autopsy. A postmortem coronary angiograms study

BackgroundIn patients presenting with an acute coronary syndrome, left over right coronary dominance appears to be independently associated with increased long-term mortality. This could lead to decreasing numbers of patients with a left dominant coronary artery system in older age groups.MethodsWe assessed the type of coronary dominance in different age groups in postmortem angiograms that were routinely performed at autopsy between 1993 and 2007. Coronary dominance was determined by identifying the origin of the posterior descending artery and posterolateral branches on postmortem angiography. Age, gender, and cause of death were recorded from the autopsy database. The prevalence of left dominant, right dominant, and codominant systems was determined in three increasing age categories, with cutoffs based on tertiles.ResultsA total 1620 coronary angiograms were assessed; 167 were excluded because it was not possible to determine coronary dominance. The median age of all patients was 71 years; 56% were male. Of all deaths, 40% were classified as cardiac. Regarding coronary dominance, 81.2% was right, 9.1% was left, and 9.7% was codominant. Overall, a decrease in prevalence of left and codominant coronary systems was observed with increasing age in the three age cohorts (≤63years, 64–75 years, and ≥76 years) (P=.001 for overall comparison).ConclusionsIn this large autopsy cohort, the prevalence of a left dominant or codominant coronary system decreased with increasing age. These findings could relate to a slightly higher risk of mortality in case of left versus right coronary artery occlusion.     

Sleep deprivation‐induced impairment of memory consolidation is not mediated by glucocorticoid stress hormones

The general consensus is that sleep promotes neuronal recovery and plasticity, whereas sleep deprivation (SD) impairs brain function, including cognitive processes. Indeed, a wealth of data has shown a negative impact of SD on learning and memory processes, particularly those that involve the hippocampus. The mechanisms underlying these negative effects of sleep loss are only partly understood, but a reoccurring question is whether they are in part caused by stress hormones that may be released during SD. The purpose of the present study is therefore to examine the role of glucocorticoid stress hormones in SD‐induced memory impairment. Male C57BL/6J mice were trained in an object‐location memory paradigm, followed by 6 hr of SD by mild stimulation. At the beginning of the SD mice were injected with the corticosterone synthesis inhibitor metyrapone. Memory was tested 24 hr after training. Blood samples taken in a separate group of mice showed that SD resulted in a mild but significant increase in plasma corticosterone levels, which was prevented by metyrapone. However, the SD‐induced impairment in object‐location memory was not prevented by metyrapone treatment. This indicates that glucocorticoids play no role in causing the memory impairments seen after a short period of SD.     

Health-related quality of life at hospital discharge as a predictor for 6-month unplanned readmission and all-cause mortality of acutely admitted older medical patients

Quality of Life Research - To assess whether health-related quality of life (HRQOL) status, using the European Quality of life-5 dimensions (EQ5D), in acutely admitted older medical patients was...